Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
  • C07D275/04—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems
  • C07D275/06—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems with hetero atoms directly attached to the ring sulfur atom
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
  • A61P25/34—Tobacco-abuse
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D291/00—Heterocyclic compounds containing rings having nitrogen, oxygen and sulfur atoms as the only ring hetero atoms
  • C07D291/02—Heterocyclic compounds containing rings having nitrogen, oxygen and sulfur atoms as the only ring hetero atoms not condensed with other rings
  • C07D291/06—Six-membered rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

• nicotine has a taste which, when consumed alone, is perceived as unpleasant. It is generally described as sharp to pepper-like and bitter. This unpleasant taste hinders the acceptance of chewing gum with added nicotine which should be chewed regularly for withdrawal from smoking, particularly in the initial phase. In order to improve the acceptance of nicotine-containing chewing gums or other preparations which can be consumed orally, there is therefore the requirement for improving or masking the unpleasant taste of nicotine.
• WO 99/04822 describes 1:1 salts of a sweetener and an unpleasantly tasting pharmaceutical. Salts of an anionic sweetener and nicotine are not described.
• WO 00/12067 describes 1:1 salts of saccharin with synthetic non-alkaloidal medicinal organic bases. Salts of an anionic sweetener and nicotine are not described.
• EP-B 0 046 506 describes Vincamine saccharinate and medicaments containing this. Salts of an anionic sweetener and nicotine are not described.
• salts prepared here from one molecule of nicotine and one molecule of sweetener are salts prepared here from one molecule of nicotine and one molecule of sweetener, but also defined compounds of one molecule of nicotine and two molecules of sweetener may be prepared, in which even two different sweeteners can be used. Surprisingly, all of these compounds are distinguished by a pleasant sweet taste, from which the unpleasant components of nicotine are substantially absent. They consist only of components which are used in any case, for example in nicotine- containing chewing gums, and make further working steps, such as the preparation of inclusion compounds mentioned in WO 97/41843, superfluous. Thus this invention is an important advance in the production, composition and use of nicotine-containing preparations for withdrawal from smoking.
• the present invention thus relates to compounds or salts of nicotine and anion-forming sweeteners or their physiologically acceptable salts or sweeteners which have acid character in free form, or their physiologically acceptable salts. These compounds can also be present as what are termed acid-addition salts, preferably with HCl, or other physiologically acceptable acids, for example acetic acid or sulfuric acid.
• Suitable compounds for the preparation of these compounds are in principle all sweeteners or their physiologically acceptable salts, such as in particular the potassium salt of acesulfame (acesulfame-K), which are able to form anions, including in particular
• Acesulfame (acesulfame-H) and acesulfame-K are particularly preferred.
• a multiplicity of combinations are possible here, in particular in the case of the compounds of one molecule of nicotine and two sweetener molecules.
• the sweet taste may be modified, in particular the perception of sweetness with time, firstly with respect to masking the nicotine taste, secondly for setting an optimum overall taste impression. This is a critical advantage compared with the 1:1 compounds of 1 mol of sweetener and 1 mol of nicotine.
• the present invention thus also relates to a process for preparing the inventive nicotine-sweetener compounds by reacting nicotine with sweeteners in the form of their free acids (for example acesulfame-H) in a suitable solvent.
• suitable solvents are preferably water and/or water-miscible solvents, for example alcohols.
• Sweeteners suitable for this direct reaction are preferably acesulfame, cyclamate, glycyrrhizin, gluconic acid and/or saccharin.
• a process variant is that the sweeteners or their salts (for example acesulfame-K) are reacted with nicotine in a solvent as described above in the presence of a physiologically harmless acid, preferably hydrochloric acid, or other suitable inorganic or organic acids, for example acetic acid or sulfuric acid, and the resultant acid addition salts (cf., for example, diagram 1) of the nicotine-sweetener compounds are isolated.
• a physiologically harmless acid preferably hydrochloric acid, or other suitable inorganic or organic acids, for example acetic acid or sulfuric acid
• the starting materials for the preparation of the inventive compounds are commercially available or can be prepared according to methods known from the literature; for example acesulfame/acesulfame-K cf. EP-A 0 155 643.
• the nicotine-sweetener compounds, salts or adducts are obtained very simply from solutions, preferably from aqueous solutions, of nicotine and the corresponding acid of the respective sweetener or, for example in a hydrochloric acid solution of the respective sweetener, as shown in the examples below, in particular for acesulfame-H.
• the resulting reaction solutions are freed from the solvent in a suitable manner, for example under reduced pressure.
• the nicotine-sweetener compounds, according to 1 H-NMR are present as 1:1, preferably as 1:2 or 1:1:1 adducts.
• the invention further relates to the use of said compounds for preparing solid or liquid preparations which are suitable for oral supply of nicotine, preferably in the form of chewing gum, chewing tablets, compressed compositions or similar preparations.
• general preparations which comprise the inventive compounds are included by the invention.
• initiating initiating initiating after marked weak strong about 10 sweetness, sweetness, sweetness, seconds, persistent, metallic, persistent, paprika- initially somewhat after 5 like sour, no bitter off minutes: taste, nicotine taste and no then taste, aftertaste, nicotine pepper- after 5 after 5 taste like mild minutes: minutes: no no nicotine nicotine taste taste
• the nicotine taste in the case of 1:2 or 1:1:1 adducts of nicotine with the respective anions of the sweeteners can surprisingly even be completely eliminated, so that even after some minutes of residence time in the mouth no nicotine taste can be detected.
• inventive compounds are stable and do not decompose even during incorporation into chewing gum or other preparations suitable for withdrawal from smoking.
• they can be used in intermediate products or precursor products without nicotine and sweeteners separating. Therefore, they may be incorporated without problem into the preparations with which they are to be consumed, for example chewing gum, chewing tablets, compressed compositions or other preparations for oral use.
• sugar-free chewing gum strips are produced from the generally known ingredients chewing gum base, sugar-free sweeteners, such as sugar alcohols and synthetic sweeteners, glycerol and flavoring substances and the inventive compounds according to generally known technology, that is to say the ingredients are charged one after the other into the warmed chewing gum base and are incorporated uniformly. Shaping and portioning are then carried out as usual.
• the ingredients correspond to those customarily used, that is to say in the case of sugar alcohols, for example, sorbitol, xylitol, mannitol, maltitol, isomalt, lactitol, erythritol, mixtures of sugar alcohols and sugar alcohols in syrup form, for example sorbitol syrup and maltitol syrup.
• sugar alcohols for example, sorbitol, xylitol, mannitol, maltitol, isomalt, lactitol, erythritol, mixtures of sugar alcohols and sugar alcohols in syrup form, for example sorbitol syrup and maltitol syrup.
• all known sweeteners can be used, for example acesulfame-K, aspartame, cyclamate, saccharin, thaumatin neohesperidins DC, sucralose, brazzein, neotame.
• the dosage of the nicotine salts is dependent on the amount of nicotine which is to be present in a strip of chewing gum. In order that, for example, 2 mg of nicotine is present in a chewing strip 3 g in mass, 6 mg of the described 1:2 salt of nicotine and acesulfamic acid must be used or else 7.61 mg of the described nicotine-acesulfamic acid-aspartame salt. Similarly, the dosage of nicotine can be increased by increasing the dosage of the nicotine salts.
• the nicotine salts can also be incorporated into sugar-containing chewing gum formulas.
• the sugars customarily used for example sucrose and glucose syrup are used.
• the resulting chewing gums have a pleasant sweet taste which, even in the case of relatively long chewing, is not replaced by bitter taste components.
• sugar-free or sugar-containing compressed compositions, tablets or chewing tablets are produced with the use of sugar-free sweeteners such as sugar alcohols and synthetic sweeteners, aids, binders and flavoring substances and the inventive compounds according to generally known technology, that is to say the ingredients are homogeneously mixed one after the other and pressed to form compressed compositions or shaped to form tablets.
• the ingredients correspond to those customarily used, that is to say in the case of sugar alcohols, for example, sorbitol, xylitol, mannitol, maltitol, isomalt, lactitol and erythritol and mixtures of sugar alcohols.
• sugars for example sucrose
• all known intensive sweeteners can be used, for example acesulfame-K, aspartame, cyclamate, saccharin, thaumatin, neohesperidins DC, sucralose, brazzein, neotame.
• the dosage of the nicotine salts is dependent on the amount of nicotine which is to be present in a compressed composition or a tablet.
• a dose of 2 mg of nicotine in a compressed composition or a tablet 6 mg of the described 1:2 salt of nicotine and acesulfamic acid must be used or else 7.61 mg of the described nicotine-acesulfamic acid-aspartame salt.
• the dosage of nicotine can be increased by increasing the dosage of nicotine salts.
• the resulting compressed composition or tablet has a pleasant sweet taste which is not replaced by bitter taste components even in the event of relatively long sucking or chewing.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Addiction (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Biomedical Technology (AREA)
• Neurology (AREA)
• Neurosurgery (AREA)
• Psychiatry (AREA)
• General Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Engineering & Computer Science (AREA)
• Pharmacology & Pharmacy (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Medicinal Preparation (AREA)
• Confectionery (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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• 2000
  • 2000-03-20 DE DE10013712A patent/DE10013712A1/de not_active Withdrawn
• 2001
  • 2001-03-14 DE DE50106289T patent/DE50106289D1/de not_active Expired - Fee Related
  • 2001-03-14 EP EP01105450A patent/EP1136487B1/fr not_active Expired - Lifetime
  • 2001-03-16 US US09/810,815 patent/US20010029959A1/en not_active Abandoned
  • 2001-03-19 JP JP2001078220A patent/JP2001302513A/ja not_active Withdrawn
• 2004
  • 2004-03-12 US US10/800,364 patent/US20040173224A1/en not_active Abandoned

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