GB2131688A

GB2131688A - Pharmaceutical use of aurone- type compounds

Info

Publication number: GB2131688A
Application number: GB08234669A
Authority: GB
Inventors: Stephen Richard Baker; William James Ross
Original assignee: Lilly Industries Ltd
Current assignee: Lilly Industries Ltd
Priority date: 1982-12-04
Filing date: 1982-12-04
Publication date: 1984-06-27

Abstract

The anti-inflammatory use of the following compounds is disclosed <IMAGE> in which R<1>, R<2> and R<3> are each hydrogen, halogen, C1-4 alkyl, C1-4 alkoxy, C3-8 cycloalkyl, optionally substituted phenyl, C1-4 haloalkyl, C1-4 acylamino, C1-6 alkylaminocarbonyl, amino, cyano, hydroxy, nitro C2-4 alkenyl, tetrazol-5- yl or carboxyvinyl or in which R<1> and R<2> taken together at adjacent carbon atoms represent a phenyl ring, at least one of R<1>, R<2> and R<3> being other than hydrogen, and in which R<4>, R<5>, R<6> are each hydrogen, halogen, C1-4 alkyl, C1-4 alkoxy, C3-8 cycloalkyl, optionally substituted phenyl, C1-4 haloalkyl, C1-4 acylamino, C1-4 alkylaminocarbonyl, amino, cyano, hydroxy, nitro C2-4 alkenyl, carboxyl, tetrazol-5-yl or carboxyvinyl, provided that at least one of R<1>, R<2>, R<3>, R<4>, R<5> and R<6> is carboxyl, tetrazol-5-yl or carboxyvinyl; or a pharmaceutically- acceptable salt or ester thereof.

Description

SPECIFICATION Pharmaceutical compounds and their use This invention relates to the use of pharmaceutical compounds in the treatment of disease.

British Patent 2 030 142 discloses some aurone compounds having the formula

where R and R1 take various substituent values, these compounds being described as principally for use in the treatment of immediate hypersensitivity diseases such as asthma. We have now discovered that certain of these compounds have useful properties in the treatment of anti-inflammatory diseases.

The invention provides compounds of the following formula for use in the treatment of antiinflammatory diseases:

in which R', R2 and R3 are each hydrogen halogen, C14alkyl, C1~4alkoxy, C3~8cycloalkyl, optionally substituted phenyl, C1-4haloalkyl, C1~4acylamino, C 16alkylaminocarbonyl, amino, cyano, hydroxy, nitro, C,,alkenyl, tetrazol-5-yl or carboxyvinyl or in which R1 and R2 taken together at adjacent carbon atoms represent a phenyl ring, at least one of R1, R2 and R3 being other than hydrogen, and in which R4, R5, R6 are each hydrogen, halogen, C,,alkyl, C,,alkoxy, C38cycloalkyl, optionally substituted phenyl, C1~4haloalkyl, C1-4acylamino, C1~4alkylaminocarbonyl, amino, cyano, hydroxy, nitro, C24alkenyl, carboxyl, tetrazol-5-yl or carboxyvinyl, provided that at least one of R1, R2, R3, R4, Ras and R6 is carboxyl, tetrazol-5-yl or carboxyvinyl; or a pharmaceutically-acceptable salt or ester thereof. A preferred group is one in which at least one of R4, R5 and R6 is carboxyl or at least one of R1, R2, R3, R4, Ras and Rs is tetrazol5-yl or carboxyvinyl.

Thus the invention also provides a method for the prophylactic or therapeutic treatment of an anti-inflammatory disease, which comprises administering to a mammal, including a human, a compound of formula (I) as defined above.

The anti-inflammatory disease can be such as for example a chronic arthritic disease, rheumatoid arthritis or osteoarthritis. More particularly the invention includes a method of treating a mammal, including a human, suffering from or susceptible to an anti-inflammatory disease, which comprises administering to the mammal an amount which is effective for such treatment of a compound of formula (I) above.

In the above formula, the term "halogen" means especially chlorine, bromine and fluorine.

The terms "C,,alkyl" includes, for example, methyl, ethyl, propyl, isopropyl, butyl and tert butyl, being preferably methyl, ethyl or tert-butyl.

The term "C1~4aikoxy" includes, for example, methoxy, ethoxy, propoxy and butoxy, and is preferably methoxy. The term "C38cycloalkyl" includes, for example, cyclopropyl, cyclopentyl and cycloheptyl, and is preferably cyclohexyl. The term "optionally substituted phenyl" includes, for example, phenyl optionally substituted with 1 to 3 substituents selected from methyl, methoxy, halogen and nitro. The term "C1-4haloalkyl" can be, for example, any of the groups listed for "C1~4alkyl" substituted with one to three halo atoms such as fluorine or chlorine, and is especially trifluoromethyl. The term "C2alkenyl" is preferably allyl.The term "C1-4acylamino" includes, for example, acetamido and groups of the formula RCONH-- where R has the value of C~3alkyl, and C 14alkylaminocarbonyl includes, for example, N-isopropylcarboxamido, and groups of the formula

where R is hydrogen or C1~salkyl. "Amino" includes, for example, NH2, mono-C1alkylamino and di-C1 4alkylamino, especially dimethylamino.

It is preferred that R', R2, R3, R4, R5 and R6 be selected from hydrogen, halogen, C 14alkyl, C 14alkoxy, cyclohexyl, trifluoromethyl, dimethylamino, hydroxy, carboxyl, tetrazol-5-yl or carboxyvinyl.

It is further preferred that R1 be selected from C1~4alkoxy, C,,alkyl and halogen and R2 and R3 are both hydrogen. Similarly R4 is preferably chosen from carboxyl, tetrazol-5-yl or carboxyvinyl, and R5 and R6 are both hydrogen, and an especially preferred group of compounds is one having the following formula

in which R1 is C1~4alkoxy, C,,alkyl or halogen and R4 is carboxyl, tetrazol-5-yl or carboxyvinyl, or a salt or ester thereof.

Suitable salts of compounds of 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. When the compounds contain an amino group or a basic nitrogen, acid addition salts are included such as those with inorganic acids, for example hydrochloric, hydrobromic, nitric, sulphuric or phosphoric acids, or with organic acids, such as organic carboxylic acids, for example, glycollic, maleic, hydroxymaleic, fumaric, malic, tartaric, citric, salicylic, o-acetoxybenzoic, nicotinic or isonicotinic acid, or organic sulphonic acids for example methane sulphonic, ethane sulphonic, 2hydroxyethane sulphonic, toluene-p-sulphonic or naphthalene-2-sulphonic acid.Preferred esters are those derived from C,,alkanols, for example the methyl, ethyl, propyl, isopropyl, butyl and t-butyl esters. Also included are esters having a substituted alkyi group in view of the fact that it is often desirable to attach an ester group that cleaves to give the free acid. Examples of such substituted aikyls include acetoxymethyl, methylthiomethyl, methoxyethyl, ethoxyethyl, methyisulphinylmethyi and methylsulphonyl methyl.

The compounds are known to the art and can be prepared by the methods disclosed in British Patent 2 030 142 referred to above. They exist in both Z and E forms, the Z form being preferred for the purpose of this invention.

The compounds of formula (I) have shown activity in tests devised to indicate antiinflammatory activity as, for example, the adjuvant arthritis test, and are accordingly indicated for prophylactic or therapeutic use in the treatment of anti-inflammatory diseases. For example the compounds are active in the adjuvant arthritis test (B. B. Newbould Chemotherapy of Arthritis Induced in Rats by Mycobacterial Adjuvart Br. J. Pharmacol. 21, 127-136(1963)).

As examples of compounds that are active in this test there may be mentioned Z-4-[(5-methoxy3-oxo-2-(3 H)-benzofu ranylidene)-methyl] benzoic acid, Z,E-3-[4-{(5-chloro-3-oxo-2-(3H) benzofuranylidene)methyllphenyl]-2-propenoic acid and Z-3-[(5-methoxy-3-oxo-2-(3H)benzofuranylidene)methyl]benzoic acid. The lastnamed compound inhibited the primary swelling of adjuvant arthritis by 23%, and the secondary swelling by 49% at 33 mg/kg per day p.o.

The compounds may be administered by various routes, for example, by the oral or rectal route, by inhalation, topically or parenterally, for example by injection, being usually employed in the form of a pharmaceutical composition. Such compositions 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, elixires, suspensions, aerosols as a solid or in a liquid medium, ointments containing for example up to 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 includs 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 propyl-hydroxybenzoate, talc, magnesium stearate and mineral oil. The compositions of the invention may, as is well i < nown in the art, be formulated so as to provide quick, sustair,ed or delayed release of the active ingredient after administration to the patient.

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 that the amount administered will be determined by the physician in the light 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 iimit the scope of the invention in any way.

Claims

1. A compound of the formula

in which R', R2 and R3 are each hydrogen, halogen, C1 4alkyl, C1~4alkoxy, C36cycloalkyl, optionally substituted phenyl, C,,haloalkyl, C1~4acylamino, C1~6alkylaminocarbonyl, amino, cyano, hydroxy, nitro, C,,alkenyl, tetrazol-5-yl or carboxyvinyl or in which R1 and R2 taken together at adjacent carbon atoms represent a phenyl ring, at least one of R1, R2 and R3 being other than hydrogen, and in which R4, R5, R6 are each hydrogen, halogen, C1~4alkyl, C1~4alkoxy, C35cycloalkyl, optionally substituted phenyl, C1~4haloalkyl, C,,acylamino, C1alkylaminocarbonyl, amino, cyano, hydroxy, nitro, C24alkenyl, carboxyl, tetrazol-5-yl or carboxyvinyl, provided that at least one of R1, RZ, R3, R4, R5 and R6 is carboxyl, tetrazol-5-yl or carboxyvinyl; or a pharmaceutically-acceptable salt or ester thereof; for use in the treatment of anti-inflammatory diseases.

2. A method for the prophylactic or therapeutic treatment of an anti-inflammatory disease, which comprises administering to a mammal, including a human, a compound of formula (I) as defined in claim 1.

3. A method according to claim 2 which comprises administering a compound of the formula

in which R1 is C,,alkoxy, C,, alkyl or halogen and R4 is carboxyl, tetrazol-5-yl or carboxyvinyl.

4. A pharmaceutical composition for use in the treatment of an anti-inflammatory disease comprising a compound as defined in claim 1 in association with a diluent or carrier therefor.