GB2143817A

GB2143817A - Novel pharmaceutical compounds and their preparation

Info

Publication number: GB2143817A
Application number: GB08417753A
Authority: GB
Inventors: David James Steggles; John Pomfret Verge
Original assignee: Lilly Industries Ltd
Current assignee: Lilly Industries Ltd
Priority date: 1983-07-13
Filing date: 1984-07-12
Publication date: 1985-02-20
Also published as: IL72363A; HU192056B; ATE29878T1; ES534269A0; PT78870B; DE3466389D1; KR850001177A; FI842724A0; CA1222517A; NZ208837A; AR242197A1; AU3052684A; SU1340585A3; GB8318889D0; EP0132124B1; ZA845299B; DK343684A; IL72363A0; HUT37920A; EP0132124A1

Description

1 R R R 10 2 3 15 c R 1 R 1 6 R 7-5p-z (I) GB 2 143 817 A 1

SPECIFICATION

Novel pharmaceutical compounds and their preparation This invention relates to compounds having pharmaceutical activity, to intermediates and processes for the 5 preparation thereof.

The compounds of the invention have the formula wherein R,, R2 and R3 are each independently selected from H, OH, Cl-C4 alkyl, R4--CO and halogen, where R4 is Cl-C4 alkyl; R5 and R6 are each independently selected from H, Cl-C4 alkyl and optionally-substituted phenyl; R7 is an alkylene group having from 1 to 4 carbon atoms, optionally substituted with a phenyl or substituted phenyl group; pis 0 or 1; and Z is a 1 H-tetrazol-5-yl or aCN group; and salts thereof.

The compounds of formula (1) wherein Z is tetrazoly] are pharmacologically active and those wherein Z is -CN are intermediates employed in the preparation of the active compounds.

The term---Cl-C4 alkyl- refers to straight chain or branched hydrocarbons, and includes methyl, ethyl, propy], isopropy], butyl, iso-butyl and tertiary-butyl. The term "halogen" refers particularly to chlorine, bromine or fluorine. The term "optionally substituted phenyl" refers, for example, to unsubstituted phenyl 25 orto phenyl with 1-3 substituents selected from OH, halogen, N02, Cl-C4 alkyl and Cl-C4 haloalkyl. The term "alkylene group having from 1 to 4 carbon atoms" includes straight and branched Cl-C4 groups such as -CH27, -CH(CH3)-, -C(CH3)2-, -C(CH3)(C2H5)-, -CH(C3H7)-, -CHz--CH2-, - CH(CH3)-CH2-, -CH(CH3)-CH(CH3)-, -CH(C2Hs)-CH2-, -(CH2)3-, -CH(CH3)-CH27CH27 and -CH2-CH(CH3)-CHz--. Alkylene groups substituted with a phenyl or substituted phenyl group refers to the above alkylene groups wherein one or more of the H atoms is replaced by a phenyl or substituted group as defined above.

A preferred group of compounds are those of formula R2 R 3 R 5 35 1 R 1--- 0-9 -<:

1 R 7-SI3-Z (n) "6 40 in which R7 is -(CH2)n-, where n is 1 to 3 and R5 and R6 are both hydrogen. Most preferably R, is CH3-CO, R2 is OH and R3 is propyl.

The preferred compounds of the invention are 1 -{2-Hydroxy-3-propy]-4-[4-(1 H-tetrazo 1-5-yl methyl) phenyl m ethoxy] phenyl ethanone 1 -{2-Hydroxy-3-propy]-4-{4-[3-(1 H-tetrazol-5-yi)propyi]phenyimethoxy phenyl} ethanone 1-{2-Hydroxy-3-propyl-4-[4-(1 H-tetrazo 1-5-yIth i o methyl) phenyl m ethoxy]phenyi} ethanone 1-{2-Hydroxy-3-propyl-4-[3-(1 H-tetrazol-5-yithiomethyi) phenyl methoxy]phenyl ethanone 1-{2-Hydroxy-3-propyi-4-{4-[2-(1 H-tetrazol-5-ylthio)ethyi]phenyimethoxy} phenyl} ethanone 1-{2-Hydroxy-3-propyl-4- 4-[3-(1 H-tetrazol-5ylthio)propyllphenyimethoxy} phenyl} ethanone The most performed compounds are 1-{2-Hydroxy-3-propyi-4- 4-[3-(1 H-tetrazol-5-yl)propyi]phenyimethoxy} phenyl} ethanone 1 -{2-Hyd roxy-3-p ro pyl -4-{4-[2-(1 H-tetrazol-5-yith io)ethyl] phenyl m ethoxy} phenyl} ethanone The invention also provides a process for preparing a compound of formula (1) wherein Z is tetrazolyl which comprises reacting a compound of formula (1) wherein Z is CN with a source of azide ions preferably in 55 the presence of a source of ammonium ions. Preferably the reaction is carried out using an alkali metal azide, such as sodium azide, in the presence of an ammonium halide, such as ammonium chloride. The reaction may be carried out in the presence of an inert solvent. When p is 1 the reaction is preferably carried out at a temperature of from 60-90'C, in the presence of dioxan as solvent. When p is 0 the preferred reaction temperature is from 80 to 1 00'C, using DIVIF (dimethylformamide) as solvent.

Suitable salts of compounds of the invention include for example, those of mineral bases such as alkali metal hydroxides, especially the potassium or sodium salts, or alkaline earth metal hydroxides, especially the calcium salts, or of organic bases such as amines.

The preferred salts of the compounds of formula (1) wherein Z is tetrazolyl are those which are pharmaceutically acceptable, but other derivatives are also included in the invention in as much as they are 65 useful as intermediates in the preparation, purification or, charactization of the pharmaceutical end product.

2 GB 2 143 817 A 2 The intermediate compounds of formula (1) wherein Z is M may be prepared by reacting a compound of formula R R R 5 2 3 1 - O-C 5 2 -OR Br R.C 1 1 7- R 6 wherein R,-R7 and pare as defined above, with an alkali metal cyanide orthiocyanate in an organic solvent at 10 a temperature of from O'C to WC. Preferably the reaction is carried out at room temperature using DMSO as a solvent.

The compounds of formula Ill may be prepared by reacting a compound of formula R 2 3 2CH R 1 2 with a compound of formula R 1 5 -C R Eir L 25 R1 6 7-8r in an organic solvent at a temperature in the range 40-120'C in the presence of a base. The preferred solvent 30 is a ketone, such as methyl ethyl ketone (MEK) or methyl isobutyl ketone (MIBK).

The overall preferred process for producing compounds of formula (1) is indicated in the following reaction scheme.

R, 2 R 3 R 1 - CH - + -Y CH 2) \ er -X -0 sr INa CC bl 2 c/Nal blechy thyl Ketone/& Rj: 0-X R Br YK5M DMEO.

\r MSO - R n C1M 2 3 3 _X 1- X 0 1 R a-. A R 1 \ A 891C laN 3 /NH Cl dioxanA,0 1000C N-N R R X\ z -:-X M N N R 1 H NaNINH4,Cl OMF R (CH), N-N 2 n,N wii:fsi cl 1== N 3 GB 2 143 817 A 3 [twill be appreciated that the compounds of formulae (1) may have one or more asymmetric carbon atoms.

Thus if R5 and R6 are different groups their associated carbon atom will be optically active. Likewise R7 may contain one or more optically active carbon atoms, thus giving rise to a number of possible enantiomers and diastereomers, mixtures of which can be separated by conventional methods.

The compounds of the present invention in which Z is tetrazolyl are pharmacologically active, being 5 leukotriene antagonists as shown by the following tests; the in vitro test on guinea pig ileum segments at concentrations of from 10 ng to 50 I.Lg, according to the method of Schild, 1947 Brit. J. Pharm. 2 197-206 (the pharmacological compounds of the following Examples exhibited an IC50 against LTD4 of less than 10-5 molar); the in vivo Guinea Pig Pulmonary Function Test of Austen and Drazen 1974 J. Clin. Invest.

53:1679-1685 at intravenous dosage levels of from 0.05 pg to 5.0 mg/kg; and a modified "Herxheimer" test at 10 doses of from 25 to 200 mg/kg. The "Herxheimer" test is based on an allergic bronchospasm induced in guinea pigs and which closely resembles an asthmatic attack in man. The mediators causing the bronchospasm are very similar to those released when sensitised human lung tissue is challenged with an antigen. In the modified test employed in respect of compounds of the present invention, the animals were pretreated with a histamine antagonist, mepyramine, at a dose of 0.5 mg/kg i.p., 30 minutes before challenge. This modification masks the histamine effect to reveal better the leukotriene effect.

The compounds are accordingly indicated for therapeutic use in the treatment of diseases in which leukotrienes are implicated. These include allergic reactions of the pulmonary system in which leukotrienes are thought to be causal mediators of bronchospasm, for example, in allergic lung disorders such as extrinsic asthma and industrial asthmas such as Farmers lung and Pigeon Fanciers lung, and in other inflammatory disorders, for example, those associated with acute or chronic infectious diseases such as allergic skin diseases, ectopic and atopic eczemas, psoriasis, contact hypersensitivity and angioneurotic oedema, bronchitis, cystic fibrosis and rheumatic fever.

The compounds may be administered in free acid form, or in pharmaceutically acceptable salt form. They may be administered by various routes, for examples by the oral or rectal route, by inhalation, topically or parenterally, e.g. by injection, being usually employed in the form of a pharmaceutial composition. Such compositions form part of the present invention and are prepared in a manner well known in the pharmaceutical art and normally comprise at least one active compound in association with a pharmaceutically acceptable diluent or carrier. In making the compositions of the present invention, the active ingredient will usually be mixed with a carrier, or diluted by a carrier, and/or enclosed within a carrier which may, for example, be in the form of a capsule, sachet, paper or other container. Where the carrier serves as a diluent, it may be a solid, semi-solid, or liquid material which acts as a vehicle, excipient or medium for the active ingredient. Thus, the composition may be in the form of tablets, lozenges, sachets, cachets, elixirs, suspensions, aerosols (as a solid or in a liquid medium), ointments containing for example upto 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, injection solutions and suspensions and sterile packaged powders. For administration by inhalation, particular forms of presentation include aerosols, atomisers and vaporisers.

Some examples of suitable carriers are lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, syrup, methyl cellulose, methyl- and propylhydroxybenzoate, tale, magnesium stearate and mineral oil. The compositions of the invention may, as is well known in the art, be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient.

Where the compositions are formulated in unit dosage form, it is preferred that each unit dosage form contains from 10 mg to 1 g such as from 5 mg to 500 mg or from 25 mg to 200 mg. The term "unit dosage form" refers to physically discrete units suitable as unit dosages for human subjects and namials, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with the required pharmaceutical carrier.

The active compounds are effective over a wide dosage range and, for example, dosages per day will normally fall within the range of from 0.5 to 300 mg/kg, more usually in the range of from 5 to 100 mg/kg.

However, it will be understood thatthe amount administered will be determined by the physician in the light 50 of the relevant circumstances including the condition to be treated, the choice of compound to be administered and the chosen route of administration, and therefore the above dosage ranges are not intended to limit the scope of the invention in any way.

The following Examples illustrate the invention.

EXAMPLE 1

1-[2-Hydroxy-3-propyl-4-(4-bromomethylphenylmethoxy)phenyflethanone To a solution of 1-(2,4-dihydroxy-3-propyl phenyl) ethanone (10.0 g; 0. 051 m) in dry methylethyl ketone (100 mi) was added dried anhydrous sodium carbonate (27 g; 5 mol. eq) and sodium iodide (0.5 g). To the stirred suspension was then added (x,a'-dibromo-p-xylene (13.5 g; 0.051 m) and the suspension gently 60 heated at refluxforfive hours. The cooled suspension was evaporated under reduced pressure, the residue dissolved in water extracted with clichloremethane (x 2). The organic extract was washed with aqueous sodium hydroxide (2N), then water, dried over magnesium sulphate, filtered, and evaporated to dryness under reduced pressure to give a yellow solid. The solid was stirred with ether (200 mi) for 1 hour and filtered to remove any disubstituted impurity. The filtrate was evaporated under reduced pressure to leave a yellow 65 4 GB 2 143 817 A 4 solid. The solid was chromatographed on a U30 Sorbsil solumn using clichloromethane to give a white solid; recrystallised from ethanol, m.p. 98-99'C.

EXAMPLE 2 5 1-2-Hydroxy-3-propyl-4-[4-(2-bromoethyl)phenylmethoxy]-phenylethanone To a solution of 1-(2,4-dihydroxy-3-propyl phenyl)etha none (10.0 g; 0. 051 m) in dry methyl ethyl ketone (100 mi) was added dried anhydrous sodium carbonate (27 g; 5 mol eq) and sodium iodide (0.5 g). To the stirred suspension was added 4-(2-bro moethyl) phenyl methyl bromide (14. 2 g; 0.051 m) (literature preparation) and the suspension gently heated at reflux overnight. The cooled suspension was evaporated under reduced pressure, the residue taken up in water and extracted with dichloromethane (x 2). The organic extract was washed with aqueous soidum hydroxide (2N), then water, dried over magnesium sulphate, filtered and evaporated under reduced pressure to give a yellow oil. The oil was chromatographed on a U30 Sorbsil column using dichloromethane to give a pale yellow oil which crystallised on standing to a white crystalline solid; recrystallised from ethanol m.p. 66-70'C.

EXAMPLES 3 - 5 Similarly prepared were:

1-[2-Hyd roxy-3-pro pyl-4-(2-bro mo methyl phenyl methoxy) p henyl]etha none m.p. 137-139'C (EtOH) 11-[2-Hyd roxy-3-propyl-4-(3-bro mo methyl phenyl methoxy) phenyl]etha none m.p. 135-136'C (EtOH) 112-Hydroxy-3-propyi-4-[4-(3-bro mo pro pyi) phenyl m ethoxylphenyl ethanone m.p. 66-68'C (EtOH) 20 EXAMPLE 6

1-[2-Hydroxy-3-propyl-4(4-cyanomethylphenylmethoxy)phenyflethanone 1-[2-Hyd roxy-3-propyi-4-(4-brom o methyl phenyl methoxy) phenyl]ethanone (7.2 g; 0.02 m) and potassium cyanide (2.5 g; 0.04 m) where dissolved in dry dimethyisulphoxide (60 mi) and stirred at room temperature 25 for 2 hours. The solution was poured onto water with stirring and filtered to give a cream solid, which was dried at WC under reduced pressure; Recrystallised from ethanol to give a pale cream crystalline solid m.p.

75-760C.

EXAMPLES7-10

Similarly prepared were:

1 [2-Hyd roxy-3-propyl-4-(3-cya no methyl phenyl methoxy) p henyl]ethan one m.p. 114-116'C (EtOH) 11-[2-Hyd roxy-3-propyl-4-(2-cya no methyl phenyl methoxy) p henyl]etha none m.p. 157-159'C (EtOH) 112-Hydroxy-3-propyi-4-[4-(2-eyanoethyi)phenyimethoxy]phenyl - ethanone m.p. 1120-123'C (EtOH) 11- 2 Hyd roxy-3-p ro pyl-4-[4-Q-cyano pro pyl) phenyl methoxy]p henyl - ethanone m.p. 37-38'C (EtOH) EXAMPLE 11 1-[2-Hydroxy-3-propyl-4-(4-thiocyanomethylphenylmethoxy)phenyl- ethanone 1-[2-Hyd roxy-3-pro pyl-4-(4-bro mo methyl phenyl methoxy) phenyl]etha none (6.4 g; 0.017 m) and potassium thiocyanate (3.3 g; 0.034m) were dissolved in dry climethylsulphoxide (60 mi) and stirred at room temperature for 4 hours. The solution was then poured onto water, stirred and filtered to give a white solid; dried at WC under reduced pressure. Recrystallised from ethanol to give a white crystalline solid m.p. 110-11 10C.

EXAMPLES 12-15 Similarly prepared were:

1-[2-Hyd roxy-3-propyl-4-(3-th iocyan ao methyl methoxy) p h enyl]etha none m.p. 87-88'C (EtOH).

1-[2-Hyd roxy-3-pro pyl -4-(2-th iocyan o methyl phenyl methoxy) phenyl] ethanone m.p. 118-120'C (EtOH) 11- 2-Hyd roxy-3-p ro pyl-4-[4-(2-th iocya n oethyl) phenyl m ethoxy]p h enyl ethanone m.p. 87-89'C (EtOH) 12-Hydroxy-3-propyi-4-[4-(3-thiocyanopropyl)phenyimethoxy]phenyl ethanone m.p. 53-55'C (EtOH) 50 EXAMPLE 16 12-Hydroxy-3-propyl-4-[4-(1H-tetrazol-5- ylmethyl)phenylmethoxy]phenyI ethanone 1-[2Hyd roxy-3-p ro pyl-4(4-cya no methyl phenyl m ethoxy) ph enyl]etha none (4.25 g; 0.013 m) was dissolved in dry climethylformamaicle (70 mi) to which was added sodium azicle (3. 42 g; 0.052 m) and ammonium chloride (1.4 g; 0.026 m). The resulting suspension was heated at 1OWC for 20 hours with stirring under a capillary air condenser. The cooled suspension was poured onto water with stirring, acidified and filtered to give a pale brown solid. The solid was taken up in aqueous sodium hydroxide (2N), washed with chloroform and acidified with concentrated hydrochloric acid with cooling and stirring, filtered to give a pale brown solid. Recrystallised from methanol to give a fawn crystalline solid m.p. 184-1187'C.

EXAMPLES 17-20 Similarly prepared were:- 1- 2-Hydroxy-3-propyi-4-[2-(1 H-tetrazol-5-yl methyl) phenyl m ethoxy]phenyl ethanone m.p. 202-2WC 65 (MeOH) GB 2 143 817 A 5 1- 2-Hydroxy-3-propyl-4-[3-(1 H-tetrazol-5-yimethyi)phenyimethoxy]phenyl ethanone m.p. 170-1730C (MeOH) 1- 2-Hydroxy-3-propyl-4- 4-[2-1 H-tetrazol-5-y1)ethyl phenyl methoxy phenyl ethanone m.p. 202-2040C (MeOH) 1- 2-Hydroxy-3-propyl-4- 4-[3-0 H-tetrazol-5-yl) pro pyi]ph enyl m ethoxy phenyl ethanone m.p. 136-1380C 5 (MeOH) EXAMPLE 21 1- 2-Hydroxy-3-propyl-4-[4-(1H-tetrazol-5ylthiomethyl)phenylmethoxy]phenyl ethanone 1-[2-Hyd roxy-3-pro pyl-4-(4-th iocya n om ethyl phenyl methoxy)p henyl]etha none (6.0 g; 0.017m) was dissolved in dioxan:water (80:20; 100mi) to which was added sodium azicle (4. 4 g; 0.068m) and ammonium chloride (1.8 g; 0.034m). The resulting solution was heated at WC for 18 hours, cooled and poured onto water. The resulting solution was acidified with concentrated hydrochloric acid, filtered and washed with water to leave a white solid. Recrystallised from methanol to give a cream crystalline solid m.p. 160-1610C.

EXAMPLES 22-25 Similarly prepared were 12-Hydroxy-3-propyi-4-[2-(1H-tetrazo 1-5-y1th io methyl) phenyl meth oxy]p h enyl ethanone m.p. 174-176'C (MeOH) 1- 2-Hydroxy-3-propyi-4-13-(1 H-tetrazol-5- yithiomethyi)phenyimethoxy]phenyl ethanone m.p. 146-148'C 20 (MeOH) 1- 2-Hydroxy-3-propyl-4- 4-[2-(1 H-tetrazol-5-yithio)ethyi]phenyimethoxy phenyl elthanone m.p. 165-168'C (MeOH) 1- 2-Hydroxy-3-propyl-4- 4-[3-(11 H-tetrazol-5yithio)propyi]phenylmethoxy phenyl ethanone m.p. 11 9-12loC (MeOH) EXAMPLE 26

Tablet

Active ingredient 10Orng 30 Microcrystalline cellulose 200 mg Polyvinyl pyrro lido ne 30 mg Sodium carboxymethyl starch 30 mg Magnesium stearate 5mg 35 The active ingredient and the microcrystal line of cellulose are blended together and massed with a solution of polyvinyl pyrrol idone in water. The mass is extruded through a screen, dried and starch and magnesium stearate. The granules are compressed on a suitable tablet machine.

EXAMPLE 27 40

Capsule Active ingredient 50 mg Starch flowable 200 mg Silicone fluid 1 mg 45 A portion of the starch is blended with the silicone fluid. To this mixture is added the active ingredient and the remainder of the starch. After mixing, the powder is filling into hard gelatine capsules.

EXAMPLE 28 50

Aerosol Active ingredient 10 mg Ethanol 50 mg Dichlorodifluoromethane (Propellant 12) 658 mg 55 Dichlorotetrafluoroethane (Propellant 114) 282 mg The active ingredient is dissolved in the ethanol. The concentrate is filled into extruded aluminium cans for inhalation aerosols. The cans are degassed with propellant 12 and sealed with an appropriate metered dose valve. The volume of product expelled per actuation is 50 or 100 jil equivalent to 0.5 - 1 mg active ingredient.60 6 GB 2 143 817 A

Claims

1. A compound of formula 6 5 R R R 2 3 15 0- c --C R R 1 2p R 1 6 7-5p-Z 10 wherein R,, R2 and R3 are each independently selected from H, OH, Cl-C4 alkyl, R4-CO and halogen, where R4 is Cl-C4 alkyl; R5 and R6 are each independently selected from H, Cl-C4 alkyl and optionally-substituted phenyl; R7 is an alkylene group having from 1 to 4 carbon atoms, optionally containing a subsituted or unsubstituted phenyl group; p is 0 or 1; and Z is a 1 H-tetrazol-5-yl or a -CN group; and salts thereof.

2. A compound of claim 1 wherein R7 is-(CH2),r-, and n is 1, 2 or3.

3. A compound of claim 1 or2 wherein R, is C1-1j---CO-.

4. Acompound of anyone of claims 1 to 3wherein oneof R2 and R3 is a 3-011 group andthe other is methyl, ethyl or propyl in the 2-position.

5. A compound of claim 4 in which the substituted phenyl moiety attached to the 0 atom is 2-propyi-3-hydroxy-4-acetyl phen-l-yl.

6. A compound of anyone of claims 1-5 wherein Z is tetrazolyl.

7. Acompoundofciaim6whichis 1 -{2-Hyd roxy-3-propyl-4- 4-[3-(1 H-tetrazo 1-5-y1) propyi]phenyl methoxy}phenyi} etha none 1-{2-Hydroxy-3-propyi-4-4-[2-(1H-tetrazol-5yithio)ethyi]phenyimethoxy}pheny i}ethanone

8. A process for preparing a compound of formula (1) wherein Z is tetrazolyl, as defined in claim 1, which comprises reacting a compound of formula (1) wherein Z is CN with a source of azide ions preferably, in the presence of a source of ammonium ions.

9. A process according to claim 7 wherein the reaction is carried out using an alkali metal azide in the 30 presence of an ammonium halide.

10. A process according to claim 9 wherein pis land which is carried out in dioxan at a temperature in the range of from 60 to 90T.

11. A process according to claim 9 wherein pis 0 and which is carried out in dimethylformamide at a temperature in the range of from 80to 100T.

12. A process for preparing a compound of formula 1, wherein Z is CN, as defined in claim 8, which comprises reacting a compound forformuia R R 3 40 -OH R 45 with a compound of formula R 5 50 c -OR 8r R' 6 7_ 55 wherein 111-137 are as defined in claim 1, in an organic solvent at a temperature in the range of 40 - 1200C in the presence of a base, and reacting the resulting compound with an alkali metal cyanide orthiocyanate.

13. A pharmaceutical composition comprising a compound of formula I in which Z is tetrazolyl in 60 association with a pharmaceutically acceptable diluent or carrier.

14. A compound of formula I as herein described, with particular reference to the Examples.

15. A method for producing a compound of formula I as herein described, with particular reference to the Examples.

Printed in the UK for HMSO, D8818935, 12184, 7102.

Published by The Patent Office, 25 Southampton Buildings, London, WC2A lAY, from which copies may be obtained.