EP1009730A1 - Neue derivate des pentaerythrits, deren herstellung und verwendung sowie intermediate zur synthese derselben - Google Patents

Neue derivate des pentaerythrits, deren herstellung und verwendung sowie intermediate zur synthese derselben

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Publication number
EP1009730A1
EP1009730A1 EP97945736A EP97945736A EP1009730A1 EP 1009730 A1 EP1009730 A1 EP 1009730A1 EP 97945736 A EP97945736 A EP 97945736A EP 97945736 A EP97945736 A EP 97945736A EP 1009730 A1 EP1009730 A1 EP 1009730A1
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EP
European Patent Office
Prior art keywords
bis
compounds according
nitryloxymethyl
compounds
nitryloxy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP97945736A
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German (de)
English (en)
French (fr)
Inventor
Ulrich Hess
Anne-Katrin Windeck
Holger Brosig
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Puren Pharma GmbH and Co KG
Original Assignee
Isis Pharma GmbH
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Filing date
Publication date
Priority claimed from DE19641667A external-priority patent/DE19641667A1/de
Priority claimed from DE1996152345 external-priority patent/DE19652345A1/de
Priority claimed from DE19726812A external-priority patent/DE19726812A1/de
Application filed by Isis Pharma GmbH filed Critical Isis Pharma GmbH
Publication of EP1009730A1 publication Critical patent/EP1009730A1/de
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C243/00—Compounds containing chains of nitrogen atoms singly-bound to each other, e.g. hydrazines, triazanes
    • C07C243/24—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids
    • C07C243/26—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C243/28—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms to hydrogen atoms or to carbon atoms of a saturated carbon skeleton
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/06—Free radical scavengers or antioxidants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • C—CHEMISTRY; METALLURGY
    • C06—EXPLOSIVES; MATCHES
    • C06B—EXPLOSIVES OR THERMIC COMPOSITIONS; MANUFACTURE THEREOF; USE OF SINGLE SUBSTANCES AS EXPLOSIVES
    • C06B25/00—Compositions containing a nitrated organic compound
    • C—CHEMISTRY; METALLURGY
    • C06—EXPLOSIVES; MATCHES
    • C06B—EXPLOSIVES OR THERMIC COMPOSITIONS; MANUFACTURE THEREOF; USE OF SINGLE SUBSTANCES AS EXPLOSIVES
    • C06B25/00—Compositions containing a nitrated organic compound
    • C06B25/10—Compositions containing a nitrated organic compound the compound being nitroglycerine
    • C—CHEMISTRY; METALLURGY
    • C06—EXPLOSIVES; MATCHES
    • C06B—EXPLOSIVES OR THERMIC COMPOSITIONS; MANUFACTURE THEREOF; USE OF SINGLE SUBSTANCES AS EXPLOSIVES
    • C06B25/00—Compositions containing a nitrated organic compound
    • C06B25/32—Compositions containing a nitrated organic compound the compound being nitrated pentaerythritol
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C203/00—Esters of nitric or nitrous acid
    • C07C203/02—Esters of nitric acid
    • C07C203/04—Esters of nitric acid having nitrate groups bound to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C235/06—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C07C29/36—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal
    • C07C29/38—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal by reaction with aldehydes or ketones
    • C07C29/42—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal by reaction with aldehydes or ketones with compounds containing triple carbon-to-carbon bonds, e.g. with metal-alkynes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/08—Esters of oxyacids of phosphorus
    • C07F9/09—Esters of phosphoric acids
    • C07F9/091—Esters of phosphoric acids with hydroxyalkyl compounds with further substituents on alkyl

Definitions

  • the invention presented here relates to new derivatives of pentaerythritol, their preparation and use, which can be used in particular as pharmaceuticals, and intermediates for the synthesis thereof.
  • GTN glycerol trinitrate
  • PETN pentaerythrityl tetranitrate
  • Patent 2,370,437 Isosorbide-5-mononitrate (ISMN) (DE-OS-22 21 080, DE-OS-27 51 934, DE-OS-30 28 873, DE-PS-29 03 927, DE-OS-31 02 947 , DE-OS-31 24 410, EP-Al-045 076, EP-Al-057 847, EP-Al-059 664, EP-Al-064 194, EP-Al-067 964, EP-Al-143 507 , U.S. Patent 3,886, U.S. Patent 4,065,488, U.S. 4,417,065, U.S. 4,431,829), Isosorbide Dinitrate (ISDN) (L.
  • ISMN Isosorbide-5-mononitrate
  • ISDN Isosorbide Dinitrate
  • Comparable and improved pharmacological activity when used in the above-mentioned indication areas have organic “nitrates” of a newer type such as, for example, SPM 3672 (N- [3-nitratopivaloyl] -L-cysteine ethyl ester) (US Pat. No. 5,284,872) and its derivatives or 1, 4-dihydropyridine derivatives (WO-Al-92/02503).
  • endothelial protective agents DE-Al-44 10 997
  • agents against pathologically increased intraocular pressure WO-Al-95/13812
  • agents against dysmenorrhea dysfunctional uterine bleeding, premature labor or after-pains by reducing uterine contractility
  • WO-Al-95/13802 as a remedy for climacteric symptoms
  • WO-Al -95 / 13800 a remedy for erectile dysfunction
  • the previously known organic nitric acid esters have a number of therapeutic disadvantages.
  • the so-called nitrate tolerance can be observed, i.e. the decrease in the nitrate effect with high doses or with the application of long-acting nitric acid esters.
  • There are also side effects such as headache, dizziness, nausea, weakness, skin redness and The risk of a greater drop in blood pressure is demonstrated by reflex tachycardia (Mutschier, Arzneiffenantsen, Academic Members Verlagsgesellschaft mbH, Stuttgart, 1991)
  • PETN as an active ingredient has a number of outstanding properties, in particular little to no occurrence of the above-mentioned side effects, which favor a preferred use of this compound as a pharmaceutical justify other organic nitric acid esters (series "Pentaerythrityltetranitrat", Dr Dietrich Steinkopff Verlag, Darmstadt, 1994 to 1996)
  • the galenic processing of the organic nitric acid esters into pharmaceutical preparations for the treatment of angina pecto ⁇ s or ischemic heart disease is generally known. It is carried out according to the procedures and rules generally familiar to the pharmaceutical expert, the choice of the technologies to be used and the galenic auxiliaries used being primarily based on the active ingredient to be processed Questions regarding its chemical-physical properties of the chosen form of administration, the desired duration of action and the avoidance of drug-auxiliary incompatibilities are of particular importance.
  • the platelet activation factor (platelet activation factor), an l-alkyl-2-acetvl ether analog of the phosphatidylcho ns of the formula
  • H C-CO-0-CH (CH 2 -O- (CH 2 ) 15 -CH.) - CH 2 -0-P0 2 -0-CH 2 -CH 2 -N (CH,), is capable of extremely low concentration of 0.1 nM in the blood to trigger platelet aggregation and vasodilation (Stryer, Biochemie, Spektrum dermaschineen Heidelberg, 1990)
  • R 1 , R 2 , R 1 are identical or different from one another CH 2 -ONO 2 , CH 2 -OR 4 or R 5 , but at least one of the substituents R 1 to R 3 is R 5 , R 4 is H or C to C 6 -alkanoyl,
  • R 5 COR ⁇ , R 6 OH, OR 7 , NH 2 , NHR 7 , NR 7 2 , N + R 7 3 X " , NR 8 , NR 9 R 10 , NR n R 12 or NH-NH 2 ,
  • R 7 straight-chain or branched Cj- to C ⁇ -alkyl, straight-chain or branched d- to C 6 -alkenyl, aryl, aralkyl, hetaryl or hetaralkyl, R 8 C ⁇ - to C ⁇ -al ylidene, R 9 , R 10 from each other different R 7 ,
  • R 1 1 , R 12 are the same or different, NR 7 2 , N + R 7 3 X " , NR 8 and
  • X represents a halogen or a group capable of forming anions, and their therapeutically contractual salts
  • R 6 are OH, OR 7 , NH 2 , NHR 7 , NR 7 2 or N + R 7 3 X " , namely in particular the esters and mixed esters, amides, half-amides, amide esters and ammonium salts
  • Further preferred embodiments are compounds with one, two and three hydrophilic groups. This relates in particular to the metal and ammonium salts, esters, amides and hydrazides of carboxylic acids.
  • the compounds of the formulas are particularly preferred
  • nitric acid esters of pentaerythritol serve as starting compounds, with respect to their representation expressly referring to the process of partial denitration of pentaerythrityl tetranitrate using hydrazine (Simecek, Coll. Czech. Chem. Comm. 27 (1962), 363 and US Pat. No. 3,408,383 )
  • Another method is the nitration of pentaerythritol to trinitrate, followed by its hydrazinolysis to pentaerythrityldi and mononitrate and by the chromatographic separation of the resulting mixture.
  • 2,2-bis (hydroxymethyl) malonic acid (Gault, Roesch, CR Hebd. Seances Acad.
  • Suitable for this purpose are in particular straight-chain and branched primary, secondary and tertiary C ⁇ -C f, alkanols, -alkenols and aryl, hetaryl, aralkyl, Hetaralkylalkohole.
  • the homologous acid amides, half-amides or hydrazides are obtained by reacting the acid halides and esters mentioned with NH 3 , primary and secondary amines or hydrazine or 1-substituted hydrazines.
  • Primary and secondary aliphatic, aromatic and heteroaromatic amines or hydrazine and 1 -substituted are suitable for this Hydrazine.
  • a further embodiment of the invention are the compounds of the general formula XIV,
  • R 13 is a group of the formula XV
  • the compounds of formula XIV are in particular obtained from the compounds of formulas VIII to XIII e.g. 3-Nitryloxy-2,2-bis (nitryloxymethyl) propionic acid (Tri-PS), 2,2-bis (nitryloxymethyl) malonic acid (Bis-MS) or 2-carboxy-2-nitryloxymethylmalonic acid (CN-MS) by reaction with Pentaerythritol derivatives of the formula XV 1,
  • Derivatives of the compounds of the formulas VIII to XIII such as, for example, of tri- PS, Bis-MS, CN-MS or XV 1 can be used as starting compounds for the synthesis of the compounds XIV, the functional groups of which, as suitable leaving groups, enable the person skilled in the art to access the target compounds via esterification reactions.
  • the reaction is carried out according to the generally known methods and processes for the preparation of esters
  • a further embodiment of the invention are the compounds of the general formula XVI,
  • R 14 , R 15 , R 1 are identical or different from one another H, OR 19 , ONO 2 , OR 17 or R 18 , R 17 COR 19 or R 23 ,
  • R 19 H straight-chain or branched d- to C f , -alkyl, R 20 straight-chain or branched C to Cc-alkyl-R 21 ,
  • R 22 R 19 aryl or NR , 9 2 ,
  • R 23 is a 3- or 5-carbonyl radical of a 1,4-dihydropyridine-3,5-dicarboxylic acid optionally substituted in the 2, 4 and / or 6-position, a 1-substituted pyrrolidine-2-carbonyl radical, an N-carbonyl radical of a substituted one Sydnonimins, a residue -CO-CH (NHCOR 19 ) -CR 19 2 -S-NO, a residue -CO-CH (NH 2 ) -CR 19 2 -S-NO or a residue -NH-CH (COOR 19 ) -CR 19 2 -S-NO and X represent a halogen or a group capable of forming anions, and also their therapeutically acceptable salts, the combinations
  • R 18 are COOR 19 , in particular the compounds of the formula XVII,
  • R 19 is H, methyl, ethyl, Na or K, and the compounds of the formula XVIII,
  • R 19 is methyl or ethyl
  • Nitric acid to 3-nitryloxy-2,2-bis (nitryloxymethyl) propyl bromide D.E. Elrik et al., Am.Soc. 76 [1954] 1374) followed by its grignardation and reaction with carbon dioxide.
  • the 2,2-bis (hydroxymethyl) malonic acid diethyl ester (Gault, Roesch, CR Hebd Seances Acad.
  • methyl-2,2 is used to prepare the 2,2-bis (nitryloxymethyl) malonic acid diethyl ester , 2-tris (nitryloxymethyl) ethyl ether is obtained after the ether synthesis according to WILLIAMSON or by reacting pentaerythrityl trinitrate with ethereal diazomethane solution in the presence of catalytic amounts of boron trifluoride.
  • a further embodiment is represented by the compounds in which the 3- or 5-carbonyl radical of a 1,4-dihydropyridine-3,5-dicarboxylic acid optionally substituted in the 2, 4 and / or 6-position is replaced by a radical of unsymmetrical esters which are 1- substituted pyrrolidine-2-carbonyl radical by a radical or the N-carbonyl radical of a substituted sydnonimine are formed by a radical, which are known to the person skilled in the art that they belong to the substance classes of the calcium antagonists, the ACE inhibitors or the coronary dilators
  • R 26 is H, represent a further embodiment of the invention, the compounds of the formula XX in particular compound of the formula XXI,
  • An additional embodiment of the present invention are the compounds of the general formula XXII,
  • R 27 is independently NO 2 or R 17 to R 23 , each with the meaning defined above, and n is an integer from 0 to 10, preferably from 0 to 4.
  • the method of partial denitration of bis [2,2,2-tris (nitryloxymethyl)] ethyl ether using hydrazine is used, for example, to prepare the symmetrical bis (2,2-bis (nitryloxymethyl) -2-hydroxymethyl) ethyl ether.
  • various end products are obtained either as free acid or base, base or acid addition salt or betaine, each of which is within the scope of the invention.
  • Acidic, basic, neutral or mixed salts and hydrates can be obtained in this way.
  • the respective salts can be converted into the free acid or base in a manner known per se using appropriate means or by ion exchange.
  • the free acids or bases obtained can form salts with organic or inorganic bases or acids.
  • base addition salts above all bases used which form suitable therapeutically acceptable salts.
  • Such bases are, for example, hydroxides or hydrides of the alkali and alkaline earth metals, ammonia, amines and hydrazines or guanidines.
  • Such acids are, for example, hydrogen halide, sulfone, phosphorus , Nitric and perchloric acid, furthermore aliphatic, acyclic, aromatic, heterocyclic carbon or sulfonic acids such as formic, acetic, propionic, amber, glycolic, lactic, apple, wine, lemon, gluconic, sugar -, Glucuron-, Ascorbin-, Maiein-, Hydroxymalein-, Pyruv-, Phenylacetic-, Benzoe-, p-Aminobenzoe-, Anthranil-, p-Hydroxybenzoe-, Salicyl-, Acetylsalicyl-, p-Aminahacyl-, Embon- Methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, ethylene sulfonic, halobenzenesulfonic, toluenesulfonic, naphthyl
  • salts of the new compounds can serve as agents for the purification of the free acids or bases obtained.
  • Salts of the acids or bases can be formed and separated from solutions, and then the free acid or base can be obtained from a new salt solution in a purer state. Because of the relationship between the new compounds in their free form and their salts, the salts are within the Scope of the invention.
  • the new compounds can be present as optical isomers or racemates, or if they contain at least two asymmetric centers, they can be present as an isomer mixture (racemate mixture).
  • the isomer mixtures (racemate mixtures) obtained can be obtained using the
  • Racemates obtained can be prepared according to known methods Methods are separated, such as by conversion from an optically active solvent, by using microorganisms, by reaction with optically active agents to form compounds which can be separated, by separation on the basis of the different solubilities of the diastereoisomers.
  • Suitable optically active agents are the L and D forms of wine, di-o-tolylwem, apple, almond, glucon,
  • the compounds according to the invention can be used themselves or as part of a galenical preparation, as a single active ingredient, in combination with one another or with known cardiovascular therapies, for example ACE inhibitors, antiatherosclerotics, antihypertensives, beta-blockers, cholesterol-lowering agents, diuretics, calcium channel blockers, coronary dilatators, lipid peptides, lipid peptides Vasodilators, platelet aggregation inhibitors or other substances, also used as cardiovascular therapeutics, combined, can be used for their clinical use.
  • cardiovascular therapies for example ACE inhibitors, antiatherosclerotics, antihypertensives, beta-blockers, cholesterol-lowering agents, diuretics, calcium channel blockers, coronary dilatators, lipid peptides, lipid peptides Vasodilators, platelet aggregation inhibitors or other substances, also used as cardiovascular therapeutics, combined, can be used for their clinical use.
  • the preparation of galenical preparations is carried out according to
  • the pharmaceutical form in question should be designed in such a way that it can be achieved therapeutic plasma level contains the respective active ingredient in an amount which makes it possible to distribute the daily dose to 1 to 2 in the case of release-controlled systems and to up to 10 individual doses in the case of other dosage forms. Continuous administration by means of long-term infusion is also suitable. In general, endothelial protection effects are achieved Long-term therapeutic blood levels should be aimed for.
  • the named compounds can be administered primarily orally, intravenously, parenterally, sublingually or transdermally.
  • the respective pharmaceutical preparation is preferably in liquid form er or solid form provided. Suitable for this are solutions, in particular for the preparation of drops, injections, aerosol sprays or powder inhalers, furthermore suspensions, emulsions, syrups, tablets, film-coated tablets, dragees, capsules, pellets, powders, lozenges, implants, supplements, creams, Gels, ointments, plasters or other transdermal systems
  • the pharmaceutical preparations contain customary galenically usable, organic or inorganic carriers and auxiliaries, which should themselves be chemically indifferent to the respective active ingredients.
  • Chemical de ⁇ vatation when applied to carrier materials is also included, this concerns in particular the formation of adducts with sugar derivatives such as croscarmeloses or cyclodextins
  • Suitable pharmaceutical auxiliaries are water. Salt solutions, alcohols, vegetable oils, polyethylene glycols, gelatin, lactose, amvloses, magnesium stearate, talc, highly disperse silicon dioxide, paraffin, fatty acid mono- and diglyce ⁇ de, cellulose derivatives, polyvinyl pyrrone and the like.
  • the preparation can be sterilized and if necessary with auxiliary substances such as fillers, binders, lubricants, mold release agents, lubricants, disintegrants, moisturizers, adsorbents or counter-explosives, preservatives, stabilizers, emulsifiers, solubilizers, salts for influencing the osmotic pressure, buffer solutions, coloring, fragrance Aroma or sweeteners may be added
  • auxiliary substances such as fillers, binders, lubricants, mold release agents, lubricants, disintegrants, moisturizers, adsorbents or counter-explosives, preservatives, stabilizers, emulsifiers, solubilizers, salts for influencing the osmotic pressure, buffer solutions, coloring, fragrance Aroma or sweeteners may be added
  • auxiliary substances such as fillers, binders, lubricants, mold release agents, lubricants, disintegrants, moisturizers, adsorbents or counter-explosives
  • the compounds according to the invention surprisingly have the desired properties.
  • they are distinguished in part by an optimized NO liberation, for example by their differentiated content of reductively or oxidatively biotransforming NO precursor groups or by an improved or increased multiphase NO Liberation and, depending on the intended use, increased lipophilicity or hydrophilicity, good bioavailability, increased cGMP accumulation, as well as reduced pharmacodynamic preload, reduced increase in endothein in plasma, pronounced inhibition of platelet aggregation by platelet-active groups and endothelium-protective effect
  • the presented invention thus opens up improved and considerably expanded therapeutic options, pathological situations such as heart and vascular diseases, in particular coronary heart disease, vascular stenoses and circulatory disorders of the peripheral arteries, hypertension, micro- and macroangiopathies in the context of diabetes mellitus, atherosclerosis, oxidative stress states in vessels and tissues and the resulting complications, erectile dysfunction, increased intraocular pressure, dysmenorrhea, dysfunctional uterine bleeding, dysfunction of uterine contractility such as premature labor pains, symptoms of cacti or incontinence
  • Example 1 Pentaeryth ⁇ tylt ⁇ nitrat 158 g (0.5 mol) of Pentaerythrityltetranitrat (PETN) are dissolved in a mixture of 300 ml of dioxane and 300 ml of ethanol with boiling and for 1 hour in portions with different amounts of aqueous hydrazine hydrate solution (1, 5-4 mol) The reaction mixture is then heated to boiling under reflux for a further 2.5 hours. The solvents are evaporated off at 15 mm Hg and the residue is shaken out several times with 100 ml portions of water, as required, until the volume of the oil layer no longer decreases when shaken out The water extracts (A) are collected and the remaining oily layer is dissolved in twice the volume of ethanol.
  • PETN Pentaeryth ⁇ tylt ⁇ nitrat
  • the filtrate is evaporated at 15 mm Hg ethanol.
  • the viscous, oily residue consists of the crude pentaerythritol itrat (PET ⁇ N), corresponds to nitrogen content
  • Pentaeryth ⁇ tyldinitrat and Pentaeryth ⁇ tylmononitrat The combined aqueous extracts A according to Example 1 are shaken three times with ether and evaporated from the ether layer separated from the aqueous layer B after drying over anhydrous Na 2 SO 4.
  • the very viscous, oily evaporation pressure consists of crude pentaerythritol (NED) dinitrate aqueous portion B, which in addition to the pentaerytonic mononitrate (PEMN) and pentaerythric denitization products, mainly hydrazine nitinate, is successively acidified with 2N H 2 SÜ until gas evolution ceases (N 2 , N 2 O, NO, N 3 H), then at 20 mm Hg until the onset of separation of solid products, concentrated and etherified.
  • the crystalline substance remaining after evaporation of the ether from F p 62 ° C is crude PEMN. Then it is washed with cold chloroform and converted from chloroform.
  • F p 79 ° C (HCC1 3 )
  • PETriN is represented by nitration of pentaerythritol with HN0 3 (95%) in the presence of urea
  • PEDN and PEMN are prepared from PETriN by hydrazinolysis (4 mol NH 2 NH 2 (50%)) followed by separation of the 1 1 mixture by column chromatography
  • a clay cell is hung in a beaker as a diaphragm.
  • 25% H 2 SO 4 serves as the catholyte
  • the cathode consists of lead, a lead plate as the anode is immersed in the anolyte solution consisting of
  • Tri-PS 1.0 g (0.0032 mol) of Tri-PS are dissolved in 30 ml of water. The solution is aqueous with 1%
  • Tri-PSCl oily 3-nitryloxy-2,2-bis (nitryloxymethyl) propionic acid chloride
  • Carboxy-2-nitryloxymethylmalonic acid (CN-MS) is obtained analogously to embodiment 10.
  • bis-MSDCl 2,2-bis (n ⁇ tryloxymethyl) malonic acid dichloride
  • thionyl chloride double the amount of thionyl chloride and 2-chlorocarbonyl-2-nitryloxymethylmalonic acid dichloride
  • Tri-PS 1 g (3.5 mmol) of Tri-PS is mixed with 10.5 mmol of ethanol, 20 mg of toluenesulfonic acid and 30 ml of chloroform and heated under reflux for 12 hours on a water separator
  • Chloroform phase is washed with aqueous bicarbonate solution and with water that
  • 3-Nitryloxy-2,2-bis (nitryloxymethyl) propionic acid ethyl ester (tri-PS ethyl ester) is obtained as a colorless 01 yield of 85% elemental analysis (C corresponds to H corresponds to N corresponds to)
  • T ⁇ -PSCl 1 g (3.4 mmol) of T ⁇ -PSCl is dissolved in 25 ml of dioxane and concentrated with excess Ammonia solution added. After 30 minutes, pour into 100 ml of ice water and weakly acidify with dilute hydrochloric acid. The oily, deposited 2,2-bis (nitryloxymethyl) -3-nitryloxypropaneureamide (Tri-PS amide) is purified by column chromatography. Yield 65% elemental analysis - (C corresponds to H corresponds to N corresponds to)
  • Tri-PS Tri-PS 7 mmol are mixed with 1 ml of thionyl chloride and 1 drop of dry DMF and stirred for 20 minutes at room temperature with exclusion of moisture. Then 3 ml of cold concentrated NH 3 solution are added to the reaction mixture and the solution is left on
  • Embodiments 23 and 26 represented by doubling or tripling the reagents a) Bis-MS-diamid
  • reaction mixture is gasified for a further 120 min at -5 ° C. and then poured into ice water.
  • the precipitated product is filtered off, washed with water or 5% sodium hydrogen carbonate solution and then recrystallized from ethanol. Yield 91%
  • Tri-BS Tri-BS are mixed with a 5-fold excess of thionyl chloride and at
  • Example 38 Methyl 2,2,2-tris (nitryloxymethyl) ethyl ether 0.025 mol sodium and 0.12 mol abs. Methanol is used to prepare the methanolate solution. 0.02 mol of 3-nitryloxy-2,2-bis (nitryloxymethyl) propyl bromide is added and the mixture is heated under reflux for 5 hours with exclusion of moisture and stirring. The reaction mixture is cooled to 5 times the amount Water was added, the ether (Me-PETriN ether) was separated off, washed again with water, dried and purified by column chromatography. Yield 75%
  • Methyl 2,2,2-tris (nitryloxymethyl) ethyl ether 0.02 mol PETriN are dissolved in methanol / water (10 l) with the addition of catalytic amounts of boron trifluoride and mixed with as much ethereal diazomethane solution at room temperature with stirring until a weak yellow color persists or until no more N 2 development
  • the solvent is distilled off and the residue is taken up with diethyl ether. Then the mixture is washed with dilute sodium hydroxide solution and water, dried and, after the solvent has been distilled off, the crude product (Me-PETriN ether) is purified by column chromatography. Yield 49% elemental analysis (C corresponds to H corresponds to N corresponds to N) )
  • Example 41 Bis- [2,2,2-tris (nitryloxymethyl)] ethyl ether
  • a typical tablet has the following composition:
  • Active ingredient x mg a) PETriNAc 20 mg b) PETriNAc 80 mg cc)) P PEETTrriiNNAAcc 160 mg d) PEDNdAc 20 mg e) PETriN 7 3 H 2 O 20 mg
  • a pump spray contains: a) Tri-PS 0.05% by weight / ci in water b) Tri-PS 0.3% by weight in water c) Tri-PS 5% by weight in water d) Tri -PS 10% by weight in water e) Tri-PS sodium salt 0.3% by weight in water f) Tri-PS sodium salt 5% by weight in water g) Tri-PS potassium salt 0.3% by weight in water h) Tri-PS potassium salt 5% by weight in water i) Tri-BS sodium salt 0.3% by weight in water j) Tri-BS sodium salt 5% by weight in water k) Tri-BS potassium salt 0.3% by weight in water
  • the detonation properties of the compounds are determined by the known methods for determining the expansion performance, the detonation speed, the impact pressure and the initiation (Ulimanns Encyklopadie der technical chemistry, Vol 16, 3 Auf!, Urban & Schwarzenberg, Kunststoff-Berlin, 1965)

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EP97945736A 1996-10-10 1997-10-10 Neue derivate des pentaerythrits, deren herstellung und verwendung sowie intermediate zur synthese derselben Withdrawn EP1009730A1 (de)

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DE19641667 1996-10-10
DE19641667A DE19641667A1 (de) 1996-10-10 1996-10-10 Neue Ester der Salpetersäure sowie deren Herstellung und Verwendung
DE1996152345 DE19652345A1 (de) 1996-12-17 1996-12-17 Neue Salpetersäureester, deren Herstellung und Verwendung
DE19652345 1996-12-17
DE19726812A DE19726812A1 (de) 1997-06-25 1997-06-25 Neue Derivate des Pentaerythrits, deren Herstellung und Verwendung sowie Intermediate zur Synthese derselben
DE19726812 1997-06-25
PCT/DE1997/002328 WO1998015521A1 (de) 1996-10-10 1997-10-10 Neue derivate des pentaerythrits, deren herstellung und verwendung sowie intermediate zur synthese derselben

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IL133410A0 (en) 1997-06-11 2001-04-30 Isis Pharma Gmbh Novel pentaerythrite derivatives, the production and use thereof and intermediate products for the synthesis of the same
EP1087926A2 (de) * 1998-06-24 2001-04-04 Alpharma-Isis GmbH & Co. KG Analytische substrate und antioxidative mittel
DE19950483A1 (de) * 1999-10-19 2001-05-10 Isis Pharma Gmbh Verfahren zur Herstellung von 3-Nitryloxy-2,2-bis(nitryloxymethyl)-propanal
US20050203142A1 (en) * 2002-10-24 2005-09-15 Zeldis Jerome B. Methods of using and compositions comprising immunomodulatory compounds for treatment, modification and management of pain
US20040087558A1 (en) * 2002-10-24 2004-05-06 Zeldis Jerome B. Methods of using and compositions comprising selective cytokine inhibitory drugs for treatment, modification and management of pain
WO2005020984A2 (en) * 2003-08-29 2005-03-10 Aaipharma Inc. Method of reducing the risk of oxidative stress
CN103848704A (zh) * 2012-11-30 2014-06-11 陕西省汉阴华能新材料研究有限公司 回收油的应用

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US1883045A (en) * 1931-11-20 1932-10-18 Du Pont Explosive composition
GB442850A (en) * 1934-05-14 1936-02-17 Bombrini Parodi Delfino Improvements in and relating to the production of explosives
US2389228A (en) * 1943-04-14 1945-11-20 Trojan Powder Co Preparation of tripentaerythritol octanitrate
NL110701C (ru) * 1960-03-14
US3419571A (en) * 1966-04-06 1968-12-31 Warner Lambert Pharmaceutical Method for relieving coronary insufficiency
US4394329A (en) * 1979-06-26 1983-07-19 Thiokol Corporation 2-Hydroxymethyl-1,3-propanediol nitrate ester
CS221031B1 (en) * 1981-12-28 1983-04-29 Svatopluk ZEMAN Method of making the nitrates,derivatives of the trimethylmethane

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CA2267129A1 (en) 1998-04-16
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PL332594A1 (en) 1999-09-27
NZ335057A (en) 2000-09-29
CN1239944A (zh) 1999-12-29
WO1998015521A1 (de) 1998-04-16
IL129339A0 (en) 2000-02-17
TR199900791T2 (xx) 1999-07-21
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CZ9901223A3 (cs) 2002-10-16
EA199900363A1 (ru) 1999-12-29
BG103303A (bg) 2000-01-31

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