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  • 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
  • C07D213/60—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D213/72—Nitrogen atoms
  • C07D213/73—Unsubstituted amino or imino radicals
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  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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  • A61K31/47—Quinolines; Isoquinolines
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  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
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  • A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
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  • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
  • C07C323/64—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and sulfur atoms, not being part of thio groups, bound to the same carbon skeleton
  • C07C323/66—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and sulfur atoms, not being part of thio groups, bound to the same carbon skeleton containing sulfur atoms of sulfo, esterified sulfo or halosulfonyl groups, bound to the carbon skeleton
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  • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
  • C07D233/06—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to ring carbon atoms
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  • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
  • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
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  • C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
  • C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
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  • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
  • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
  • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
  • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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  • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
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  • C07D489/00—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula:
  • C07D489/02—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: with oxygen atoms attached in positions 3 and 6, e.g. morphine, morphinone
  • C07D489/04—Salts; Organic complexes
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  • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated

Definitions

• the present invention relates to therapeutic compounds having a mucolytic activity and to the process of their preparation. It relates also to therapeutic compositions containing said mucolytic compounds and to the process of their preparation. Furthermore, the invention relates to a mucolysis process wherein said mucolytic compounds and compositions are used.
• the salts of mercaptoalkane-sulfonic acids constitute very active mucolytic agents having a very low toxicity. These salts can therefore be used whenever it is desired to fluidify mucus.
• the numerous possibilities of application of the fluidization of mucus mention may be made of the mucolysis of secretions of the stomachal, intestinal, vaginal, etc. mucous membranes, the liquefaction of expectorations or pathological mucus with the view of their bacteriologic examination, the dissolution of all kinds of mucus during the cleaning of surgical instruments, and the like.
• the application for which the mucolytic compounds suit best is the treatment of the respiratory tract diseases.
• mucus in the respiratory tract considerably complicates the treatment of numerous diseases of the respiratory tract.
• the evacuation of this mucus is often difiicult and its presence has the effect of considerably reducing the action of medicines, such as vasoconstrictors, bronchodilators, anti-histaminics, antibiotics, anti-bacterials, anaesthetics, sedatives and the like.
• This mucus contains considerable quantities of mucoproteins. From the chemical point of view, these substances contain, in particular, disulfide bonds. It is well known that the breaking of these disulfide bridges by means of certain thiols in order to form new disulfides having a lower molecular weight, results in a considerable reduction of the viscosity of the mucus, thus facilitating its evacuation.
• mucolytic agents such as Z-mercaptoethanol, Z-mercaptoethylamine and cysteine, which compounds may be substituted, for example, on the amine nitrogen.
• mucolytic agents such as Z-mercaptoethanol, Z-mercaptoethylamine and cysteine
• Z-mercaptoethanol Z-mercaptoethanol
• Z-mercaptoethylamine Z-mercaptoethylamine
• cysteine which compounds may be substituted, for example, on the amine nitrogen.
• the disadvantage of hitherto known mucolytics is their Patented Mar. 2, 1971 chemical instability. These compounds are, indeed, very sensitive to oxidation; in addition, they have a very disagreeable odour, which considerably restricts their medical use.
• Mercaptoalkane-sulfonic acids are, in fact, compounds which are already known and certain of their salts have already been proposed for use outside the medical field, such as the permanent waving of hair in cosmesis. As far as is known, however, it has not been shown that these compounds possess mucolytic properties.
• salts of mercaptoalkane-sulfonic acids with pharmaceutically-inactive inorganic or organic bases, if desired, mixed with suitable excipients.
• suitable excipients for example, sodium, ammonium or Z-amino-pyrimidine salts of 2- mercaptoethane-sulfonic acid may be used for this purpose.
• a very advantageous method of utilisation consists in administering the compounds according to the present invention together with pharmaceutically-active compounds which are basic or not.
• these pharmaceutically-active compounds are not basic, they are mixed with the salts according to the present invention in the desired proportions in order to obtain simultaneously efficacious therapeutic and mucolytic activities.
• the mercaptoalkane-sulfonic acids may be completely or partially neutralised with them.
• the mercaptoalkane-sulfonic acids it is also possible for the mercaptoalkane-sulfonic acids to be completely neutralized with a pharmaceutically-active base when the respective activities of the acid and of the base so permit.
• a pharmaceutically-active base it is also possible for the mercaptoalkane-sulfonic acids to be completely neutralized with a pharmaceutically-active base when the respective activities of the acid and of the base so permit.
• an appropriate quantity of a salt of a mercaptoalkane-sulfonic acid and a pharmaceutically inactive base may be added and the obtained mixture used for the preparation of a medicine.
• the mercaptoalkane-sulfonic acids are capable of forming, with the inorganic and organic bases, stable, odourless salts which have clearly determined physical constants, particularly a sharp melting point.
• bases include not only pharmaceutically-inactive bases, such as Z-aminopyridine, Z-aminopyrimidine, guanidine and the like, but also pharmaceutically-active bases used as vasoconstrictors, bronchodilators, antihistaminics, antibiotics, bactericidals, anaesthetics, sedatives and the like.
• toxicity LD 50 (intravenously in the rat): 4 g./Kg. (by way of comparison, the LD 50 of N-acetyl-cysteine is 2.6 g./kg.);
• the compounds according to the present invention are prepared by the conventional methods for preparing salts, preferably in aqueous solution, either by reacting a mercapt0alkane-sulfonic acid with a given inorganic or organic base, or by reacting an alkali metal or ammonium salt of a mercaptoalkane-sulfonic acid with a hydrohalogenide of a suitable organic base, or yet by double decomposition of a weak base salt of a mercaptoalkanesulfonic acid with a hydrohalogenide of a given inorganic or organic base. Other methods may also be used.
• the salts obtained are preferably purified by recrystallization from suitable solvents or mixtures of solvents.
• the compounds according to the present invention are administered in a manner depending on the kind of mucus to be fiuidified.
• administration in the form of aerosol is one of the preferred manners and the one best indicated in the majority of cases.
• the compounds according to the present invention are advantageously presented in the form of aqueous solutions for aerosolization.
• Another equally possible form is the use of a micronized suspension in an inert propellant such as the Freons.
• aqueous solutions to be aerosolized is remarkably simple, because it is suflicient to dissolve, in degasified water, definite quantities of the salts according to the present invention and optionally of other water soluble pharmaceutically active compounds.
• Pharmaceutically acceptable stabilizing and Wetting agents may advantageously be added. If one or more of the pharmaceutically-active substances is not basic and is insoluble in water, stable emulsions can very easily be obtained by using conventional, pharmaceutically-acceptable emulsifiers. It is also possible to effect complete neutralisation of an aqueoussolution of mercaptoalkane-sulfonic acids with pharmaceutically-active bases, or partial neutralisation with said bases, followed by complete neutralisation with pharmaceutically-inactive inorganic or organic bases.
• aqueous solutions or emulsions are preferably used in an aerosolizer operating under gas pressure;
• the propelling gas thus used is preferably inert, for example, nitrogen.
• the aerosol liberated is absorbed by the patient through the nose and is very elfectively distributed along the trachea so as to reach the less accessible parts of the bronchi.
• the administration of the compounds or compositions according to the present invention is thus preferably done through the nose or by inhalation in the form of aqueous solutions, suspensions or emulsions, but they may also be administered per os in the form of syrups, solutions, drops, capsules, tablets, pills and the like or even by way of parenteral or rectal administration in the pharmaceutically known forms of aqueous or oily solutions, suspensions or emulsions or suppositoria.
• These various pharmaceutical forms are prepared according to methods currently used by pharmacists.
• the to be administered dose of mucolytic agents according to the present invention varies within wide limits depending on the mode of administration. Since the agents are substances of low toxicity, the upper dosage limit depends on the tolerance of the mucous membranes rather than on the toxicity of these agents. Clinical tests have shown that the upper limit of concentration of such solutions of emulsions reaches 30%, solutions or emulsions containing up to 20-25% of mucolytic agent being generally well tolerated. Thus, when the mucolytic agent is administered in the form of aerosol, the quantity of mucolytic agent may reach 1 g. per application, and such an application may be repeated several times a day. For nasal instillations the best tolerated concentration in mucolytic agent varies from 2 to 5% for adults and is about 1% for children.
• X Percent of fluidization
• the standard taken is the mucolytic activity of l.cysteine, to which the value of 100% is given, and the mucolytic activities of the compounds of the present invention are expressed in relation to those of l.cysteine.
• the results obtained are shown in the following table:
• the mucolytic activity of the products according to the present invention has been studied making use of the fact that this activity brings about a breaking up of the water-insoluble molecular aggregates into molecular fragments that are soluble in water.
• the determination of the dry weight of the water-soluble fraction, after centrifugation at high speed, is used to evaluate the mucolytic activity on human bronchial mucus.
• the aforesaid method enables to study the characteristics of the activity of the salts of the mercaptoalkane-sulfonic acids according to the present invention and to compare them with other mucolytic agents. For example:
• the same biologic sample is treated under the same conditions with equivalent molar quantities of N-acetyll-cysteine.
• the water-soluble fraction is increased by 32 and 42% respectively.
• CLINIC TESTS A marked mucolytic activity is observed in tests by aerosolization under pressure of 6 ml. of a 10% aqueous solution of 2-aminopyrimidine mono-2-mercaptoethanesulfonate.
• a saline solution (placebo) has been administered to the same patients under the same experimental conditions.
• the table herebelow is an example that shows results of treatment of 3 patients (chronic bronchitis).
• the figures correspond to percentages by weight of dry matter of the water-soluble fraction of mucus compared with the weight of dry matter of the total amount of the expectoration.
• a sample of expectoration is collected before aerosolization and is used as control sample (sample 1).
• the aerosolization lasts about 30' minutes. A second sample is collected in the course of treatment, 15 minutes after beginning (sample 2) and another immediately after ceasing the aerosolization (sample 3).
• mucolytic agent use is made, in the tests, of 2-aminopyrimidine mono-2- mercaptoethanesulfonate (Aerosol A) in comparison with an aerosol of placebo (Aerosol B).
• Aerosol A Patient 1 Patient 2 Patient 3 Aerosol B This stability has been estimated under different conditions of temperature and treatment by dosage of the SH groups in dependence upon time.
• Example 1 hereafter illustrates the preparation of several therapeutic salts according to the present invention, Whereas Examples 2 to 11 illustrate therapeutic compositions having a mucolytic activity according to the present invention. It is, however, obvious that these examples do not limit the bearing of the present invention.
• EXAMPLE 1 (a) Preparation of 1-phenyl-2-(N-methylamino)- propanol 2mercaptoethane-sulfonate 0.1 mol l-phenyl-2-(N-methylamino)-propanol dissolved in ethanol is added to a 30% aqueous solution containing 0.1 mol Z-mercaptoethane-sulfonic acid. The mixture is evaporated to dryness and the residue recrystallized from an isopropanol-aoetone mixture. Melting point of the obtained salt: 168169 C.
• codeine Z-mercaptoethane-sulfonate uncrystallizable oil
• EXAMPLE 2 An aqueous solution meant for the treatment of the respiratory tract by inhalation has the following composition:
• the pH of the solutions is adjusted to 7-8 by addition of a suitable quantity of sodium hydroxide.
• a bactericide may also be added to these solutions, e.g. a mixture of proply and methyl phydroxybenzoates.
• EXAMPLE 6 The following powder is to be dissolved in distilled water when used and is meant as nasal drops:
• Neomycin in the form of its sulfate
• EXAMPLE 7 For application by micronization, a 1% by weight suspension is prepared of sodium Z-mercaptoethane-sulfonate in a mixture of fluorinated hydrocarbons (l/ 1 mixture of Freon l1 and Freon 12).
• a vasoconstrictive mucolytic preparation for nasal use contains the following:
• An antihistaminic mucolytic preparation for nasal use contains the following:
• a vasoconstrictive mucolytic preparation for nasal use contains the following:
• a vasoconstrictive mucolytic preparation for nasal use contains the following:
• a mucolytic process which comprises contacting mucus in humans with a mucolytically effective amount of a pharmaceutically acceptable salt of a mercaptoalkane-sulfonic acid of the formula HSXSO H wherein X is an alkylene radical having from '2 to 6 carbon atoms.

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Families Citing this family (4)

• 1965
  • 1965-05-07 GB GB19370/65A patent/GB1119721A/en not_active Expired
• 1966
  • 1966-04-29 NL NL666605816A patent/NL148237B/xx not_active IP Right Cessation
  • 1966-05-04 IT IT09675/66A patent/IT1052280B/it active
  • 1966-05-04 BE BE680486D patent/BE680486A/xx not_active IP Right Cessation
  • 1966-05-06 ES ES0326448A patent/ES326448A1/es not_active Expired
  • 1966-05-06 FR FR60523A patent/FR5784M/fr not_active Expired
  • 1966-05-06 BR BR179308/66A patent/BR6679308D0/pt unknown
  • 1966-05-07 DE DE1620629A patent/DE1620629C3/de not_active Expired
• 1968
  • 1968-12-13 US US807147A patent/US3567835A/en not_active Expired - Lifetime

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