GB2193719A - Antiallergic phenoxypropanol thioether derivatives - Google Patents

Abstract

Compounds of formula I <IMAGE> [wherein R1 and R2 are independently C1-3 alkyl; Y is a straight-chained or branched C1-8 alkylene group; and Z is -COOR, -CONRR', <IMAGE> (in which R and R' are independently hydrogen or C1-3 alkyl; R'' is hydroxy, C1-3 alkoxy or -NH-R''a [in which R''aNH- is the residue of an amino acid R''aNH2]; and R''' is hydrogen or <IMAGE> [in which m is 1 or 2]), or Z is the group -CO-(CH2)n-COOH (in which n is an integer from 0 to 4)] and, where applicable, addition salts thereof with metals or with nitrogen bases exhibit anti-allergic properties. Processes for their preparation and pharmaceutical compositions containing them are described.

Description

SPECIFICATION Chemical compounds The present invention relates to phenoxypropyl derivatives and their salts, to a process for their preparation and to their use as medicaments.

According to one feature of the invention, there are provided compounds of formula I

[wherein R1 and R2, which may be the same or different, each represents a C, 3 alkyl group; Y represents a straight-chained or branched C1 8 alkylene group; and Z represents a group of formula -COOR, -CONRR',

[in which R and R', which may be the same or different, each represents a hydrogen atom or a C13 alkyl group;R" represents a hydroxy or C13 alkoxy group, or a group of formula -NH-R"a (in which R"aNH- is the residue of an amino acid R"aNH2); and R"' represents a hydrogen atom or a group of formula

(in which m is 1 or 2)], or Z represents a group of formula -CO-(CH,),-COOH (in which n is an integer from 0 to 4)] and, where applicable, salts thereof with metals or with nitrogen bases.

It is to be understood that the expression "an amino acid R"aNH2" mentioned hereinabove relates to any amino acid (including, but not restricted to, naturally occurring amino acids) and includes, for example, glycine or alanine.

The term "C13 alkyl group" as used herein refers to a methyl, ethyl, n-propyl or isopropyl group.

The term "straight-chained or branched C18 alkylene group" as used herein includes, for example, a methylene, ethylene, propylene, butylene, pentylene, hexylene, 2-methylethylene or 2methylpropylene group.

It will be appreciated that, for pharmaceutical use, the salts referred to above will be physiologically acceptable galls, but other salts may find use, for example in the preparation of compounds of formula I and physiologically acceptable salts thereof. Suitable salts include, for example, metal salt, such as, for example, alkali metal (e.g. sodium, potassium or iithium) salts, alkaline earth metal (e.g. calcium) salts, or aluminium or magnesium salts; or salts with nitrogen bases such as, for example, ammonium salts or amine (e.g. tromethamine, lysine, arginine or triethanolamine) salts.

From amongst the compounds according to the invention, mention may be made of those compounds of formula I and, where applicable, salts thereof with metals or with nitrogen bases wherein R1 represents a methyl group; R2 represents an n-propyl group; Y is as hereinbefore defined; and Z represents a group of formula -COOR or

(in which R, R" and R"' are as hereinbefore defined).

Especially preferred compounds according to the invention are: [3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropylthio]-acetic acid and salts thereof; and S-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropyl]-L-cysteine, methyl ester.

The compounds according to the invention may be prepared by the following process, which process constitutes a further feature of the present invention: Reaction of a compound of formula II

(wherein R1 and R2 are as hereinbefore defined) with a compound of formula III H-S-Y-Z (III) (wherein Y and Z are as hereinbefore defined) and subsequent isolation of the compound of formula I thereby obtained.

The reaction is preferably carried out in the presence of an organic solvent such as, for example, a lower alkanol, e.g. methanol, and of an organic base such as, for example, a tertiary amine, e.g. triethylamine.

Those compounds of formula I wherein Z represents a carboxy group (i.e. compounds of formula 1A

wherein R1, R2 and Y are as hereinbefore defined) may additionally be prepared by an extension of the above process, which comprises saponifying an ester of formula 18

(wherein R1, R2 and Y are as hereinbefore defined; and Alk represents a C1 3 alkyl group) followed, if desired, by salification of the compound of formula 1A thereby obtained.

The saponification reaction is preferably effected in basic medium using an alkaline hydroxide (such as, for example, lithium hydroxide monohydrate) as the base, and in the presence of a suitable organic solvent such as, for example, tetrahydrofuran/methanol/water.

Certain of the compounds of formula I otaindd from the process according to the invention are acidic in character and, where applicable, may subsequently, if desired, be converted into salts thereof, particuiarly physiologically acceptable salts thereof, for example by conventional methods such as by reacting the relevant compound of'formula I as an acid with a stoichiometric amount of a suitable salt-forming agent, e.g. the hydroxide of a metal or of a nitrogen base, in the presence of a solvent. Such salts may be prepared in situ in the reaction mixture without the necessity for intermediate isolation of compounds of formula I themselves. Conversely the salts of the compounds of formula I obtained may, if desired, subsequently be converted into com pounds of formula I or into further salts thereof.

The compounds according to the present invention possess interesting pharmacological properties. In particular, they have been found to exhibit remarkable anti-allergic activity; these effects are demonstrated in the Examples hereinbelow. In view of their anti-allergic properties, the compounds according to the invention are suitable for use as medicaments. The present invention therefore provides compounds of formula I and physiologically acceptable salts thereof for use in therapy.

In this connection, mention may be made of those compounds of formula I and, where applicable, salts thereof with metals or with nitrogen bases wherein R1 represents a methyl group; R2 represents an n-propyl group; Y is as hereinbefore defined; and Z represents a group of formula -COOR or

(in which R, R" and R"' are as hereinbefore defined).

Especially preferred in this connection are: [3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxy- propylthio]-acetic acid and salts thereof; and S-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydrox- ypropyl]-L-cysteine, methyl ester.

Such compounds are thus of use in the treatment of, for example, allergic asthmatic conditions and asthmatiform bronchitis having allergic origin.

According to a still further feature of the present invention there are provided pharmaceutical compositions containing, as active ingredient, at least one compound of formula I as hereinbefore defined or a physiologically acceptable salt thereof in association with one or more pharmaceutical carriers and/or excipients.

For pharmaceutical administration the compounds of formula I and their physiologically acceptable salts may be incorporated into compositions currently used in human medicine for oral, parenteral or local administration, optionally in combination with other active ingredients. The pharmaceutical compositions may be in either solid or liquid form, using carriers and excipients conventionally employed in the pharmaceutical art. Preferred forms include, for example, tablets (including plain or coated tablets), capsules (including gelatin capsules), powders, suppositories, syrups, aerosols, creams, ointments and injectable preparations, prepared in traditional manner.

The active ingredient(s) may be used in conjunction with excipients customarily employed in pharmaceutical compositions such as, for example, talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, animal or vegetable fats, paraffin derivatives, glycols, various wetting, dispersing or emulsifying agents and/or preservatives.

Advantageously the compositions may be formulated as dosage units, each unit being adapted to supply fixed dose of active ingredient. The total daily dosage will vary depending on the compound used, but will generally be within the range of from 1 to 250 mg for oral administration to adult humans. This dosage may, however, also be varied according to the subject treated, the route of administration and the complaint concerned.

According to a yet further feature of the present invention, there is provided a method for the treatment of a patient suffering from, or susceptible to, allergic conditions which comprises administering to the patient an effective amount of a compound of formula I or a physiologically acceptable salt thereof.

The following non-limiting Examples serve to illustrate the present invention more fully: Example 1: [3-(4-A cetyl-3-hydroxy-2-propylphenoxy)2-hydroxypropylthio]-acetic acid, methyl ester 4-(2,3-Epoxy)-propoxy-2-hydroxy-3-propylacétophenone (4.0 g, 16 mmol) in methanol (15 ml) was treated with methyl thioglycolate (1.4 ml, 16 mmol) and triethylamine (6.7 ml). The reaction mixture was stirred for 1 h and the solvent was then removed in vacuo. Purification by flash chromatography, eluting with 30-40% ethyl acetate in petroleum ether (60-800C), gave the desired product (5.15 g, 90%), m.p. 58-600C - (ether/petroleum ether).

NMR (CDCl3): a 12.78 (s, ArOH); 7.66 (d, ArH); 6.48 (d, ArH); 4.04-4.28 (m, 3H, OCH2, OCH), 3.79 (s, OMe); 3.38 (s, SCH2CO); 3.65 and 2.88 (2odd, 2H, CH2S); 2.66 (dd, CH2Ar); 1.55 (m, CH2CH3); 0.95 (t, 3H, CH2CH3).

IR (KBr): 3430, 1715, 1705 cm-1.

C17H24O6S requires C, 57.29%; H, 6.79%; S, 8.99%.

Found: C, 57.13%; H, 6.75%; S, 8.80%.

Example 2: [3-(4-A cetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropylthio]-acetic acid A solution of [3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropylthio]-acetic acid, methyl ester (7.0 9, 19.7 mmol), obtained from the process described in Example 1, in tetrahydrofuran/methanol/water (3:2:1; 120 ml) was stirred at ambient temperature with lithium hydroxide monohydrate (5 9, 120 mmol). After 6 hours' stirring, the solution was brought to pH 5 with conc. hydrochloric acid. The organic solvents were removed in vacuo and the remaining oil/aqueous solution was extracted twice with ethyl acetate. The extracts were washed with brine and dried over MgSO4. The isolated oil was purified by flash chromatography using a deactivated column and eluting with 5% methanol in dichloromethane.Recrystallisation from dichloromethane/petroleum ether (60-80"0) gave the desired product (6.35 g, 94%), m.p. 100-102 C.

NMR (CDCl3): a 12.75 (s, ArOH); 7.60 (d, ArH); 6.44 (d, ArH); 4.03-4.31 (m, -CHO-, OCH2); 3.41 (s, SCH2CO); 3.05 and 2.90 (2xdd, CH2S); 2.64 (t, ArCH2); 2.59 (s, CH3CO); 1.54 (m, CH2CH3); 0.94 (t, Me).

IR (KBr): 3230, 1695, 1495, 1275, 1125, 790cm-1.

C,6H2206S requires C, 56.12%; H, 6.48%; S, 9.36%.

Found: C, 56.15%; H, 6.45%; S, 9.51%.

Example 3: 3-[3-(4-A cetyl-3-hydroxy-2-propylphenoxyl-2-h ydroxyprop ylthio]-propionic acid 4-(2,3-Epoxy)-propoxy-2-hydroxy-3-propylacetophenone (2 g, 8 mmol) in methanol (10 ml) was stirred for 2 days with 3-mercaptopropionic acid (1.52 ml) and triethylamine (6.6 ml). The solvent was evaporated in vacuo, and the oil residue was then dissolved in ethyl acetate, washed with 0.5 M hydrochloric acid and brine, and dried over sodium sulphate. Purification by flash chromatography and recrystallisation from ether/petroieum ether (60-80"0) gave the desired product (1.58 g, 55%) as colourless crystals, m.p. 96-97"C.

NMR (CDCl3): a 12.78 (s, OH); 7.63 and 6.48 (2xd, 2xArH); 4.05-4.29 (m, 3H, -CHOH, OCH2); 2.75-3.03 (m, 8H, SCH2, CH2S, CH2Ar, CH2COOH); 2.84 (s, 3H, CH3CO); 1.54 (m, CH2Me); 0.94 (t, 3H, Me).

IR (KBr): 3410, 3190, 1735, 1630, 1605, 1495, 1300, 1125, 795 cm-'.

C,7H2406S requires C, 57.29%; H, 6.79%; S, 8.99%.

Found: C, 57.26%; H, 6.72%; S, 8.92%.

Example 4: S-[3-(4-A cetyl-3-hydroxy-2-prop ylphenoxy)-2-hydroxypropyl]-L-cysteine, methyl ester 4-(2,3-Epoxy)-propoxy-2-hydroxy-3-propylacetophenone (3 9, 12 mmol) in methanol (15 ml) was stirred with L-cysteine, methyl ester hydrochloride (2.27 9, 13.2 mmol) and triethylamine (5 ml). After 4 hours' stirring, the solvent was removed in vacuo, ether was added and the precipitated triethylamine hydrochloride was filtered off. Purification by flash chromatography gave the desired product (3.75 g, 81%) as a pale yellow oil which slowly deteriorated at room temperature.

NMR (CDCl3): a 12.73 (s, OH); 7.63 and 6.49 (d, 2xArH); 3.95-4.28 (m, -CHO-, OCH2); 3.79 (t+s, CHN, Ore); 2.70-3.18 (m, 7H, CH2SCH2, NH2 and OH); 2.70 (t, CH2Ar); 2.58 (s, CH3CO); 1.54 (m, CH2Me); 0.94 (t, Me).

IR (film): 3360, 3290, 1735, 715 cm-'.

ClaH27No6s requires C, 56.08%; H, 7.06%; N, 3.63%; S, 8.32%.

Found: C, 56.08%; H, 6.82%; N, 3.53%; S, 8.27%.

Example 5 Tablets were prepared according to the following formulation: Coumpound of Example 2 .... .... 15-mg Excipient q.s. for one tablet up to 100 mg (details of the excipient: lactose, starch, talc, magnesium stearate).

Example 6 An aerosol was prepared delivering per dose: Compound of Example 4 ... ......... 2 mg Emulsifier . . .. ........... 0.15 mg Propellant . ..... 50 mg Example 7 Tablets were prepared according to the following formulation: Compound of Example 4 ........................ 15 mg Excipient q.s. for one tablet up to 100 mg (details of the excipient: lactose, starch, talc, magnesium stearate).

Pharmacological Activity I. Inhibition of antigen-induced bronchoconstriction Animals Male Dunkin Hartley guinea pigs (Porcellus, 450-700 g) (four per drug concentration), housed in cages, were used. Animals were sensitised by two weekly exposures to aerosolised ovalbumen (1% w/v).

Drugs Animals were anaesthetised with 2.5 mg/kg valium (RTM) i.p. and 1 ml/kg Hypnorm (RTM) i.m.

Method Following anaesthesia, the animals were exsanguinated by severing both carotid arteries. The chest was opened and the lungs removed and split into two at the carina. Both were then cannulated via the main lobar bronchus and connected to a perfusion system. Lungs were perfused with aerated krebs fluid (95% 02 5% CO2) at 37 C. Ovalbumen (5 ,ug in 0.1 ml) was injected through an injection port proximal to each lung. Elevation of perfusion pressure by the antigen was recorded. Sixty minutes later, 15 89 ovalbumen was administered. Research compounds were added to the krebs fluid reservoir thirty minutes prior to the second antigen dose.

For each weekly batch of animals used, control measurements were made without drug treatment (n 10).

The second antigen response is expressed as a percentage of the first. For drug treatments at least four lungs (from four different animals) were used per concentration. Percentage inhibition of antigen-induced bronchoconstriction is calculated as follows:

C, =control series first response (mmHg).

C2 =control series second response (mmHg).

d1 =drug series first control response (mmHg).

d2 =drug series second drug-treated response (mmHg).

The resuits obtained are displayed in the Table below.

Mean +SEM are used, Student t-test is used to compare drug-treated responses with initial responses.

% Inhibition at Compound 10 pM 100 2 68.9 93.3 3 29.7 81.9 4 79.9 91.8

II. Methodology for assessment of inhibitory activity against guinea pig lung phosphodiesterase The assay method relies on the hydrolysis of cyclic AMP and cyclic GMP to the corresponding 5-AMP and 5-GMP by the phosphodiesterase enzyme. These products are subsequently further hydrolysed to-adenosine and guanosine respectively by nucleotidase obtained from snake venom (Crotalus atrox). This is based on the method of Thompson et al. (1971), Biochemistry, 10, 311-316.

The phosphodiesterase enzyme is prepared from homogenised guinea-pig lung tissue by centrifugation; the supernatant is used as the source of enzyme and is aliquoted and stored at --20"C untii used.

The assay procedure consists of an incubation of phosphodiesterase enzyme with cyclic nucleotide substrates (3H-cyclic AMP or 3H-cyclic GMP) together with a suitable dilution of test compound in physiological buffer at 37"C for 10 minutes. This reaction is stopped by heating at 80"C for 3 minutes to inactivate this enzyme. After cooling, snake venom nucleotidase is added and further incubated at 37"C for -60 minutes. After addition of an ion-exchange resin and centrifugation, the supernatant is assayed for the presence of labelled adenosine or guanosine by liquid scintillation counting.

The results given in the Table below are the concentrations of test compounds which cause 50% inhibition of enzyme activity.

IE50/rM Compound Cyclic AMP Cyclic GMP 2 74.1 11.2 4 166 166

Claims (22)

1. Compounds of formula I

[wherein R1 and R2, which may be the same or different, each represents a C13 alkyl group; Y represents a straight-chained or branched C18 alkylene group; and Z represents a group of formula -COOR, -CONRR',

[in which R and R', which may be the same or different, each represents a hydrogen atom or a C13 alkyl group;R" represents a hydroxy or C13 alkoxy group, or a group of formula -NH-Ra" (in which R"aNH is the residue of an amino acid R"aNH2); and R"' represents a hydrogen atom or a group of formula

(in which m is 1 or 2)], or Z represents a group of formula -CO-(CH,),-COOH (in which n is an integer from 0 to 4)] and, where applicable, salts thereof with metals or with nitrogen bases.

2. Compounds as claimed in claim 1 wherein R1 represents a methyl group; R2 represents an n-propyl group; Y is as defined in claim 1; and Z represents a group of formula -COOR or

(in which R, R" and R"' are as defined in claim 1).

3. Compounds as claimed in claim 1 selected from: [(3-(4-acetyl-3-hydroxy-2-propyl phenoxy)-2-hydroxypropylthio]-acetic acid and salts thereof; and S-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropyl]-L-cysteine, methyl ester.

4. Physiologically acceptable addition salts of compounds of formula I as defined in claim 1.

5. Compounds as claimed in claim 1 as herein specifically disclosed in any one of Examples 1 to 4.

6. A process for the preparation of a compound of formula I as defined in claim 1 which comprises reacting a compound of formula II

(wherein R1 and R2 are as defined in claim 1) with a compound of formula Ill H-S-Y-Z (III) (wherein Y and Z are as defined in claim 1).

7. A process as claimed in claim 6 wherein the reaction between the compound of formula II and the compound of formula Ill is carried out in an organic solvent and in the presence of an organic base.

8. A process for the preparation of a compound of formula 1A

wherein Rl, R2 and Y are as defined in claim 1) and addition salts thereof which comprises saponifying an ester of formula 13

(wherein R1, R2 and Y are as defined in claim 1; and R" represents a C13 alkyl group).

9. A process as claimed in claim 8 wherein the saponification reaction is effected in the presence of an alkaline hydroxide and an organic solvent.

10. A process as claimed in any one of claims 6 to 9 wherein a compound of formula I initially obtained is subsequently converted into an addition salt thereof and/or an addition salt of a compound of formula I is subsequently converted into a compound of formula I

11. A process for the preparation of compounds as claimed in claim 1 substantially as herein described.

12. A process for the preparation of compounds as claimed in claim 1 substantially as herein described in any one of Examples 1 to 4.

13. Compounds as claimed in claim 1 whenever prepared by a process as defined in any one of claims 6 to 12.

14. Compounds as claimed in any one of claims 1 to 5 for use in therapy.

15. The use of a compound as claimed in any one of claims 1 to 5 for the manufacture of an anti-allergic medicament.

16. Pharmaceutical compositions comprising, as active ingredient, at least one compound of formula I as defined in claim 1 or a physiologically acceptable salt thereof in association with a pharmaceutical carrier and/or excipient.

17. Compositions as defined in claim 16 wherein the active ingredient comprises a compound as defined in any one of claims 2 to 5.

18. Compositions as claimed in claim 16 or claim 17 in the form of dosage units.

19. Compositions as claimed in claim 18 wherein each dosage unit contains from 1 to 250 mg of active ingredient.

20. Pharmaceutical compositions as claimed in claim 16 substantially as herein described.

21. Pharmaceutical compositions substantially as herein described in any one of Examples 5 to 7.

22. Each and every novel method, process, compound and compositions herein disclosed.