CA1051890A - Esters of theophyllinylacetic acid - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
Compounds of the formula (I) are disclosed:

Description

~o~so ~ne present in~-ention relates to pharmaceutically active compounds, to their preparation and to compositions containing them.
A common problem encountered whe~n administering medi~aments i8 that they sometimes tend to become les~ effecti~e than expected in br~nging about the desired pharmacological effect because of the so called 'Rebound Effectl. It has been discovered that tki~ problem c~n be reduced for certain acidic medicaments if they are ~d~ini~tered in the form of certain ester6. Furthermore use of certain of these ester6 can ~ ~o prolong the ef~ective period after admini~tration.
Accordingly the present inYention provides compo~nd6 of the formula (I):

~ c ~ f 2 CO - O - C~R - (C~2) - O - ~cyl (I) wherein P~ is a hydrogen atom or a methyl group; n i6 a number from 1 to 4 and 'Acyl' is a nicotinoyl, 3-methylpyrazole-5-carboyl, 3-methyl-i~oxazolyl-5-carboyl, 5-n-butylpyridin-2-carboyl, 2-(4-chloropheno~y)-

2-methyl-propionyl, 2-acetoxybenzoyl or theophyllinyl-7-acetyl group.

lG~ 5~ ~T9a~
Sui-tably 'Acyl' is a nicoti~oyl, 3-methylpyra~ole-5-carboyl, 5-n-butylpyridin-2-csrboyl, 2-(4-cnlorophenoxy)-2-methyl~propionyl, 2-acetoxybenzoyl or theophyllinyl-7-acetyl group.
Particularly ~uitable co~pounds of the ~o~nula (I) ~hich have improved phaImacodynamic properties include those of the ormula (II):

~ 2 CO - O - CE~ - (C~2) - O - CO (II) wherein n and R are as defined in relation to formula (I~.
Most 6uitably ~ i~ the compounds of the formulae (I~ and (II) rep-esents a hydrogen atom.
Most suitably n in the compounds of the formulae (I) and (II) is 1 or 2.
~ particularly favoured -CHR-~CH2)~- residue in the compound6 of formNlae (I) and (II) is the -CH2-CH2- group.
A preferTed compound of this invention is 1-(theophyllinyl-7-methylenecarboyloxy)-2 (nicotinoyloxy)ethane which has particularly accep-table pharmacological effects on 6erum lipids.

The present inYention also provi(les a proces~ for the preparation o the compounds of the formula (I3 wh:ich proce~s compri~es:
(a) The re~ction of a compound o the for~ula (III):

- CO - O - C~R - (C~2) - X (III) wi-th a compound o the formula (I~):

~O.~cyl (IV~

or an acylating derivative thereof, wherein R~ n and ~cyl are a~ defined in relation to formula (I) and X is a hydroxyl group or a readily displaceable group; or (b) ~he reaction of a compound of the formula (V):

X - CHR - (CH2)n - O - ~cyl (V) with theophyllinylacetic acid or an acylati~g derivative thereof; wherein R, n and ~cyl are as defined in relation to foDmNla (I) a~d X iR a hydroxyl group or a readily displaceable group.

~or the rezction of a corpound o the fo~mul2~ (III) or (V~
wberein X is a hy~ro~yl group suitable compound~ of the formula (n) or suitable derivatives o theophyllinylæcetic acid include the free acid in the ~resence of a dehydrating age~t ~uch a~ dicyclohe~ylcarbodiimide9 or derivatives of the free acid such as an acid halide 6uch a~ the acid chloride or the æcid annydride or mixed auhydrideO
For the reaction of a compound of the formulae (III) or (V) wherein X is a displaceable group 6uch a6 a chlorin0, bromine or iodine atom or an activated ester such æg a methane sulphonyl or toluene ~ulphonyl ester, the preferTed derivative of the compound of formula (IY) or of theophyllinylacetic acid is a ~alt such a6 an al~ali metal or like ~alt, for example the sodium salt.
~le preceding reactions can be brought about under conditions con~entionally used for the preparation of esters.
Suitable 601vent8 for 6uch reactions include inert organic solven-t6 ~uch as dimethylforma~ide, benzene, pyridine or the like.
The present invention al~o provides a pharmaceutical composition ~hich compri~e~ a compound of the formula (I) together with a pharmaceutic~lly acceptable carrier.
The composition6 of the invention are specially u6eful in treati~g adver6e hyperlipedemic states in humans. For such treatment, the compounds are generally admini6tered orally lthough parenteral methods of administration may also be uced.

9~
Typical oral for~ulations ~rill include table-ts, pills, c~psules, 6achets, granules, powders, chewing gwn, suspersions~ e~lsions and solutions, particularly preferred oral fo~mulations are tablet~ and caps~les. ~ere appropriate, the fo~m~lations may include conventional diluents, binding agents, dispersing agents9 ~urface-active agents, lubricating agents, coating materi~l~? 1avouring a~ents, colouring ægent6, solvents, thickening agents, ~uspending agents, sweeteners cr ny other pharmaceutically acceptable additives7 for example, gelatin7 lactose7 starch, talc7 ~agne~ium stearate, hydroger,ated oils, polyglycols and ~yrup8. ~ere the formulations are tablet~ or cap~ules and the like, they will represent pre-measured unit do~es but in the case of granules, powders9 suspensions and the like, the formulations may be preOEented as pre-measured unit doses or in multi-do6e containers from which the appropriæte unit dose may be withdrawn.
Injectable compositions may be a~ aqueous or non-aqueous ~olutions, 6u6pen6ions or emulsions in a pharmaceutic~lly acceptable li~uid.
Preferred do~age forms of the composition will be conventional tablets or capsules containing a pre-measured dose for oral administration.
Such dosage forms will norm~lly contain between 10 and 500 mgs of compound of formula (I3 and preferably between 25 and 300 mgs. Such dosage forms will normally be taken rom 1 to 6 ti~e~ d~ily. The maxi~um daily dose for a 70 kg adult will not normally exceed 1500 mgs and a daily dose of not more than 1000 mg3 i~ generally preferred. ~ormally, the daily dose for a 70 kg adult will be at least 25 mgs and u~ually at least 50 mgs.
m e compositions of the invention may be prep~red by conventional methods of mixing, blending, tabletting and the like.
~ne following Examples illustrate the invention:

10~

v~ ,//o~
heophyl'lin31-7-meth~ylencarbo~vlo ~ 2 ¦~ - ~ } ~ C ~, Iheophylliny1-7-acetic acid ~ droxyethyl ester (56.5 g), pyridine (32 ~l)andchloroform (500 mL) were stirred together for an hour. To this was added nicotinoylchloride hydrochloride (42 g) i~
a mixture of chloroform (200 ml~ and pyrid~ne (32 ml). The reaction was stirred for 24 hours at room temperature. ~he reac-tion mixture was diluted with water (500 ml) and the chlorofor~ pha~e separated, dried and ev~porated to yield a crystalline material (77.1 g).
sample of this material recryst~llised from water yielded the des;red compound (m.p. 187C).
~he title compound has an oral LD50 in rats of greater than lg/kg. When administered to 17 hour starved rats at 300 mg/kg the title compound produced a fall in serum triglyceride and cholesterol f about 3~/~ each at 1 hour post dose.
An analogous procedure may be used to prepare l-(theophyllinyl-n,~C~ o~/Ox~
7-methylenecarboyloxy)~4-(nioe~in~-Jl~butane, m.p. 148 - 150 C.

~s~
~}~

2~-(T~eoph ~lin,yl-7-methylencarbo~lo~,~)- ~ lo ~

~icotinic acid-2-hydro~.ypropyl ester (15.03 g) was diseo ved in pyridine (100 ml). ~o this WaB added dropwise over 1 hour theophyllinyl-7-methylen-carboyl chloride (210 33 g) in chlorof'orm (250 ml). The reaction mixturs was maintæined at room temperature for 24 hours and then the solvent removed by evaporation. The residue wa6 taken up in chloroform (400 ml) and washed with sodium carbo~ate ~olution (3 x 100 ml) and dried (sodium sulphate). The chloroform was removed by ev~poration to yield a bro~ish crystalline material (28.1 g). The product was recry6talli~ed xom ethyl acetate to yield the de~ired co~pound m.p. 137C.

Claims (14)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for the preparation of a compound of formula (II):

(II) wherein n is a number from 1 to 4 and R is a hydrogen atom or a methyl group;
which process comprises:
(a) reacting a compound of the formula (III) (III) wherein R and n are as already defined and X is a hydroxy group or a readily displaceable group, with nicotinic acid or an acylating derivative thereof and recovering the compound of formula II, or (b) reacting a compound of formula with theophyllinylacetic acid or an acylating derivative thereof wherein R and n are as already defined and X is a hydroxyl group or a readily displaceable group, and recovering the compound of formula II.

2. The process of claim 1 wherein n is 1.

3. The process of claim 1 wherein R is a hydrogen atom.

4. The process of claim 2 wherein R is a hydrogen atom.

5. A process for the preparation of 1-(theophyllinyl-7-methylene-carboyloxy)-2-(nicotinoyloxy) ethane which comprises reacting theophyllinyl-7-acetic acid .beta.-hydroxyethyl ester with nicotinoyl chloride hydrochloride in a solvent and recovering the 1-(theophyllinyl-7-methylenecarboyloxy)-2(nico-tinoyloxy) ethane.

6. A process for the preparation of 1-(theophyllinyl-7-methylene-carboyloxy)-4(nicotinoyloxy) butane which comprises reacting theophyllinyl-7-acetic acid (4-hydroxybutyl) ester with nicotinoyl chloride hydrochloride in a solvent and recovering the 1-(theophyllinyl-7-methylenecarboyloxy)-2(nicotinoyloxy) butane.

7. A process for the preparation of 2-(theophyllinyl-7-methylene-carboyloxy)-3-(nicotinoyloxy) propane which comprises reacting nicotinic acid-2-hydroxypropyl ester with theophyllinyl-7-methylene-carboyl chloride in a solvent and recovering the 2-(theophyllinyl-7-methylenecarboyloxy)-3-(nico-tinoyloxy) propane.

8. A compound of the formula (II) wherein n is a number from 1 to 4 and R is a hydrogen atom or a methyl group whenever prepared by a process according to claim 1 or an obvious chemical equivalent.

9. A compound of the formula (II) wherein n is 1 when prepared by a process according to claim 2 or an obvious chemical equivalent.

10. A compound of the formula (II) wherein R is a hydrogen atom, when prepared by a process according to claim 3 or an obvious chemical equivalent.

11. 1-(Theophyllinyl-7-methylenecarboyloxy)-2-(nicotinoyloxy) ethane when prepared by a process according to claim 4 or an obvious chemical equivalent.

12. 1-(Theophyllinyl-7-methylenecarboyloxy)-2-(nictinoyloxy) ethane when prepared by the process of claim 5 or an obvious chemical equivalent.

13. 1-(Theophyllinyl-7-melhylenecarboyloxy)-4-(nicotinoyloxy) butane when prepared by the process of claim 6 or an obvious chemical equivalent.

14. 2-(Theophyllinyl-7-methylenecarboyloxy)-3-(nicotinoyloxy) propane when prepared by the process of claim 7 or an obvious chemical equivalent.