GB1586466A

GB1586466A - Diphenyl methane derivatives

Info

Publication number: GB1586466A
Application number: GB4268176A
Authority: GB
Original assignee: Lilly Industries Ltd
Current assignee: Lilly Industries Ltd
Priority date: 1977-10-12
Filing date: 1977-10-12
Publication date: 1981-03-18

Description

(54) DIPHENYL METHANE DERIVATIVES (71) We, LILLY INDUSTRIES LIMITED, a British Company of Lilly House, Hanover Square, London W1R OPA, England, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- This invention relates to a class of novel diphenyl methane derivatives, to methods of preparing such derivatives, and to pharmaceutical formulations containing such derivatives.

2 - Hydroxy - 5 - methylbenzhydrol has been described by Moerhle and Miller, Monatsh. Chem., 1974, 105(6), 1151-63 (C.A. 83, 9711d). However no utility and in particular no pharmacological activity, is disclosed therein for this compound.

According to the present invention there is provided a diphenyl methane derivative of formula (I):

wherein R' is hydrogen, C14 alkyl or C25 acyl; R2, R3 and R4 are selected from hydrogen, methyl and ethyl, at least one being other than hydrogen; Y is -OH, C14 alkoxy or C25 acyloxy; and Ar is a phenyl group optionally substituted by from one to three groups selected from halogen, methyl, carboxy, -COOR5, nitro, and trifluoromethyl, R5 being C14 alkyl, or a pharmaceutically acceptable salt thereof provided that when R', R2 and R3 are all hydrogen, Y is -OH and Ar is phenyl, R4 is ethyl.

Preferably R' is hydrogen or C14 alkyl, Y is -OH or C14 alkoxy, and Ar is phenyl optionally substituted by from one to three groups selected from halogen, methyl and nitro.

The invention also provides a pharmaceutical formulation containing an active ingredient in association with a pharmaceutically acceptable carrier therefor, the active ingredient being a compound of formula (I) as hereinbefore defined or, additionally, 2-hydroxy-5methylbenzhydrol, and a method of preparing such a pharmaceutical formulation which comprises bringing a compound of formula (I) as hereinbefore defined or 2-hydroxy-5-methylbenzhydrol into association with a pharmaceutically acceptable carrier therefor.

Further in accordance with this invention there is provided a method of treating a non-human animal suffering from or susceptible to an allergic condition, and particularly a method of treating immediate hypersensitivity diseases such as asthma, which comprises administering to said animal a therapeutically effective amount of a compound of formula (I) as hereinbefore defined or 2-hydroxy-5-methylbenzhydrol.

Preferred compounds of formula (I) are those having one or more of the following features: (a) Y is -OH, (b) Y is -OCH3, (c) R' is hydrogen, (d) R1 is -CH3, (e) one of R2, R3 and R4 is ethyl, the other two being hydrogen, (f) R3 is ethyl, R2 and R4 being hydrogen, (g) R4 is ethyl, R2 and R3 being hydrogen, (h) Ar is unsubstituted phenyl, (i) Ar is phenyl substituted by halogen, (j) Ar is a 4-fluorophenyl group, (k) Ar is a 4-chlorophenyl group, (1) Ar is a 4-methyl group.

Particularly preferred compounds are those having features (a), (c), (e), and (i); (a), (c), (f) and (j); (a), (c), (g) and (k); (a), (d), (e) and (1); (a), (d), (g) and (1); (b), (d), (e) and (i); and (b), (d), (g) and (k).

The present invention also provides a method of preparing a compound of formula (I) as defined above which comprises reacting a compound of formula:

wherein R' is hydrogen C14 alkyl or C25 acyl, and R2, R3, R4 and Ar are as defined above with LiAIH4 or NaB H4, or with aluminium isopropoxide in isopropanol, to produce a compound of formula (I) in which Y is -OH, optionally alkylating or acylating this product to give a compound of formula (I) in which Y is C14 alkoxy or C25 acyloxy, and where R' is C25 acyl, hydrolysing to give a compound of formula (I) in which R' is hydrogen.

In addition the present invention provides a method of preparing a compound of formula (I) as defined above comprising reacting a compound of formula:

wherein R', R2, R3 and R4 are as defined above with an organometallic compound of formula: Ar Z wherein Ar is as defined above and Z is a cationic group selected from alkali metal ions, alkaline earth metal ions and a group of formula -MgX, where X is chlorine, bromine or iodine, and hydrolysing the resulting organometallic complex, preferably with acid, to give a compound of formula (I) in which Y is -OH. It is preferred for the compound of formula Ar Z to be an organolithium compound of formula ArLi, or a Grignard reagent of formula ArMgBr.

The compounds of the present invention are useful in the prophylactic treatment of immediate hypersensitivity diseases including asthma and in the alleviation of status asthmaticus in humans. The compounds have low toxicity.

The compounds or compositions of the present invention may be administered by various routes and for this purpose may be formulated in a variety of forms. Thus the compounds of compositions may be administered by the oral, rectal and vaginal routes, topically, parenterally e.g. by injection and by continuous or discontinuous intra-arterial infusion, in the form of, for example, tablets, lozenges, sublingual tablets, sachets cachets, elixirs, suspensions, aerosols, ointments, for example, containing from 1 to 10 /" by weight of the active compound in a suitable base, soft and hard gelatin capsules, suppositories, injection solutions and suspensions in physiologically acceptable media, sterile packaged powders absorbed onto a support material for making injection solutions, vaginal pessaries, tampons, creams to be used with vaginal applicators and diaphragms. Advantageous for this purpose, compositions may be provided in dosage unit form, preferably each dosage unit containing from 5 to 500 mg. (from 5.0 to 50 mg. in the case of parenteral administration, from 5.0 to 50 mg. in the case of inhalation and from 25 to 500 mg. in the case of oral or rectal administration) of a compound of formula (I).

Dosages of from 0.5 to 90 mg/kg per day, preferably 2 to 20 mg/kg, of active ingredient may be administered. It will have readily be understood that the amount of the compound or compounds of formula (I) actually to be administered will be determined by a physician, in the light of all the relevant circumstances including the condition to be treated, the choice of compound to be administered and the choice of route of administration and therefore the above preferred dosage range is not intended to limit the scope of the present invention in any way.

In this specification, the expression "dosage unit form" is used as meaning a physically discrete unit containing an individual quantity of the active ingredient, generally in admixture with a pharmaceutical diluent therefor, or otherwise in association with a pharmaceutical carrier, the quantity of the active ingredient being such that one or more units are normally required for a single therapeutic administration or that, in the case of severable units such as scored tablets, at least one fraction such as a half or a quarter of a severable unit is required for a single therapeutic administration.

The formulations of the present invention normally will consist of at least one compound of formula (I) associated with a pharmaceutically acceptable carrier therefor, i.e. mixed with a carrier, or diluted by a carrier, or enclosed or encapsulated by an ingestible carrier in the form of a capsule, sachet, cachet, paper or other container or by a disposable container such as an ampoule. A carrier or diluent may be a solid, semi-solid or liquid material, which serves as a vehicle, excipient or medium for the active therapeutic substance.

Some examples of the diluents or carriers which may be employed in the pharmaceutical compositions of the present invention are lactose, dextrose, sucrose, sorbitol, mannitol, propylene glycol, liquid paraffin, white soft paraffin, kaolin, fumed silicon dioxide, microcrystalline cellulose, calcium silicate, silica, polyvinylpyrrolidone, cetostearyl alcohol, starch, modified starches, gum acacia, calcium phosphate, cocoa butter, ethoxylated esters, oil of theobroma, arachis oil, alginates, tragacanth, galatin, syrup B.P., methyl cellulose, polyoxyethylene sorbitan monolaurate, ethyl lactate, methyl and propyl hydroxybenzoate, sorbitan trioleate, sorbitan sesquioleate and oleyl alcohol and propellants such as trichloro-monofluoromethane, dichloro-difluoro-methane and dichlorotetrafluoroethane. In the case of tablets, a lubricant may be incorporated to prevent sticking and binding of the powdered ingredients in the dies and on the punch of the tabletting machine. For such purpose there may be employed for instance aluminium, magnesium or calcium stearates, talc or mineral oil.

The invention will be further understood from the following examples.

EXAMPLE 1 2-Hydroxy-4-ethyl-4'-fluorobenzhydrol (a) 2-Acetoxy4-ethyl-4'-fluorobenzophenone To 2 - hydroxy - 4 - ethyl - 4' - fluorobenzophenone (5 g, 2.05x 10-2 mol) was added acetic anhydride in excess, and the mixture was refluxed for 5 hours. The excess acetic anhydride was evaporated off, 2N sodium hydroxide (10 ml, 2x10-2 mol) was added and the mixture was extracted with chloroform and dried (over magnesium sulphate). The chloroform solution was filtered and evaporated to leave 2 acetoxy - 4 - ethyl - 4' - fluoro benzophenone (1.8g, 30%) as an oil which solidified on standing, mp 57-580C.

(b) 2-Hydroxy-4-ethyl-4!-fluorobenzhydrol The product of step (a) (3g, 1.05x10-2 mol) in ether (20 ml) was added to a stirred suspension of lithium aluminium hydride (0.5g, 1.32x10-2 mol) in refluxing ether (50 ml) over the course of 15 minutes. The mixture was refluxed for a further 30 minutes, cooled and treated with water (0.5 ml), SN sodium hydroxide (0.5 ml), and more water (1.5 ml). When effervescence had ceased the ether fraction was separated, dried (over magnesium sulphate), filtered and evaporated to give the title product which was recrystallised from n-hexane as white needles (0.95g, 29%), mp 94--950C.

EXAMPLE 2 2-Hydroxy-5-ethyl-4'-chlorobenzhydrol This product was prepared using lithium aluminium hydride as in Example l(b), except that the reaction mixture was processed by adding 2N hydrochloric acid until the pH of the mixture was 4. The ether fraction was then separated, dried (over magnesium sulphate) filtered and evaporated to give the title product (9.1 g, 93 /n) m.p. 69-710C.

EXAMPLE 3 2-Methoxy-5-ethyl-4'-methylbenzhydrol This product was prepared by the method of Example 2. The product (0.7g, 41 /,) was purified by preparative thin layer chromatography and had mp 57-580C.

EXAMPLE 4 2-Methoxy-5-ethyl-4'-chlorobenzhydrol Sodium borohydride (0.4g, 0.01 mol) was added to a stirred solution of 2 - methoxy 5- ethyl - 4' - chlorobenzophenone (2.75g, 0.01 mol) (b p 15152"C/0.25 mm) (prepared by methylation of 2hydroxy - 5 - ethyl - 4' - chlorobenzophenone) in isopropyl alcohol (40 ml) and refluxed for 2+ hours. The solution was treated with 2N hydrochloric acid (5 ml) and filtered. The filtrate was extracted with ether. The ether fraction was dried (over magnesium sulphate) filtered, and evaporated. The residue was recrystallised from aqueous methanol and further purified by preparative thin layer chromatography to give the pure title product (0.78g 28%, mp 71-730C.

EXAMPLE 5 (2-Methoxy-5-ethylphenyl) (4 chlorophenyl)methoxymethane 2 - Methoxy - 5 - ethyl - 4' - chlorobenzhydrol (3g, 0.011 mol) was treated with 60% hydrogen bromide solution (20 ml) and the mixture was refluxed gently for 30 minutes. The mixture was then cooled, water was added, and the solution was extracted with chloroform. The chloroform extract was washed with 10% sodium carbonate solution, dried (over magnesium sulphate), filtered and evaporated to give (2 - methoxy - 5 - ethylphenyl) (4 - chloro phenyl) bromomethane as an orange-brown oil (3.63g).

This oil was dissolved in methanol and the solution was added with stirring to a solution of sodium hydroxide (0.8g, 0.02 mol) in methanol (30 ml). The solution was refluxed for 1+ hours, cooled, acidified with dilute hydrochloric acid and extracted with chloroform. The chloroform fraction was dried (over magnesium sulphate), filtered, and evaporated to yield the crude title product as an oil. Two recrystallisations from methanol, with decolourisation using animal charcoal yielded the pure title product in the form of white crystals (0.7g, 22%), mp 48--500C.

EXAMPLE 6 2-Hydroxy-4-ethyl-4'-nitrobenzhydrol To aluminium isopropoxide (13 g, 0.06 mol) in isopropanol (100 ml) was added 2 hydroxy - 4 - ethyl - 4' - nitrobenzophenone (10.8g, 0.04 mol). The mixture was heated and acetone formed by the reaction distilled off. When no further acetone was formed, after about 6 hours, the solvent was evaporated off and the residue hydrolysed with dilute hydrochloric acid. This residue was extracted with ether and the ether extract was then washed with water, dried over magnesium sulphate and evaporated to yield a yellow crystalline product which was purified by column chromatography, eluting with chloroform, to give the pure title product (10g, 77%) mp 107--8"C.

EXAMPLE 7 2-Hydroxy-4-ethyl-benzhydrol A solution of 2 - hydroxy - 4ethylbenzophenone (9.05g, 0.04 mol) in dry ether (50 ml) was added, with stirring, over a period of 15 minutes to a solution of lithium aluminium hydride (1.5g, 0.04 mol) in dry ether (150 ml) at 100C. The mixture was allowed to warm to room temperature, and, with continued stirring. hydrolysed at 100C with 2N hydrochloric acid. Water was added and the aqueous layer was extracted with ether. The ether solution was dried over magnesium sulphate and the ether evaporated off to yield a viscous oil which was purified by preparative thin layer chromatography using chloroform as eluent to give the title product (1.8g, 20%) n,2'=1.5879.

WHAT WE CLAIM IS: 1. A diphenyl methane derivative of formula (I):

wherein R' is hydrogen, C14 alkyl or C25 acyl; R2, R3 and R4 are selected from hydrogen, methyl and ethyl, at least one being methyl or ethyl; Y is -OH, C14 alkoxy or C25 acyloxy; and Ar is a phenyl group optionally substituted by from one to three groups selected from halogen, methyl, carboxy, --COOR5, nitro and trifluoromethyl, R5 being C14 alkyl, or a pharmaceutically-acceptable salt thereof, provided that when R', R2 and R3 are all hydrogen, Y is -OH and Ar is phenyl, R4 is ethyl.

2. A diphenyl methane derivative according to Claim 1 wherein R' is hydrogen or C14 alkyl, Y is -OH or C14 alkoxy, and Ar is phenyl optionally substituted by from one to three groups selected from halogen, methyl and nitro.

3. A derivative according to Claim 1 or 2 wherein R' is hydrogen or methyl; one of R2, R3 and R4 is ethyl, the others being hydrogen; and Ar is phenyl or phenyl singly substituted by chlorine, fluorine, methyl or nitro.

4. A derivative according to any of Claims 1 to 3 wherein R', R2 and R4 are hydrogen, R3 is ethyl, Y is -OH and Ar is phenyl, pfluorophenyl, p-chlorophenyl or pnitrophenyl.

5. 2 - Hydroxy - 4 - ethyl - 4' - fluorobenzhydrol or a pharmaceuticallyacceptable salt thereof.

6. (2 - Methoxy - 5 - ethylphenyl)(4 chlorophenyl) methoxymethane.

7. A method of preparing a diphenyl methane derivative of formula (I) as defined in any of Claims 1 to 6 which comprises reacting a compound of formula

wherein R', R2, R3, R4 and Ar are as defined in any of Claims 1 to 6, with Li Al H4 or Na BH4, or with aluminium isopropoxide in isopropanol, to produce a compound of formula (I) in which Y is -OH, and optionally alkylating or acylating this product to give a compuond of formula (I) in which Y is C14 alkoxy or C25 acyloxy, and optionally hydrolysing a compound of formula (I) in which R1 is C2 acyl to give a compound of formula (I) in which R' is hydrogen.

8. A method of preparing a diphenyl methane derivative of formula (I) as defined in any of Claims 1 to 6 which comprises reacting a compound of formula

**WARNING** end of DESC field may overlap start of CLMS **.

Claims

**WARNING** start of CLMS field may overlap end of DESC **.

dilute hydrochloric acid and extracted with chloroform. The chloroform fraction was dried (over magnesium sulphate), filtered, and evaporated to yield the crude title product as an oil. Two recrystallisations from methanol, with decolourisation using animal charcoal yielded the pure title product in the form of white crystals (0.7g, 22%), mp 48--500C.

EXAMPLE 6

2-Hydroxy-4-ethyl-4'-nitrobenzhydrol To aluminium isopropoxide (13 g, 0.06 mol) in isopropanol (100 ml) was added 2 hydroxy - 4 - ethyl - 4' - nitrobenzophenone (10.8g, 0.04 mol). The mixture was heated and acetone formed by the reaction distilled off. When no further acetone was formed, after about 6 hours, the solvent was evaporated off and the residue hydrolysed with dilute hydrochloric acid. This residue was extracted with ether and the ether extract was then washed with water, dried over magnesium sulphate and evaporated to yield a yellow crystalline product which was purified by column chromatography, eluting with chloroform, to give the pure title product (10g, 77%) mp 107--8"C.

EXAMPLE 7

2-Hydroxy-4-ethyl-benzhydrol A solution of 2 - hydroxy - 4ethylbenzophenone (9.05g, 0.04 mol) in dry ether (50 ml) was added, with stirring, over a period of 15 minutes to a solution of lithium aluminium hydride (1.5g, 0.04 mol) in dry ether (150 ml) at 100C. The mixture was allowed to warm to room temperature, and, with continued stirring. hydrolysed at 100C with 2N hydrochloric acid. Water was added and the aqueous layer was extracted with ether. The ether solution was dried over magnesium sulphate and the ether evaporated off to yield a viscous oil which was purified by preparative thin layer chromatography using chloroform as eluent to give the title product (1.8g, 20%) n,2'=1.5879.

WHAT WE CLAIM IS: 1. A diphenyl methane derivative of formula (I):

wherein R' is hydrogen, C14 alkyl or C25 acyl; R2, R3 and R4 are selected from hydrogen, methyl and ethyl, at least one being methyl or ethyl; Y is -OH, C14 alkoxy or C25 acyloxy; and Ar is a phenyl group optionally substituted by from one to three groups selected from halogen, methyl, carboxy, --COOR5, nitro and trifluoromethyl, R5 being C14 alkyl, or a pharmaceutically-acceptable salt thereof, provided that when R', R2 and R3 are all hydrogen, Y is -OH and Ar is phenyl, R4 is ethyl.
2. A diphenyl methane derivative according to Claim 1 wherein R' is hydrogen or C14 alkyl, Y is -OH or C14 alkoxy, and Ar is phenyl optionally substituted by from one to three groups selected from halogen, methyl and nitro.
3. A derivative according to Claim 1 or 2 wherein R' is hydrogen or methyl; one of R2, R3 and R4 is ethyl, the others being hydrogen; and Ar is phenyl or phenyl singly substituted by chlorine, fluorine, methyl or nitro.
4. A derivative according to any of Claims 1 to 3 wherein R', R2 and R4 are hydrogen, R3 is ethyl, Y is -OH and Ar is phenyl, pfluorophenyl, p-chlorophenyl or pnitrophenyl.
5. 2 - Hydroxy - 4 - ethyl - 4' - fluorobenzhydrol or a pharmaceuticallyacceptable salt thereof.
6. (2 - Methoxy - 5 - ethylphenyl)(4 chlorophenyl) methoxymethane.
7. A method of preparing a diphenyl methane derivative of formula (I) as defined in any of Claims 1 to 6 which comprises reacting a compound of formula

wherein R', R2, R3, R4 and Ar are as defined in any of Claims 1 to 6, with Li Al H4 or Na BH4, or with aluminium isopropoxide in isopropanol, to produce a compound of formula (I) in which Y is -OH, and optionally alkylating or acylating this product to give a compuond of formula (I) in which Y is C14 alkoxy or C25 acyloxy, and optionally hydrolysing a compound of formula (I) in which R1 is C2 acyl to give a compound of formula (I) in which R' is hydrogen.
8. A method of preparing a diphenyl methane derivative of formula (I) as defined in any of Claims 1 to 6 which comprises reacting a compound of formula

wherein R1, R2, R3 and R4 are as defined in any of Claims 1 to 6 with an organometallic compound of formula: ArZ wherein Ar is as defined in any of Claims 1 to 6 and Z is a cationic group selected from alkali metal ions, alkaline earth metal ions and a group of formula -MgX, where X is chlorine, bromine or iodine, and hydrolysing the resulting organometallic complex, preferably with acid, to give a compound of formula (I) in which Y is -OH, and optionally alkylating or acylating to give a compound of formula (I) in which Y is C14 alkoxy or C25 acyloxy.
9. A method according to Claim 7 substantially as hereinbefore described in any one of the Examples.
10. A diphenyl methane derivative as defined in Claim 1 whenever prepared by a method according to any of Claims 7 to 9.
11. A diphenyl methane derivative as defined in Claim 1 substantially as hereinbefore described in any one of the Examples.
12. A pharmaceutical formulation comprising a diphenyl methane derivative according to any of Claims l to 6, 10 and 11 or 2 - hydroxy - 5 - methylbenzhydrol in association with a pharmaceuticallyacceptable carrier therefor.
13. A method of preparing a pharmaceutical formulation which comprises bringing a diphenyl methane derivative according to any of Claims 1 to 6, 10 and 11 or 2 - hydroxy - 5 - methylbenzhydrol into association with a pharmaceutically-acceptable carrier therefor.
14. A method of treating non-human animals which comprises administering to said animal a therapeutically effective amount of a compound of formula I as defined in claim 1 or 2 - hydroxy - 5 methylbenzhydrol.