BACKGROUND OF THE INVENTION :
The present invention relates to derivatives and salt forms of the pharmaceutical active compound 5-amino salicylic acid .
The pharmaceutical active compound 5-amino salicylic acid is commonly known by its name mesalamine . Mesalamine and its preparation are described in US patent no 2,198,249. Mesalamine of the formula (I) is useful in the treatment of Chron's disease and ulcerative colitis.

Basic pharmaceutical active compounds are commonly formulated into pharmaceutical preparations as an acid addition salt form, particularly as a crystalline acid addition salt. Although it is known that the preparation of salt forms may improve the physical or pharmaceutical properties of a basic pharmaceutical active compound, it is not possible to predict which salt forms possess advantages for a particular therapeutic purpose prior to the actual preparation and characterization of the salt form. The present invention relates to derivatives and salt forms mesalamine, that are useful for the manufacture of solid or liquid pharmaceutical dosage forms, particularly solid oral dosage forms., such as tablets and capsules, and liquid oral dosage forms, such as orally administered solutions and suspensions, as well as suppositories and other pharmaceutical dosage forms. Each of these salt forms possesses one or more properties that provides advantages when used as a pharmaceutical active ingredient, such as physical properties that make it easier to manufacture one or

more dosage forms, improved stability, improved bioavailability and other such properties that are known to one of skill in the art.
The salt forms of mesalamine are prepared by methods known in the art for making acid addition salts of amines, e. g., by treatment of mesalazine with an acid or a suitable anion exchange reagent. Typically, mesalamine or a solution of mesalamine is combined with a solution of an organic or mineral acid in, e. g., a lower alcohol, such as methanol or ethanol, with or without heating, the salt is isolated by crystallization or by evaporation of the solvent and, if desired, purified by re-crystallization from an appropriate re-crystallization solvent by methods known to one of skill in the art.
For the purpose of administering a salt of mesalamine by means of an oral solution, in general those salts are preferred having an increased water solubility compared to the free base. Salts having a lower water solubility compared to the free base, render them in general more suitable for the manufacture of sustained . release formulations compared to the free base.
Important embodiments of this invention include salts of 5-amino salicylic acid selected from the group consisting, nitrate salt, a hydrobromide salt, a sulfate salt, a methane sulfonic acid salt, a ethane sulfonic acid salt, a trifluoro methane sulfonic acid salt, benzene sulfonic acid salt, , a fumarate salt, a succinate salt, a benzoate salt, a hydrochloride salt, a citrate salt, a malate salt, a salicylate salt, a formate salt, a lactate salt and a p-toluene sulfonic acid salt.
Further important embodiments of this invention include aldimine derivatives of 5-amino salicylic acid with aldehydes selected from a group consisting p-tolualdehyde , p-fluoro benzaldehyde, benzaldehyde and butyraldehyde

In a preferred embodiment of the present invention, the acid addition salt is selected from the group consisting of mesalamine hydrobromide, mesalamine nitrate, mesalamine sulfate, mesalamine methane sulfonate, mesalamine ethane sulfonate, mesalamine trifluoromethane sulfonate, mesalamine benzene sulfonate, mesalamine p-toluene sulfonate
The present invention further relates to a pharmaceutical composition comprising one of the above mentioned salts of mesalamine and pharmaceutically acceptable carrier.
The invention relates also to a process for the treatment of warm-blooded animals suffering from a Chron's disease and ulcerative colitis, wherein a quantity of one of acid addition salts of 5-Amino salicylic acid disclosed herein which is effective against the disease concerned, Depending on species, age, individual condition, mode of administration, and the clinical picture in question, effective doses, for example daily doses of about 100-2000 mg, preferably 250-2000 mg, especially 400-800 mg, are administered to warm-blooded animals of about 70 kg bodyweight.

The following Examples illustrate the invention without limiting the scope thereof. Example 1 :
5-amino salicylic acid benzenesulphonate :
5-Amino salicylic acid (2.9 g, 0.02m) in methanol(10ml) was added to a solution of benzenesulphonic acid (Fluka, 3.8 g, 0.02m) in methanol(10ml_) and water(lml). The solution was refluxed for 2 hrs and is evaporated to dryness under reduced pressure and the resulting residue was re-crystallized from Methanol and acetone . The product was filtered-off and dried to afford, 5-amino salicylic acid benzenesulphonate as a yellow crystalline solid, having the following analytical properties: MR- 162°C , Chemical assay - 100%, Example 2:
5-amino salicylic acid trifluoro methane sulphonate : 5-Amino salicylic acid (5.0 0.3m) in methanol(2ml) was added to a solution of trifluoromethane sulphonic acid (4.5g, 0.03m) in methanol(20ml). The solution was stirred overnight at room temperature and evaporated to dryness under reduced pressure and the resulting residue was re-crystallized from ethylacetate and Isopropyl ether. The product was filtered-off and dried to afford, 5-amino salicylic acid trifluoro methane sulphonate as purple white crystalline solid having the following analytical properties: MR- 225°C Chemical assay-98%
Example 3
5-amino salicylic acid p-toluene sulphonate :
5-Amino salicylic acid (5.4g, 0.035m) in methanol(20ml) was added to a solution of p-toluene sulfonic acid (6.7g, 0.035m) in methanol(20ml). The solution was heated on reflux temperature for 3 hours and evaporated to dryness under reduced pressure and the resulting residue was recrystallized twice from Isopropyl alcohol. The product was filtered-off and dried to afford, 5-amino salicylic acid p-toluene sulphonate as bluish white crystalline solid

having the following analytical properties: MR- 243°C Chemical assay -101.7%
Example 4
5-amino salicylic acid ethane sulphonate :
5-Amino salicylic acid (5.4g, 0.035M) in methanol(20ml) is added to a solution of ethane sulfonic acid (3.85g, 0.035M) in methanol(20ml). The solution was heated on reflux temperature for 8 hours and evaporated to dryness under reduced pressure and the resulting residue was recrystallized from ethyl alcohol. The product was filtered-off and dried to afford, 5-amino salicylic acid ethane sulphonate as white crystalline solid having the following analytical properties: MR- 255°C Chemical assay -100.3%,
Example 5
5-amino salicylic acid methane sulphonate :
5-Amino salicylic acid (5.5g, 0.036m) in methanol(20ml) was added to a solution of methane sulfonic acid (3.43g, 0.035m) in methanol(20ml). The solution was heated on reflux temperature for 6 hours and evaporated to dryness under reduced pressure and the resulting residue was recrystallized from methyl alcohol. The product was filtered-off and dried to afford, 5-amino salicylic acid methane sulphonate as off white crystalline solid having the following analytical properties: MR- 267°C Chemical assay -98%,
Example 6
5-amino salicylic acid Nitrate :

5-Amino salicylic acid (10.0g, 0.065m) in methanol(30ml) was added to a solution of Nitric acid (4.1g, 0.065m) in methanol(30ml) under cooling. The solution was stirred at 5-10°C for 3 hours and evaporated to dryness under reduced pressure and the resulting residue was re-crystallized from Methyl alcohol. The product was filtered-off and dried to afford, 5-amino salicylic acid nitrate as. dark brown solid having the following analytical properties: MR- 230°C Chemical assay -97%,
Example 7
5-amino salicylic acid hydrobromide :
5-Amino salicylic acid (5.0g, 0.03m) in methanol(20ml) was added to a solution of aqueous hydrobromic acid (2.4g, 0.03m) in methanol(20ml) . The solution was heated to reflux temperature 3 hours and evaporated to dryness under reduced pressure and the resulting residue was recrystallized from methyl alcohol. The product was filtered-off and dried to afford, 5-amino salicylic acid hydrobromide as pinkish white crystalline solid having the following analytical properties: MR- 282°C Chemical assay -99.9% ,
Example 8
5-amino salicylic acid sulphate:
5-Amino salicylic acid (5.0g, 0.03m) in methanol(20ml) was added to a solution of sulfuric acid (2.9g, 0.03m) in methanol(20ml) . The solution was heated to . reflux temperature 2 hours and evaporated to dryness under reduced pressure and the resulting residue was recrystallized from methyl alcohol. The product is filtered-off and dried to afford, 5-amino salicylic acid sulphate as white crystalline solid having the following analytical properties: MR- 236°C Chemical assay-100%

Example 9
Derivative of 5-amino salicylic acid with para fluoro benzaldehyde
(5-N-p-fluoro benzylidene salicylic acid):
p-Fluorb benzaldehyde (29.8g, 0.24m) was added to a solution of 5-Amino salicylic acid (10.0g, 0.06m) in acetic acid (50ml) The solution was heated to reflux temperature for 16 hours and poured into ice under stirring. The resulting product was filtered and is recrystallized from methyl alcohol. The product was filtered-off and dried to afford 5-N-p-fluoro benzylidene salicylic acid, as pinkish brown crystalline solid having the following analytical properties: MR- 222°C
Example 10
Derivative of 5-amino salicylic acid with paratolualdehyde
(5-N-p-Methyl benzylidene salicylic acid):
p-tolualdehyde (10.0g, 0.24m) is added to a solution of 5-Amino salicylic acid (10.0g, 0.06m) in acetic acid (50ml) The solution was heated to reflux temperature for 16 hours and poured into ice under stirring. The separated solid was filtered off and the aqueous layer is extracted with ethyl acetate. The ethyl acetate layer was completely distilled off and the residue was recrystallized from ethyl acetate. The product was filtered-off and dried to afford 5-N-p-Methyl benzylidene salicylic acid, as crystalline solid having the following analytical properties: MR- 220°C Example 11
Derivative of 5-amino salicylic acid with butyraldehyde (5-N-Butyrylidene salicylic acid):
Butyraldehyde (12.9g, 0.18m) was added to a solution of 5-Amino salicylic acid (10.0g, 0.06m) in acetic acid (50ml) The solution was heated to reflux temperature for 16 hours and poured into ice under stirring. The separated solid was filtered off and the aqueous layer was extracted with ethyl acetate. The ethyl acetate layer was completely distilled off and the residue was re-crystallized from methanol. The product was filtered-off and dried to afford 5-N-Butyrylidene

salicylic acid as fluorescent green solid having the following analytical properties: MR- 254°C
Example 12
Derivative of 5-amino salicylic acid with benzaldehyde
(5-N-benzylidene salicylic acid):
benzaldehyde (6.4g, 0.06m) was added to a solution of 5-Amino salicylic acid (5.0g, 0.03m) in acetic acid (25ml) The solution was heated to reflux temperature for 16 hours and brought to room temperature . The separated product was filtered and was recrystallized from methanol to afford 5-N-benzylidene salicylic acid, as cream white solid having the following analytical properties: MR- 220°C
Example 13- formulations;
Tablets containing 400mg of a 5-amino salicylic acid addition salt are prepared in the following composition

We Claim :
1. Acid addition salts of 5-amino salicylic acid selected from the group
consisting, nitrate salt, a hydrobromide salt, a sulfate salt, a Methane sulfonic
acid salt, a Ethane sulfonic acid salt, a Trifluoro methane sulfonic acid salt.
Benzene sulfonic acid salt, , a fumarate salt, a succinate salt, a benzoate salt, a
hydrochloride salt, a citrate salt, a malate salt, a salicylate salt, a formate salt, a
lactate salt and a p-Toluene sulfonic acid salt.
2. A pharmaceutical composition which comprises a pharmaceutically
acceptable carrier and an addition salt of 5-amino salicylic acid selected from the
group consisting, nitrate salt, a hydrobromide salt, a sulfate salt , a Methane
sulfonic acid salt, a Ethane sulfonic acid salt, a Trifluoro methane sulfonic acid
salt, Benzene sulfonic acid salt, , a fumarate salt, a succinate salt, a benzoate
salt, a hydrochloride salt, a citrate salt, a malate salt, a salicylate salt, a formate
salt, a lactate salt and a p-Toluene sulfonic acid salt.
3. Aldimine derivatives of 5-amino salicylic acid selected from a group
consisting p-tolualdehyde , p-fluoro benzaldehyde, benzaldehyde, butyraldehyde
4. Use of acid addition salt of 5-amino salicylic acid according to claims 1 to 2 for
the manufacture of a pharmaceutical composition for the treatment of Chron's
disease and ulcerative colitis.