JPS59110688A - Novel drug compound and manufacture - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel compounds, processes for their preparation and their use as medicaments.

British Patent No. 2,030. No. /4L discloses this aurone compound with the formula having pharmaceutical properties: (wherein R and R1 have various substituent values. We have discovered a group of related compounds that can be derived from them.

Compounds of the invention have the formula: or different, hydrogen, halodane, cN4 alkyl, ClN4 alkoxy, cs18 cycloalkyl, optionally substituted phenyl, C1-4
'%0 alkyl, cl,, 4 acylamino, clN4
Alkylaminocarbonyl, amino, cyano, hydroxy, nitro, C3-4 alkenyl, C3-4 alkenyloxy, carboxy, 2-alkoxy, carboxyl, tetrazole-! -yl or carboxyvinyl, or R1 and R2 together with adjacent carbon atoms represent phenyl m), or a salt or ester thereof.

A preferred group of Ω compounds according to the invention is of the formula: (wherein R1, R2 and R3 are the same or different, hydrogen, halodane, Cl~4el4alkyl~4alkoxy, C3,8cycloalkyl, optionally Optionally substituted phenyl, C)10al-4kyl, ClN4 acylamino, ClN4 alkylaminocarzanyl, amino, cyano, hydroxy, nitro, C
3-4 alkenyl, tetrazol-j-yl or cal is xyvinyl, or R1 and R2 taken together with adjacent carbon atoms represent a phenyl ring, 111, R'' and at least 7 of R30 are other than hydrogen; Also R4,
R5 and R6 are each hydrogen, halodane 1+v4 alkyl, C1,4 alkoxy, 03-8 cycloalkyl,
optionally substituted phenyl, C1+V4
haloalkyl, C1,4 acylamino, ClN4 alkylaminocarzanyl, amino, cyano, hydroxy, nitro, C3,4 alkenyl, carboxyl, tetrazol-y-yl or carboxyvinyl, with the proviso that R
, at least one of R and R6 is carboxyl, or at least one of R1, R2, R3, R4, R5 and R6 is tetrazol-y-yl or carboxyvinyl), or a salt thereof or an ester.

A further preferred group of compounds of the invention is of the formula:
and R2 are both hydrogen, or R1 is carboxyl and R2 is hydrogen, C3_4 alkenyl or Cyl4 alkyl, Rs R and R6 are hydrogen, nitro, hydroxyl, car is xyA-, carboxyl, respectively. Goxy C1-2 alkoxy, C3-4 alkenyl, C alkyl, C3,4 al1-4 kenyloxy, C 4 alkoxy t-group: (in the formula,
R7 and R8 are each hydrogen or C1. alkyl) and salts and esters thereof.

The term "-location" specifically refers to chlorine, bromine and fluorine. The term "C□~4el4alkyl, such as methyl, ethyl, provil, improvil, butyl,
Includes tert-butyl, preferably methyl, ethyl or tert-butyl. The term "C-4 alkoxy" includes, for example, methoxy, ethoxy, propoxy and butoxy, preferably methoxy. The term "cycloalkyl" includes, for example, Schiff 3-80 zorobyl, cyclopentyl and cyclohebutyl, preferably cyclohexyl. The term "optionally substituted phenyl" is, for example, selected from methyl, methoxy, halogen and nitro.
Included is phenyl optionally substituted with ~3 substituents. The term "C4 haloalkyl" is
It can be any group listed under "C1-4 alkyl" substituted with /-3 halo atoms, such as fluorine or chlorine, in particular trifluoromethyl. term"
03-4alkenyl" is preferably allyl. The term rcm-4 acylaminocarbohydrate includes, for example, ``acetamide'' and groups of the formula: RCONH-, where R is Cl-3alkyl; , such as N-isoflovir lupoxamide, and groups of the formula: % where R is hydrogen or Cyl4 alkyl. "Amino" K is, for example, -NH2, monoC
Included are 1-4 alkylamino and di-C alkyl 1-4 amino, especially dimethylamino, which can be of the form, for example, where R7 and 'R8 are each hydrogen or C1-4 alkyl. . The term ``carboxyCel2alkoxy'' includes carboxymethoxy,! -carboxyethoxy and/-car? Includes xyethoxy. Preferred substituents for R1, R2, R3, R4, R5 and R6 are hydrogen, halogen, C1e4alkyl, c
4 alkoxy, cyclohexyl, trifluoromethyl, dimethylamino, hydroxy, cal 4? xyl, tetrazol-yl or carboxyvinyl.

A preferred group of compounds of formula (1) is R1, R2 and R3
is selected from hydrogen, hydrogen, cl, 4 alkyl, cl, 4 alkoxy, cyclohexyl, trifluoromethyldimethylamino, hydroxy, tetrazol-yol or carboxyvinyl, and at least one of R1, R2 and R is hydrogen , R is cal is xyl,
R5 and R are hydrogen, halogen, cl, 4 alkyl,
C1,,,alkoxy, cyclohexyl, trifluoromethyl, dimethylamino, hydroxy, carxyl,
It is selected from tetrazol-5-yl or carboxyvinyl.

It is more preferable that R'b is selected from C1-4a'3x1C1,4 alkyl and halokeryl, and R2 and R are both hydrogen. Similarly, R4 is preferably selected from car4
? ii from xyl, tetrazol-3-yl or carboxyvinyl! and R5 and R are both hydrogen, and a particularly preferred group of compounds is of the formula: 5
or carboxyvinyl), or salts or esters thereof.

A further preferred group of compounds is in which R1 is xyl (especially in the j-position), R2 (especially in the 7-position) is hydrogen, 03
~4 alkenyl or C□~4el4al/R4,
R5 and R6 are each hydrogen, hydroxyl, C alkenyl, C1-4 alkyl, 3-4 C alkenyloxy, C alkoxy or 3-4
1 to 4 are groups: (wherein R and R8 are each hydrogen or C1-4 alkyl), and in these compounds, R1 is carboxyl (especially at the 5-position). ), R is hydrogen, and R4, R5 and R6 are each hydrogen, carboxyl, Cel4alkyl or C
Alkoxy is most preferred.

Suitable salts of the compounds according to the invention include, for example, mineral bases such as alkali metal hydroxides, in particular potassium salts or rum salts, or alkaline earth metal hydroxides, in particular calcium salts. Salts or salts of organic bases such as amines such as trimethylamine are included. When the compound contains an amine group or a basic atom, acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid or phosphoric acid 1 or organic acids such as glycolic acid and maleic acid are used. , hydroxymaleic acid, fumaric acid, malic acid, tartaric acid, citric acid, salicylic acid, 0
-acetoxybenzoic acid, nicotinic acid or isonicotinic acid, or organic sulfonic acids, such as meta/sulfonic acid, ethanesulfone rl! , 2-hydroxyethanesulfonic acid, toluene-p-sulfonic acid, and acid addition salts with organic acids such as toluene-p-sulfonic acid. Preferred esters are those derived from Cel4 alkanols such as methyl, ethyl, propyl, improvil and n-butyl.

Also included are esters with substituted alkyl groups in view of the fact that it is often desirable to attach the ester group to cleavage to give the free acid; examples of such substituted alkyls include acetoxymethyl, methylthiomethyl, methoxyethyl, ethoxyethyl. Includes methylsulfinylmethyl and methylsulfonylmethyl.

The preferred salts and esters are those that are pharmaceutically acceptable, but also the derivatives are suitable for use in the manufacture, purification or characterization of pharmaceutical end products.
ization) and are therefore included in the present invention.

3 is included. The reduction is preferably carried out by the use of hydrogen and a metal catalyst, the latter preferably being a metallic catalyst such as platinum or palladium.

Tensile of palladium on charcoal has been found to be a convenient catalyst for this purpose. Generally, the reduction step is carried out in a solvent, such as acetic acid, at a temperature of 0 to 700°C, such as room temperature.

As mentioned above, the compound of formula (III) is known, and its preparation method is described, for example, in British Patent No. 2.030. /≠λ, R2
, 0i4t, ill, issue and Uftg2. o(H,AE
No. i FC is listed. They may best be prepared by condensing a suitably substituted benzaldehyde with a benzofuranone as shown below; Compounds of Formula (III) Many of the compounds of the present invention may be prepared in one of the intermediate steps during the production reaction. It will be appreciated that one can be converted into a pond by the introduction or conversion of a group in the benzofuranone or phenyl ring in the intermediate or final product.Thus, for example, a tetrazol-j-yl compound can be prepared from the corresponding cyanide by reaction with an azide. can be manufactured. When a nitro substituent is desired in the benzofuranone or phenyl nucleus,
The corresponding unsubstituted compounds can be nitrated in conventional manner with a mixture of concentrated nitric acid and concentrated sulfuric acid. The nitro compound can then be converted to other substituents such as amino or acylamino. Amino compounds can be diazotized and the resulting diazonium salts converted to various other products, for example decomposition in alcohols to give the corresponding alkoxy-substituted compounds, or reaction with cupric heronides. This gives rise to the corresponding halo-substituted compounds. Hydroxy-substituted compounds can be prepared, for example, from the corresponding methoxy compounds by cleavage with boron tribromide.

The compound of the present invention has an asymmetric center at the carbon atom (carbon number 2) of the benzofuranone moiety bonded to the benzyl group, and this asymmetry gives rise to the existence of optical isomers.

Substantially pure optical isomers can be produced by chemical reactions in the presence of chiral catalysts. Alternatively, two semi-mixtures of both isomers can be prepared by conventional chemical methods, such as by preparing the diastereoisomer as a salt with an optically active base and then liberating the enantiomer. and the antiallergic activity of the drug's acceptable salts and Estes, published in the Journal of Otsu, Physiology.
f Physi-ology) (London), /3/
, 107C/Rizt> by Mongar and Shield (5child), or Journal, Otsu, Physiology (London), /,! ;/
, 11tll, C/9 Otsu. ) to Pocket Burst (B
The Guinea-Pig Chopped Lung Test (Guinea-Pig C)
hopped lung test) J or Journal, Op, Physiology (London).

This was demonstrated in guinea pigs using the Herxheimer J test described in http://7.2j/(/ri!2). In the "Herxheimel" test, which is based on the fact that allergic bronchial spasm induced in guinea pigs closely resembles asthmatic attacks in humans, the compound was tested at 2, fm 91 kg to 200 m? It showed activity at dosages in the A11 range.

The compounds of the invention may also be used, for example, in adjuvant arthritis tests [Arthritis induced in rats with mycobacterial adjuvants, Bee, New Gold (s, 8.
Newbould) Chemotherapy, Pritish, Journal, Otsu, 7 Armacology (Br, J, Ph
armacol, ), 2/ # /27~/3 Otsu (
/1.3')) showed activity in a test designed to show anti-inflammatory activity.

The compounds of the invention therefore have shown therapeutic utility in the treatment of direct susceptibility reactions, particularly in the treatment of asthma, and also in the treatment of anti-inflammatory diseases. ¥? It is useful for medical treatment.

The compounds of the invention can be administered by various routes, for example by the oral or rectal route, by inhalation, topically or parenterally, for example by injection, and are usually used in the form of pharmaceutical compositions. Accordingly, the present invention encompasses methods of administering a compound according to formula (1) to a mammal suffering from an allergic reaction or inflammatory disease, or for the prevention of such an allergic reaction or inflammatory disease. Pharmaceutical compositions also form part of the invention and are manufactured in a manner well known in the pharmaceutical art and usually contain at least one active compound together with a pharmaceutically acceptable diluent or carrier. In preparing the compositions of the invention, the active ingredient is usually mixed with or diluted with a carrier and/or a carrier which may be in the form of, for example, a capsule, sachet, paper bag or other container. enclosed within. When the carrier acts as a diluent, it can be a solid, semi-solid or liquid material that acts as a vehicle, excipient or medium for the active ingredient. The compositions may therefore be tablets, lozenges, sachets, cachets, elixirs, suspensions, aerosols as solids or in liquid media, e.g. ointments, soft and hard formulations containing up to 70% by weight of the active compound. They can be in the form of gelatin capsules, base agents, infusion solutions and suspensions, and sterile packaged powders. Individual delivery forms for administration by inhalation include aerosol containers, nebulizers and vaporizers. Examples of suitable carriers include lactose, dextrose, sucrose, nrubitol, mannitol, starch, acacia, calcium phosphate, alginate, tragacanth, gelatin, cilolagu, methylcellulose, methyl and hyfuropyruhydroxybenzoate, talc, stearin. magnesium acid as well as mineral oil. The compositions of the present invention are formulated into unit dosage forms that can be formulated to provide rapid, sustained or delayed release of the active ingredient after administration to a patient, as is well known to those skilled in the art. If each unit dosage form is
og, more usually from 2j to 2001/19.

The term "unit dosage form" refers to physically discrete units suitable as unit dosages for large patients and animals, each unit containing a predetermined amount calculated to produce the desired therapeutic effect in association with the required drug carrier. Contains active substances.

The active compounds are effective over a wide dosage range, for example a 7 day dosage is usually 0. j~300m97 in the range 9, more usually j~/00H9/9 in the range. It is understood, however, that the dosage will be determined by the physician in light of the relevant circumstances, including the condition being treated, the choice of compound to be administered and the route of administration chosen, and therefore the above dosage ranges are not intended to limit the scope of the invention. It will be.

The following examples are illustrative of the invention.

Example /~3 3-CC2,3-dihydro-yo-methoxy-3-oxo-2-benzofuranyl)methyl)benzoic acid (Z) 14(
j-Methoxy-3-oxo-,2-(j'H)-penzofuranylidene)methyl]benzoic acid (10fi) was suspended in glacial acetic acid (,l!jom) and poured over charcoal (500g).
Room temperature, 4L, -2ky/cI in the presence of 0% palladium
Hydrogenation was carried out at L2 (1 psi) pressure for 7 hours. The catalyst was filtered and the almost colorless F solution was evaporated in vacuo to give a viscous oil which crystallized easily. This crystalline solid was slurried with a small amount of diethyl ether and filtered again to yield the title compound as an off-white crystalline solid, mp /4L3~/!
Obtained at 2°C (decomposed).

The following compounds were similarly prepared.

≠-((,2,3-dihydro-j-methoxy-3-okino-2-benzofuranyl)methyl]benzoic acid, melting point/g℃ (decomposition) ≠-((2,3-dihydro-2-methyl-3 -Okinokopenzofuranyl)methyl]benzoic acid, melting point ig~
/ 0℃ (decomposition).

Example Hiro (a) Z -3-((2,3-dihydryl-1-methoxyl-3-okino-2-benzofuranyl)
methylene]benzoic acid j-methoxyrugonylpenzofuran-3-C,2H)
on (445;', y > warm dioxane C!;0.
nl) Dissolved. Then 3-cal? Xybenzaldehyde (41,j,9) was added followed by concentrated hydrochloric acid <iow). The mixture was heated on a steam bath for 75 minutes resulting in yellow crystals. After cooling and addition of an equal volume of water, the crystalline product was filtered and recrystallized from dimethylformamide to give the title compound, mp 2gθ°C.

(b) The product (7 g) of 3-CC,2,3-dihydro-j-methoxycaryl-3-oquino-2-benzofuranyl)methyl]benzoic acid (a) in glacial acetic acid (/θo,z) Suspended and hydrogenated at 4', 2 klt/J (ops 1) in the presence of 70% radium on carbon (ioom9). After 1 hour the catalyst was filtered and the colorless filtrate was evaporated in vacuo to give a pale straw colored oil which crystallized on standing. Recrystallization from ethyl acetate/petrol gave the required product as gray crystals, mp ≠0 to ≠3°C.

(GB) 34671 0 Inventor Terry Donald Lindstrom 1335 West 79th Street, Indianapolis, Indiana, USA 46260 0 Inventor William James Ross Keswick Drive, Lightwater, Surrey, United Kingdom 8

Claims (1)

[Claims] Formula (1): (wherein R1, R2, R3, R4, R5 and R6 are the same or different, hydrogen, halogen, C~4 alkyl, C1, alkoxy, Q~ 8 cycloalkyl, optionally substituted phenyl, ClN4 haloalkyl, C1,4 acylamino, C1-4 alkylaminocarbonyl, amino, cyano, hydroxy, nitro, C alkenyl, 3-4 C3,4 alkenyloxy, carboxy C1,2 alkoxy, carboxyl, natho2zol-j-yl or carboxyvinyl, or R1 and R2 taken together with adjacent carbon atoms represent a 7-enyl ring), or a salt or ester thereof. (2) R1, R2 and R3 are the same or different, hydrogen, halogen, C1-4 alkyl, ClN4 alkoxy, C cycloalkyl, optionally substituted 3-8 substituted phenylN C1-4 haloalkyl , C1,,,4 acylamino, C alkylamino 1-4 Nocal? Nyl, amino, cyanide, hydroxy, nitro,
C alkenyl, tetrazole-j3-4 monoyl or carboxyvinyl, or R1 and R2 together with adjacent carbon atoms represent a phenyl ring, at least 7 of R1, R2 and R3 are other than hydrogen, and R, R, R are hydrogen, halogen, C1
,,,4 alkyl, C1e4 alkoxy, C3,8 cycloalkyl, optionally substituted phenyl, C□~4 haloalkyl, C acylamino, C1,47
1-4 rukylaminocarginyl, amino, cyano, hydroxy, nitro, C alkenyl, carbo3-4xyl, tetrazol-thalyl or carboxyvinyl, provided that at least 7 of R, R and R are carzaxyl or R1, R2, R3, R4, R
Claim 1, wherein at least seven of 5 and R6 are nat-2zol-j-yl or carbaxibir
), or a salt or ester thereof. (3) R1, R2 and R3 are hydrogen, halogen, C
4-alkyl, C1,,,4-alkoxy, cyclohexyl, trifluoromethyl, dimethylamine, hydroxy, tetrazol-j-yl or carol is selected, and at least seven of R1, R2 and R are other than hydrogen; , R' is carboxyl, R5 and R6
is selected from hydrogen, halogen, C1,4 alkyl, C1-4 alkoxy, cyclohexyl, trifluoromethyl, dimethylamino, hydroxy, cargyl, tetrazol-y-yl or carboxyvinyl. Compounds described in Section. (4) R is C alkoxy, C alkyl or 1~4
1 to 4...Rogon, and R2 and R3 are both hydrogen! -ilmata is a compound according to claim (2), wherein Cal is xyvinyl and both R5 and R are hydrogen. , (5) Formula (■): O [wherein R1 and R2 are both hydrogen, or R1 is carboxyl and R is hydrogen, C3-4 alkenyl or C alkyl, and 1-4 R, R and R6 is hydrogen, nitro, hydroxyl, carboxyl, clN2 alkoxy, 0, respectively
3-4 alkenyl, clN4 alkyl, C3,4 alkenyloxy, clPv4 alkoxy or group: (wherein R7 and R8 are each hydrogen or C1,4
alkyl), and salts and esters thereof. (6) R' is carzaxyl, R2 is hydrogen, C
3,4 alkenyl or Cel4 alkyl, R,
R and R are each hydrogen, hydroxyl, C3-4 alkenyl, C1-4 alkyl, C3,,4akenyloxy, C alkoxy or a group: 1 to 4 (wherein R and R are each hydrogen or C1-4 alkyl ) The compound according to claim (5). (7) A pharmaceutical formulation comprising a compound according to claim (1) or a pharmaceutically acceptable salt thereof in admixture with a diluent or carrier. Claims comprising reducing a compound of formula (8): (wherein R1, R2, R3, R4, R5 and R have the values shown in claim (1)) A method for producing the compound described in item (1). (9) A compound according to claim (1) for use as a drug or a drug-acceptable salt thereof.