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US20060035903A1 - Storage stable perfusion solution for dihydropteridinones - Google Patents

Storage stable perfusion solution for dihydropteridinones Download PDF

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Publication number
US20060035903A1
US20060035903A1 US11/197,927 US19792705A US2006035903A1 US 20060035903 A1 US20060035903 A1 US 20060035903A1 US 19792705 A US19792705 A US 19792705A US 2006035903 A1 US2006035903 A1 US 2006035903A1
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Prior art keywords
acid
compound
alkyl
active substance
infusible
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US11/197,927
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Inventor
Detlef Mohr
Claus Veit
Fridtjof Traulsen
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Boehringer Ingelheim International GmbH
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Boehringer Ingelheim International GmbH
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Assigned to BOEHRINGER INGELHEIM INTERNATIONAL GMBH reassignment BOEHRINGER INGELHEIM INTERNATIONAL GMBH ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: TRAULSEN, FRIDTJOF, VEIT, CLAUS, MOHR, DETLEF
Assigned to BOEHRINGER INGELHEIM INTERNATIONAL GMBH reassignment BOEHRINGER INGELHEIM INTERNATIONAL GMBH ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: TRAULSEN, FRIDTJOF, VEIT, CLAUS, MOHR, DETLEF
Publication of US20060035903A1 publication Critical patent/US20060035903A1/en
Priority to US12/366,730 priority Critical patent/US8445675B2/en
Priority to US13/868,591 priority patent/US20130245013A1/en
Abandoned legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
    • A61J1/05—Containers specially adapted for medical or pharmaceutical purposes for collecting, storing or administering blood, plasma or medical fluids ; Infusion or perfusion containers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
    • A61J1/05—Containers specially adapted for medical or pharmaceutical purposes for collecting, storing or administering blood, plasma or medical fluids ; Infusion or perfusion containers
    • A61J1/10—Bag-type containers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to storage stable aqueous infusible or injectable solutions containing an active substance of formula (I) wherein the groups L, R 1 , R 2 , R 3 , R 4 and R 5 have the meanings given in the claims and in the specification, and an amount of a physiologically acceptable acid or mixture of acids sufficient to dissolve the active substance and act as a stabiliser, optionally together with other formulating excipients suitable for parenteral administration, and a process for preparing the infusible or injectable solutions according to the invention.
  • an active substance of formula (I) wherein the groups L, R 1 , R 2 , R 3 , R 4 and R 5 have the meanings given in the claims and in the specification, and an amount of a physiologically acceptable acid or mixture of acids sufficient to dissolve the active substance and act as a stabiliser, optionally together with other formulating excipients suitable for parenteral administration, and a process for preparing the infusible or injectable solutions according to the invention.
  • the dihydropteridinones of formula (I) according to the invention are an innovative new cytostatic active substance in the oncological treatment of fast-growing types of cancer.
  • cytostatic medications are administered as parenteral preparations, even though their oral bioavailability may be perfectly adequate.
  • treatment with cytostatics is generally accompanied by a range of gastrointestinal side-effects which is frequently characterised by nausea, vomiting and/or diarrhoea, and consequently effective treatment by oral route would be jeopardised thereby.
  • EP 0219784 and WO 01/78732 describe methods of preparing and stabilising solutions for infusion containing ciprofloxacin by using one or more physiologically acceptable acid(s) of organic or inorganic origin.
  • EP A 0287926 relates that the risk of particle formation can be greatly reduced by the use of highly pure grades of ciprofloxacin.
  • EP 0143478 A1 describes the preparation of a stable hydrochloric acid solution of cisplatin, suitable for injection, which is particularly free from other additives.
  • DE 197 03023 discloses that the stability of infusible solutions with regard to the formation of particulate impurities can be vastly improved by the use of glass containers with siliconised surfaces.
  • the aim of the present invention is to provide a stable infusible or injectable solution of dihydropteridinones of formula (I) for the desired dosage range tailored to treatment.
  • the stable infusible or injectable solution should be suitable both as a ready-to-use solution and as a concentrate for further dilution with solutions commonly used for parenteral administration such as for example isotonic NaCl solution, isotonic dextrose solution or Ringer lactate solution, to allow flexible adaptation of the dosage.
  • the present invention therefore relates to storage stable aqueous infusible or injectable solutions containing the active substance of general formula (I) wherein
  • Preferred storage stable solutions are those containing compounds of formula (I), wherein
  • the invention also relates to a storage stable solution containing a dihydropteridinone of general formula (I) as hereinbefore described, the dihydropteridinone being selected from among the following dihydropteridinones of general formula (I) Config. Ex.
  • Long-term stability is defined as a shelf-life of at least 12 months at 25° C./60% r.h. and 30° C./70% r.h., preferably at least 36 months at 25°/60% r.h. and 30° C./70% r.h.
  • the infusible or injectable solutions according to the invention apart from the addition of a physiologically acceptable acid or mixture of acids, may be free from solubilising additives or organic cosolvents, particularly organic cosolvents.
  • Preferred aqueous infusible or injectable solutions are those wherein the content of dissolved active substance of formula (I) is 0.1 mg to 10.0 mg, particularly preferably 0.5 to 5 mg, in 1 ml of infusible or injectable solution.
  • aqueous infusible or injectable solutions wherein one or more acids used as storage and dilution stabilisers are selected from among hydrochloric acid, acetic acid, hydroxyacetic acid, methanesulphonic acid, ethanesulphonic acid, phosphoric acid, nitric acid, sulphuric acid, citric acid, tartaric acid, fumaric acid, succinic acid, glutaric acid, adipic acid, propionic acid, ascorbic acid, maleic acid, malic acid, glutamic acid, gluconic acid, glucuronic acid, galacturonic acid and lactic acid, preferably acetic acid, hydrochloric acid, phosphoric acid, tartaric acid, citric acid and fumaric acid, particularly preferably hydrochloric acid, citric acid and acetic acid.
  • one or more acids used as storage and dilution stabilisers are selected from among hydrochloric acid, acetic acid, hydroxyacetic acid, methanesulphonic
  • aqueous infusible or injectable solutions are preferred wherein the molar ratio of the physiologically acceptable acid or mixture of acids to the active substance is at most 3:1, preferably 1.25:1 to 3:1, particularly preferably 1.5:1 to 3:1, in order to ensure that the pH is above 2.4.
  • the invention also relates to infusible or injectable solutions which contain 0.1 mg to 10.0 mg active substance per millilitre of aqueous solution and up to 3.0 mol of hydrochloric acid, based on one mol of active substance.
  • the amounts of hydrochloric acid are preferably 1.25 mol to 3.0 mol, particularly 1.5 to 2.4 mol.
  • the invention also relates to infusible or injectable solutions of 4-[[(7R)-8-cyclopentyl-7-ethyl-5,6,7,8-tetrahydro-5-methyl-6-oxo-2-pteridinyl]amino]-3-methoxy-N-(1-methyl-4-piperidinyl)-benzamide which contain 1.6 to 2.0 mol hydrochloric acid per mol of active substance.
  • the infusible or injectable solutions according to the invention may also be modified so as to contain up to 10 mg/ml of the active substance, and up to 1 mol hydrochloric acid per mol of active substance, as well as one or more other physiologically acceptable acid(s), with the proviso that the total amount of acid is at least 1.25 mol per mol of active substance, but does not exceed 3.0 mol per mol active substance.
  • the minimum amount of acid needed per mol of active substance depends on the active substance concentration, and the acid(s) used, and is thus not constant. However, it may be determined within the limits according to the invention by simple tests as described for example in EP 0219784 and WO 01/78732.
  • aqueous infusible or injectable solutions which contain one or more other formulation aids selected from among complexing agents, crystallisation inhibitors, thickeners, isotonic agents, preservatives, light protecting agents and antioxidants.
  • Suitable complexing agents are e.g. genuine and substituted cyclodextrins, EDTA, albumins, as well as citric acid and the salts and derivatives thereof.
  • Suitable crystallisation inhibitors are e.g. PVP, cellulose derivatives, alginates, poloxamers and polysorbates.
  • Suitable thickeners are for example dextrans, glycerol and soluble cellulose derivatives, particularly carboxymethylcellulose and the salts thereof, as well as hydroxyalkyl celluloses.
  • Suitable isotonic agents are for example NaCl, mannitol, sorbitol, xylitol, saccharose, lactose, glucose and glycerol, preferably NaCl, mannitol, glucose, saccharose and glycerol, particularly preferably NaCl, mannitol and glucose.
  • Suitable preservatives are for example the esters of p-hydroxybenzoic acid, benzylalcohol, sorbic acid and benzoic acid.
  • Suitable light protecting agents are for example derivatives of p-hydroxybenzoic acid as well as cinnamic acid and the derivatives thereof.
  • a suitable antioxidant is for example ascorbic acid and the salts thereof.
  • aqueous infusible or injectable solutions wherein the osmolality of the infusible or injectable solutions is 200-600 mOsmol/kg, preferably 260-350 mOsmol/kg. They may be prepared using isotonic agents such as NaCl, mannitol, sorbitol, glucose, saccharose, xylitol, fructose and glycerol or mixtures of the above-mentioned substances.
  • infusible or injectable solutions which contain, in addition to the active substance, water, acid(s) and other formulation aids, an amount of NaCl or other isotonic agent such that a solution is obtained which is isotonic with the tissue fluid of the human or animal body or slightly hypotonic or hypertonic solution.
  • aqueous infusible or injectable solutions which have a pH in the range from 2.4 to 5.3, preferably from 3.5 to 5.0, particularly preferably from 3.9 to 4.5.
  • the infusible or injectable solutions according to the invention are also suitable for dilution with standard commercial infusion or injection carrier solutions for supplying electrolyte without carbohydrates, such as isotonic NaCl solution, isotonic glucose solution, Ringer lactate solution and the like (Red List 2004, Verzeichnis des für für für Industrie e.V., [Directory of Drug Products of the Members of the Federal Association of the Pharmaceutical Industry], Editio Cantor, Aulendorf/Württ., main groups 52.1 and 52.2.1) to give the desired concentration or dose without having any physical or chemical incompatibilities.
  • standard commercial infusion or injection carrier solutions for supplying electrolyte without carbohydrates, such as isotonic NaCl solution, isotonic glucose solution, Ringer lactate solution and the like (Red List 2004, Verzeichnis des Bundesviouses der Pharmazeutician Industrie e.V., [Directory of Drug Products of the Members of the Federal Association of the Pharmaceutical Industry], Editio Cantor, Aul
  • aqueous infusible or injectable solutions which contain 1.25 to 3.0 mol, preferably 1.5 to 2.4 mol, of hydrochloric acid per mol of active substance, based on 100 ml of infusible or injectable solution, 0.75 to 1.2 g NaCl, preferably 0.85 to 0.95 g NaCl, and have an osmolality of 260 to 350 mOsmol/kg and a pH of 3.5 to 5.0.
  • the invention further relates to lyophilisates, concentrates and suspensions which by the addition of water yield one of the aqueous infusible or injectable solutions according to the invention.
  • the invention also relates to the infusible or injectable solutions according to the invention for use as pharmaceutical compositions with an antiproliferative activity.
  • the invention further relates to the use of the infusible or injectable solutions according to the invention for preparing a pharmaceutical composition for the treatment of tumoral diseases, infections, inflammatory and autoimmune diseases.
  • the invention further relates to a method for the treatment and/or prevention of tumoral diseases, infections, inflammatory and autoimmune diseases, preferably tumoral diseases, in which an effective amount of an infusible or injectable solution according to the invention is administered to a patient.
  • the invention further relates to the use of the infusible or injectable solutions according to the invention, which corresponds to a dosage range of from 0.1 to 50 mg active substance/kg body weight, preferably 0.5 to 25 mg active substance/kg body weight.
  • the infusible or injectable solutions according to the invention may be stored in suitable glass containers for parenteral preparations or in flexible plastic containers, preferably non-PVC materials based e.g. on polyolefin, with removable volumes of 20 to 1000 ml, preferably 50 to 500 ml.
  • the containers may be designed so as to provide particular protection for the infusible or injectable solutions according to the invention, e.g. to protect them from light or oxygen.
  • Special surface treatment of the primary packaging e.g. (stoved) siliconisation of the surfaces of glass containers
  • Flexible plastic containers may contain additional protection, e.g. in the form of aluminium packaging.
  • the infusible or injectable solutions according to the invention are suitable for terminal sterilisation, e.g. with pressurised steam, and can thus be made sterile and free from pyrogens in a particularly economical manner and with high product safety (low risk of contamination).
  • the infusible or injectable solution according to the invention may be prepared by methods of producing aqueous liquid formulations known from the literature.
  • the present invention relates to a process for preparing the infusible or injectable solutions according to the invention, containing 0.1 to 10 mg per millilitre of the active substance of formula (I).
  • the process is characterised in that a suitable amount of active substance, optionally in the form of a salt, is combined with an anionic counter-ion, a hydrate or hydrates of a salt, or mixtures of these salts/hydrates with the quantity of a physiologically acceptable acid or mixture of acids which constitutes an excess in relation to the precise [amount needed] to dissolve the active substance or the salts or hydrates thereof and to prevent physical instabilities, other formulating excipients are optionally added, and the preparation is made up with water (for injections) such that a range of concentrations of from 0.1 to 10 mg of active substance per millilitre of infusible or injectable solution is obtained.
  • the active substance or the salt or hydrate thereof is optionally suspended in water, and up to 3.0 mol of physiologically acceptable acid or mixture of acids, preferably hydrochloric acid, are added per mol of active substance.
  • the other formulating excipients are added, particularly isotonic agents, preferably NaCl, which may optionally also be produced by a neutralising reaction in the formulation mixture, before it is adjusted to the desired active substance concentration with water.
  • isotonic agents preferably NaCl
  • the pH of the infusible or injectable solutions according to the invention can be adjusted to the pH values specified above with (physiologically) acceptable acids and/or bases, particularly NaOH.
  • the solutions may be heated slightly as a whole or in parts, preferably to temperatures between 20° C. and 80° C.
  • the solutions according to the invention may be prepared particularly economically using concentrated solutions.
  • the amount of active substance required for a preparation is combined with the majority (>90%) of the physiologically acceptable acid or mixture of acids and dissolved, optionally with gentle heating and/or the addition of a small amount of water.
  • This concentrate is then diluted with water before the other formulating excipients are added, and lastly made up to the nominal weight with the remainder of the acid(s) or water.
  • solutions according to the invention have good stability on storage which is not limited either by the number of particles in the visible and subvisual range, or by significant active substance breakdown reactions.
  • solutions according to the invention have sufficient local compatibility with respect to the pharmacodynamic properties of the active substance, and are not haemolytic.
  • FIG. 1 shows the dependency of the pH of the ready-to-use solution on the molar ratio of acid/mixture of acids to active substance.
  • the active substance here is 4-[[(7R)-8-cyclopentyl-7-ethyl-5,6,7,8-tetrahydro-5-methyl-6-oxo-2-pteridinyl]amino]-3-methoxy-N-(1-methyl-4-piperidinyl)-benzamide (Example 46 from Table 1).
  • the maximum molar ratio of acid(s) to active substance in the infusible or injectable solution according to the invention is restricted to a maximum of 3:1, in order to ensure a pH above 2.4.
  • WFI Water For Injections
  • the active substance is one of the dihydropteridinones of general formula (I) as hereinbefore described.
  • active substance 1-10 mg/ml organic or inorganic 1.0-3.0 mol acid, or acid mixture (calculated on the basis of the active substance) isotonic agent e.g. 9 mg/ml or (e.g. NaCl/mannitol) 50 mg/ml WFI ad final volume, e.g. 1.0 ml pH 3.0-4.5
  • isotonic agent e.g. 9 mg/ml or (e.g. NaCl/mannitol) 50 mg/ml WFI ad final volume, e.g. 1.0 ml pH 3.0-4.5
  • the active substance is 4-[[(7R)-8-cyclopentyl-7-ethyl-5,6,7,8-tetrahydro-5-methyl-6-oxo-2-pteridinyl]amino]-3-methoxy-N-(1-methyl-4-piperidinyl)-benzamide (Example 46 from Table 1).
  • active substance 500 mg hydrochloric acid 1N 1.6 ml NaCl 450.0 mg WFI ad 50 ml pH 4.0 mOsmol/kg 290
  • active substance 100 mg acetic acid 16.4 ⁇ l dextrose 2.5 g WFI ad 50 ml pH 4.4 mOsmol/kg 305
  • the active substance is N-[trans-4-[4-(cyclopropylmethyl)-1-piperazinyl]cyclohexyl]-4-[[(7R)-7-ethyl-5,6,7,8-tetrahydro-5-methyl-8-(1-methylethyl)-6-oxo-2-pteridinyl]amino]-3-methoxy-benzamide (Example 110 from Table 1).
  • the compounds according to the invention may be prepared by the methods of synthesis A described hereinafter, whereby the substituents of general formulae (A1) to (A9) have the above meanings. This method is to be understood as an illustration of the invention without limiting it to the content thereof.
  • a compound of formula (A1) is reacted with a compound of formula (A2) to yield a compound of formula (A3) (Diagram 1A).
  • This reaction may be carried out according to WO 00/43369 or WO 00/43372.
  • Compound (A1) is commercially available, for example from City Chemical LLC, 139 Allings Crossing Road, West Haven, Conn., 06516, USA.
  • Compound (A2) may be prepared by methods known from the literature, e.g. from (a) F. Effenberger, U. Burkhart, J. Willfahrt Liebigs Ann. Chem. 1986, 314-333, (b) T. Fukuyama, C.-K. Jow, M. Cheung, Tetrahedron Lett.
  • Step 1A 1 equivalent of the compound (A1) and 1 to 1.5 equivalents, preferably 1.1 equivalents of a base, preferably potassium carbonate, potassium hydrogen carbonate, sodium carbonate, sodium hydrogen carbonate or calcium carbonate, particularly preferably potassium carbonate, are stirred in a diluent, optionally mixed with water, for example acetone, tetrahydrofuran, diethyl ether, cyclohexane, petroleum ether or dioxane, preferably cyclohexane or diethyl ether.
  • a base preferably potassium carbonate, potassium hydrogen carbonate, sodium carbonate, sodium hydrogen carbonate or calcium carbonate, particularly preferably potassium carbonate
  • a diluent optionally mixed with water, for example acetone, tetrahydrofuran, diethyl ether, cyclohexane, petroleum ether or dioxane, preferably cyclohexane or diethyl ether.
  • an amino acid of formula (A2) dissolved in an organic solvent, for example acetone, tetrahydrofuran, diethyl ether, cyclohexane or dioxane, is added dropwise.
  • the reaction mixture is heated to a temperature of 18° C. to 30° C., preferably about 22° C., with stirring and then stirred for a further 10 to 24 hours, preferably about 12 hours.
  • Step 2A 1 equivalent of the nitro compound (A3) is dissolved in an acid, preferably glacial acetic acid, formic acid or aqueous hydrochloric acid, preferably glacial acetic acid, and heated to 50 to 70° C., preferably about 60° C. Then a reducing agent, for example zinc, tin or iron, preferably iron powder, is added until the exothermic reaction has ended and the mixture is stirred for 0.2 to 2 hours, preferably 0.5 hours, at 100 to 125° C., preferably at about 117° C. After cooling to ambient temperature the iron salt is filtered off and the solvent is distilled off.
  • an acid preferably glacial acetic acid, formic acid or aqueous hydrochloric acid, preferably glacial acetic acid
  • a reducing agent for example zinc, tin or iron, preferably iron powder
  • the residue is taken up in a solvent or mixture of solvents, for example ethyl acetate or dichloromethane/methanol 9/1 and semisaturated NaCl solution and filtered through kieselguhr for example.
  • the organic phase is dried and evaporated down.
  • the residue (compound (A4)) may be purified by chromatography or by crystallisation or used as the crude product in Step 3A of the synthesis.
  • the compound (A4) obtained in Step 2A may be reacted by electrophilic substitution according to Diagram 3A to form the compound of formula (A5).
  • Step 3A 1 equivalent of the amide of formula (A4) is dissolved in an organic solvent, for example dimethylformamide or dimethylacetamide, preferably dimethylacetamide, and cooled to about ⁇ 5 to 5° C., preferably 0° C.
  • organic solvent for example dimethylformamide or dimethylacetamide, preferably dimethylacetamide
  • 0.9 to 1.3 equivalents of sodium hydride and 0.9 to 1.3 equivalents of a methylating reagent, for example methyliodide are added.
  • the reaction mixture is stirred for 0.1-3 hours, preferably about 1 hour, at about 0 to 10° C., preferably at about 5° C., and may optionally be left to stand for a further 12 hours at this temperature range.
  • the reaction mixture is poured onto ice water and the precipitate is isolated.
  • the residue (compound (A5)) may be purified by chromatography, preferably on silica gel, or by crystallisation or used as the crude product in Step 4A of the synthesis.
  • the amination of the compound (A5) obtained in Step 3A to form the compound of formula (A9) may be carried out according to the methods of variants 4.1 A known from the literature from e.g. (a) M. P. V. Boarland, J. F. W. McOmie J. Chem. Soc. 1951, 1218-1221 or (b) F. H. S. Curd, F. C. Rose J. Chem. Soc. 1946, 343-348, and 4.2 A from e.g. (a) Banks J. Am. Chem. Soc. 1944, 66, 1131, (b) Ghosh and Dolly J. Indian Chem. Soc. 1981, 58, 512-513 or (c) N. P. Reddy and M. Tanaka Tetrahedron Lett. 1997, 38, 4807-4810.
  • 1 equivalent of the compound (A5) and 1 to 3 equivalents, preferably about 2 equivalents of the compound (A6) may be heated without a solvent or with an organic solvent such as for example sulpholane, dimethylformamide, dimethylacetamide, toluene, N-methylpyrrolidone, dimethylsulphoxide, or dioxane, preferably sulpholane over 0.1 to 4 hours, preferably 1 hour, at 100 to 220° C., preferably at about 160° C.
  • the product (A9) is crystallised by the addition of org. solvents or mixtures of solvents, e.g. diethyl ether/methanol, ethyl acetate, methylene chloride, or diethyl ether, preferably diethyl ether/methanol 9/1, or purified by chromatography.
  • 1 equivalent of the compound (A5) and 1 to 3 equivalents of the compound (A6) are refluxed for 1 to 48 hours, preferably about 5 hours, with acid, for example 1-10 equivalents of 10-38% hydrochloric acid and/or an alcohol such as ethanol, propanol or butanol, preferably ethanol, with stirring.
  • acid for example 1-10 equivalents of 10-38% hydrochloric acid and/or an alcohol such as ethanol, propanol or butanol, preferably ethanol, with stirring.
  • the precipitated product (A9) is filtered off and optionally washed with water, dried and crystallised from a suitable org. solvent.
  • a solvent for example toluene or dioxane and combined with a phosphine ligand, for example 2,2′-bis-(diphenylphosphino)-1,1′-binaphthyl and a palladium catalyst, for example tris(dibenzylideneacetone)-dipalladium(0) and a base, for example caesium carbonate, and refluxed for 1-24 h, preferably 17 h.
  • a phosphine ligand for example 2,2′-bis-(diphenylphosphino)-1,1′-binaphthyl
  • a palladium catalyst for example tris(dibenzylideneacetone)-dipalladium(0)
  • a base for example caesium carbonate
  • the product (A8) is dissolved in a suitable solvent, for example dioxane, and mixed with acid, for example semiconcentrated hydrochloric acid, for example in a solvent to an acid ratio of 3:1. Then the mixture is refluxed for 1-48 h, for example 12 h, and the precipitate formed is isolated. If desired the product (A9) is purified by crystallisation. Step 5A
  • 1 equivalent of the compound (A9) is dissolved with 1 equivalent of an activating reagent, for example O-benzotriazolyl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) and a base, for example about 1.5 equivalents, diisopropylethylamine (DIPEA) in an organic diluent, for example dichloromethane, tetrahydrofuran, dimethylformamide, N-methylpyrrolidone, dimethylacetamide, preferably dichloromethane or dimethylformamide.
  • an activating reagent for example O-benzotriazolyl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) and a base, for example about 1.5 equivalents, diisopropylethylamine (DIPEA) in an organic diluent, for example dichloromethane, tetrahydrofuran, dimethylform
  • D-alaninemethylester ⁇ HCl 50.0 g (0.36 mol) D-alaninemethylester ⁇ HCl is suspended in 500 mL dichloromethane and 35 mL acetone and combined with 30.0 g (0.37 mol) sodium acetate and 80.0 g (0.38 mol) sodium triacetoxyborohydride. The mixture is stirred for 12 h and then poured onto 400 mL 10% sodium hydrogen carbonate solution. The organic phase is dried over Na 2 SO 4 and evaporated down.
  • trans-dibenzyl-4-morpholino-cyclohexylamine may be prepared as follows:
  • the cis-isomer may be prepared analogously.
  • the cis-isomer may be prepared analogously.
  • the cis-isomer may be prepared analogously.
  • the trans-isomer may be prepared analogously.
  • 0.2 g compound Z8, 0.2 g TBTU, 0.3 mL DIPEA are dissolved in 5 mL dichloromethane and the mixture is stirred for 1 h at 25° C. Then 0.13 g 4-amino-1-benzylpiperidine is added and the mixture is stirred for a further hour at 25° C. The solution is then diluted with 10 mL methylene chloride and extracted with 20 mL water. Then the product is purified on silica gel and crystallised by means of ethyl acetate and ether.
  • 0.1 g compound Z10, 0.09 g TBTU, 0.3 mL DIPEA are dissolved in 4 mL dichloromethane and stirred for 20 minutes at 25° C. Then 67 mg 1,1-dimethyl-N-methylpiperazin-1-yl-ethylamine is added and the mixture is stirred for a further 2 hours at 25° C. The solution is then diluted with dichloromethane and extracted with water. It is then chromatographed on silica gel and the residue is dissolved in acetone, combined with ethereal HCl and the precipitate formed is isolated.
  • 0.2 g of the compound Z4, 0.2 g TBTU, 0.1 mL DIPEA are dissolved in 10 mL dichloromethane and stirred for 30 minutes at 25° C. Then 0.1 g 1-methyl-4-aminopiperidine are added and the mixture is stirred for a further 17 hours at 25° C. The solution is then extracted with aqueous potassium carbonate solution and then evaporated down. The product is crystallised using ether.
  • the suitable fractions are evaporated down in vacuo, dissolved in 2 mL dichloromethane, combined with 2 mL trifluoroacetic acid and stirred for 2 h at RT, again combined with 100 ml water and 200 mg potassium carbonate and the precipitate is suction filtered and washed with water. Then the precipitate is purified through a silica gel column.
  • the desired fractions are evaporated down in vacuo and the residue is crystallised from ethanol and conc. hydrochloric acid.
  • Example 232 60 mg of the compound Example 232 is dissolved in 10 mL ethyl acetate and stirred with 1 mL acetic anhydride and 1 mL triethylamine for 30 min. at RT. The solvent is eliminated in vacuo, the residue is combined with water and ammonia, the precipitated crystals are suction filtered and washed with water and a little cold acetone.
  • the methanol is eliminated in vacuo, the precipitate is suction filtered, washed with water and dried.
  • the residue is taken up in 20 mL dichloromethane and stirred with 0.5 g thiomorpholine and 0.5 g NaBH(OAc) 3 for 12 h at RT. Then the mixture is combined with water and potassium carbonate, the org. phase is separated off, dried and the solvent is eliminated in vacuo.
  • the residue is purified on a silica gel column. The desired fractions are evaporated down in vacuo and the hydrochloride is precipitated with ethereal HCl.

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