DE2136961A1 - Urea derivatives and processes for their preparation - Google Patents

Description

PÄTENTANWXUE DR.-ItK-. H. Fi'C'i-

MÖNCHEN 5 MOUERSTR. 31

Imperial Chemical Industries Limited Great Britain

Urea derivatives and processes for their preparation

The invention relates to new urea derivatives, in particular new o-carboxycarbanilides with useful ones

109885/1986

biological properties.

It has already been proposed in British Patent 1,055,786 to use urea derivatives the following formula:

COOK

m.CO.HH.X I

wherein H is a hydrogen atom or an alkyl, cycloalkyl, alkenyl or aralkyl radical or an optionally aryl radical substituted by one or more halogen atoms or alkoxy radicals, X represents a by a or more halogen atoms or alkoxy, alkyl, haloalkyl, Alkoxycarbonyl, nitro, cyano, methylsulfonyl or aryl radical substituted by phenyl radicals and the ring A is optionally substituted by one or several halogen atoms or alkoxy, alkyl, alkoxycarbonyl, nitro, carboxy or aminosulfonyl radicals can be substituted, as well as to produce their pharmaceutically acceptable salts, with exception the following known compounds: N -2-carboxyphenyl-N ^ -3-chlorophenylurea, N -S-Xthoxycarbonylphenyl-N ^ -4-iodophenylurea, N -3-nitrophenyl-N ^ -2-carboxyphenylurea, N -2-ethoxycarbonyl-

- 3 109885/1986

phenyl-Hr-4-methyl-3-nitrophenylurea, Μ "-2-methoxycarboron-phenyl-li ^ -2,4,6-triiodopheny-urea f,

and B "-2-ltho ^ carbonylphei ^ lH ^ -3-do ^ pb-e ⁿ y3Ji ^a i ' ^ns " t ^{o: f} f ·

It has been suggested in British Patent 1,055 to manufacture pharmaceutical hates, from at least one urea derivative of the formula I, in which a hydrogen atom or a Alkyl, cycloalkyl, alkenyl or aralkyl radical or an optionally by one or more halogen atoms or aryl radical substituted by alkoxy radicals, X represents a by one or more halogen atoms or alkoxy, alkyl, haloalkyl, alkoxycarbonyl, Nitro, cyano, methylsulfonyl or phenyl radicals represents substituted aryl radical and the ring A optionally by one or more halogen atoms or alkoxy, alkyl, alkoxycarbonyl, HItro, carboxy or aminosulfonyl radicals may be further substituted, or a pharmaceutically acceptable one thereof in admixture with a pharmaceutically acceptable diluent or other suitable type.

In the two patent specifications mentioned, it is stated that the compound of formula 1 for the treatment from. allergic and incompetent states in humans

109885/1986

are useful and promote the healing of wounds *

The compounds of the formula I disclosed in the patents mentioned are

a) in the case of a delayed hypersensitivity of the Guinea pig's well-known biological testing active and

b) other than induced with an adjuvant Arthritis in rats known biological test not active «,

For these reasons, the compounds of the formula I, which can be found in the patents mentioned generally refer to as compounds with anti-allergic properties.

A group of new connections has now been found, some of which come under the collective definition of the Compounds of the formula I according to the patents mentioned and on the other hand not below this collective definition fall, but none of the new compounds in the patent mentioned apply very much specifically disclosed. The new compounds have properties that are noticeably different from those of c \ ie Properties of the compounds specifically disclosed in the cited patents. In particular are the new connections

- I ₁ "

109885/1986

ο) when examining delayed hypersensitivity of the guinea pig not significantly active (cf. (a))

and
d) Active to prevent the formation of secondary injuries in arthritis induced by adjunctrans in rats (cf. (b)) "

For these reasons, the new compounds can generally be used as compounds with immunosuppressive properties, i. _E. Compounds that suppress immunological processes denote. Based on these properties, it can be assumed that these compounds are suitable for the treatment of diseases in which immune mechanisms prevail, ζ · Β. Arthritis, multiple sclerosis, hephritis or Ihyreoi & itis due to an autoimmune reaction, or sympathetic ophthalmic anemia, autoimmune hemolytic anemia, or lupus erythematosus. It is also believed that these compounds can prevent the shedding of transferred body parts.

According to the invention there are compounds of the formula

COOH

-HH.CO.HH- (v / V Y (II)

6 -

109885/198 8,

where X and T, which can be the same or different from one another, each represent a fluorine, chlorine »bromine or iodine atom and Z an alkoscyradicol with a maximum of 7 carbon atoms, an alkyltmoradical with a maximum of 5 carbon atoms, a dialkylamino radical in which the alkyl radicals are identical or different and each contain a maximum of 5 carbon atoms, or represents an alkylidene amino radical with a maximum of 5 carbon atoms,
as well as their pharmaceutically acceptable salts created

In particular, the invention relates to compounds of the formula II in which Σ and Y are identical or different and ^ each represent a chlorine or bromine atom and Z is an alkoxy radical with a maximum of 7 carbon atoms or a methylthio or dimethylamino radical dr represents.

As specific examples of the radical Z can be a methoxy, ithoxy, propoxy, butoxy, amyloxy, Hexyloxy, heptyloxy, methylthio, dirnethylamino or mention piperidino radical

The preferred compounds according to the present invention are H ^ 2-Carboxypherqrl-! R-2, ^ dichloro-5 ~ isopropoxyphenylurea and N-2-carboxyphenyl-H ^ -2,4-dichloro-5-a-propoxyphenylurea.

109885/1986 - _

Any S.ils with a non-toxifiCA © ii, pharmaceutically acceptable cation can be mentioned as a suitable salt. Al $ examples of this can be alkali metal salts; Alkaline earth metal salts, aluminum · »or ammonium salts, and salts with non-toxic, pharmaceutically acceptable organic bases, such" B _e triethanolamine, mention _c When the compound of formula II which is sufficiently basic, comes as a salt and a non-toxic, pharmaceutically acceptable acid addition salt, the is derived from an inorganic or organic acid such as _e a hydrochloride or citrate, in question.

According to a further feature of the invention, a Process for the production of the invention Compounds proposed that consist of anthranilic acid, or a salt thereof, to react with a compound of the formula

KCO III

where X, Y and Z have the meanings given above will.

The heaktion can be in a dry organic

- 8 10 9 8 8 5/1986 BAD ORIGINAL

Solvents free of active water atoms, e .g. Ethyl acetate, benzene, fyridine, ET, N-dimethylformamide or 1,2-Dimetkox2rathan, at a temperature of not more than 50 ⁰ O carry out.

It goes without saying that the starting materials of the formula III and the salts according to the invention by generally known Eeaktionen can be produced.

According to a further feature of the invention, pharmaceutical compositions are created which consist of a Compound of the formula II in which X, Y and Z have the o.a «, Have meanings, or a non-toxic, pharmaceutically acceptable salt thereof, in admixture with consist of a suitable, non-toxic, pharmaceutically acceptable diluent or carrier

The compositions of the invention may, for example, take the form of orally administrable compositions, e.g. Tablets, capsules or non-sterile aqueous or non-aqueous solutions or suspensions, or from parenterally administrable registers, e.g., sterile injectable aqueous or non-aqueous Have solutions or suspensions, or from suppositories. These pharmaceutical compositions contain conventional ones Diluents and / or carriers and can be prepared by known methods.

- Q _ 109885/1986

Lifting the compound of formula II after Invention, the pharmaceuticals according to the invention can seutic masses at least one more pharmaceutical, contain an active agent, such as "a bacteria * - preventive agent, e.g., tetracycline, penicillin, or sulfonaside, and / or an anti-inflammatory Means, e.g. aspirin, phenylbutazone, indomethacin, flufenamic acid or ibuprofen

The pharmaceutical compositions of the invention may be 5 to 50 wt%, in particular 10 to 25 wt%, of a compound of SOrmel II or a nontoxic pharmaceutically acceptable salt contained thereof, the pharmaceutical compositions of the invention can warm-blooded animals, including _e people in Dosing units, for example as tablets or capsules, are administered in an amount of 100 to 1,500 mg, in particular 250 to 1,000 mg, per 70 kg of body weight in a person.

The invention is explained in more detail below with the aid of exemplary embodiments purely by way of example »

example 1

A solution of 2,4-dibromo-5-niethoxyphenyl isocyanate (6.14 g) in dry ethyl acetate (40 ml; dried by adding sodium aluminum silicate or

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109885/1986

anhydrous calcium chloride) was added to a solution of anthranilic acid (2.74 g) in dry ethyl acetate (50 ml j dried in the same way) within 2 minutes with stirring at room temperature. After the addition, the mixture was stirred for 1 hour. The mixture was then filtered and the solid residue was washed with dry ethyl acetate. The filter material was dissolved in N, F-dimethylforinamide (10 ml; previously dried with calcium hydride) and reprecipitated from this solution with methanol (100 ml). The mixture was filtered and the bodice blow dried in vacuo "Thus, there was obtained N -2-carboxyphenyl-Ir-2,4-dibromo-5-methoxyphenylharns tο ff, m.p. <= 202 to 204 ⁰ C.

The isocyanate used as the starting material was like is shown as follows:

m-Methoxyacetanilide (48.2 g) was dissolved in glacial acetic acid (690 ml) and bromine (32 ml) was added over 15 minutes. After a further 10 minutes at room temperature, the mixture was poured into water (8 l), stirred for a further 30 minutes and then filtered. The filter residue consisted of crude 2,4-Dibroni-5-methoxyacetanilide and had after recrystallization from ethanol has a melting point of 160-161 ⁰ C.

This anilide (64.3 g) was washed with ethanol (400 ml) and

- 11 109885/1986

Potassium hydroxide (20 g) refluxed for 10 hours. After cooling, the solution was evaporated to dryness in vacuo and the residue was textured with water (200 ml). An oil separated out which slowly crystallized on standing and then separated out Petroleum ether (b.p. 40 to 60 °) was recrystallized. The 2,4-dibromo-5-methoxyaniline obtained in this way had a melting point of 46 to 47 ^° C.

A solution of 2,4-dibromo-5hniethoxyaniline (48.3 s) in dry ethyl acetate (100 ml) was added over 1 hour to a saturated solution of phosgene in dry ethyl acetate (400 ml). The mixture was then refluxed for 4 hours The solvent was then evaporated from the reaction mixture in vacuo, and the residue was purified by vacuum distillation. This gave 2,4-dibromo-5-methoxyphenyl isocyanate, ep. 118 to 124 ° C at 0.8! Dorr; Mp. 79 to 81 ⁰ C.

Example 2

The procedure was as in Example 1, _except that the corresponding isocyanate was used as the starting material, so that the following compounds of the formula II were formed:

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109885/1986

. ( ⁰ C)

Br Br O-Itnyl 200-202 Br Br O-iso-propyl 193-195 Br Br O-n-propyl, 183-185 Br Br O-n-butyl 194 ^ 195 Br Br O-n-amyl 166-167 Cl Cl O-methyl 214-216 Cl Cl O-ethyl 192-193 Cl Cl O-iso-propyl 190-192 Br Cl O-methyl 212-214 Cl Br O-methyl 215-217 Br Br S-methyl 207-208 Br Br N-dimethyl 170-172 example 3

The procedure was as in Example 1, but the corresponding isocyanate was used as a starting material, so that the following compounds of the Formula XI was created:

. ( ⁰ O)

Cl Cl O-n-propyl 178-180 Cl Cl O-sec-butyl 178-179 Cl • egg O-n-butyl 182-183

109885/1986

Example 4-

It was worked as in Beiaxjiei 1, but the corresponding isoeyanate was used as a starting material, so that the following compounds of the Formula II emerged:

XY, Z Fp "( ⁰ C)

Cl Cl O (OH ₂ ) ₅ C (CH ₃ ) ₅ 189-191 Br Br OCH (Ch ₂ CH ₅ ) CH ₂ CE ₂ GH ₃ 139-1 ^ 2

Example _v J?

• ί 2

N "~ -2-carboxyphenyl ~ N -2,4-dichloro-5-n-propoxyphilienylurea (250 g) was mixed with a solution of sodium dioctyl sulfosuccinate (2.5 g) in ethanol (180 ml) and the resulting granules became passed through a 30 Maechengibter "It Wirde then conducted at 60 ⁰ C dried and then again through a 30 mesh * The dry granules ■ was (217.5 g), corn starch mixed with lactose (25 g) and magnesium stearate (5 g), whereupon the mixture was compressed into tablets, each containing 100 or 250 mg of active ingredient and suitable for oral administration in humans for therapeutic purposes.

- 14 .. BATH ORIGINAL 109885/1986

Claims (1)

Claims or a non-toxic, pharmaceutically acceptable one Salt from it, wherein X and Y, which can be the same or different from one another, are each a fluorine, chlorine, Represent bromine or iodine atom and 2 © in Alkoixyradikal with at most 7 carbon atoms, an alkylthio radical with a maximum of 5 carbon atoms, a dialkylamino radical in which the alkyl radicals are identical or different and each contain a maximum of 5 carbon atoms, or an alkylidene amino radical having at most 5 ring carbon atoms represents » 2. Compound of the formula II or a non-toxic, pharmaceutically acceptable salt thereof, characterized in that X and Y are identical or different and each represents a fluorine, chlorine, bromine or iodine atom - 15 109885/1988 represent and Z is an alkoxy radical with at most 5 Carbon atoms, an alkylthio radical with at most 5 carbon atoms, a dialkylamino radical in which the alkyl radicals have a maximum of 5 carbon atoms each or represents an alkylidene amino radical having at most 5 carbon atoms. 3β compound according to claim 1, characterized in that that X and T are identical to or different from one another and are each a chlorine or bromine atom and Z represent an alkoxy radical having at most 7 carbon atoms or a methylthio or dimethylthio radical represents 4 ·. Connection according to claim 2, characterized in that that X and Y are identical to or different from one another and are each a chlorine or bromine atom and Z represent an alkoxy radical having at most 5 carbon atoms or a methylthio or dimethylthio radical represents 5 · The compound IT-2-Carboxyphenyl-] iI ² -2,4-dichloro-5-isopropoxyphenylurea · 6. The compound N-2-carboxyphenyl-H ² -2,4-dichloro-5-n-propoxyphenylurea. - 16 109885/19 8 6 7 · Salt according to one of claims 1 to 4, characterized in that it is an alkali metal salt, an alkaline earth salt, an aluminum salt, an ammonium salt or a salt with a non-toxic, pharmaceutical, permissible organic base is " 8, salt according to claim 1 or 2, characterized in, that it is a non-toxic, pharmaceutically acceptable acid addition salt. 9 »A method for producing a connection according to any one of claims 1 to 8, characterized in that Anthranilic acid, or a salt thereof, for reaction with a compound of the formula NCO III in which X, Y and Z have the above meanings, is brought » 10. The method according to claim 9 »characterized in that that it is in a dry organic solvent free of active hydrogen atoms at a temperature of not more than 50 ° 0 is carried out. - 17 109885/1986 11 _β method according to claim 1O _9, characterized in that the solvent used Ithylacetat, benzene, Pjridin, H, H "~ Dimethyliorsiajnid or 1,2 ~ Bimethokyäthan ver" · is spent. 12 =, compound of the formula II, wherein X ₈ Y and Z have the meanings given in claim 1, or a non-toxic, pharmaceutically acceptable salt thereof, characterized in that they or · @s according to a method according to claim 9 * 10 or 11 was made 13 »Pharmaceutical mass, marked by the fact that they consist of a compound of the formula II in which X, Y and Z have the meanings given in claim 1 or a non-toxic, pharmaceutically acceptable salt thereof, in admixture with a suitable one non-toxic, pharmaceutically acceptable diluent or carrier. 14. Composition according to claim 13 »characterized in that they take the form of tablets, capsules, non-sterile aqueous or non-aqueous solutions or suspensions, sterile injectable aqueous or non-aqueous solutions or suspensions or Has suppositories. - 18 109885/1986 o Mass nacli claim Odei 1.3 »14, gekemi in that it comprises at least a baktei'i en-preventing agent, for ₉ B" tetracycline, Oeiiicillin or sulfonamide, uiul / ode.f a entzündiingshemmeP-des agents, aB * aspirin, phenylbutazone -Pa , Indomethacin, flufenamic acid, or ibuprofen. 16. Composition according to one of claims 13 to 15 * thereby characterized in that they are 5 to 50% by weight of a Compound of formula II or a non-toxic, pharmaceutically acceptable salt thereof Dt-ING H FiNiIC- 'η · ΡΙ.-Ι' = Ί <. ». W. “OMP ORIGINAL 109885/1986