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WO1986003199A1 - Amino-salicylic acid derivatives and pharmaceutical compositions - Google Patents

Amino-salicylic acid derivatives and pharmaceutical compositions Download PDF

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Publication number
WO1986003199A1
WO1986003199A1 PCT/EP1985/000645 EP8500645W WO8603199A1 WO 1986003199 A1 WO1986003199 A1 WO 1986003199A1 EP 8500645 W EP8500645 W EP 8500645W WO 8603199 A1 WO8603199 A1 WO 8603199A1
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Prior art keywords
amino
hydroxy
benzoic acid
formula
chain
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Application number
PCT/EP1985/000645
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French (fr)
Inventor
Giancarlo Sportoletti
Original Assignee
Italfarmaco S.P.A.
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Application filed by Italfarmaco S.P.A. filed Critical Italfarmaco S.P.A.
Publication of WO1986003199A1 publication Critical patent/WO1986003199A1/en
Priority to DK346486A priority Critical patent/DK346486D0/en
Priority to KR1019860700507A priority patent/KR870700608A/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/56—Amides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
    • C07H13/12—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by acids having the group -X-C(=X)-X-, or halides thereof, in which each X means nitrogen, oxygen, sulfur, selenium or tellurium, e.g. carbonic acid, carbamic acid

Definitions

  • the present invention refers to (5-amino-2-hydro- xy)benzoic acid derivatives having formula I
  • B ⁇ is the. imidazolium or C- or N-substituted imidazolium cation, lysine or similar basic aminoacids or methyl- glucamine;
  • R represents:
  • n is an integer from 1 to 10 and R and R , which may be the same or different, are H, halogens, is hydrogen or C -C lower alkyl; - a chain of formula:
  • m is an integer from 0 to 20 and Het is an op ⁇ tionally substituted 5- or 6-membered heterocyclic group containing one or more N, 0 or S atoms such as pyrrole, pyridine, furan, pyran, thiophene, oxazole, isoxazole, imidazole, pyrazole, thiazole groups ⁇ - a chain of formula:
  • p is an integer from 0 to 16;
  • q is an integer from 1 to 16;
  • ary ' l or aralkyl residue such as phenyl; phenyl sub ⁇ stituted by one or more fluorine or chlorine atoms, fluoroalkyl, alkoxy, alkoxycarbonyl, C -C lower alkyl, amino, dialkylamino, hydroxy, cyano groups or by groups of formula NHCOR wherein R has the above defined mean ⁇ ings; diphenyl; naphtyl groups;
  • R_, R_ and R which may be the same or diffe- 5 6 7 rent, are H, OR (R having the above defined meanings), NH , NHCOR , chlorine or fluorine atoms, fluoroalkyl groups;
  • R is hydrogen, lower alkyl, fluorine or fluoro- 8 alkyl
  • R 3 wherein R and n have the above defined meanings, n" is an integer from 1 to 10 and X and Y are an oxygen, ni ⁇ trogen, sulphur atom or a CH group;
  • r is an integer from 1 to 3 and R has the above defined meanings;
  • Another object of the invention is provided by a process for the preparation of the compounds I as well as by pharmaceutical compositions containing them as the active principle.
  • the acids 5-(2,4-dichlorobenzoylamino)-2-hydroxy benzoic, 5-(cyclohexylmethylamino)-2-hydroxy benzoic, 5-(linoleylamin ' o)-2-hydroxy benzoic, 5-(arachidylami.no)- 2-hydroxy benzoic, 5-(arachidonylamino)-2-hydroxy benzoic, 5-(2,6 or 3,5-difluoro-phenyl)-2-hydroxy benzoic, 5-(4-cy- clohexyl-butanoylamino)-2-hydroxy benzoic, 5-/2-(3-pyri- dyl)acetylamino7-2-hydroxy benzoic, 5- 4-(phenyl)benzoyl- aminq/-2-hydroxy benzoic, 5-(m-trifluoromethyl-cinnamo
  • the preparation of the compounds of the invention is carried out starting from 5-amino-salicylic acid, whi- ch, in the presence of a suitable base (pyridine, triethy- la ine etc.), optionally diluted in a suitable solvent, is treated with equimolar amounts of an activate derivative, such as the acyl chloride or anhydride, of an acid of formula RCOOH wherein R has the above defined meanings.
  • a suitable base pyridine, triethy- la ine etc.
  • an activate derivative such as the acyl chloride or anhydride
  • RCOOH an acid of formula RCOOH
  • Said method is characterized by treating the acyl derivatives mixture, recovered from the reaction medium and dissolved in suitable solvent, with catalytic amounts of imidazole base in the presence of minor amounts of water. After stirring at room temperature, for different times according to the considered acyl group, the recovery of the N-acyl derivative is carried out by solvent evapo ⁇ ration and subsequent recrystallization from a suitable solvent.
  • the imidazole or substituted imidazole salts, as well as the pharmacologically acceptable metals or other organic bases salts are prepared by mixing in a suitable solvent equimolar amounts of the corresponding acid and base. The recovery of the salt is carried out either by spontaneous precipitation from the reaction medium or by solvent evaporation under vacuum or by addition to the medium itself of a miscible precipitating solvent.
  • EXAMPLE 2 • 2) 5-Hexadecanoylamino-2-hydroxy benzoic acid 15.31 Grams (0.1 mole) of 5-amino-salicylic acid are dissolved in 300 ml of anhydrous py idine. After cool ⁇ ing to 0°C, under nitrogen and in the dark, 41.23 g (0.15 moles) of hexadecanoyl chloride are slowly added under stirring. When the addition is over, stirring is continued for 3 hours, - the mixture is poured in 100 ml of water-ice and then extracted with ethyl acetate. The organic phase is washed with diluted hydrochloric acid, water and the solvent is evaporated under reduced pressure.
  • the residue is taken up with 100 ml of acetone and 10 ml of water, 0.68 g of imidazole base are added and the mixture is stirred overnight. After solvent evaporation under reduced pressure, the residue is treated with ethyl acetate. The organic phase is washed with water, diluted hydrochloric acid- and water to neutrality. After drying on sodium sul- phate and filtration, the solvent is evaporated under vacuum. The residue is crystallized from ethanol/water. Yield: 28 g (72%) .
  • 26- 2-hydroxy-5-( 4-phenyl-benzoyl)-amino benzoic acid m.p. : 178-180°C
  • I.R. 3520, 3260, 1680, 1640, 1530, 1300;
  • This assay allows to show the presence of an inhi ⁇ bitory activity on soy lipoxygenase considered as a model of the human enzyme.
  • this enzymatic system promotes the arachidonic acid transformatipn in leukotrie- nes A4 and B4.
  • These compounds are indicated to be funda ⁇ mentally responsible for the flogosis.
  • the leuko- trienes A4 and B4 show a relevant pro-inflammatory acti ⁇ vity in the bowel1 inflammatory disease and in the Crohn' disease.
  • the inhibition activity was evaluated as ED50 (in mM) , i.e. the dose which antagonizes 50% of the aggregat ⁇ ing effect of arachidonic acid.
  • the thromboxane A2 production was measured by a bioassay test according to Moncada et al. (Moncada S., Ferreira S.H., Vane J.R. - Adv. Prost. & Thromboxanes Res. - Frolich J.C. Ed., Vol. 5, 211, 1978 - Raven Press). At scheduled times after the addition of arachidonic acid, 200 ul of P.R.P. was bioassayed for the TXA2 production and prostaglandin-like activity, on a tissue ' sequence (cascade), composed of a spiral strip of rabbit aorta and a stomach fundus strip of rat.
  • a tissue ' sequence cascade
  • the inhibition activity of the tested compounds on TXA2 production was evaluated as ED50 (in M) , i.e. the concentration able to decrease the contracturant effects of TXA2 on tissues.
  • the tested compounds were dissolved in Tween 80 and added to the P.R.P. at increasing concentrations, until the determination of the ED50 was achieved.
  • Table 3 as not limiting example, the results obtained using some of the compounds of the invention are reported.
  • the test has been performed according to Di Rosa et al. (Di Rosa M. , Giround J.P., Willoughby D.A. - J. Path. Bact., vol. 104, 15, 1971).
  • a 1% solution (0.15 ml) of carrageenin in 0.9% NaCl was injected into the pleural cavity of Sprague-Dawley rats, weighing about 250 g.
  • the animals were sacrificed, the pleural exudate volumes were measured and the leukocytes total number was counted by a micro- cell-counter, being the cavity rinsed by 0.5 ml of a sali- ne medium.
  • the % inhibition of leukocytes total number was calcu ⁇ lated versus control animals.
  • the assayed compounds were administered orally, 1 mM/kg, 30' before the carrageenin injection in the pleural cavity.
  • Table IV as not limi ⁇ ting example, the results obtained with some of the compo ⁇ unds of the invention are reported.
  • the assay has been performed according to Gemmel et al. (Gemmel D.K. Cottney J., Lewis A.J. - Agents Actions, vol. 9, 107, 1979). 1 Ml of a rabbit anti-bovine-albumin serum (freeze-dried antibodies, dissolved in 2 ml of 0.9% NaCl) was injected into the caudal vena of Sprague-Dawley male rats.
  • bovine albumin in 0.1 ml sali ⁇ ne was injected in the subplantar paw.
  • the volume of the paw was measured 5 hours later, by a mercury plethysmome- ter.
  • the tested compounds were orally administered 3 hours before the bovine albumin treatment.
  • the % inhibition of the rat foot volume increase was calculated in confront to the increase of the foot volume of untreated animals. The results obtained with some of the compounds of the inven ⁇ tion are reported in Table 5.
  • the numbers in parenthesis indicate the administered dose in mg/kg.
  • the assay has been performed according to Sharon (Sharon P., Stenson W.F. - Gastroenterology, vol. 88, 55, 1985) .
  • the administered doses (via intra-bowel, during the bowel ligature and the local injection of the acetic acid) were 0.5 mM/kg, for all the tested compounds, dispersed" in carboxymethylcellulose. The % reduction of the ulceration index has been calculated versus untreated animals.
  • the compounds of Table 1 have been subjected to the acute toxicity test in mice, by the oral route, in carbo ⁇ xymethylcellulose suspensions. All the LD proved to be higher than 1600 mg/kg.
  • the present invention refers also to all the indu ⁇ strial applicable aspects connected with the use of the compounds I and of the corresponding free acids as thera ⁇ Commissionic agents.
  • An essential aspect, of the invention is therefore provided by pharmaceutical compositions contain ⁇ ing, as the active principle, predetermined and therapeu- tically effective amounts of at least one of the above compounds in addition to conventional excipients and/or carriers.
  • the compositions of the Invention can be administered by the oral, parenteral, rectal or topical route, for instance in form of tablets, capsules, syrups, sachets, solutions, vials, bottles, suppositories.
  • the doses will be dependent on the patient's weight, age and conditions and will be anyhow ranging from 50 to 1000 mg, from 1 to 4 times a day.

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Abstract

(5-Acylamino-2-hydroxy)benzoic acid and salts thereof with imidazole, substituted imidazole, lysine or methyl-glucamine are endowed with remarkable antiinflammatory, antiaggregating and antithrombotic properties.

Description

Amino-Salicylic acid derivatives and pharmaceutical compositions
The present invention refers to (5-amino-2-hydro- xy)benzoic acid derivatives having formula I
Figure imgf000003_0001
wherein: B^ is the. imidazolium or C- or N-substituted imidazolium cation, lysine or similar basic aminoacids or methyl- glucamine; R represents:
- hydrogen or a linear C -C alkyl chain, optionally substituted by one or more chlorine or fluorine atoms, free, etherified or esterified hydroxy groups, carboxy, carboxyalkyl, aminocarbonyl or N-substituted aminocarbo- nyl groups, one or more of the -CH - groups being optio¬ nally substituted by keto groups; - a chain of formula:
Figure imgf000003_0002
wherein n is an integer from 1 to 10 and R and R , which may be the same or different, are H, halogens, is hydrogen or C -C
Figure imgf000004_0001
lower alkyl; - a chain of formula:
-(CH_) -Het 2 m wherein m is an integer from 0 to 20 and Het is an op¬ tionally substituted 5- or 6-membered heterocyclic group containing one or more N, 0 or S atoms such as pyrrole, pyridine, furan, pyran, thiophene, oxazole, isoxazole, imidazole, pyrazole, thiazole groups^ - a chain of formula:
Figure imgf000004_0002
wherein p is an integer from 0 to 16;
- a chain of-formula:
Figure imgf000004_0003
wherein q is an integer from 1 to 16;
- an ary'l or aralkyl residue such as phenyl; phenyl sub¬ stituted by one or more fluorine or chlorine atoms, fluoroalkyl, alkoxy, alkoxycarbonyl, C -C lower alkyl, amino, dialkylamino, hydroxy, cyano groups or by groups of formula NHCOR wherein R has the above defined mean¬ ings; diphenyl; naphtyl groups;
- a chain of formula:
Figure imgf000005_0001
wherein m has the above defined meanings and R is hy¬ drogen or a linear or branched, saturated or unsaturat- ed, C -C alkyl group; - a chain of the formula:
Figure imgf000005_0002
wherein R_, R_ and R , which may be the same or diffe- 5 6 7 rent, are H, OR (R having the above defined meanings), NH , NHCOR , chlorine or fluorine atoms, fluoroalkyl groups;
- a chain of formula:
Figure imgf000005_0003
wherein R is hydrogen, lower alkyl, fluorine or fluoro- 8 alkyl;
- a linear or branched chain of the formula:
-(CH2_)n-X-CrH-(CH2_)n,1-Y-
R3 wherein R and n have the above defined meanings, n" is an integer from 1 to 10 and X and Y are an oxygen, ni¬ trogen, sulphur atom or a CH group;
- a chain of formula:
-(CH ) -S-R. 2 r 3 wherein r is an integer from 1 to 3 and R has the above defined meanings;
- an aminoacid residue, namely L-leucyl, of or "-L-glu- tamyl- in a free form or protected with the conventional amine protecting group, such as BOC; - an Arg-Pro-D(Phe) chain or the like;
- an uronic residues of formula:
Figure imgf000006_0001
Another object of the invention is provided by a process for the preparation of the compounds I as well as by pharmaceutical compositions containing them as the active principle. The acids 5-(2,4-dichlorobenzoylamino)-2-hydroxy benzoic, 5-(cyclohexylmethylamino)-2-hydroxy benzoic, 5-(linoleylamin'o)-2-hydroxy benzoic, 5-(arachidylami.no)- 2-hydroxy benzoic, 5-(arachidonylamino)-2-hydroxy benzoic, 5-(2,6 or 3,5-difluoro-phenyl)-2-hydroxy benzoic, 5-(4-cy- clohexyl-butanoylamino)-2-hydroxy benzoic, 5-/2-(3-pyri- dyl)acetylamino7-2-hydroxy benzoic, 5- 4-(phenyl)benzoyl- aminq/-2-hydroxy benzoic, 5-(m-trifluoromethyl-cinnamo- yl)-amino-2-hydroxy benzoic, 5- 8-(1-imidazolyl)-octano- yl7amino-2-hydroxy benzoic are per se new and are therefo- re comprised within the scope of the present invention, as well as the salts thereof with pharmacologically accepta¬ ble organic or inorganic bases and the pharmaceutical compositions containing them.
On the other hand, while the imidazole salts I are of course new, some of the corresponding acids (the anio- nic component) are known, for instance from EP-A-45955, Ger. Offen. No. 2,031,227, 2,919,545, 2,920,292, Japan Kokai No. 78-9651, Biochem. Biophys. Res. Commun. V. 101, 258, 1981 and Bio ed. Mass Spectrom. 11, 539, 1984: no pharmacological activity thereof has been however describ¬ ed.
It has now been found that also these known compo¬ unds are endowed with surprising and advantageous pharma¬ cological properties. A further object of the invention is therefore provided by pharmaceutical compositions containing as the active principle said known acids, which will be herein¬ after specifically defined.
The preparation of the compounds of the invention is carried out starting from 5-amino-salicylic acid, whi- ch, in the presence of a suitable base (pyridine, triethy- la ine etc.), optionally diluted in a suitable solvent, is treated with equimolar amounts of an activate derivative, such as the acyl chloride or anhydride, of an acid of formula RCOOH wherein R has the above defined meanings. After stirring at the room temperature or under heating, a mixture of N,0-diacyl and of N-acyl product is usually obtained w'- ich is subjected to selective hydrolysis of the 0-acyl group in extremely mild conditions so as to respect both the N-acyl group and the nature of the acyl group itself. Said method is characterized by treating the acyl derivatives mixture, recovered from the reaction medium and dissolved in suitable solvent, with catalytic amounts of imidazole base in the presence of minor amounts of water. After stirring at room temperature, for different times according to the considered acyl group, the recovery of the N-acyl derivative is carried out by solvent evapo¬ ration and subsequent recrystallization from a suitable solvent. The imidazole or substituted imidazole salts, as well as the pharmacologically acceptable metals or other organic bases salts, are prepared by mixing in a suitable solvent equimolar amounts of the corresponding acid and base. The recovery of the salt is carried out either by spontaneous precipitation from the reaction medium or by solvent evaporation under vacuum or by addition to the medium itself of a miscible precipitating solvent.
The following examples further illustrate the in¬ vention, without limiting the scope thereof. * EXAMPLE 1
1) 5-(2,4-Dichlorobenzoylaιτιino)-2-hydroxy-benzoic acid
20.95 Grams (0.1 mole) of 2,4-dichlorobenzoyl-chlo- ride are slowly added to a solution of 15.31 g (0.1 mole) of 5-amino-salicylic acid in 150 ml of anhydrous pyridine under stirring, in the dark and in nitrogen atmosphere. The solution is then poured in water-ice, filtered under reduce pressure and the obtained precipitate is washed with water to neutrality and dissolved in humid methanol.0.5 Grams of imidazole base are then added, and the mixture is stirred at the room temperature for 3 hours. The solvent is distilled off under vacuum and the residue is taken up with ethyl acetate,- washed with acidic H O (HCl) then with water to neutrality and dried on sodium sulphate. After solvent's evaporation, the residue is crystallized from methanol, yielding 17.49 g (53,63%), m.p. 233-235°C; I.R.: elemental analysis, found (calc): C = 51.74 (51.55); H = 2.85 (2.78) ; N = 4.21 (4.29) . la) Imidazole salt
10 Grams (30.66 m oles) of the product 1 are dis- solved in 100 ml of methanol and added with 2.09 g (30.66 mmoles) of imidazole. The mixture is stirred for 3 hours and the solvent is then removed under reduced pressure. The residue is crystallized from methanol-water. 10.65 Grams of la are obtained (88.11%) having a melting point of 87-89°C; I.R. : 3140, 1650, 1585, 1320 cm"1; U.V. : 233, 253, 325 nm; elemental analysis, found (calc): C = 50.83 (51.80); H = 3.47 (3.23); N = 10.72 (10.66).
EXAMPLE 2 • 2) 5-Hexadecanoylamino-2-hydroxy benzoic acid 15.31 Grams (0.1 mole) of 5-amino-salicylic acid are dissolved in 300 ml of anhydrous py idine. After cool¬ ing to 0°C, under nitrogen and in the dark, 41.23 g (0.15 moles) of hexadecanoyl chloride are slowly added under stirring. When the addition is over, stirring is continued for 3 hours, - the mixture is poured in 100 ml of water-ice and then extracted with ethyl acetate. The organic phase is washed with diluted hydrochloric acid, water and the solvent is evaporated under reduced pressure. The residue is taken up with 100 ml of acetone and 10 ml of water, 0.68 g of imidazole base are added and the mixture is stirred overnight. After solvent evaporation under reduced pressure, the residue is treated with ethyl acetate. The organic phase is washed with water, diluted hydrochloric acid- and water to neutrality. After drying on sodium sul- phate and filtration, the solvent is evaporated under vacuum. The residue is crystallized from ethanol/water. Yield: 28 g (72%) .
The product melts at 185-187°C; I.R. : 3500, 3290, 1680, 1650, 1540, 1310 cm" ; U.V.: 223, 250, 325 nm; ele- mental analysis, found (calc): C = 70.13 (70.55); H = 9.41 (9.52) ; N = 3.42 (3.58) . 2a) Imidazole salt
11.74 Grams (30 mmoles) of the compound obtained in 2 are dissolved in 100 ml of acetone and added with 2.04 g (30 mmoles) of imidazole base. After stirring at room temperature for 5 hours, the solvent is evaporated under reduced pressure and the residue is crystallized from methanol-water.
11.35 Grams (82.34%) are obtained. M.p. 132-134°C; I.-R.: 3310, 1650, 1525, 1300 cm" ; U.V. : 233, 253, 325 nm; elemental analysis, found (calc): C = 67.58 (67.95); H = 8.78 (8.99) ; N = 8.82 (9.14) .
EXAMPLES 3-23 Using the same methods above described, starting from the suitable acyl derivatives, the compounds reported in the following table were prepared.
The integers followed by an a) designate the imida¬ zole salts while the free acids are designated by progres¬ sive integers. The melting points are in °C and the I.R. values are in cm . All the compounds have elemental ana¬ lysis in agreement with the calculated values.
Figure imgf000011_0001
Figure imgf000012_0001
- continued - TABLE 1 (follows)
Figure imgf000013_0001
(*) Known from E.P. 45,955; r * * \ " " Biochem. Biophys. Res. Commun.-v.101, 258, 1981;
Ger. Offen. 2-031-227; ****** " Biomed. Mass Spectrom, v. 11, 539, 1984. EXAMPLES 24-28 According to the same methods of the previous cla¬ ims, the following 5-acyloyl-amino-salicylic acids were prepared (I.R. values in cm .and elemental analysis in agreement) :
24- 2-hydroxy-5-( 4-cyclohexyl-butanoyl)-amino benzoic acid; m.p. : 196-198°C; I.R.: 3500, 3250, 1680, 1650, 1540, 1310;
25- 2-hydroxy-5-(2-(3-pyridyl)-acetyl)-amino benzoic acid; m.p. : 221-223°C; I.R.: 3510, 3260, 1680, 1640, 1540, 1300;
26- 2-hydroxy-5-( 4-phenyl-benzoyl)-amino benzoic acid; m.p. : 178-180°C; I.R.: 3520, 3260, 1680, 1640, 1530, 1300;
27- 2-hydroxy-5-(m-trifluoromethyl-cinnamoyl) -amino benzoic acid; m.p. : 162-168°C; I.R.: 3500, 3250, 1660, 1635, 1500, 1300; 28- 2-hydroxy-5-( 8-( 1-imidazolyl)-octanoyl ) -amino ben- zoic acid; m.p. : 183-186°C; I.R.: 3510, 3260, 1680, 1635, 1510, 1300. The corresponding imidazolium salts as well as other pharmaceutically acceptable salts of the above com- pounds are prepared according to the above described me¬ thods. BIOLOGICAL ACTIVITIES
The hereinabove mentioned compounds have been te¬ sted on in vitro and in vivo assays, with the aim of giv- ing evidence to their potential biological activities. Soy lipoxygenase inhibition activity
This assay allows to show the presence of an inhi¬ bitory activity on soy lipoxygenase considered as a model of the human enzyme. In mammals, this enzymatic system promotes the arachidonic acid transformatipn in leukotrie- nes A4 and B4. These compounds are indicated to be funda¬ mentally responsible for the flogosis. Namely, the leuko- trienes A4 and B4, show a relevant pro-inflammatory acti¬ vity in the bowel1 inflammatory disease and in the Crohn' disease.
The soy lipoxygenase (E.C. 1.13.11.12), has been tested according to the method of Axelrod et al. (Axelrod B. - Cheesbrough T.H., Laakso S. in Methods in Enzymology, vol. 71, pag. 441, 1981 - Academic Press N.Y.), in the presence and in-the-absence of the—products to be assayed, using nordihydroguaiaretic acid as test reference, at room temperature.
In Table 2, as not limiting example, the results obtained with the compounds 1, la to 18, 18a are shown. In this and in the following tables, as in Table 2, the integers designate the free acids while the integers followed by the letter a relate to the corresponding imi¬ dazolium salts.
TABLE 2
Figure imgf000015_0001
- continued - TABLE 2 ( follows )
Compound Inhibition (%) Concentration (Mxl0~6)
13 14 150
13a 22 150
14 42 75
14a 78 75
15 24 150
15a 38 150
16 35 150
16a 51 150
17 26 150
17a - 42 150
18 50 250
18a 82 250
Activity on platelet aggregation and thromboxane A2 pro¬ duction Measurements were carried out on in vitro tests with citrated platelet-rich plasma (P.R.P.), obtained from New-Zealand rabbits. Platelet aggregation was carried out according to the method of Born (Born G.V.R. - Nature, vol. 162, 67) using arachidonic acid 0.25 mM as aggrega- ting agent.
The inhibition activity was evaluated as ED50 (in mM) , i.e. the dose which antagonizes 50% of the aggregat¬ ing effect of arachidonic acid.
The thromboxane A2 production was measured by a bioassay test according to Moncada et al. (Moncada S., Ferreira S.H., Vane J.R. - Adv. Prost. & Thromboxanes Res. - Frolich J.C. Ed., Vol. 5, 211, 1978 - Raven Press). At scheduled times after the addition of arachidonic acid, 200 ul of P.R.P. was bioassayed for the TXA2 production and prostaglandin-like activity, on a tissue 'sequence (cascade), composed of a spiral strip of rabbit aorta and a stomach fundus strip of rat.
The inhibition activity of the tested compounds on TXA2 production was evaluated as ED50 (in M) , i.e. the concentration able to decrease the contracturant effects of TXA2 on tissues.
The tested compounds were dissolved in Tween 80 and added to the P.R.P. at increasing concentrations, until the determination of the ED50 was achieved. In- Table 3, as not limiting example, the results obtained using some of the compounds of the invention are reported.
TABLE 3 Inhibition (ED50, in M) on arachidonic acid induced:
Figure imgf000018_0001
ANTIINFLAMMATORY ACTIVITY ON NON-IMMUNE AND IMMUNE INFLAM¬ MATION 1 - Carrageenin induced pleurisy in rats (non-immune in¬ flammation)
The test has been performed according to Di Rosa et al. (Di Rosa M. , Giround J.P., Willoughby D.A. - J. Path. Bact., vol. 104, 15, 1971). A 1% solution (0.15 ml) of carrageenin in 0.9% NaCl, was injected into the pleural cavity of Sprague-Dawley rats, weighing about 250 g. Six hours later, the animals were sacrificed, the pleural exudate volumes were measured and the leukocytes total number was counted by a micro- cell-counter, being the cavity rinsed by 0.5 ml of a sali- ne medium.
The % inhibition of leukocytes total number was calcu¬ lated versus control animals. The assayed compounds were administered orally, 1 mM/kg, 30' before the carrageenin injection in the pleural cavity. In Table IV, as not limi¬ ting example, the results obtained with some of the compo¬ unds of the invention are reported.
TABLE 4 % Inhibition on:
Figure imgf000019_0001
- continued - TABLE 4 (follows)
Figure imgf000020_0001
- continued - TABLE 4 ( follows )
Figure imgf000021_0001
(*) L-Leucyl-5-amino-salicylic, described in Ger. Offen. ' 2,919,545;
(**) T-L-Glutam"yl-5-amino-salicylic, described in Ger.
Offen. 2,920,292; (***) Aceto acetyl-5-amino-salicylic, described in Japan Kokai 78-9651.
2 - Reserve passive Arthus reaction in rat paws (Immune inflammation)
The assay has been performed according to Gemmel et al. (Gemmel D.K. Cottney J., Lewis A.J. - Agents Actions, vol. 9, 107, 1979). 1 Ml of a rabbit anti-bovine-albumin serum (freeze-dried antibodies, dissolved in 2 ml of 0.9% NaCl) was injected into the caudal vena of Sprague-Dawley male rats.
30' Later, 0.025 mg of bovine albumin (in 0.1 ml sali¬ ne) was injected in the subplantar paw. The volume of the paw was measured 5 hours later, by a mercury plethysmome- ter. The tested compounds were orally administered 3 hours before the bovine albumin treatment. The % inhibition of the rat foot volume increase was calculated in confront to the increase of the foot volume of untreated animals. The results obtained with some of the compounds of the inven¬ tion are reported in Table 5.
TABLE 5
Figure imgf000023_0001
- continued - TABLE 5 ( follows )
Figure imgf000024_0001
Na-5-ASA: 5-amino salicylic acid sodium salt
The numbers in parenthesis indicate the administered dose in mg/kg.
The orally administrations are equivalent to one mM/kg for each tested compound. 3 - Acetic acid bowel inflammation in rats (non immune bowel inflammation)
The assay has been performed according to Sharon (Sharon P., Stenson W.F. - Gastroenterology, vol. 88, 55, 1985) .
Considering the nature of the assay, the test was performed mainly on the compounds of * the invention not well absorbed, according to the results, obtained in the previous tests.* It should be noted, however, that all the claimed derivatives can be usefully applied in the therapy of the bowel inflammation and in the Crohn' disease.
The results are reported in the following Table 6.
The administered doses (via intra-bowel, during the bowel ligature and the local injection of the acetic acid) were 0.5 mM/kg, for all the tested compounds, dispersed" in carboxymethylcellulose. The % reduction of the ulceration index has been calculated versus untreated animals.
TABLE 6
Compounds % Reduction of the ulceration index
2 -36
2a -51
14 -38
14a -58
19 -42
19a -65
20 -42
20a • -65 Acute toxicity
The compounds of Table 1 have been subjected to the acute toxicity test in mice, by the oral route, in carbo¬ xymethylcellulose suspensions. All the LD proved to be higher than 1600 mg/kg.
The present invention refers also to all the indu¬ strial applicable aspects connected with the use of the compounds I and of the corresponding free acids as thera¬ peutic agents. An essential aspect, of the invention is therefore provided by pharmaceutical compositions contain¬ ing, as the active principle, predetermined and therapeu- tically effective amounts of at least one of the above compounds in addition to conventional excipients and/or carriers. The compositions of the Invention can be administered by the oral, parenteral, rectal or topical route, for instance in form of tablets, capsules, syrups, sachets, solutions, vials, bottles, suppositories.
The doses will be dependent on the patient's weight, age and conditions and will be anyhow ranging from 50 to 1000 mg, from 1 to 4 times a day.

Claims

COO ,Θ H©
Figure imgf000027_0001
wherein:
B Θ^ i •s the i •midazolium or C- or N-substituted imidazolium cation, lysine or similar basic aminoacids or methyl- glucamine; R represents:
- hydrogen or a linear C -C alkyl chain, , optionally substituted by one or more chlorine or fluorine atoms, free, etherified or esterified hydroxy groups, carboxy, carboxyalkyl, aminocarbonyl or N-substituted aminocarbo- nyl groups, one or more of the -CH - groups being optio¬ nally substituted by keto groups;
- a chain of formula:
Figure imgf000027_0002
wherein n is an integer from 1 to 10 and R and R , which may be the same or different, are H, halogens, -OR or COOR groups wherein R is hydrogen or C -C lower alkyl; - a chain of formula: -(CH ) -Het 2 m wherein m is an integer from 0 to 20 and Het is an op¬ tionally substituted 5- or 6-membered heterocyclic group containing one or more N, 0 or S atoms such as pyrrole, pyridine, furan, pyran, thiophene, oxazole, isoxazole, imidazole, pyrazole, thiazole groups; a chain of formula:
N N-(CH„) -CO-
\_____/ 2 P wherein p is an integer from 0 to 16; a chain of formula:
Figure imgf000028_0001
wherein q is an integer from 1 to 16;
- an aryl or aralkyl residue such as phenyl; phenyl sub¬ stituted by one or more fluorine or chlorine atoms, fluoroalkyl, alkoxy, alkoxycarbonyl, C -C lower alkyl, amino, dialkylamino, hydroxy, cyano groups or by groups of formula NHCOR wherein R has the above defined mean¬ ings; diphenyl; naphtyl groups;
- a chain of formula:
Figure imgf000028_0002
wherein m has the above defined meanings and R is hy¬ drogen or a linear or branched, saturated or unsaturat- ed, c ~C alkyl group; - a chain of the formula:
Figure imgf000029_0001
wherein R , R and R , which may be the same or diffe- 5 6 7 rent, are H, OR (R having the above defined meanings), NH , NHCOR , chlorine or fluorine atoms, fluoroalkyl groups; - a chain of formula:
Figure imgf000029_0002
wherein R is hydrogen, lower alkyl, fluorine or fluoro- 8 alkyl; * " ■ - a linear or branched chain of the formula:
*
-(CH_j -X-CH-(CH-) ,-Y- 2 n I 2 n'
wherein R and n have the above defined meanings, n1 is an integer from 1 to 10 and X and Y are an oxygen, ni- trogen, sulphur atom or a CH group;
- a chain of formula:
-(CH2)r-S-R3 wherein r is an integer from 1 to 3 and R has the above defined meanings; - an aminoacid residue, namely -leucyl, Of or Y-L-glu- tamyl- in a free form or protected with the conventional amine protecting group, such as BOC;
- an Arg-Pro-D(Phe) chain or the like;
- an uronic residues of formula:
Figure imgf000030_0001
2. Compounds according to claim 1 wherein B is imidazo lium or 2-aminoimidazolium.
3. A compound according to claim 1 wherein B is the imidazolium residue and the anionic component is selected in the group consisting of: - 2-hydroxy-5-(2, 4-dichlorobenzoyl)amino-benzoic acid;
- 2-hydroxy-5-hexadecanoyl-amino-benzoic acid;
- 2-hydroxy-5-isovaleroyl-amino-benzoic acid;
- 2-hydroxy-5-cyclohexylacetyl-amino-benzoic acid;
- 2-hydroxy-5-succinoyl-amino-benzoic acid; * _ - 2-hydroxy-5-benzoyl-amino-benzoic acid;
- 2-hydroxy-5-salicyloyl-amino-benzoic acid;
- 2-hydroxy-5-/4-( 2 ' , 4 ' -difluorophenyl) salicyloyl-amino/- benzoic acid;
- 2-hydroxy-5-( -ethoxycarbonyl)glycyl-amino-benzoic acid; - 2-hydroxy-5*-/( 6-ethoxycarbonylamino)capropylamino/-ben- zoic acid;
- 2-hydroxy-5-(N-ethoxycarbonylglutamoylamino)-benzoic acid;
- 2-hydroxy-5-glucuronyl-amino-benzoic acid; - 2-hydroxy-5-formyl-amino-benzoic acid;
- 2-hydroxy-5-stearoyl-amino-benzoic acid;
- 2-hydroxy-5-( 4-methoxy)benzoyl'-amino-benzoic acid;
- 2-hydroxy-5-( 4-eptyloxy)benzoyl-amino-benzoic acid;
- 2-hydroxy-5-( 4-fluoro)benzoyl-amino-benzoic acid; - 2-hydroxy-5-acetyl-amino-benzoic acid; - 2-hydroxy-5-linoleyl-amino-benzoic acid;
- 2-hydroxy-5-arachidyl-amino-benzoic acid;
- 2-hydroxy-5-arachidonyl-amino-benzoic acid;
- 2-hydroxy-5-( 2, 6-difluoro)benzoyl-amino-benzoic acid; - 2-hydroxy-5-( 3 , 5-difluoro)benzoyl-amino-benzoic acid;
- 2-hydroxy-5-( 4-cyclohexyl-butanoyl)-amino-benzoic acid;
- 2-hydroxy-5-( 2-( 3-pyridyl)-acetyl)-amino-benzoic acid;
- 2-hydroxy-5-( 4-phenyl-benzoyl)-amino-benzoic acid;
- 2-hydroxy-5-(m-trifluoromethyl-cinnamoyl) -amino-benzoic acid;
- 2-hydroxy-5-( 8-( 1-imidazolyl) -octanoyl)-amino-benzoic acid
- L-leucyl-5-amino-salicylic acid;
- 7"-L-glutamyl-5-amino-salicylic acid; - aceto acetyl-5-amino-salicylic acid.
4. As a novel compound, a compound selected in the group consisting of:
- 2-hydroxy-5-( 4-cyclohexyl-butanoyl)-amino-benzoic acid;
- 2-hydroxy-5-( 2-( 3-pyridyl)-acetyl)-amino-benzoic acid; - 2-hydroxy-5-( 4-phenyl-benzoyl)-amino-benzoic acid;
- 2-hydroxy-5-(m-trifluoromethyl-cinnamoyl)-amino-benzoic acid;
- 2-hydroxy-5-( 8-( 1-imidazolyl)-octanoyl)-amino-benzoic acid.
5. A process for the preparation of compounds of formula I characterized in that the 2-hydroxy-5-amino-benzoic acid is reacted with acyl chlorides or anhydrides of acids having formula RCOOH, wherein R has the above defined meanings, and that the obtained N,0-diacyl derivatives are hydrolyzed in the presence of imidazole and subsequently reacted with the base B.
6. Pharmaceutical compositions endowed with antiinflam- matory, antiaggregant, antithrombotic activity containing as the active principle one or more of the compounds of cla ims 1-4.
7. Pharmaceutical compositions endowed with antiinflam- matory, antiaggregant, antithrombotic activity contain¬ ing as the active principle at least a compound of formula:
Figure imgf000032_0001
wherein R has the* above defined meanings or of pharmaceuti cally acceptable salts thereof.
8. A method of treatment of inflammatory, thrombotic or hyperaggregating conditions in a living subject characteri¬ zed by administering to said living subject a composition of claims 6-7.
PCT/EP1985/000645 1984-11-29 1985-11-26 Amino-salicylic acid derivatives and pharmaceutical compositions WO1986003199A1 (en)

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