WO2013051159A1 - Nop receptor antagonist - Google Patents
Nop receptor antagonist Download PDFInfo
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- WO2013051159A1 WO2013051159A1 PCT/JP2011/073464 JP2011073464W WO2013051159A1 WO 2013051159 A1 WO2013051159 A1 WO 2013051159A1 JP 2011073464 W JP2011073464 W JP 2011073464W WO 2013051159 A1 WO2013051159 A1 WO 2013051159A1
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- Prior art keywords
- amino
- methylquinazolin
- carboxamide
- cyclohexyl
- methanol
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- 0 C*(cc1)cc2c1nc(C(N(*)*)=O)nc2N[C@@](CCCC1)[C@@]1NC(*)=* Chemical compound C*(cc1)cc2c1nc(C(N(*)*)=O)nc2N[C@@](CCCC1)[C@@]1NC(*)=* 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/94—Nitrogen atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
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- 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
-
- 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
- A61P9/12—Antihypertensives
Definitions
- the present invention relates to a non-opioid branch of the opioid peptide family of receptors (hereinafter referred to as NOP receptor) antagonist.
- a narcotic analgesic such as morphine
- a non-narcotic analgesic such as aspirin or indomethacin
- a narco-antagonistic analgesic such as pentazocine
- a narcotic analgesic exerts its analgesic effect mainly by inhibiting a central algesic excitatory transmission.
- a non-narcotic analgesic exerts its analgesic effect mainly by inhibiting the production of a peripheral dolorogenic substance.
- a narco-antagonistic analgesic exerts its analgesic effect in a mechanism similar to that of a narcotic analgesic.
- Nociceptin is a neuropeptide related to various nervous activities including an in vivo algesia.
- Japanese Unexamined Patent Publication No. 10-212290 describes that a NOP receptor agonist and/or antagonist may be effective in treating a mental disorder, neuropathy and physiological disorder, and particularly effective in ameliorating anxiety and stress disorder, depression, traumatic disorder, amnesia due to Alzheimer's disease or other dementia, symptoms of epilepsy and spasm, acute and/or chronic pain, drug abuse withdrawal symptoms, water balance control, Na+ excretion, arterial blood pressure disorder, and eating disorder such as an obesity.
- quinazoline derivatives according to the present invention are known as antipruritic agents (International Publication WO2007/040231), it is not described that quinazoline derivatives have a NOP receptor antagonist effect.
- the present invention is directed to a NOP receptor antagonist which is a compound represented by the following general formula [1] or a pharmaceutically acceptable salt thereof (hereinafter referred to as the "inventive antagonist").
- R 1 represents hydrogen or alkyl.
- R 2 represents hydrogen, alkoxy, tetrahydropyranyl, phenyl, cycloalkyl, (cycloalkyl)alkyl or alkyl.
- the alkoxy, tetrahydropyranyl, phenyl, cycloalkyl, (cycloalkyl)alkyl and alkyl may be substituted with 1 to 3 groups selected from the group consisting of (1) alkoxy, (2) halogen, (3) alkoxyalkyl, (4) hydroxy, (5) alkylthio, (6) a 5- to 10-membered aromatic heterocyclic group containing 1 to 3 heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, (7) a 5- to 7-membered saturated aliphatic heterocyclic group which may be substituted with acyl and contains 1 to 3 nitrogen atoms, and (8) phenyl which may be substituted with halogen or alkoxy.
- R 3 and R 4 are the same or different and each represents hydrogen, alkyl, alkoxy or halogen.
- R 5 is combined with R 6 to represent alkylene, or represents hydrogen, hydroxy, alkyl, phenyl or alkoxy.
- the alkylene may be substituted with hydroxy or oxo, and may be condensed with a benzene ring.
- the alkyl, phenyl and alkoxy represented by R 5 may be substituted with 1 to 3 groups selected from the group consisting of alkoxy, alkylthio and halogen.
- R 6 represents (1) alkyl, (2) cycloalkyl, (3) phenyl, (4) a 5- to 10-membered aromatic heterocyclic group containing 1 to 3 heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom or (5) -N(R 61 )(R 62 ).
- the alkyl, cycloalkyl, phenyl and aromatic heterocyclic group may be substituted with 1 to 3 groups selected from the group consisting of (1) alkoxy, (2) hydroxy, (3) phenyl, (4) pyridyl, (5) furyl, (6) halogen and (7) ⁇ , ⁇ -dialkylamino.
- R 61 is combined with R 62 to represent -0-(CH2)n-, or represents hydrogen or alkyl.
- R 62 represents hydrogen or alkoxy which may be substituted with 1 to 3 groups selected from the group consisting of alkoxy, alkylthio and halogen.
- n represents an integer of 3 to 5.
- a preferred compound in the present invention may include the following (1) to (28) the quinazoline derivatives and pharmaceutically acceptable salts thereof.
- the present invention is also directed to a pharmaceutical composition for the treatment of pain, which comprises the inventive antagonist as an active ingredient.
- alkyl may include a linear or branched alkyl having 1 to 10 carbon atoms, and specific examples thereof may include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl, n-nonyl, and n-decyl.
- Preferred is alkyl having 1 to 8 carbon atoms and more preferred is alkyl having 1 to 6 carbon atoms.
- alkylthio and N,N-dialkylamino may include the same alkyl as those described above.
- tetrahydropyranyl may include 2-tetrahydropyranyl
- cycloalkyl may include cyclic alkyl having 3 to 10 carbon atoms which is monocyclic to tricyclic, and specific examples thereof may include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecanyl, adamanthyl (1-adamanthyl, 2-adamanthyl, and the like), 2-bicyclo[3.1.1]heptyl and 2-bicyclo[2.2.1]heptyl.
- Preferred is the cyclic alkyl having 4 to 9 carbon atoms, and more preferred is the cyclic alkyl having 5 to 8 carbon atoms.
- Examples of the cycloalkyl moiety of the "(cycloalkyl)alkyl” may include the same cycloalkyl as those described above.
- halogen may include fluorine, chlorine, bromine and iodine.
- aromatic heterocyclic group may include a 5- to 10-membered aromatic heterocyclic group containing 1 to 3 heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, and specific examples thereof may include pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (2-pyrimidinyl,
- saturated aliphatic heterocyclic group may include a 5- to 7-membered saturated aliphatic heterocyclic group containing 1 to 3 nitrogen atoms, and specific examples thereof may include pyrrolidinyl (1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl), piperidinyl (1-piperidinyl, 2-piperidinyl, 3 -piperidinyl, 4-piperidinyl), piperazinyl (1-piperazinyl, 2-piperazinyl), homopiperazinyl (1-homopiperazinyl,
- Examples of the “pyridyl” may include 2-pyridyl, 3-pyridyl and 4-pyridyl.
- furyl may include 2-furyl and 3-furyl.
- alkylene may include linear or branched alkylene having 1 to 6 carbon atoms, and specific examples thereof may include methylene, ethylene, trimethylene, tetramethylene, pentamethylene and hexamethylene. Among these, preferred is alkylene having 2 to 5 carbon atoms, and more preferred is alkylene having 3 to 5 carbon atoms.
- Examples of the "pain” may include neuropathy and physiological disorder, and acute and/or chronic pain.
- the inventive antagonist [1] can be produced according to, for example, the following method from a known compound or an intermediate which can be easily synthesized.
- a raw material has a substituent which has an influence on a reaction
- it is general that the reaction is carried out after the raw material is protected with a suitable protecting group by a known method in advance. It may be easily understood that the protecting group is detached by a known method after the reaction.
- the inventive antagonist [1] can be produced according to, for example, the following reaction step.
- L represents a leaving group (for example, alkoxy, halogen, pyrazole-l-yl or methylthio).
- the inventive antagonist [1] can be obtained by a reaction of a compound [2] with one equivalent to an excess amount of a compound [3] in a solvent, for example, an alcoholic solvent such as methanol or ethanol, a hydrocarbon solvent such as benzene or toluene, an ethereal solvent such as dioxane or tetrahydrofuran, a halogenated hydrocarbon solvent such as chloroform or 1 ,2-dichloroethane, dimethylformamide, or the like in the presence or absence of a base such as triethylamine or N,N-diisopropylethylamine at a temperature of 0°C to the boiling point of the solvent employed for several hours to several days. It is preferred that the reaction is carried out in the presence of triethylamine by using ethoxy as the leaving group L of the compound [3] and ethanol as the solvent at 80°C for 1 to 48 hours.
- a solvent for example, an alcoholic solvent such as
- the compound [2] which is a raw compound, can be produced by a known method (International Publication WO03/091224).
- the compound [3] which is a raw compound, is commercially available, can also be produced by a known method (J. Am. Chem. Soc. , 1975, 97, 2512 / J. Am. Chem. Soc. , 1942, 64, 1827).
- the inventive antagonist [la] wherein R 5 is alkoxy, R 6 is -N(R 61 )(R 62 ), and R 61 and R are both hydrogen, can also be produced according to the following reaction step.
- R 51 represents alkoxy which may be substituted with 1 to 3 groups selected from the group consisting of alkoxy, alkylthio and halogen.
- the inventive antagonist [lb] wherein R 5 is hydrogen and R 6 is -N(R 6I )(R 62 ), can also be produced according to the following reaction step.
- R 1 to R 4 , R 61 and R 62 have the same meanings as defined above.
- the inventive antagonist [la] or [lb] can be obtained by a reaction of a compound [4] with one equivalent to an excess amount of a compound [5] or [6] in a solvent, for example, an alcohol solvent such as methanol or ethanol, a hydrocarbon solvent such as benzene or toluene, an ethereal solvent such as dioxane or tetrahydrofuran, a halogenated hydrocarbon solvent such as chloroform or 1,2-dichloroethane, dimethylformamide, or the like in the presence or absence of an inorganic base such as sodium carbonate or potassium carbonate, or an organic base such as triethylamine or ⁇ , ⁇ -diisopropylethylamine at a temperature of 0°C to the boiling point of the solvent employed for several hours to several days. It is preferred that the reaction is carried out in the presence of sodium carbonate by using ethanol or dioxane as the solvent at 50°C to 80°C for 1 hour to 24 hours
- the compound [4] which is a raw compound, can be produced according to the following reaction step.
- the compound [4] can be obtained by a reaction of the compound [2] with one equivalent to an excess amount of BrCN in a solvent, for example, a hydrocarbon solvent such as benzene or toluene, an ethereal solvent such as dioxane or tetrahydrofuran, a halogenated hydrocarbon solvent such as chloroform or 1 ,2-dichloroethane, dimethylformamide, or the like in the presence of an inorganic base such as sodium carbonate or potassium carbonate, or an organic base such as triethylamine or ⁇ , ⁇ -diisopropylethylamine at a temperature of -78°C to the boiling point of the solvent employed for several minutes to several days. It is preferred that the reaction is carried out in the presence of triethylamine by using tetrahydrofuran as the solvent at -50°C to 0°C for 10 minutes to 1 hour.
- a solvent for example, a hydrocarbon solvent such as benzene or
- the compound [4] which is a raw compound, can also be produced according to the following reaction step.
- a compound [7] can be obtained by a reaction of the compound [2] with one equivalent to an excess amount of potassium cyanate in a solvent, for example, water, an alcohol solvent such as methanol or ethanol, or the like in the presence or absence of an acid such as hydrochloric acid or sulfuric acid, or a base such as triethylamine, ⁇ , ⁇ -diisopropylethylamine, sodium hydroxide or potassium hydroxide at a temperature of 0°C to the boiling point of the solvent employed for several hours to several days. It is preferred that the reaction is carried out in the presence of triethylamine by using hydrous ethanol as the solvent at 50°C to 100°C for 1 hour to 5 hours.
- the compound [4] can be obtained by a reaction of the compound [7] with methanesulfonyl chloride in pyridine at -10°C to 50°C for 30 minutes to 5 hours.
- the inventive antagonist according to the present invention can be used as a pharmaceutical in the form of a free base itself, or can be used by formulating it in the form of a pharmaceutically acceptable salt by a known method.
- a mineral acid such as hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid
- organic acid such as acetic acid, citric acid, tartaric acid, maleic acid, succinic acid, fumaric acid, p-toluenesulfonic acid, benzenesulfonic acid or methanesulfonic acid, and the like.
- a hydrochloride salt of the inventive antagonists according to the present invention can be obtained by dissolving the quinazoline derivative according to the present invention in a suitable solvent and adding an alcohol solution, an ethyl acetate solution or an ether solution of hydrogen chloride thereto, followed by concentration to dryness.
- optical isomer can be produced by, for example, starting from a racemate obtained as described above, utilizing the basicity thereof and using an optically active acid (tartaric acid, dibenzoyltartaric acid, mandelic acid, 10-camphorsulfonic acid or the like) through a known method for optical resolution, or by using a optically active compound as a starting material. In addition to this, it can also be obtained by asymmetric synthesis or separation using a chiral column.
- an optically active acid tartaric acid, dibenzoyltartaric acid, mandelic acid, 10-camphorsulfonic acid or the like
- inventive antagonists [1] there are also those compounds which may exist in the geometric isomer, and each isomer and mixtures thereof are also included in the present invention.
- the inventive antagonist when administered as a pharmaceutical, is administered to mammals including humans by itself or in a pharmaceutically acceptable non-toxic inert carrier, for example, as a pharmaceutical composition comprising the inventive antagonist in an amount of 0.001% to 99.5%, preferably 0.1% to 90%.
- auxiliary agents for a formulation such as solid, semi-solid or liquid diluents, fillers and other auxiliary agents for a drug formulation may be used. It is preferred that a pharmaceutical composition according to the present invention is administered in a unit dosage form.
- the administration of the pharmaceutical composition can be carried out by intra-tissue administration, oral administration, intravenous administration, local administration (transdermal administration, instillation, or the like) or transrectal administration. It may be easily understood that a dosage form suitable for any of these administration routes is employed. For example, oral administration or local administration (transdermal administration or instillation) is preferred.
- a daily dose as an active ingredient of the inventive antagonist in an adult is usually in the range from 0.1 mg to 5 g per adult, preferably from 1 mg to 500 mg per adult in the case of oral administration.
- transdermal administration it is in the range from 0.001% to 5%, preferably from 0.01% to 0.1%.
- instillation it is in the range from 0.0001%) to 0.5%, preferably from 0.001% to 0.01%.
- a lower dose may be sufficient or a higher dose may be required.
- the dose is given once daily or several times daily as divided portions, or it can be given intravenously and continuously over a period of 1 to 24 hours a day.
- Oral administration can be accomplished in a solid or liquid dosage unit such as a bulk powder, a powder, a tablet, a sugar-coated preparation, a capsule, a granule, a suspension, a liquid, a syrup, a drop, a sublingual tablet, a suppository or other dosage forms.
- a bulk powder is produced by pulverizing an active ingredient into a suitable size.
- a powder is produced by pulverizing an active ingredient into a suitable size followed by mixing with a pharmaceutical carrier such as an edible carbohydrate including starch or mannitol, which has been pulverized in a similar manner into a suitable size. If necessary, a flavor, a preservative, a dispersing agent, a colorant, a fragrance or other additive may be mixed therein.
- a capsule is produced by filling a bulk powder or a powder which has previously been pulverized into a powder form as described above or a granule obtained as described in the section of a tablet, for example, in a capsule shell such as a gelatin capsule. It is also possible to perform such a filling operation after mixing a lubricant, a fluidizing agent such as colloidal silica, talc, magnesium stearate, calcium stearate or solid polyethylene glycol with the material in a powder form.
- a fluidizing agent such as colloidal silica, talc, magnesium stearate, calcium stearate or solid polyethylene glycol
- a disintegrant or a solubilizing agent such as carboxymethyl cellulose, carboxymethyl cellulose calcium, low substituted hydroxypropyl cellulose, croscarmellose sodium, carboxy starch sodium, calcium carbonate or sodium carbonate is added, the effectiveness of the pharmaceutical taken as a capsule can be enhanced.
- the finely pulverized powder of the inventive antagonist can be suspended and dispersed in a vegetable oil, polyethylene glycol, glycerin or a surfactant, and then encapsulated in a gelatin sheet, thereby being prepared as a soft capsule.
- a tablet is produced by formulating a powder mixture, converting it into a granule or a slug, adding a disintegrant or a lubricant thereto and then compressing it into a tablet.
- the powder mixture is obtained by mixing an appropriately pulverized material with a diluent or a base described above, and if necessary, a binder (for example, carboxymethyl cellulose sodium, hydroxypropyl cellulose, methyl cellulose, hydroxypropylmethyl cellulose, gelatin, polyvinyl pyrrolidone, polyvinyl alcohol or the like), a dissolution retardant (for example, paraffin, wax, hydrogenated castor oil or the like), a resorption promoter (for example, a quaternary salt), or an adsorbent (for example, bentonite, kaolin, calcium diphosphate or the like) may also be mixed together.
- a binder for example, carboxymethyl cellulose sodium, hydroxypropyl cellulose, methyl cellulose, hydroxypropylmethyl cellulose, gelatin, polyvinyl pyrrolidone, polyvinyl alcohol or the like
- a dissolution retardant for example, paraffin, wax, hydrogenated castor oil or the
- the powder mixture can be granulated by wetting it with a binder such as syrup, starch glue, gum arabic, a cellulose solution or a polymeric material solution and then passing it forcibly through a sieve.
- a binder such as syrup, starch glue, gum arabic, a cellulose solution or a polymeric material solution
- the powder can be subjected first to a tabletting machine to obtain an incompletely shaped slug which is then pulverized to obtain a granule.
- the granule thus obtained can be prevented from adhering to one another by adding a lubricant such as stearic acid, a stearate, talc or mineral oil, or the like.
- the mixture thus lubricated is then compressed into a tablet.
- the plane tablet thus obtained can be film-coated or sugar-coated.
- inventive antagonist may also be compressed directly into a tablet after mixing it with a fluidized inert carrier without being subjected to the granulating or slugging process as described above.
- a transparent or semi-transparent protective film made of a shellac sealing film, a film made of a sugar or a polymeric material and a glossy film made of a wax may also be employed.
- oral dosage forms such as a solution, a syrup and an elixir can also be formulated into a unit dosage form such that a certain amount of the preparation contains a certain amount of the inventive antagonist.
- a syrup is produced by dissolving the inventive antagonist in a suitable flavored aqueous solution, while an elixir is produced by using a non-toxic alcoholic carrier.
- a suspension is formulated by dispersing the inventive antagonist in a non-toxic carrier.
- a solubilizing agent for example, an emulsifying agent (for example, an ethoxylated isostearyl alcohol or a polyoxyethylene sorbitol ester), a preservative, a flavor-imparting agent (for example, peppermint oil or saccharin), or any other additive may also be added if necessary.
- an emulsifying agent for example, an ethoxylated isostearyl alcohol or a polyoxyethylene sorbitol ester
- a preservative for example, a preservative, a flavor-imparting agent (for example, peppermint oil or saccharin), or any other additive may also be added if necessary.
- a flavor-imparting agent for example, peppermint oil or saccharin
- a unit dosage formulation for an oral administration may be formulated as a microcapsule if necessary.
- Such a formulation may be coated or embedded in a polymer, a wax or the like to achieve a prolonged action or a sustained release.
- Rectal administration can be accomplished by using a suppository obtained by mixing the inventive antagonist with a water-soluble or water-insoluble solid having a low melting point such as polyethylene glycol, cocoa butter, a higher ester (for example, myristyl palmitate) and a mixture thereof.
- a water-soluble or water-insoluble solid having a low melting point such as polyethylene glycol, cocoa butter, a higher ester (for example, myristyl palmitate) and a mixture thereof.
- Intra-tissue administration can be accomplished by using a liquid unit dosage form, for example in the form of a solution or a suspension as a subcutaneous, intramuscular, intrabladder or intravenous injection formulation.
- a liquid unit dosage form for example in the form of a solution or a suspension as a subcutaneous, intramuscular, intrabladder or intravenous injection formulation.
- a non-toxic liquid carrier suitable for the purpose of the injection such as an aqueous or oily vehicle followed by sterilizing the resulting suspension or solution.
- a certain amount of the inventive antagonist may be placed in a vial, which is then sterilized together with its content and then sealed.
- An auxiliary vial and a carrier may be provided in combination with a powdered or lyophilized active ingredient for the purpose of dissolving or mixing just before administration.
- a non-toxic salt or salt solution may be added for the purpose of making an injection solution isotonic. It is also possible to use a stabilizer, a preservative, an emul
- Transdermal administration can be accomplished in a solid or liquid dosage unit such as an aerosol, a liquid, a suspension, an emulsion, an adhesive preparation, an ointment, a cataplasm, a liniment, a lotion or another dosage form.
- a solid or liquid dosage unit such as an aerosol, a liquid, a suspension, an emulsion, an adhesive preparation, an ointment, a cataplasm, a liniment, a lotion or another dosage form.
- An ointment is produced by, for example, mixing and kneading a certain amount of the inventive antagonist with a pharmaceutically acceptable solid base suitable for an ointment, for example, a water-soluble base or a lipid-soluble base described in the Japanese pharmacopoeia. It is also possible to use an additive such as a stabilizer, a preservative, an emulsifying agent or a suspending agent.
- Instillation can be accomplished in a liquid unit dosage form, for example, in the form of a solution or a suspension.
- a liquid unit dosage form for example, in the form of a solution or a suspension.
- Any of these formulations can be produced by suspending or dissolving a certain amount of the inventive antagonist in a non-toxic liquid carrier suitable for instillation such as an aqueous or oily vehicle followed by sterilizing the resulting suspension or solution.
- a certain amount of the inventive antagonist may be placed in a vial, which is then sterilized together with its content and then sealed.
- An auxiliary vial and a carrier may be provided in combination with a powdered or lyophilized active ingredient for the purpose of dissolving or mixing just before administration.
- a pharmaceutically acceptable salt or salt solution may be added for the purpose of making an eye drop isotonic. It is also possible to use a stabilizer, a preservative, an emulsifying agent or the like in combination.
- Step 2j 4-i ⁇ (1 S.2RV2-aminocvclohexyllarninol -N-(2- memoxyethylV6-methylquinazolin-2-carboxamide
- Step L 4- ( [d S,2R>2-Cethanimidoylamino)cyclohexyl] amino 1 -N-(2-methoxyethyn-6-methylquinazolin-2-carboxamide
- Step 2 4- ⁇ [nS,2R -2-(ethanimidoylamino cyclohexyll amino ⁇ -N-(2-methoxyethyl 6-methylquinazolin-2-carboxamide dihvdrochloride
- Elemental analysis value (as C 2 6H 37 N 6 0C1 / 2 HCl / 1.8 H 2 0)
- N- 2 2-dimethylpropylV4-( ⁇ iS,2R)-2-[(2-methoxyethanimidoyl amino]cyclohexyl ⁇ amino) -6-methylquinazolin-2-carboxamide dihydrochloride
- Elemental analysis value (as C 2 5H3 6 N 6 0 2 / 2 HC1 / 2 H 2 0)
- Elemental analysis value (as C ⁇ FLioNeOs / 2 HC1 / H 2 0)
- Elemental analysis value (as C 24 H 36 FN 6 0 3 / 2 HC1 / 1.8 H 2 0)
- Elemental analysis value (as C 24 H 3 6N 6 0 3 / 2 HC1 / 2.4 H 2 0)
- Elemental analysis value (as C 18 H 23 N 6 0 2 C1 / 2 HC1 / 3 H 2 0)
- Example 86 4- ( [O S.2RV2-(ethanimidoylamino1cyclohexyl] amino ⁇ -N-C3 -isopropoxypropyD-6-methylq uinazolin-2-carboxamide dihydrochloride
- Elemental analysis value (as C 25 H 35 N 6 0 2 C1 / 2 HC1 / 1.4 H 2 0)
- Elemental analysis value (as C 2 2H 3 2N 6 0 2 / 2 HCl / 2 H 2 0)
- Example 112 4- 1
- Example 118 4- ([( 1 S.2RV2-(3.4-dihvdro-2H-pyrrol-5 -ylamino cyclohexyll amino ⁇ -6-fluoro-N-(3 -metho xy-2,2-dimethylpropyDquinazolin-2-carboxamide dihydrochloride
- Elemental analysis value (as C2 5 H3 5 N 6 0 2 F / 2 HC1 / H 2 0)
Abstract
A novel excellent non-opioid branch of the opioid peptide family of receptors antagonist is provided, which exhibit an analgesic effect on a varuous pains. The present invention is directed to a non-opioid branch of the opioid peptide family of receptors antagonist represented by the general formula [1] or a pharmaceutically acceptable salt thereof. In the general formula [1], R1 represents hydrogen or the like, R2 represents hydrogen or the like, R3 and R4 are the same or different and represent hydrogen, alkyl, alkoxy or halogen, R5 is combined with R6 to represent alkylene or represents hydrogen, hydroxy, alkyl, phenyl or alkoxy, R6 represents (1) alkyl, (2) cycloalkyl, (3) phenyl, (4) a 5- to 10-membered aromatic heterocyclic group containing 1 to 3 heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, or (5) -N(R61)(R62).
Description
DESCRIPTION
NOP RECEPTOR ANTAGONIST TECHNICAL FIELD
[0001] The present invention relates to a non-opioid branch of the opioid peptide family of receptors (hereinafter referred to as NOP receptor) antagonist.
BACKGROUND ART
[0002] As an analgesic, a narcotic analgesic (such as morphine), a non-narcotic analgesic (such as aspirin or indomethacin) or a narco-antagonistic analgesic (such as pentazocine) is employed. A narcotic analgesic exerts its analgesic effect mainly by inhibiting a central algesic excitatory transmission. A non-narcotic analgesic exerts its analgesic effect mainly by inhibiting the production of a peripheral dolorogenic substance. A narco-antagonistic analgesic exerts its analgesic effect in a mechanism similar to that of a narcotic analgesic.
[0003] However, there is no analgesic which is effective against a chronic pain which is not suppressed by morphine, an allodynia accompanied with herpes zoster or hyperalgesia, and an excellent analgesic has been desired to be created.
[0004] Nociceptin is a neuropeptide related to various nervous activities including an in vivo algesia. Japanese Unexamined Patent Publication No. 10-212290 describes that a NOP receptor agonist and/or antagonist may be effective in treating a mental disorder, neuropathy and physiological disorder, and particularly effective in ameliorating anxiety and stress disorder, depression, traumatic disorder, amnesia due to Alzheimer's disease or other dementia, symptoms of epilepsy and spasm, acute and/or chronic pain, drug abuse withdrawal symptoms, water balance control, Na+ excretion, arterial blood pressure disorder, and eating disorder such as an obesity.
[0005] Though the quinazoline derivatives according to the present invention are known as
antipruritic agents (International Publication WO2007/040231), it is not described that quinazoline derivatives have a NOP receptor antagonist effect.
DISCLOSURE OF INVENTION
[0006] In order to achieve the development of a novel analgesic, the present inventors earnestly synthesized and studied various compounds. As a result, that the compound represented by the following general formula (1) has a NOP receptor antagonist effect and has an excellent analgesic effect.
[0007] The present invention is directed to a NOP receptor antagonist which is a compound represented by the following general formula [1] or a pharmaceutically acceptable salt thereof (hereinafter referred to as the "inventive antagonist").
[Chemical Formula 1]
R1 represents hydrogen or alkyl.
R2 represents hydrogen, alkoxy, tetrahydropyranyl, phenyl, cycloalkyl, (cycloalkyl)alkyl or alkyl. The alkoxy, tetrahydropyranyl, phenyl, cycloalkyl, (cycloalkyl)alkyl and alkyl may be substituted with 1 to 3 groups selected from the group consisting of (1) alkoxy, (2) halogen, (3) alkoxyalkyl, (4) hydroxy, (5) alkylthio, (6) a 5- to 10-membered aromatic heterocyclic group containing 1 to 3 heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, (7) a 5- to 7-membered saturated aliphatic heterocyclic group which may be substituted with acyl and contains 1 to 3 nitrogen atoms, and (8) phenyl which may be substituted with halogen or
alkoxy.
R3 and R4 are the same or different and each represents hydrogen, alkyl, alkoxy or halogen.
R5 is combined with R6 to represent alkylene, or represents hydrogen, hydroxy, alkyl, phenyl or alkoxy. The alkylene may be substituted with hydroxy or oxo, and may be condensed with a benzene ring. The alkyl, phenyl and alkoxy represented by R5 may be substituted with 1 to 3 groups selected from the group consisting of alkoxy, alkylthio and halogen.
R6 represents (1) alkyl, (2) cycloalkyl, (3) phenyl, (4) a 5- to 10-membered aromatic heterocyclic group containing 1 to 3 heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom or (5) -N(R61)(R62). The alkyl, cycloalkyl, phenyl and aromatic heterocyclic group may be substituted with 1 to 3 groups selected from the group consisting of (1) alkoxy, (2) hydroxy, (3) phenyl, (4) pyridyl, (5) furyl, (6) halogen and (7) Ν,Ν-dialkylamino. R61 is combined with R62 to represent -0-(CH2)n-, or represents hydrogen or alkyl. R62 represents hydrogen or alkoxy which may be substituted with 1 to 3 groups selected from the group consisting of alkoxy, alkylthio and halogen. Here, n represents an integer of 3 to 5.
with the proviso that a compound wherein R5 is hydrogen and R6 is -NH2 is excluded.
[0008] A preferred compound in the present invention may include the following (1) to (28) the quinazoline derivatives and pharmaceutically acceptable salts thereof.
( 1 ) 4- { [( 1 S,2R)-2-(ethanimidoylamino)cyclohexyl] amino } -N-(2-methoxyethyl)-6- methylquinazolin-2-carboxamide
(2) N-(2,2-dimethylpropyl)-4-( {(I S ,2R)-2- [(2-methoxy-2-methylpropanimidoyl)- amino]cyclohexyl}amino)-6-methylquinazolin-2-carboxamide
(3) 4-({(lS,2R)-2-[(3-methoxypropanimidoyl)amino]cyclohexyl}amino)-N-(3- methoxypropyl)-6-methylquinazolin-2-carboxamide
(4) 4-( { ( 1 S,2R)-2- [(3 -hydroxypropanimidoyl)amino] cyclohexyl } amino)-N- isopropyl-6-methylquinazolin-2-carboxamide
(5) 4-( { ( 1 S,2R)-2-[(3 -hydroxypropanimidoyl)amino] cyclohexyl } amino)-N-(3 - methoxypropyl)-6-methylquinazolin-2-carboxamide
(6) 4-({(l S,2R)-2-[(2-hydroxy-2-methylpropanimidoyl)amino]cyclohexyl}- amino)-N-isobutyl-6-methylquinazolin-2-carboxamide
(7) N-(2-ethoxyethyl)-4-({(l S,2R)-2-[(3-hydroxypropanimidoyl)amino]- cyclohexyl } amino)-6-methylquinazolin-2-carboxamide
(8) 4-( { ( 1 S ,2R)-2-[(2-hydroxy-2-methylpropanimidoyl)amino] cyclohexyl } - amino)-N-isopropyl-6-methylquinazolin-2-carboxamide
(9) 4-({(lS,2R)-2-[(2 -hydroxy-2 -methylpropanimidoyl)amino] cyclohexyl } - amino)-N-(2-methoxyethyl)-6-methylquinazolin-2-carboxamide
( 10) 4-( { ( 1 S,2R)-2- [(2-methoxyethanimidoyl)amino] cyclohexyl } amino)-N-(2- methoxyethyl)-6-methylquinazolin-2-carboxamide
(11) 4-{ [(1 S,2R)-2-(ethanimidoylamino)cyclohexyl]amino}-N-(3-methoxypropyl)-
6-methylquinazolin-2-carboxamide
( 12) 4-( { ( 1 S,2R)-2- [(2-methoxyethanimidoyl)amino]cyclohexyl } amino)-N-(3 - methoxypropyl)-6-methylquinazolin-2-carboxamide
(13) 4- { [(1 S,2R)-2-(emanimidoylamino)cyclohexyl]amino} -N-(2-ethoxyethyl)-6- methylquinazolin-2-carboxamide
( 14) N-(2-ethoxyethyl)-4-( {(IS ,2R)-2- [(2-methoxyethanimidoyl)amino] - cyclohexyl } amino)-6-methylquinazolin-2-carboxamide
(15) 4- {[(1 S,2R)-2-(ethanimidoylamino)cyclohexyl] amino } -N-isopropyl-6- methylquinazolin-2-carboxamide
(16) 4-[((l S,2R)-2- { [amino(methoxyimino)memyl] amino } cyclohexyl)amino]-N-
(2-methoxyethyl)-6-methylquinazolin-2-carboxamide
( 17) 4- [(( 1 S,2R)-2- { [amino(methoxyimino)methyl]amino } cyclohexyl)amino] -N-
isobutyl-6-methylquinazolin-2-carboxamide
(18) 4-[((l S,2R)-2- { [amino(hydroxyimino)methyl]amino } cyclohexyl)amino] -N- isobutyl-6-methylquinazolin-2-carboxamide
(19) 4-[((lS,2R)-2-{[amino(methoxyimino)methyl]amino}cyclohexyl)amino]-N- (cyclopropylmethyl)-6-methylquinazolin-2-carboxamide
(20) 4-[((lS,2R)-2-{[amino(methoxyimmo)methyl]amino}cyclohexyl)amino]-N- isopropyl-6-methylquinazolin-2-carboxamide
(21) 4- { [( 1 S,2R)-2-( { imino[methoxy(methyl)amino]methyl } amino)cyclohexyl] - amino } -N-isobutyl-6-methylquinazolin-2-carboxamide
(22) 4-[((l S,2R)-2-{ [amino(methoxyimino)methyl]amino}cyclohexyl)amino)-N- (3-methoxypropyl)-6-methylquinazolin-2-carboxamide
(23) 4-[(( 1 S,2R)-2- { [amino(hydroxyimino)methyl]amino } cyclohexyl)amino]-N- (3-methoxypropyl)-6-methylquinazolin-2-carboxamide
(24) 4-[(( 1 S ,2R)-2- { [amino(methoxyimino)methyl]amino } cyclohexyl)amino] -N- (2-ethoxyethyl)-6-methylquinazolin-2-carboxamide
(25) 4-[((l S,2R)-2-{ [amino(ethoxyimino)methyl] amino }cyclohexyl)amino]-N- (2-methoxyethyl)-6-methylquinazolin-2-carboxamide
(26) 4- { [( 1 S,2R)-2-( {amino [(2-methoxyethoxy)imino]methyl } amino)cy clohexyl] - amino } -N-(2-methoxyethyl)-6-methylquinazolin-2-carboxamide
(27) 4- { [( 1 S,2R)-2-( { amino [(2-fluoroethoxy)imino]methyl } amino)cyclohexyl] - amino } -N-(2-methoxyethyl)-6-methylquinazolin-2-carboxamide
(28) 4-({(lS,2R)-2-[(amino{[2-(methylthio)ethoxy]imino}methyl)amino]- cyclohexyl}amino)-N-(2-methoxyethyl)-6-methylquinazolin-2-carboxamide.
[0009] Further, the present invention is also directed to a pharmaceutical composition for the treatment of pain, which comprises the inventive antagonist as an active ingredient.
[0010] Hereinafter, the present invention will be described in detail.
Examples of the "alkyl" may include a linear or branched alkyl having 1 to 10
carbon atoms, and specific examples thereof may include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl, n-nonyl, and n-decyl. Preferred is alkyl having 1 to 8 carbon atoms and more preferred is alkyl having 1 to 6 carbon atoms.
Examples of the alkyl moiety of the "alkoxy", "(cycloalkyl)alkyF', "alkoxyalkyl",
"alkylthio" and "N,N-dialkylamino" may include the same alkyl as those described above.
Examples of the "tetrahydropyranyl" may include 2-tetrahydropyranyl,
3- tetrahydropyranyl and 4-tetrahydropyranyl.
Examples of the "cycloalkyl" may include cyclic alkyl having 3 to 10 carbon atoms which is monocyclic to tricyclic, and specific examples thereof may include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecanyl, adamanthyl (1-adamanthyl, 2-adamanthyl, and the like), 2-bicyclo[3.1.1]heptyl and 2-bicyclo[2.2.1]heptyl. Preferred is the cyclic alkyl having 4 to 9 carbon atoms, and more preferred is the cyclic alkyl having 5 to 8 carbon atoms.
Examples of the cycloalkyl moiety of the "(cycloalkyl)alkyl" may include the same cycloalkyl as those described above.
Examples of the "halogen" may include fluorine, chlorine, bromine and iodine. Examples of the "aromatic heterocyclic group" may include a 5- to 10-membered aromatic heterocyclic group containing 1 to 3 heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, and specific examples thereof may include pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (2-pyrimidinyl,
4- pyrimidinyl, 5 -pyrimidinyl), pyrazinyl (2-pyrazinyl, and the like), pyridazinyl (3-pyridazinyl, 4-pyridazinolyl), pyrrolyl (2-pyrrolyl, and the like), furyl (2-furyl, 3-furyl), thienyl (2-thienyl, 3-thienyl), imidazolyl (1-imidazolyl, 4-imidazolyl, and the like), pyrazolyl (3-pyrazolyl, 5-pyrazolyl, and the like), oxazolyl (4-oxazolyl, 5-oxazolyl, and the like), thiazolyl (l,3-thiazol-2-yl, l,3-thiazol-5-yl, and the like), isoxazolyl (isoxazol-4-yl, isoxazol-5-yl, and the like), and l,3,4-thiadiazol-2-yl.
Examples of the "acyl" may include acyl having 1 to 11 carbon atoms, and specific examples thereof may include formyl, acetyl, propyonyl, butyryl, isobutyryl, benzoyl,
1- naphthoyl and 2-naphthoyl.
Examples of the "saturated aliphatic heterocyclic group" may include a 5- to 7-membered saturated aliphatic heterocyclic group containing 1 to 3 nitrogen atoms, and specific examples thereof may include pyrrolidinyl (1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl), piperidinyl (1-piperidinyl, 2-piperidinyl, 3 -piperidinyl, 4-piperidinyl), piperazinyl (1-piperazinyl, 2-piperazinyl), homopiperazinyl (1-homopiperazinyl,
2- homopiperazinyl, 3 -homopiperazinyl, 6-homopiperazinyl), morpholinyl (2-morpholinyl,
3- morpholinyl, 4-morpholinyl), and thiomorpholinyl (2-thiomorpholinyl, 3-thiomorpholinyl,
4- thiomorpholinyl) .
Examples of the "pyridyl" may include 2-pyridyl, 3-pyridyl and 4-pyridyl.
Examples of the "furyl" may include 2-furyl and 3-furyl.
Examples of the "alkylene" may include linear or branched alkylene having 1 to 6 carbon atoms, and specific examples thereof may include methylene, ethylene, trimethylene, tetramethylene, pentamethylene and hexamethylene. Among these, preferred is alkylene having 2 to 5 carbon atoms, and more preferred is alkylene having 3 to 5 carbon atoms.
[0011] Examples of the "pain" may include neuropathy and physiological disorder, and acute and/or chronic pain.
BEST MODE FOR CARRYING OUT THE INVENTION
[0012]
[Chemical Formula 2]
[1]
[0013] The inventive antagonist [1] can be produced according to, for example, the following method from a known compound or an intermediate which can be easily synthesized. In the production of the inventive antagonist [1], in the case where a raw material has a substituent which has an influence on a reaction, it is general that the reaction is carried out after the raw material is protected with a suitable protecting group by a known method in advance. It may be easily understood that the protecting group is detached by a known method after the reaction.
[0014]
Production method 1
The inventive antagonist [1] can be produced according to, for example, the following reaction step.
[Chemical Formula 3]
[2] [1]
[Wherein; R1 to R6 have the same meanings as defined above. L represents a leaving group (for example, alkoxy, halogen, pyrazole-l-yl or methylthio).]
The inventive antagonist [1] can be obtained by a reaction of a compound [2] with
one equivalent to an excess amount of a compound [3] in a solvent, for example, an alcoholic solvent such as methanol or ethanol, a hydrocarbon solvent such as benzene or toluene, an ethereal solvent such as dioxane or tetrahydrofuran, a halogenated hydrocarbon solvent such as chloroform or 1 ,2-dichloroethane, dimethylformamide, or the like in the presence or absence of a base such as triethylamine or N,N-diisopropylethylamine at a temperature of 0°C to the boiling point of the solvent employed for several hours to several days. It is preferred that the reaction is carried out in the presence of triethylamine by using ethoxy as the leaving group L of the compound [3] and ethanol as the solvent at 80°C for 1 to 48 hours.
[0015] The compound [2], which is a raw compound, can be produced by a known method (International Publication WO03/091224).
The compound [3], which is a raw compound, is commercially available, can also be produced by a known method (J. Am. Chem. Soc. , 1975, 97, 2512 / J. Am. Chem. Soc. , 1942, 64, 1827).
[0016]
Production method 2
The inventive antagonist [la] wherein R5 is alkoxy, R6 is -N(R61)(R62), and R61 and R are both hydrogen, can also be produced according to the following reaction step.
[Chemical Formula 4]
[4] [la]
[Wherein; R1 to R4 have the same meanings as defined above. R51 represents alkoxy which may be substituted with 1 to 3 groups selected from the group consisting of alkoxy,
alkylthio and halogen.]
[0017]
Production method 3
The inventive antagonist [lb] wherein R5 is hydrogen and R6 is -N(R6I)(R62), can also be produced according to the following reaction step.
[Chemical Formula 5]
[4] [lb]
[Wherein ; R1 to R4, R61 and R62 have the same meanings as defined above.]
The inventive antagonist [la] or [lb] can be obtained by a reaction of a compound [4] with one equivalent to an excess amount of a compound [5] or [6] in a solvent, for example, an alcohol solvent such as methanol or ethanol, a hydrocarbon solvent such as benzene or toluene, an ethereal solvent such as dioxane or tetrahydrofuran, a halogenated hydrocarbon solvent such as chloroform or 1,2-dichloroethane, dimethylformamide, or the like in the presence or absence of an inorganic base such as sodium carbonate or potassium carbonate, or an organic base such as triethylamine or Ν,Ν-diisopropylethylamine at a temperature of 0°C to the boiling point of the solvent employed for several hours to several days. It is preferred that the reaction is carried out in the presence of sodium carbonate by using ethanol or dioxane as the solvent at 50°C to 80°C for 1 hour to 24 hours.
[0018] The compound [4], which is a raw compound, can be produced according to the following reaction step.
[Chemical Formula 6]
[Wherein ; R1 to R4 have the same meanings as defined above.]
The compound [4] can be obtained by a reaction of the compound [2] with one equivalent to an excess amount of BrCN in a solvent, for example, a hydrocarbon solvent such as benzene or toluene, an ethereal solvent such as dioxane or tetrahydrofuran, a halogenated hydrocarbon solvent such as chloroform or 1 ,2-dichloroethane, dimethylformamide, or the like in the presence of an inorganic base such as sodium carbonate or potassium carbonate, or an organic base such as triethylamine or Ν,Ν-diisopropylethylamine at a temperature of -78°C to the boiling point of the solvent employed for several minutes to several days. It is preferred that the reaction is carried out in the presence of triethylamine by using tetrahydrofuran as the solvent at -50°C to 0°C for 10 minutes to 1 hour.
[0019] Further, the compound [4], which is a raw compound, can also be produced according to the following reaction step.
[Chemical Formula 7]
[2] [7] [4]
[Wherein ; R1 to R4 have the same meanings as defined above.]
A compound [7] can be obtained by a reaction of the compound [2] with one
equivalent to an excess amount of potassium cyanate in a solvent, for example, water, an alcohol solvent such as methanol or ethanol, or the like in the presence or absence of an acid such as hydrochloric acid or sulfuric acid, or a base such as triethylamine, Ν,Ν-diisopropylethylamine, sodium hydroxide or potassium hydroxide at a temperature of 0°C to the boiling point of the solvent employed for several hours to several days. It is preferred that the reaction is carried out in the presence of triethylamine by using hydrous ethanol as the solvent at 50°C to 100°C for 1 hour to 5 hours. The compound [4] can be obtained by a reaction of the compound [7] with methanesulfonyl chloride in pyridine at -10°C to 50°C for 30 minutes to 5 hours.
[0020] The compounds [5] and [6], which are raw compounds, are commercially available, can also be produced by a known method (J. Org. Chem., 1942, 432 / J. Chem. Soc. Perkin trans 2, 2000, 1435 / J. Med. Chem., 1997, 40, 2363).
[0021] The inventive antagonist according to the present invention can be used as a pharmaceutical in the form of a free base itself, or can be used by formulating it in the form of a pharmaceutically acceptable salt by a known method. Examples of such salts include these with a mineral acid such as hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid, these with an organic acid such as acetic acid, citric acid, tartaric acid, maleic acid, succinic acid, fumaric acid, p-toluenesulfonic acid, benzenesulfonic acid or methanesulfonic acid, and the like.
For example, a hydrochloride salt of the inventive antagonists according to the present invention can be obtained by dissolving the quinazoline derivative according to the present invention in a suitable solvent and adding an alcohol solution, an ethyl acetate solution or an ether solution of hydrogen chloride thereto, followed by concentration to dryness.
[0022] Among the inventive antagonists [1], some compounds may have an asymmetric carbon, and all of the optical isomers and mixtures thereof are also included in the present invention. Such an optical isomer can be produced by, for example, starting from a
racemate obtained as described above, utilizing the basicity thereof and using an optically active acid (tartaric acid, dibenzoyltartaric acid, mandelic acid, 10-camphorsulfonic acid or the like) through a known method for optical resolution, or by using a optically active compound as a starting material. In addition to this, it can also be obtained by asymmetric synthesis or separation using a chiral column.
Further, in the inventive antagonists [1], there are also those compounds which may exist in the geometric isomer, and each isomer and mixtures thereof are also included in the present invention.
[0023] When the inventive antagonist is administered as a pharmaceutical, the inventive antagonist is administered to mammals including humans by itself or in a pharmaceutically acceptable non-toxic inert carrier, for example, as a pharmaceutical composition comprising the inventive antagonist in an amount of 0.001% to 99.5%, preferably 0.1% to 90%.
As the carrier, one or more types of auxiliary agents for a formulation such as solid, semi-solid or liquid diluents, fillers and other auxiliary agents for a drug formulation may be used. It is preferred that a pharmaceutical composition according to the present invention is administered in a unit dosage form. The administration of the pharmaceutical composition can be carried out by intra-tissue administration, oral administration, intravenous administration, local administration (transdermal administration, instillation, or the like) or transrectal administration. It may be easily understood that a dosage form suitable for any of these administration routes is employed. For example, oral administration or local administration (transdermal administration or instillation) is preferred.
While it is preferred that the dose as an agent is adjusted depending on the conditions of the patient such as the age, body weight, nature and degree of the disease as well as the administration route, a daily dose as an active ingredient of the inventive antagonist in an adult is usually in the range from 0.1 mg to 5 g per adult, preferably from 1 mg to 500 mg per adult in the case of oral administration. In the case of transdermal
administration, it is in the range from 0.001% to 5%, preferably from 0.01% to 0.1%. In the case of instillation, it is in the range from 0.0001%) to 0.5%, preferably from 0.001% to 0.01%. In some cases, a lower dose may be sufficient or a higher dose may be required. Usually, the dose is given once daily or several times daily as divided portions, or it can be given intravenously and continuously over a period of 1 to 24 hours a day.
[0024] Oral administration can be accomplished in a solid or liquid dosage unit such as a bulk powder, a powder, a tablet, a sugar-coated preparation, a capsule, a granule, a suspension, a liquid, a syrup, a drop, a sublingual tablet, a suppository or other dosage forms. A bulk powder is produced by pulverizing an active ingredient into a suitable size. A powder is produced by pulverizing an active ingredient into a suitable size followed by mixing with a pharmaceutical carrier such as an edible carbohydrate including starch or mannitol, which has been pulverized in a similar manner into a suitable size. If necessary, a flavor, a preservative, a dispersing agent, a colorant, a fragrance or other additive may be mixed therein.
A capsule is produced by filling a bulk powder or a powder which has previously been pulverized into a powder form as described above or a granule obtained as described in the section of a tablet, for example, in a capsule shell such as a gelatin capsule. It is also possible to perform such a filling operation after mixing a lubricant, a fluidizing agent such as colloidal silica, talc, magnesium stearate, calcium stearate or solid polyethylene glycol with the material in a powder form. If a disintegrant or a solubilizing agent such as carboxymethyl cellulose, carboxymethyl cellulose calcium, low substituted hydroxypropyl cellulose, croscarmellose sodium, carboxy starch sodium, calcium carbonate or sodium carbonate is added, the effectiveness of the pharmaceutical taken as a capsule can be enhanced.
The finely pulverized powder of the inventive antagonist can be suspended and dispersed in a vegetable oil, polyethylene glycol, glycerin or a surfactant, and then encapsulated in a gelatin sheet, thereby being prepared as a soft capsule. A tablet is
produced by formulating a powder mixture, converting it into a granule or a slug, adding a disintegrant or a lubricant thereto and then compressing it into a tablet. The powder mixture is obtained by mixing an appropriately pulverized material with a diluent or a base described above, and if necessary, a binder (for example, carboxymethyl cellulose sodium, hydroxypropyl cellulose, methyl cellulose, hydroxypropylmethyl cellulose, gelatin, polyvinyl pyrrolidone, polyvinyl alcohol or the like), a dissolution retardant (for example, paraffin, wax, hydrogenated castor oil or the like), a resorption promoter (for example, a quaternary salt), or an adsorbent (for example, bentonite, kaolin, calcium diphosphate or the like) may also be mixed together. The powder mixture can be granulated by wetting it with a binder such as syrup, starch glue, gum arabic, a cellulose solution or a polymeric material solution and then passing it forcibly through a sieve. Instead of granulating the powder as described above, the powder can be subjected first to a tabletting machine to obtain an incompletely shaped slug which is then pulverized to obtain a granule. The granule thus obtained can be prevented from adhering to one another by adding a lubricant such as stearic acid, a stearate, talc or mineral oil, or the like. The mixture thus lubricated is then compressed into a tablet. The plane tablet thus obtained can be film-coated or sugar-coated.
Further, the inventive antagonist may also be compressed directly into a tablet after mixing it with a fluidized inert carrier without being subjected to the granulating or slugging process as described above. A transparent or semi-transparent protective film made of a shellac sealing film, a film made of a sugar or a polymeric material and a glossy film made of a wax may also be employed.
Other oral dosage forms such as a solution, a syrup and an elixir can also be formulated into a unit dosage form such that a certain amount of the preparation contains a certain amount of the inventive antagonist. A syrup is produced by dissolving the inventive antagonist in a suitable flavored aqueous solution, while an elixir is produced by using a non-toxic alcoholic carrier. A suspension is formulated by dispersing the inventive
antagonist in a non-toxic carrier. A solubilizing agent, an emulsifying agent (for example, an ethoxylated isostearyl alcohol or a polyoxyethylene sorbitol ester), a preservative, a flavor-imparting agent (for example, peppermint oil or saccharin), or any other additive may also be added if necessary.
A unit dosage formulation for an oral administration may be formulated as a microcapsule if necessary. Such a formulation may be coated or embedded in a polymer, a wax or the like to achieve a prolonged action or a sustained release.
[0025] Rectal administration can be accomplished by using a suppository obtained by mixing the inventive antagonist with a water-soluble or water-insoluble solid having a low melting point such as polyethylene glycol, cocoa butter, a higher ester (for example, myristyl palmitate) and a mixture thereof.
[0026] Intra-tissue administration can be accomplished by using a liquid unit dosage form, for example in the form of a solution or a suspension as a subcutaneous, intramuscular, intrabladder or intravenous injection formulation. Any of these formulations can be produced by suspending or dissolving a certain amount of the inventive antagonist in a non-toxic liquid carrier suitable for the purpose of the injection such as an aqueous or oily vehicle followed by sterilizing the resulting suspension or solution. Alternatively, a certain amount of the inventive antagonist may be placed in a vial, which is then sterilized together with its content and then sealed. An auxiliary vial and a carrier may be provided in combination with a powdered or lyophilized active ingredient for the purpose of dissolving or mixing just before administration. A non-toxic salt or salt solution may be added for the purpose of making an injection solution isotonic. It is also possible to use a stabilizer, a preservative, an emulsifying agent or the like in combination.
[0027] Transdermal administration can be accomplished in a solid or liquid dosage unit such as an aerosol, a liquid, a suspension, an emulsion, an adhesive preparation, an ointment, a cataplasm, a liniment, a lotion or another dosage form.
An ointment is produced by, for example, mixing and kneading a certain amount of
the inventive antagonist with a pharmaceutically acceptable solid base suitable for an ointment, for example, a water-soluble base or a lipid-soluble base described in the Japanese pharmacopoeia. It is also possible to use an additive such as a stabilizer, a preservative, an emulsifying agent or a suspending agent.
Instillation can be accomplished in a liquid unit dosage form, for example, in the form of a solution or a suspension. Any of these formulations can be produced by suspending or dissolving a certain amount of the inventive antagonist in a non-toxic liquid carrier suitable for instillation such as an aqueous or oily vehicle followed by sterilizing the resulting suspension or solution. Alternatively, a certain amount of the inventive antagonist may be placed in a vial, which is then sterilized together with its content and then sealed. An auxiliary vial and a carrier may be provided in combination with a powdered or lyophilized active ingredient for the purpose of dissolving or mixing just before administration. A pharmaceutically acceptable salt or salt solution may be added for the purpose of making an eye drop isotonic. It is also possible to use a stabilizer, a preservative, an emulsifying agent or the like in combination.
EXAMPLES
[0028] Hereinafter, the present invention will be described in more detail with reference to Reference examples, Examples, Test examples and Preparation examples. However, the invention is not limited only to these.
Reference example 1
4- ( [f 1 S.2RV2-aminocvclohexyl]amino } -N-(2-memoxyethylV6-methylquinazolin-2-carbox amide
Step L tert-butyl (flR.2SV2-f(2-( (2-methoxyethvn amino]carbonyU-6-methylquinazolin-4-ynamino]cyclohexyl)carbamate
To a suspension of 15.0 g of ethyl
4-( { ( 1 S,2R)-2-[(tert-butoxycarbonyl)amino]cyclohexyl} amino)-6-methylquinazolin-2-carb
oxylate in 15 ml of methanol, 7.89 g of 2-methoxyethylamine was added, and the mixture was stirred at 50°C for 15 hours. After the reaction solution was cooled to room temperature, 45 ml of diisopropyl ether was added thereto, and the mixture was stirred at 0°C for 30 minutes. The deposited crystal was collected by filtration, washed with diisopropyl ether and dried under reduced pressure, whereby 12.2 g of a desired compound was obtained as a white powder.
Step 2j 4-i \(1 S.2RV2-aminocvclohexyllarninol -N-(2- memoxyethylV6-methylquinazolin-2-carboxamide
To a suspension of 2.24 g of tert-butyl {(lR,2S)-2-[(2-{[(2-methoxyethyl)amino]carbonyl}-6-methylquinazolin-4-yl)amino]cycloh exyl} carbamate in 10 ml of ethyl acetate, 10 ml of a 4 N hydrogen chloride-ethyl acetate solution was added, and the mixture was stirred at room temperature for 48 hours. To the reaction solution, 20 ml of diethyl ether was added, and the mixture was stirred for 30 minutes. Then, the deposited substance was collected by filtration, washed with diethyl ether and dried under reduced pressure. The resulting powder was purified by Fuji Silysia
NH silica gel column chromatography (chloroform : methanol = 20 : 1), whereby 1.61 g of a desired compound was obtained as a colorless powder.
[0029]
Example 1
4- { [( 1 S,2RV2-(ethanimidoylamino)cyclohexyl]amino ) -N-(2-memoxyethylV6-methylquina zolin-2 -carboxamide dihvdrochloride
Step L 4- ( [d S,2R>2-Cethanimidoylamino)cyclohexyl] amino 1 -N-(2-methoxyethyn-6-methylquinazolin-2-carboxamide
To a solution of 450 mg of 4-{[(lS,2R)-2- aminocyclohexyl]amino}-N-(2-methoxyethyl)-6-methylquinazolin-2-carboxamide and 467 mg of ethylacetoimidate hydrochloride in 10 ml of ethanol, 764 mg of triethylamine was added, and the mixture was stirred at 80°C for 8 hours. After the reaction solution was
concentrated, the residue was purified by silica gel column chromatography (chloroform : methanol = 20 : 1), whereby 391 mg of a desired compound was obtained as a pale yellow powder.
Step 2: 4-{[nS,2R -2-(ethanimidoylamino cyclohexyll amino } -N-(2-methoxyethyl 6-methylquinazolin-2-carboxamide dihvdrochloride
To a solution of 391 mg of 4-{[(lS,2R)-2-
(ethanimidoylamino)cyclohexyl] amino } -N-(2-methoxyethyl)-6-methylquinazolin-2-carbox amide in 5 ml of ethyl acetate, 3 ml of a 4 N hydrogen chloride-ethyl acetate solution was added, and the mixture was stirred for 10 minutes. Then, to the reaction solution, 10 ml of diethyl ether was added, and the deposited substance was collected by filtration, washed with diethyl ether and dried under reduced pressure, whereby 405 mg of a desired compound was obtained as a white powder.
Elemental analysis value (as C21H30N6O2 / 2 HC1 / 2.5 H20)
Calculated (%) C: 48.84 H: 7.22 N: 16.27
Found (%) C: 48.69 H: 6.83 N: 16.04
Positive ion FAB-MS m/z: 399 [M+H]+
Specific rotation [a] 0 D =+110.79 (c =0.500 methanol)
In the same manner as in Example 1 , the following compounds of Examples 2 to
207 were produced.
Example 2
6-chloro-N-cycloheptyl-4- [(Y 1 S .2RV2- ( [2-(2-furynethanimidoyl] amino } cvclohexyDamino] quinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C28H35N602C1 / 2HC1 / 1.3 H20)
Calculated (%) C: 54.29 H: 6.44 N: 13.57
Found (%) C: 54.22 H: 6.37 N: 13.55
Positive ion FAB-MS m/z: 523 [M+H]+
Specific rotation [a]20 D =+108.73 (c =0.504 methanol)
Appearance: pale red powder
Example 3
6-chloro-N-cycloheptyl-4-( ( ( 1 S.2RV2- [(2-pyridin-2-ylethanimidoyl amino] cyclohexyl ) am ino)quinazolin-2-carboxamide trihydrochloride
Elemental analysis value (as C29H36N70C1 / 3 HCl / 3.1 H20)
Calculated (%) C: 49.81 H: 6.52 N: 14.02
Found (%) C: 49.81 H: 6.46 N: 13.80
Positive ion FAB-MS m/z: 534 [M+H]+
Specific rotation [ct]20 D =+58.40 (c =0.565 methanol)
Appearance: pale brown powder
Example 4
4-([(lS.2RV2-(n-butanimidoylamino^vclohexyl1amino}-6-cMoro-N-cycloheptylquinazoli n-2-carboxamide dihydrochloride
Elemental analysis value (as C26H37N60C1 / 2 HCl / 1.8 H20)
Calculated (%) C: 52.89 H: 7.27 N: 14.23
Found (%) C: 52.90 H: 7.22 N: 13.98
Positive ion FAB-MS m/z: 485 [M+H]+
Specific rotation [<x]20 D =+93.61 (c =0.517 methanol)
Appearance: white powder
Example 5
N-(2-ethylbutvn-4-(((lS.2RV2-[(2-methoxyethanimidoynaminolcyclohexyllamino -6-met hylquinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C25H38N602 / 2 HCl / 0.9 H20)
Calculated (%) C: 55.22 H: 7.75 N: 15.46
Found (%) C: 55.21 H: 7.62 N: 15.44
Positive ion FAB-MS m/z: 387 [M+H]+
Specific rotation [a]20 D =+96.52 (c =0.518 methanol)
Appearance: white powder
Example 6
N-(2-ethylbutyiy4-({(lS.2R -2-[n-methoxyprop
ethylquinazolin-2 -carboxamide dihydrochloride
Elemental analysis value (as C26H40N6O2 / 2 HC1 / 0.8 H20)
Calculated (%) C: 56.17 H: 7.90 N: 15.12
Found (%) C: 56.22 H: 7.84 N: 14.96
Positive ion FAB-MS m/z: 469 [M+H]+
Specific rotation [a]20 D =+94.93 (c =0.533 methanol)
Appearance: white powder
Example 7
N-(3 -methoxy-2,2-dimethylpropyl -4-( {(I S.2RV 2-|Y3 -memoxypropanimidoyOamino] cyclo hexyl) amino 6-methylquinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C26H40N6O3 / 2 HC1 / 0.8 H20)
Calculated (%) C: 54.60 H: 7.68 N: 14.69
Found (%) C: 54.63 H: 7.59 N: 14.59
Positive ion FAB-MS m/z: 485 [M+H]+
Specific rotation [a]20 D =+84.57 (c =0.525 methanol)
Appearance: white powder
Example 8
N- 2>2-dimethylpropylV4-({ iS,2R)-2-[(2-methoxyethanimidoyl amino]cyclohexyl}amino) -6-methylquinazolin-2-carboxamide dihydrochloride
Positive ion FAB-MS m/z: 441 [M+H]+
Specific rotation [a]20 D =+98.12 (c =0.534 methanol)
Appearance: white powder
Example 9
N-(2.2-dimethylpropyiy4-[iflS.2R -2-{[2-^
-6-methylquinazolin-2-carboxamide dihydrochloride
Positive ion FAB-MS m/z: 477 [M+H]+
Specific rotation [a]20 D =+89.57 (c =0.547 methanol)
Appearance: red-brown powder
Example 10
N-(2,2-dimethylpropyD-4-( ( d S.2P -2- [(3 -memoxypropanimidoyDamino] cyclohexyl } amin oV6-methylquinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C25H38N602 / 2 HC1 / 0.9 H20)
Calculated (%) C: 55.22 H: 7.75 N: 15.46
Found (%) C: 55.28 H: 7.52 N: 15.15
Positive ion FAB-MS m/z: 455 [M+H]+
Specific rotation [a]20 D =+87.07 (c =0.526 methanol)
Appearance: white powder
[0030]
Example 11
4- |Y( 1 S ,2FQ- 2- ( [3 -(dimethylamino propanimidoyl]amino 1 cvclohexyDaminol -N-(2.2-dimet hylpropylV6-methylquinazolin-2-carboxamide trihydrochloride
Elemental analysis value (as C26H41N7O / 3 HC1 / 1.8 H20)
Calculated (%) C: 51.24 H: 7.87 N: 16.09
Found (%) C: 51.48 H: 7.49 N: 15.68
Positive ion FAB-MS m/z: 468 [M+H]+
Specific rotation [a]20 D =+57.14 (c =0.469 methanol)
Appearance: white powder
Example 12
4-( l S.2RV2-r(2-methoxyethanimidovnaminolcvclohexyl}aminoV6-methyl-N-r2.2.2-trifl uoroethyl quinazolin-2-carboxamide dihydrochloride
Positive ion FAB-MS m z: 453 [M+H]+
Specific rotation [a]20 D =+116.73 (c =0.514 methanol)
Appearance: pale brownish white powder
Example 13
N-(trans-4-methoxycyclohexyl)-4-((QS.2R)-2-[(2-methoxyethanimidoyl)amino]cvclohexyl } amino)-6-methylquinazolin-2-carboxamide dihvdrochloride
Elemental analysis value (as C26H38N603 / 2 HC1 / 1.8 H20)
Calculated (%) C: 53.11 H: 7.47 N: 14.29
Found (%) C: 53.24 H: 7.41 N: 13.92
Positive ion FAB-MS m/z: 483 [M+H]+
Specific rotation [a]20 D =+105.05 (c =0.495 methanol)
Appearance: white powder
Example 14
N-('2,2-dimethylpropyl)-6-fluoro-4-({(lS,2R)-2-[('2-methoxyethanimidoyl)amino]cyclohexy II amino)quinazolin-2-carboxamide dihydrochloride
Positive ion FAB-MS m/z: 445 [M+H]+
Specific rotation [a]20 D =+63.03 (c =0.514 methanol)
Appearance: white powder
Example 15
N-(2.2-dimethylpropyl)-4-({(lS,2R)-2-[(2-ethoxyethanimidoynamino]cvclohexy amino)- 6-methylquinazolin-2-carboxamide dihvdrochloride
Positive ion FAB-MS m/z: 455 [M+H]+
Specific rotation [a] D =+92.51 (c =0.521 methanol)
Appearance: white powder
Example 16
N-('2,2-dimethylpropyl)-4-f{(lS,2R)-2-[(2-ethoxyethanimidoyl)amino]cvclohexyl}amino)- 6-fluoroquinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C24H35N602F / 2 HC1 / 0.9 H20)
Calculated (%) C: 52.63 H: 7.14 N: 15.34
Found (%) C: 52.76 H: 7.15 N: 15.25
Positive ion FAB-MS m/z: 459 [M+H]+
Specific rotation [<x]20 D =+55.25 (c =0.514 methanol)
Appearance: white powder
Example 17
N-(2-emylbutylV6-fluoro-4-(j(lS.2RV2-[f2-mem^
o^quinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C24H35N602F / 2 HC1 / H20)
Calculated (%) C: 52.46 H: 7.15 N: 15.29
Found (%) C: 52.65 H: 7.10 N: 15.21
Positive ion FAB-MS m/z: 459 [M+H]+
Specific rotation [a]20 D =+59.34 (c =0.492 methanol)
Appearance: white powder
Example 18
6-fluoro-N-G-memoxy-2.2-dimemylpropylV4-((nS.2RV2-[ 2-methoxyethanimidoyDamin o]cyclohexyl}amino')quinazolin-2-carboxamide dihydrochloride
Positive ion FAB-MS m/z: 475 [M+H]+
Specific rotation [a]20 D =+54.82 (c =0.518 methanol)
Appearance: white powder
Example 19
N-("2.2-dimethylpropylV4-({nS.2R -2-[(2-methoxy-2-memylpropammidoyl amino]cyclohe xyl} aminoV6-methylquinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C26H40N6O2 / 2 HC1 / 0.9 H20)
Calculated (%) C: 55.99 H: 7.92 N: 15.07
Found (%) C: 55.94 H: 7.81 N: 15.07
Positive ion FAB-MS m/z: 469 [M+H]+
Specific rotation [a]20 D =+5.49 (c =0.510 methanol)
Appearance: white powder
Example 20
6-fluoro-N-isobutyl-4-(i(lS,2RV2-[(2-methoxyethanimidoynamino]cyclohexyl}amino )qui nazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C22H31N602F / 2 HC1 / 1.1 H20)
Calculated (%) C: 50.50 H: 6.78 N: 16.06
Found (%) C: 50.48 H: 6.69 N: 16.03
Positive ion FAB-MS m/z: 431 [M+H]+
Specific rotation [a]20 D =+66.42 (c =0.557 methanol)
Appearance: white powder
[0031]
Example 21
N- [( 1 -hydroxycyclohexyDmethyl] -4-( {(1 S.2RV2- [(2-methoxyethanimidoyl')amino] cyclohe xyll aminoV6-methylquinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C26H38N603 / 2 HC1 / 2.1 H20)
Calculated (%) C: 52.63 H: 7.51 N: 14.16
Found (%) C: 52.57 H: 7.12 N: 14.15
Positive ion FAB-MS m/z: 483 [M+H]+
Specific rotation [a]20 D =+98.10 (c =0.581 methanol)
Appearance: white powder
Example 22
4-({riS.2RV2-[(2-methoxyethanimidoynamino]cyclohexyllaminoVN-[2-methoxy-l-(meth oxymethylV 1 -methylethyll-6-methylquinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C25H38N604 / 2 HC1 / 1.8 H20)
Calculated (%) C: 50.73 H: 7.42 N: 14.20
Found (%) C: 50.84 H: 7.17 N: 14.46
Positive ion FAB-MS m/z: 487 [M+H]+
Specific rotation [a]20 D =+99.62 (c =0.532 methanol)
Appearance: white powder
Example 23
4-('( iS,2R)-2-[(2-methoxyethammidoyl amino]cyclohexyl}amino -N-('2-methoxy-2-methy lpropyl -6-methylquinazolin-2-carboxamide dihydrochloride
Positive ion FAB-MS m/z: 457 [M+H]+
Specific rotation [a]20 D =+99.99 (c =0.542 methanol)
Appearance: white powder
Example 24
4- 1 |Y 1 S,2R)-2-(ethanimidoylamino cyclohexyl] amino } -N-(2-methoxy-2-methylpropyl -6- methylquinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C23H34N602 / 2 HCl / 3 H20)
Calculated (%) C: 49.91 H: 7.65 N: 15.18
Found (%) C: 49.94 H: 7.49 N: 15.09
Positive ion FAB-MS m/z: 427 [M+H]+
Specific rotation [a]20 D =+94.18 (c =0.516 methanol)
Appearance: white powder
Example 25
4-{[nS.2R)-2-(ethanimidoylamino cyclohexyl]aminol-N-(2-hydroxy-2-methylpropyl -6-m ethylquinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C22H32N602 / 2 HCl / 3.4 H20)
Calculated (%) C: 48.33 H: 7.52 N: 15.37
Found (%) C: 48.27 H: 7.22 N: 15.26
Positive ion FAB-MS m/z: 413 [M+H]+
Specific rotation [a]20 D =+92.24 (c =0.529 methanol)
Appearance: white powder
Example 26
4- ( [(Ί S.2RV2-(ethanimidoylamino')cyclohexyll amino ) -N- [( 1 -hydroxycyclohexyDmethyl] - 6-methylquinazolin-2-carboxamide dihvdrochloride
Elemental analysis value (as C25H36N602 / 2 HC1 / 2 H20)
Calculated (%) C: 52.63 H: 7.60 N: 14.73
Found (%) C: 52.45 H: 7.41 N: 14.83
Positive ion FAB-MS m/z: 453 [M+H]+
Specific rotation [a]20 D =+84.35 (c =0.569 methanol)
Appearance: white powder
Example 27
4-({(lS,2R)-2-[(2-methoxy-2-memylpropanimidoyl')amino]cyclohexy amino VN-(2-metho xy-2-methylpropylV6-methylquinazolin-2-carboxamide dihvdrochloride
Elemental analysis value (as C^FLioNeOs / 2 HC1 / H20)
Calculated (%) C: 54.26 H: 7.71 N: 14.60
Found (%) C: 54.38 H: 7.46 N: 14.24
Positive ion FAB-MS m/z: 485 [M+H]+
Specific rotation [α]20ο =+5.61 (c =0.534 methanol)
Appearance: white powder
Example 28
4- { [( 1 S,2RV2-(ethanimidoylamino')cyclohexyl] amino } -N- [2-methoxy- 1 -(methoxymethyl e thyl] -6-methylquinazolin-2-carboxamide dihvdrochloride
Elemental analysis value (as Q3H3 N6O3 / 2 HC1 / 2.1 H20)
Calculated (%) C: 49.93 H: 7.32 N: 15.19
Found (%) C: 49.95 H: 7.19 N: 14.96
Positive ion FAB-MS m/z: 443 [M+H]+
Specific rotation [a]20 D =+106.37 (c =0.549 methanol)
Appearance: white powder
Example 29
4- IY( 1 S .2RV2 - { [3 -(dimethylamino propanimidoyl] amino } cyclohexy Damino] -N-(2 -methox v-2-methylpropylV6-methylquinazolin-2-carboxamide dihydrochloride
Positive ion FAB-MS m/z: 484 [M+H]+
Specific rotation [a]20 D =+61.43 (c =0.599 methanol)
Appearance: white powder
Example 30
4-({(lS,2RV2-r(2-methoxy-2-memylpropardmidoynamino]cyclohexyl}aminoVN-(3-metho xypropylV6-methylquinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C25H38N603 / 2 HC1 / H20)
Calculated (%) C: 53.47 H: 7.54 N: 14.97
Found (%) C: 53.52 H: 7.24 N: 14.92
Positive ion FAB-MS m/z: 471 [M+H]+
Specific rotation [a]20 D =+9.52 (c =0.588 methanol)
Appearance: white powder
[0032]
Example 31
N-(2-methoxy-2-memylpropylV4-({ i S.2R)-2-[(3-methoxypropanimidoyl amino]cyclohex yl I amino V6-methylquinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C2 H38N603 / 2 HC1 / 3.3 H20)
Calculated (%) C: 49.80 H: 7.79 N: 13.94
Found (%) C: 49.48 H: 7.37 N: 13.75
Positive ion FAB-MS m/z: 471 [M+H]+
Specific rotation [a]20 D =+97.21 (c =0.574 methanol)
Appearance: white powder
Example 32
N-(2-methoxyethyl -4-(((lS.2R -2-[(2-methoxy-2-methylpropanimidoyl amino]cyclohexyl
} amino V6-methylquinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C24H36N6O3 / 2 HC1 / 2.3 H20)
Calculated (%) C: 50.49 H: 7.52 N: 14.72
Found (%) C: 50.59 H: 7.23 N: 14.78
Positive ion FAB-MS m/z: 457 [M+H]+
Specific rotation [a]20 D =+21.54 (c =0.557 methanol)
Appearance: white powder
Example 33
N-isobutyl-4-({(lS,2RV2-[(2-memoxy-2-methylpropanimidoynamino]cyclohexyl}amino)- 6-methylquinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C25H38N 02 / 2 HC1 / 2.3 H20)
Calculated (%) C: 52.77 H: 7.90 N: 14.77
Found (%) C: 52.74 H: 7.53 N: 14.79
Positive ion FAB-MS m/z: 455 [M+H]+
Specific rotation [a]20 D =+5.92 (c =0.540 methanol)
Appearance: white powder
Example 34
N-(2-methoxyethylV4-(((lS.2RV2-[f3-methoxypropammidoyDamino]cyclohexyllaminoV6 -methylquinazolin-2-carboxamide dihydrochloride
Positive ion FAB-MS m/z: 443 [M+H]+
Specific rotation [<x]20 D =+113.09 (c =0.527 methanol)
Appearance: white powder
Example 35
4-( { ( 1 S.2RV2- [(3 -methoxypropanimidoyDamino] cyclohexyl } amino VN-(3 -methoxypropyD -6-methylquinazolin-2-carboxamide dihydrochloride
Positive ion FAB-MS m/z: 457 [M+H]+
Specific rotation [a]20 D =+107.53(c =0.571 methanol)
Appearance: white powder
Example 36
N-ethyl-4-( 1(1 S.2RV2- [(3 -methoxypropanimidoynaminojcyclohexyl ) amino -6-methylquin azolin-2-carboxamide dihydrochloride
Positive ion FAB-MS m/z: 413 [M+H]+
Specific rotation [a]20 D =+122.56 (c =0.545 methanol)
Appearance: white powder
Example 37
4-{ (lS,2R -2-(ethammidoylamino cyclohexyl]amino}-N-(4-memoxyphenyl)-6-methylqum azolin-2-carboxamide dihydrochloride
Elemental analysis value (as C25H3oN602 / 2 HCl / 1.5 H20)
Calculated (%) C: 54.95 H: 6.46 N: 15.38
Found (%) C: 55.26 H: 6.11 N: 15.31
Positive ion FAB-MS m/z: 447 [M+H]+
Specific rotation [a]20 D =+28.47 (c =0.576 methanol)
Appearance: pale yellow powder
Example 38
N-n-butyl-4-ir(lS.2R)-2-(ethanimidoylamino)cyclohexyl]amino>-6-methylquinazolin-2-car boxamide dihydrochloride
Elemental analysis value (as C22H32N6O / 2 HCl / 1.2 H20)
Calculated (%) C: 53.81 H: 7.47 N: 17.11
Found (%) C: 53.80 H: 7.31 N: 17.22
Positive ion FAB-MS m/z: 397 [M+H]+
Specific rotation [a]20 D =+96.42 (c =0.728 methanol)
Appearance: white powder
Example 39
N-n-butyl-6-methl-4-( ( ( 1 S.2RV2- [(2-methylpropanimidoyl amino] cvclohexyl I amino)quina
zolin-2-carboxamide dihydrochloride
Elemental analysis value (as C24H36N60 / 2 HCl / 0.8 H20)
Calculated (%) C: 56.31 H: 7.80 N: 16.42
Found (%) C: 55.99 H: 7.37 N: 16.54
Positive ion FAB-MS m/z: 425 [M+H]+
Specific rotation [a] D =+1.20 (c =0.662 methanol)
Appearance: white powder
Example 40
N-n-butyl-4-[((lS.2RV2-([cyclohexyl(imino)methyl aminolcyclohexynamino]-6-methylqu inazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C27H40N6O / 2 HCl / 1.2 H20)
Calculated (%) C: 57.99 H: 8.00 N: 15.03
Found (%) C: 58.02 H: 7.72 N: 15.14
Positive ion FAB-MS m/z: 465 [M+H]+
Specific rotation [a] D =+1.50 (c =0.665 methanol)
Appearance: white powder
[0033]
Example 41
N-(4-memoxyphenylV6-memyl-4-(((lS,2RV2-[(2-phenylethanimidoynaminolcvclohexyl amino quinazolin-2 -carboxamide dihydrochloride
Elemental analysis value (as C3iH34N602 / 2 HCl / 0.8 H20)
Calculated (%) C: 61.04 H: 6.21 N: 13.78
Found (%) C: 61.07 H: 6.00 N: 13.89
Positive ion FAB-MS m/z: 523 [M+H]+
Specific rotation [a]20 D =+79.81 (c =0.649 methanol)
Appearance: pale yellow powder
Example 42
N-n-butyl-6-methyl-4-f(OS,2R>2-{[N-phenyleth^
azolin-2-carboxamide dihvdrochloride
Positive ion FAB-MS m/z: 473 [M+H]+
Appearance: white powder
Example 43
N-(2.2-dimethylpropyl)-6-methyl-4-[(Y 1 S.2RV2- 1 |Tvf-methylethanimidoyl]amino I cvclohexy namino]quinazolin-2-carboxamide dihvdrochloride
Elemental analysis value (as C24H36N60 / 2 HC1 / 0.8 H20)
Calculated (%) C: 56.31 H: 7.80 N: 16.42
Found (%) C: 56.44 H: 7.75 N: 16.21
Positive ion FAB-MS m/z: 425 [M+H]+
Specific rotation [a]20 D =+81.03 (c =0.501 methanol)
Appearance: white powder
Example 44
4-({(lS,2RV2-[(3-hvdroxyproparumidoynamino]cyclohexyl}aminoVN-isobutyl-6-methy uinazolin-2-carboxamide dihvdrochloride
Positive ion FAB-MS m/z: 427 [M+H]+
Specific rotation [a]20 D =+102.72 (c =0.514 methanol)
Appearance: pale yellow powder
Example 45
N-(2.2-dimethylpropyl -4-( { O S,2R)-2- [(3 -hydroxypropanimidoyOamino] cyclohexyl > amin oV6-methylquinazolin-2-carboxamide dihvdrochloride
Positive ion FAB-MS m/z: 441 [M+H]+
Specific rotation [a]20 D =+58.24 (c =0.546 methanol)
Appearance: pale yellow powder
Example 46
4-( ( ( 1 S.2RV2- [(3 -hydroxypropanimidovDaminol cyclohexyl } amino)-N-('trans-4-methoxycv
clohexylV6-methylquinazolin-2-carboxamide dihvdrochloride
Positive ion FAB-MS m/z: 483 [M+H]+
Specific rotation [a]20 D =+82.74 (c =0.539 methanol)
Appearance: white powder
Example 47
4- { |Y 1 S.2RV2-(ethanimidoylamino)cvclohexyll amino } -6-fluoro-N-(trans-4-methoxycvcloh exynquinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C24H33FN602 / 2 HC1 / 2 H20)
Calculated (%) C: 50.97 H: 6.95 N: 14.86
Found (%) C: 51.07 H: 6.79 N: 15.07
Positive ion FAB-MS m/z: 457 [M+H]+
Specific rotation [a]20 D =+48.29 (c =0.468 methanol)
Appearance: white powder
Example 48
6-fluoro-N-(trans-4-methoxycyclohexylV4-({nS,2RV2-[(2-methoxyethanimidoyl')amino]c vclohexyl)amino^quinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C25H35FN603 / 2 HC1 / 1.7 H20) Calculated (%) C: 50.88 H: 6.90 N: 14.24
Found (%) C: 50.97 H: 6.59 N: 14.20
Positive ion FAB-MS m/z: 487 [M+H]+
Specific rotation [a]20 D =+69.09 (c =0.605 methanol)
Appearance: white powder
Example 49
4-{[(lS.2RV2-(ethanimidoylaminofcyclohexyl]
inazolin-2-carboxamide dihydrochloride
Positive ion FAB-MS m/z: 415 [M+H]+
Specific rotation [a]20 D =+90.97 (c =0.565 methanol)
Appearance: white powder
Example 50
4-(((lS.2RV2-[(2-methoxyemanimidoy0amino
thio^ethyl]quinazolin-2-carboxamide dihydrochloride
Positive ion FAB-MS m/z: 445 [M+H]+
Specific rotation [<x]20 D =+105.81 (c =0.550 methanol)
Appearance: white powder
[0034]
Example 51
4- { [( 1 S.2RV2-(ethanimidoylaminokyclohexyl] amino I -N-(2-methoxy- 1.1 -dimethylethyn-6
-methylquinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C23H34N602 / 2 HC1 / 2 H20)
Calculated (%) C: 51.59 H: 7.53 N: 15.69
Found (%) C: 51.53 H: 7.23 N: 15.63
Positive ion FAB-MS m/z: 427 [M+H]+
Specific rotation [a]20 D =+90.94 (c =0.530 methanol)
Appearance: pale yellow powder
Example 52
N-(2-methoxy- 1.1 -dimethylethylV4-( {(IS .2RV2- ["(2-methoxyethanimidoynamino] cyclohex yl I amino V6-methylquinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C24H36FN603 / 2 HC1 / 1.8 H20)
Calculated (%) C: 51.30 H: 7.46 N: 14.96
Found (%) C: 51.38 H: 7.18 N: 15.16
Positive ion FAB-MS m/z: 457 [M+H]+
Specific rotation [a]20 D =+107.93 (c =0.580 methanol)
Appearance: white powder
Example 53
4-l[nS,2R>2-(ethanimidoylaminofcycto^
carboxamide dihvdrochloride
Elemental analysis value (as C22H32N602 / 2 HC1 / 2.8 H20)
Calculated (%) C: 49.31 H: 7.45 N: 15.68
Found (%) C: 49.27 H: 7.10 N: 15.33
Positive ion FAB-MS m/z: 413 [M+H]+
Specific rotation [a]20 D =+123.21 (c =0.560 methanol)
Appearance: pale yellow powder
Example 54
N-isobutyl-6-methoxy-4-( { ( 1 S.2RV2- [(2-methoxyethanimidoyl amino] cyclohexyl } amino q uinazolin-2-carboxamide dihydrochloride
Positive ion FAB-MS m/z: 443 [M+H]+
Specific rotation [a]20 D =+130.87 (c =0.570 methanol)
Appearance: white powder
Example 55
4-({Π S.2R -2-[(3-hvdroxypropanimidoynamino]cyclohexy amino -N-(2-methoxy- 1 , 1 -di methylethy IV 6-methylquinazolin-2 -carboxamide dihydrochloride
Elemental analysis value (as C24H36N603 / 2 HC1 / 2.4 H20)
Calculated (%) C: 50.33 H: 7.53 N: 14.67
Found (%) C: 50.25 H: 7.30 N: 14.74
Positive ion FAB-MS m/z: 457 [M+H]+
Specific rotation [a]20 D =+91.69 (c =0.530 methanol)
Appearance: pale yellow powder
Example 56
4- { [Π S.2RV 2-(ethanimidoylamino)cyclohexyl] amino > -6-methyl-[3 -Cmethylthio propyl] qui nazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C22H32N6OS / 2 HC1 / 2.2 H20)
Calculated (%) C: 48.83 H: 7.15 N: 15.53
Found (%) C: 48.77 H: 6.76 N: 15.23
Positive ion FAB-MS m/z: 429 [M+H]+
Specific rotation [a]20 D =+81.55 (c =0.645methanol)
Appearance: pale yellow powder
Example 57
4-( { ( 1 S.2RV2- |Y3 -hydroxypropanimidoyllamino] cyclohexyl } amino V6-methyl-N-(2.2.2-trif luoroethyDquinazolin-2-carboxamide dihydrochloride
Positive ion FAB-MS m/z: 453 [M+H]+
Specific rotation [a]20 D =+109.54 (c =0.555 methanol)
Appearance: pale yellow powder
Example 58
4-({(l S.2RV2-[(3-hydroxypropanimidoyl)amino]cyclohexyl}aminoVN-isopropyl-6-memy quinazolin-2 -carboxamide dihydrochloride
Positive ion FAB-MS m/z: 413 [M+H]+
Specific rotation [a]20 D =+108.07 (c =0.570 methanol)
Appearance: pale yellow powder
Example 59
4-( ( ( 1 S .2RV2- |Y3 -hydroxypropanimidoyl)amino]cyclohexyl I amino N-(3 -methoxypropyO- 6-methylquinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C23H34N603 / 2 HC1 / 3.4 H20)
Calculated (%) C: 47.90 H: 7.48 N: 14.57
Found (%) C: 48.24 H: 7.34 N: 14.22
Positive ion FAB-MS m z: 443 [M+H]+
Specific rotation [ct]20 D =+89.92 (c =0.685 methanol)
Appearance: pale yellow powder
Example 60
4-( I ( I S.2RV2- [(2-hvdroxy-2-memylpropammidoyl amino] cvclohexyl } amino VN-isobutyl-6 -methylquinazolin-2-carboxamide dihydrochloride
Positive ion FAB-MS m/z: 441 [M+H]+
Specific rotation [a]20 D =+27.49 (c =0.560 methanol)
Appearance: white powder
[0035]
Example 61
N-(2-emoxyethyl -4-('{nS.2R)-2-[(3-hydroxyproparu^idoyl amino]cyclohexyl}aniino)-6- methylquinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C23H34N603 / 2 HCl / 3.4 H20)
Calculated (%) C: 47.90 H: 7.48 N: 14.57
Found (%) C: 48.07 H: 7.13 N: 14.21
Positive ion FAB-MS m/z: 443 [M+H]+
Specific rotation [a]20 D =+94.54 (c =0.605 methanol)
Appearance: pale yellow powder
Example 62
4-i[nS.2R -2-(n-butanimidoylamino)cyclohexyl]aminol-N-n-memoxypropyl -6-methylq inazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C24H36N602 / 2 HCl / 3.4 H20)
Calculated (%) C: 50.15 H: 7.86 N: 14.62
Found (%) C: 50.17 H: 7.48 N: 14.60
Positive ion FAB-MS m/z: 441 [M+H]+
Specific rotation [a]20 D =+97.57 (c =0.660 methanol)
Appearance: pale yellow powder
Example 63
N- 3-methoxypropyl -6-methyl-4-('( iS.2R -2-[(2-methylpropanimidoyl amino]cyclohexyl 1 amino quinazolin-2-carboxamide dihydrochloride
Positive ion FAB-MS m/z: 441 [M+H]+
Specific rotation [<x]20 D =+61.88 (c =0.585 methanol)
Appearance: white powder
Example 64
4-( I ( 1 R.2S)-2-[(3 -hvdroxypropammidoyDamino]cyclohexyl } aminoVN-isopropyl-6-methyl quinazolin-2-carboxamide dihydrochloride
Positive ion FAB-MS m/z: 413 [M+H]+
Specific rotation [<x]20 D =-113.42 (c =0.760 methanol)
Appearance: pale yellow powder
Example 65
4-(((lS.2R>2-[(2-hydroxy-2-memylpropammidoyn
-6-methylquinazolin-2-carboxamide dihydrochloride
Positive ion FAB-MS m/z: 427 [M+H]+
Specific rotation [a] D =+13.23 (c =0.665 methanol)
Appearance: pale yellow powder
Example 66
4-( ( ( 1 S.2RV2- [(2-hydroxy-2-methylpropanimidoyl1amino] cyclohexyl ) amino VN-(3 -metho xypropylV6-methylquinazolin-2-carboxamide dihydrochloride
Positive ion FAB-MS m/z: 457 [M+H]+
Specific rotation [a]20 D =+21.65 (c =0.665 methanol)
Appearance: pale yellow powder
Example 67
4-(l(lS.2RV2-[(2-hydroxy-2-methylpropanimidoynamino]cyclohexyU amino VN-(2 -metho xyethylV6-methylquinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C23H34N603 / 2 HC1 / H20)
Calculated (%) C: 51.78 H: 7.18 N: 15.75
Found (%) C: 51.79 H: 6.86 N: 15.83
Positive ion FAB-MS m/z: 443 [M+H]+
Specific rotation [a]20 D =+4.44 (c =0.495 methanol)
Appearance: white powder
Example 68
6-chloro-N-cycloheptyl-4- 1 [( 1 S.2RV 2-(ethanimidoylamino')cyclohexyl] amino } quinazolin-2 -carboxamide dihvdrochloride
Elemental analysis value (as C24H33C1N60 / 2 HC1 / 2 H20)
Calculated (%) C: 50.93 H: 6.95 N: 14.85
Found (%) C: 50.58 H: 6.86 N: 14.48
Positive ion FAB-MS m/z: 457 [M+H]+
Specific rotation [a]20 D =+99.35 (c =0.465 methanol)
Appearance: white powder
Example 69
6-chloro-N-cycloheptyl-4-[((lS,2RV2-ipyf-hvdroxyethammidoyl1aminolcyclohexyl)amino] quinazolin-2-carboxamide dihvdrochloride
Elemental analysis value (as C24H33N602C1 / 2 HC1 / 1.5 H20)
Calculated (%) C: 50.31 H: 6.68 N: 14.67
Found (%) C: 50.71 H: 6.85 N: 14.49
Positive ion FAB-MS m/z: 473 [M+H]+
Specific rotation [a]20 D =+3.99 (c =0.501 methanol)
Appearance: white powder
Example 70
N-isobutyl-4-(i(lS,2R)-2-[(2-memoxyethammidovnamino]cyclohexyl}aminoV6-methylqui nazolin-2-carboxamide dihvdrochloride
Elemental analysis value (as C23H34N602 / 2 HC1 / 2.5 H20)
Calculated (%) C: 50.73 H: 7.59 N: 15.43
Found (%) C: 50.81 H: 7.54 N: 15.59
Positive ion FAB-MS m/z: 427 [M+H]+
Specific rotation [a]20 D =+106.99 (c =0.529 methanol)
Appearance: white powder
[0036]
Example 71
6-chloro-4-(((lS.2RV2-[(2-methoxyethanimidovDa^
arboxamide dihydrochloride
Elemental analysis value (as C18H23N602C1 / 2 HC1 / 3 H20)
Calculated (%) C: 41.75 H: 6.03 N: 16.23
Found (%) C: 41.85 H: 5.84 N: 16.22
Positive ion FAB-MS m/z: 391 [M+H]+
Specific rotation [a]20 D =+154.05 (c =0.518 methanol)
Appearance: white powder
Example 72
6-chloro-N-methoxy-4-( 1(1 S,2RV2- [(2-memoxyetha midoyOaminol cvclohexyl } amino'iqu inazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C19H25N603C1 / 2 HC1 / 2.5 H20)
Calculated (%) C: 42.35 H: 5.99 N: 15.60
Found (%) C: 42.46 H: 6.41 N: 15.36
Positive ion FAB-MS m/z: 421 [M+H]+
Specific rotation [a]20 D =+21.20 (c =0.547 methanol)
Appearance: white powder
Example 73
N-n-butyl-6-cMoro-4-(|(lS.2RV2-f(2-methoxyethanimidovnaminolcyclohexyl}amino')quin azolin-2-carboxamide dihydrochloride
Elemental analysis value (as C22H31N602C1 / 2 HC1 / 1.5 H20)
Calculated (%) C: 48.31 H: 6.63 N: 15.37
Found (%) C: 48.56 H: 6.49 N: 15.41
Positive ion FAB-MS m/z: 447 [M+H]+
Specific rotation [a]20 D =+111.52 (c =0.538 methanol)
Appearance: white powder
Example 74
N-(2.2-dimethylpropylV4- 1 [( 1 S.2RV2-(ethanimidoylaminokyclohexyl]amino } -6-methylqu inazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C23H34N60 / 2 HCl / 1.6 H20)
Calculated (%) C: 53.92 H: 7.71 N: 16.40
Found (%) C: 54.31 H: 7.55 N: 15.98
Positive ion FAB-MS m/z: 411 [M+H]+
Specific rotation [a]20 D =+88.65 (c =0.467 methanol)
Appearance: white powder
Example 75
4-{[(lS.2RV2-(ethanimidoylamino cyclohexyl]amino}-N-isobutyl-6-methylquinazolin-2-ca rboxamide dihydrochloride
Elemental analysis value (as C22H32N60 / 2 HCl / 0.8 H20)
Calculated (%) C: 54.61 H: 7.42 N: 17.37
Found (%) C: 54.85 H: 7.39 N: 17.00
Positive ion FAB-MS m/z: 397 [M+H]+
Specific rotation [<x]20 D =+91.96 (c =0.523 methanol)
Appearance: pale brown powder
Example 76
4-|[riS.2RV2-(ethanimidoylamino cvclohexyl]amino}-6-methyl-N-r2.2.2-trifluoroethynqu inazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C20H25N6OF3 / 2 HCl / 0.5 H20)
Calculated (%) C: 47.63 H: 5.60 N: 16.66
Found (%) C: 47.76 H: 5.74 N: 16.56
Positive ion FAB-MS m z: 423 [M+H]+
Specific rotation [a]20 D =+96.59 (c =0.528 methanol)
Appearance: white powder
Example 77
N-(cyclopentylmethyl)-4-( I ( 1 S.2RV2- (2-methoxyethanimidoyl amino] cvclohexyl } aminoV 6-methylquinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C25H36N602 / 2 HC1 / 0.7 H20) Calculated (%) C: 55.61 H: 7.39 N: 15.56
Found (%) C: 55.72 H: 7.17 N: 15.58
Positive ion FAB-MS m/z: 453 [M+H]+
Specific rotation [a]20 D =+101.58 (c =0.443 methanol)
Appearance: white powder
Example 78
N-(cyclopentyl)-4-( { ( 1 S.2PQ-2- [f 2-memoxyethanimidoyl)amino] cvclohexyl } amino)-6-met hylquinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C24H34N603 / 2 HC1 / 0.7 H20)
Calculated (%) C: 55.00 H: 7.19 N: 16.04
Found (%) C: 55.14 H: 7.22 N: 15.78
Positive ion FAB-MS m/z: 439 [M+H]+
Specific rotation [<x]20 D =+110.19 (c =0.559 methanol)
Appearance: white powder
Example 79
N-( 1.1 -dimethylpropyl)-4-( (Π S.2R)-2-[(2-methoxyethanimidoyl)amino]cyclohexyl \ amino) -6-methylquinazolin-2-carboxamide dihydrochloride
Positive ion FAB-MS m/z: 441 [M+H]+
Specific rotation [a]20 D =+96.57 (c =0.497 methanol)
Appearance: white powder
Example 80
N-(2,2-dimethylpropyl>4-j[(lS.2R>2-(2-efa^
uinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C22H31N6OF / 2 HC1 / 0.8 H20)
Calculated (%) C: 52.65 H: 6.95 N: 16.75
Found (%) C: 52.85 H: 7.13 N: 16.53
Positive ion FAB-MS m/z: 415 [M+H]+
Specific rotation [a]20 D =+47.88 (c =0.497 methanol)
Appearance: white powder
[0037]
Example 81
4-{[(lS.2RV2-(2-emanimidoylamino cyclohexyl]amino}-6-fluoro-N-G-methoxy-2,2-dimet hylpropyl quinazolin-2-carboxarnide dihydrochloride
Positive ion FAB-MS m/z: 445 [M+H]+
Specific rotation [a]20 D =+43.24 (c =0.481 methanol)
Appearance: white powder
Example 82
4- 1 [( 1 S,2R -2-(ethanimidoylamino cyclohexyl] amino } -N-(2-isopropoxyethyl -6-methylqui nazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C23H34N602 / 2 HC1 / 1.6 H20)
Calculated (%) C: 52.29 H: 7.48 N: 15.91
Found (%) C: 52.07 H: 7.36 N: 15.89
Positive ion FAB-MS m/z: 427 [M+H]+
Specific rotation [a]20 D =+92.65 (c =0.490 methanol)
Appearance: white powder
Example 83
4- [(( 1 S.2RV2- ( [N-hydroxyethanimidoyl] amino ) cyclohexynamino] -N-isobutyl-6-methylqu inazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C22H32N602 / 2 HC1 / H20)
Calculated (%) C: 52.48 H: 7.21 N: 16.69
Found (%) C: 52.71 H: 7.31 N: 16.64
Positive ion FAB-MS m/z: 413 [M+H]+
Specific rotation [a] D =+3.23 (c =0.556 methanol)
Appearance: white powder
Example 84
N- 2-isopropoxyethvn-4-(( iS,2RV2-[(2-methoxy-2-methylpropammidoyl amino]cyclohe xyllaminoV6-methylquinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C26H40N6O3 / 2 HC1 / H20)
Calculated (%) C: 54.26 H: 7.71 N: 14.60
Found (%) C: 54.48 H: 7.61 N: 14.71
Positive ion FAB-MS m/z: 485 [M+H]+
Specific rotation [a]20 D =+10.88 (c =0.551 methanol)
Appearance: white powder
Example 85
N-(2-isopropoxyethylV4- ( iS.2RV2-[ 2-methoxyethanimidoynamino]cyclohexyl>aminoV 6-methylquinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C24H36N603 / 2 HC1 / 1.5 H20)
Calculated (%) C: 53.00 H: 7.34 N: 15.45
Found (%) C: 53.05 H: 7.50 N: 15.37
Positive ion FAB-MS m/z: 457 [M+H]+
Specific rotation [a]20 D =+119.91 (c =0.487 methanol)
Appearance: white powder
Example 86
4- ( [O S.2RV2-(ethanimidoylamino1cyclohexyl] amino } -N-C3 -isopropoxypropyD-6-methylq uinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C24H36N602 / 2 HC1 / 1.5 H20)
Calculated (%) C: 53.33 H: 7.65 N: 15.55
Found (%) C: 53.46 H: 7.49 N: 15.50
Positive ion FAB-MS m/z: 441 [M+H]+
Specific rotation [a]20 D =+91.49 (c =0.529 methanol)
Appearance: white powder
Example 87
N-(3 -isopropoxypropy0-4-( ( ( 1 S.2RV2- [(2-methoxyethanimidoyl)amino] cyclohexyl I amino
)-6-methylquinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C25H38N603 / 2 HC1 / 2 H20)
Calculated (%) C: 51.81 H: 7.65 N: 14.50
Found (%) C: 51.47 H: 7.30 N: 14.65
Positive ion FAB-MS m/z: 471 [M+H]+
Specific rotation [a]20 D =+100.40 (c =0.500 methanol)
Appearance: white powder
Example 88
4- { [( 1 S.2R>2-fethanimidoylamino)cyclohexyl]amino } -N-methoxy-6-methylquinazolin-2-c arboxamide dihydrochloride
Positive ion FAB-MS m/z: 371 [M+H]+
Specific rotation [a]20 D =+116.79 (c =0.500 methanol)
Appearance: white powder
Example 89
N-memoxy-4-((nS.2R -2-[('2-methoxyethammidoyl amino]cyclohexyl)aminoV6-methylqu inazolin-2-carboxamide dihydrochloride
Positive ion FAB-MS m/z: 401 [M+H]+
Specific rotation [a]20 D =+105.19 (c =0.500 methanol)
Appearance: white powder
Example 90
6-chloro-N-cycloheptyl-4-({(lS,2RV2-[('2-methoxyetharnmidoynamino]cyclohexyl}amino quinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C25H35N602C1 / 2 HC1 / 1.4 H20)
Calculated (%) C: 51.31 H: 6.86 N: 14.36
Found (%) C: 51.30 H: 6.71 N: 14.20
Positive ion FAB-MS m/z: 487 [M+H]+
Specific rotation [<x]20 D =+107.38 (c =0.501 methanol)
Appearance: white powder
[0038]
Example 91
4-( { ( 1 S.2RV 2- [(2-methoxyethanimidoyDamino~|cvclohexyl } amino VN-f 2-methoxyethylV 6- methylquinazolin-2-carboxamide dihydrochloride
Positive ion FAB-MS m/z: 429 [M+H]+
Specific rotation [a]20 D =+114.85 (c =0.505 methanol)
Appearance: white powder
Example 92
4- 1 [Π S.2R)-2-(ethanimidoylamino)cyclohexyl]amino ) -N-C3 -methoxypropyl -6-methylquin azolin-2-carboxamide dihydrochloride
Positive ion FAB-MS m/z: 413 [M+H]+
Specific rotation [a]20 D =+96.40 (c =0.500 methanol)
Appearance: white powder
Example 93
4-( { ( 1 S.2RV2- [(2-methoxyethanimidoyDamino] cvclohexyl } amino VN- -methoxypropyl)-6 -methylquinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C23H34N6O3 / 2 HCl / 2.5 H20)
Calculated (%) C: 49.29 H: 7.37 N: 14.99
Found (%) C: 49.15 H: 7.37 N: 14.93
Positive ion FAB-MS m/z: 443 [M+H]+
Specific rotation [a]20 D =+107.57 (c =0.515 methanol)
Appearance: white powder
Example 94
4-{[riS,2RV2-rethanimidoylaminokyclohexyllamino|-N-(2-ethoxyethylV6-methylquinazo lin-2-carboxamide dihydrochloride
Elemental analysis value (as
/ 2 HCl / 2.6 H20)
Calculated (%) C: 49.64 H: 7.42 N: 15.79
Found (%) C: 49.27 H: 7.03 N: 15.60
Positive ion FAB-MS m/z: 413 [M+H]+
Specific rotation [a]20 D =+105.74 (c =0.505 methanol)
Appearance: white powder
Example 95
N-(2-emoxyethylV4-(( iS.2RV2-[(2-methoxyethanimidoynaminolcvclohexyl}amino)-6-m ethylquinazolin-2 -carboxamide dihydrochloride
Elemental analysis value (as C23H34N6O3 / 2 HCl / 1.3 H20)
Calculated (%) C: 51.26 H: 7.22 N: 15.59
Found (%) C: 51.20 H: 7.06 N: 15.55
Positive ion FAB-MS m/z: 443 [M+H]+
Specific rotation [a]20 D =+101.38 (c =0.505 methanol)
Appearance: white powder
Example 96
4- 1 [(I S.2RV2-(ethanimidoylaminokvclohexyl1amino I -N-(3-mefooxy-2,2-dimethylpropyl> 6-methylquinazolin-2 -carboxamide dihydrochloride
Elemental analysis value (as C24H36N602 / 2 HC1 / 1.9 H20)
Calculated (%) C: 52.63 H: 7.69 N: 15.34
Found (%) C: 52.46 H: 7.39 N: 14.98
Positive ion FAB-MS m/z: 441 [M+H]+
Specific rotation [a]20 D =+83.07 (c =0.520 methanol)
Appearance: white powder
Example 97
N-n-methoxy-2.2-dimethylpropylV4-({riS.2R -2-[(2-methoxyethariimidoynamino]cycloh exyl \ amino 6-methylquinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C25H38N603 / 2 HC1 / 2.5 H20)
Calculated (%) C: 51.02 H: 7.71 N: 14.28
Found (%) C: 50.84 H: 7.32 N: 14.18
Positive ion FAB-MS m/z: 471 [M+H]+
Specific rotation [a]20 D =+95.68 (c =0.510 methanol)
Appearance: white powder
Example 98
4- { [( 1 S.2RV 2-(ethanimidoylamino")cyclohexyl] amino } -N-(2-furylmethylV6-methylquinazo lin-2-carboxamide dihydrochloride
Elemental analysis value (as C23H28N602 / 2 HC1 / 3 H20)
Calculated (%) C: 50.46 H: 6.63 N: 15.35
Found (%) C: 50.61 H: 6.24 N: 15.36
Positive ion FAB-MS m/z: 421 [M+H]+
Specific rotation [a]20 D =+100.00 (c =0.510 methanol)
Appearance: white powder
Example 99
4-i[(lS.2RV2-(ethanimidoylamino cyclohexy
ethylquinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C24H34N6C>2 / 2 HCl / 3.6 H20)
Calculated (%) C: 50.02 H: 7.55 N: 14.58
Found (%) C: 50.35 H: 7.22 N: 14.21
Positive ion FAB-MS m/z: 439 [M+H]+
Specific rotation [a]20 D =+70.58 (c =0.510 methanol)
Appearance: white powder
Example 100
N-(trans-4-hvdroxycvclohexyl V4-( {(IS >2R -2-[(2-methoxyethanimidoyl)amino] cyclohexyl ) aminoV 6-methylquinazolin-2-carboxamide dihydrochloride
Positive ion FAB-MS m/z: 469 [M+H]+
Specific rotation [a]20 D =+103.59 (c =0.500 methanol)
Appearance: white powder
[0039]
Example 101
4- ( [( 1 S.2RV2-(ethanimidoylamino cyclohexyl]amino I -N-isopropyl-6-methylquinazolin-2- carboxamide dihydrochloride
Positive ion FAB-MS m/z: 383 [M+H]+
Specific rotation [a]20 D =+107.32 (c =0.505 methanol)
Appearance: white powder
Example 102
N-isopropyl-4-( ( ( 1 S.2RV2- [(2-methoxyethanimidoyDamino] cyclohexyl I amino V6-methylq uinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C22H32N602 / 2 HCl / 2 H20)
Calculated (%) C: 50.67 H: 7.34 N: 16.12
Found (%) C: 50.94 H: 7.15 N: 16.38
Positive ion FAB-MS m/z: 413 [M+H]+
Specific rotation [a]20 D =+127.05 (c =0.510 methanol)
Appearance: white powder
Example 103
4- { [( 1 S,2RV2-(ethanimidoylamino)cvclohexyl]amino } -N-(2-fluoroethyl -6-methylquinazol in-2-carboxamide dihydrochloride
Elemental analysis value (as C20H27N6OF / 2 HC1 / 2.5 H20)
Calculated (%) C: 47.62 H: 6.79 N: 16.66
Found (%) C: 47.59 H: 6.56 N: 16.44
Positive ion FAB-MS m/z: 387 [M+H]+
Specific rotation [a]20 D =+114.79 (c =0.500 methanol)
Appearance: pale brown powder
Example 104
4-([dS.2RV2-(3.4-dihvdro-2H-pyrrol-5 - ylamino cyclohexyl] amino } -N-(3 -methoxypropy Π
-6-methylquinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C24H34N602 / 2 HC1 / 1.1 H20)
Calculated (%) C: 54.26 H: 7.25 N: 15.82
Found (%) C: 54.27 H: 7.57 N: 15.58
Positive ion FAB-MS m/z: 439 [M+H]+
Specific rotation [a]20 D =+83.61 (c =0.476 methanol)
Appearance: white powder
Example 105
4- ( [d S.2R -2-(3.4-dihydro-2H-pyrrol-5- ylamino cyclohexyl]amino \ -N-f2-methoxyethyQ- 6-methylquinazolin-2-carboxamide dihydrochloride
Positive ion FAB-MS m/z: 425 [M+H]+
Specific rotation [a]20 D =+79.21 (c =0.510 methanol)
Appearance: white powder
Example 106
N-fcyclopropylmethvO-4- { ( 1 S,2R -2-(3 ,4-dihydro-2H-pyrrol-5-ylaminokyclohexyl]amino
I -6-methylquinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C24H32N60 / 2 HCl / 1.4 H20) Calculated (%) C: 55.57 H: 7.15 N: 16.20
Found (%) C: 55.53 H: 7.00 N: 16.13
Positive ion FAB-MS m/z: 421 [M+H]+
Specific rotation [a] D =+90.67 (c =0.536 methanol)
Appearance: white powder
Example 107
4-([ iS.2RV2-n,4-dihydro-2H-pyrrol-5-ylamino cyclohexyl]amino}-N-(2-emylbutylV6-m ethylquinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C26H38N60 / 2 HCl / 0.9 H20)
Calculated (%) C: 57.86 H: 7.81 N: 15.57
Found (%) C: 57.81 H: 7.90 N: 15.34
Positive ion FAB-MS m/z: 451 [M+H]+
Specific rotation [a]20 D =+81.48 (c =0.540 methanol)
Appearance: white powder
Example 108
N-(cyclohexylmethyl -4-i[('lS.2R -2-(3,4-dihydro-2H-pyrrol-5-ylamino cyclohexyl1amino } -6-methylquinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C27H38N60 / 2 HCl / 1.4 H20) Calculated (%) C: 57.83 H: 7.69 N: 14.99
Found (%) C: 58.09 H: 7.74 N: 14.70
Positive ion FAB-MS m/z: 463 [M+H]+
Specific rotation [<X]2°D =+78.36 (c =0.513 methanol)
Appearance: white powder
Example 109
4-([ iS,2R -2-(3,4-dihydro-2H-pyiTol-5-ylamino cyclohexyl]amino>-N-(2.2-dimethylprop
yl 6-methylquinazolin-2-carboxamide dihvdrochloride
Elemental analysis value (as C25H36N60 / 2 HCl / 1.8 H20)
Calculated (%) C: 55.41 H: 7.74 N: 15.51
Found (%) C: 55.41 H: 7.78 N: 15.51
Positive ion FAB-MS m/z: 437 [M+H]+
Specific rotation [<x]20 D =+75.72 (c =0.486 methanol)
Appearance: white powder
Example 110
4-l[ri S.2R -2-r3.4-dihvdro-2H-pyrrol-5-ylamino cvclohexyllaminol-N-[riR.2R -2-methox ycyclohexyl] -6-methylquinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C27H38N602 / 2 HCl / 2.1 H20)
Calculated (%) C: 55.02 H: 7.56 N: 14.26
Found (%) C: 55.08 H: 7.48 N: 14.23
Positive ion FAB-MS m/z: 479 [M+H]+
Specific rotation [a]20 D =+61.50 (c =0.517 methanol)
Appearance: white powder
[0040]
Example 111
4- { [f 1 S.2R -2-(3.4-dihydro-2H-pyrrol-5-ylamino cyclohexyl]amino I -N-ethyl-6-methylquin azolin-2-carboxamide dihydrochloride
Elemental analysis value (as C22H30N6O / 2 HCl / 2 H20)
Calculated (%) C: 50.32 H: 7.37 N: 16.00
Found (%) C: 50.40 H: 7.14 N: 15.65
Positive ion FAB-MS m/z: 395 [M+H]+
Specific rotation [a]20 D =+95.73 (c =0.539 methanol)
Appearance: white powder
Example 112
4- 1 |Y 1 S.2RV2-0.4-dmvdro-2H-pyrrol-5-ylamino cyclohexyl]amino} -N-[ 1 -(methoxymethy Dcyclohexyl] -6-methylquinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C28H4oN602 / 2 HC1 / 1.7 H20)
Calculated (%) C: 56.41 H: 7.68 N: 14.10
Found (%) C: 56.45 H: 7.65 N: 13.84
Positive ion FAB-MS m/z: 493 [M+H]+
Specific rotation [a]20 D =+57.51 (c =0.532 methanol)
Appearance: white powder
Example 113
4-i riS.2RV2-G^-dihvdro-2H-pyrrol-5-ylamino)cvclohexyllamino)-N-(2-ethylbutylV6-m ethoxyquinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C26H38N602 / 2 HC1 / 1.6 H20)
Calculated (%) C: 54.94 H: 7.66 N: 14.79
Found (%) C: 55.02 H: 7.30 N: 14.58
Positive ion FAB-MS m/z: 467 [M+H]+
Specific rotation [a]20 D =+114.98 (c =0.534 methanol)
Appearance: white powder
Example 114
4-([dS.2R>2-(3.4-dihvdro-2H-pyrrol-5-ylaminofcvclohexyll amino } -N- \( 1 R 1 -( methoxy methylV2-methylpropyl]-6-methylquinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C26H38N602 / 2 HC1 / 2.3 H20)
Calculated (%) C: 53.75 H: 7.74 N: 14.47
Found (%) C: 53.65 H: 7.48 N: 14.52
Positive ion FAB-MS m/z: 467 [M+H]+
Specific rotation [a]20 D =+75.61 (c =0.529 methanol)
Appearance: white powder
Example 115
4- ( [Y 1 S.2RV 2-ί 3.4-dihvdro-2H-pyrrol-5-ylaminokvclohexyl1 amino I -N-(2-ethyrpropy0-6- methylquinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C25H36N60 / 2 HCl / 1.2 H20)
Calculated (%) C: 56.53 H: 7.67 N: 15.82
Found (%) C: 56.55 H: 7.62 N: 15.55
Positive ion FAB-MS m/z: 437 [M+H]+
Specific rotation [a]20 D =+91.09 (c =0.494 methanol)
Appearance: white powder
Example 116
4-1 |Y1 S.2RV2-(3.4-dihvdro-2H-pyrrol-5-ylamino)cvclohexyl1aminol-N-('2.2-dimethylprop yl)-6-fluoroquinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C24H33N OF / 2 HCl / H20)
Calculated (%) C: 54.24 H: 7.02 N: 15.81
Found (%) C: 54.47 H: 6.71 N: 15.56
Positive ion FAB-MS m/z: 441 [M+H]+
Specific rotation [a]20 D =+41.26 (c =0.504 methanol)
Appearance: white powder
Example 117
4-{[(lS,2R -2-(3.4-dihydro-2H-pyrrol-5-ylamino cyclohexyl]amino}-6-fluoro-N-isobutylq uinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C23H31N6OF / 2 HCl / 1.3 H20)
Calculated (%) C: 52.83 H: 6.86 N: 16.07
Found (%) C: 52.88 H: 6.76 N: 15.74
Positive ion FAB-MS m/z: 427 [M+H]+
Specific rotation [a]20 D =+48.82 (c =0.512 methanol)
Appearance: white powder
Example 118
4- ( [( 1 S.2RV2-(3.4-dihvdro-2H-pyrrol-5 -ylamino cyclohexyll amino } -6-fluoro-N-(3 -metho xy-2,2-dimethylpropyDquinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C25H35N602F / 2 HC1 / H20)
Calculated (%) C: 53.48 H: 7.00 N: 14.97
Found (%) C: 53.59 H: 6.98 N: 14.69
Positive ion FAB-MS m/z: 471 [M+H]+
Specific rotation [a]20 D =+33.88 (c =0.543 methanol)
Appearance: white powder
Example 119
4- { [( 1 S,2RV2-(3.4-dihydro-2H-pyrrol-5-ylamino')cyclohexyllamino } -N- [2-methoxy- 1 -(met hoxymethylV 1 -methylethyl] -6-methylquinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C26H38N603 / 2 HC1 / 1.9 H20)
Calculated (%) C: 52.95 H: 7.49 N: 14.25
Found (%) C: 52.91 H: 7.36 N: 14.02
Positive ion FAB-MS m/z: 483 [M+H]+
Specific rotation [a]20 D =+69.64 (c =0.560 methanol)
Appearance: white powder
Example 120
4- ( [( 1 S.2R -2-(3„4-dihydro-2H-pyrrol-5 -ylamino)cyclohexyl] amino } -N-(4-methoxyphenyl -6-methylquinazolin-2 -carboxamide dihydrochloride
Elemental analysis value (as C27H32N602 / 2 HC1 / 2.7 H20)
Calculated (%) C: 54.58 H: 6.68 N: 14.14
Found (%) C: 54.47 H: 7.02 N: 14.25
Positive ion FAB-MS m/z: 473 [M+H]+
Specific rotation [a]20 D =+34.84 (c =0.683 methanol)
Appearance: yellow powder
[0041]
Example 121
N-n-butyl-4-([nS.2RV2-(3.4-dihvd^
uinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C24H34N60 / 2 HCl / 2 H20)
Calculated (%) C: 54.23 H: 7.59 N: 15.81
Found (%) C: 54.36 H: 7.36 N: 15.62
Positive ion FAB-MS m/z: 423 [M+H]+
Specific rotation [ct]20 D =+86.93 (c =0.773 methanol)
Appearance: white powder
Example 122
N-n-butyl-6-methyl-4-{[(lS.2RV2-(3.4,5.6-tetrahydropyridin-2-ylamino cyclohexyl]amino 1 quinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C25H36N60 / 2 HCl / 0.9 H20)
Calculated (%) C: 57.12 H: 7.63 N: 15.99
Found (%) C: 57.25 H: 7.64 N: 15.79
Positive ion FAB-MS m/z: 437 [M+H]+
Specific rotation [a]20 D =+100.57 (c =0.696 methanol)
Appearance: white powder
Example 123
N-n-butyl-6-methyl-4-i (lS.2RV2-('3.4.5.6-tetrahvdro-2H-azepin-7-ylaminokvclohexyl1am ino}quinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C26H38N60 / 2 HCl / 1.6 H20)
Calculated (%) C: 56.54 H: 7.88 N: 15.21
Found (%) C: 56.53 H: 7.60 N: 15.28
Positive ion FAB-MS m/z: 451 [M+H]+
Specific rotation [a]20 D =+85.02 (c =0.741 methanol)
Appearance: white powder
Example 124
6-chloro-N-cycloheptyl-4-{[nS,2RV2-(3.4-dihydro-2H-pyrrol-5-ylamino cvclohexyllamin o ) quinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C26H35C1N60 / 2 HCl / 2 H20)
Calculated (%) C: 52.75 H: 6.98 N: 14.20
Found (%) C: 52.97 H: 6.86 N: 14.37
Positive ion FAB-MS m/z: 483 [M+H]+
Specific rotation [a]20 D =+67.28 (c =0.535 methanol)
Appearance: white powder
Example 125
N-n-butyl-6-cMoro-4-([(lS.2R -2-G.4-dihydro-2H-pyrrol-5-ylamino)cvclohexyl]aminolqu inazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C23H31C1N60 / 2 HCl / H20)
Calculated (%) C: 51.84 H: 6.61 N: 15.74
Found (%) C: 51.82 H: 6.74 N: 15.71
Positive ion FAB-MS m/z: 443 [M+H]+
Specific rotation [a]20 D =+88.64 (c =0.546 methanol)
Appearance: white powder
Example 126
N-cycloheptyl-4-([('lS.2RV2-(3^-dihydro-2H-pyrrol-5-ylamino')cyclohexyl]amino}-6-met hylquinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C27H38N60 / 2 HCl / 1.5 H20)
Calculated (%) C: 57.64 H: 7.70 N: 14.94
Found (%) C: 57.52 H: 7.78 N: 14.90
Positive ion FAB-MS m/z: 463 [M+H]+
Specific rotation [a]20 D =+67.56 (c =0.447 methanol)
Appearance: white powder
Example 127
6-chloro-4-([(lS.2Ry2-(3.4-dihydro-2H-pyrrol-5-ylam
carboxamide dihydrochloride
Elemental analysis value (as C19H23C1N60 / 2 HC1 / 1.3 H20)
Calculated (%) C: 47.23 H: 5.76 N: 17.39
Found (%) C: 47.21 H: 5.99 N: 17.20
Positive ion FAB-MS m/z: 387 [M+H]+
Specific rotation [a]20 D =+104.23 (c =0.520 methanol)
Appearance: white powder
Example 128
6-chloro-4-([(lS.2RV2-(3.4-dihvdro-2H-pyn-ol-5-ylamino cvclohexyl]amino>-N-methoxyq uinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C2oH25ClN602 / 2 HC1 / 1.3 H20)
Calculated (%) C: 46.80 H: 5.81 N: 16.37
Found (%) C: 46.87 H: 5.55 N: 16.30
Positive ion FAB-MS m/z: 417 [M+H]+
Specific rotation [<x]20 D =+53.81 (c =0.524 methanol)
Appearance: white powder
Example 129
4- { [( 1 S.2RV 2-Γ3.4-dihvdro-2H-pyrrol-5 -ylaminolcvclohexyll amino I -N-(3-methoxy-2.2-di methylpropyl)-6-methylquinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C26H38N602 / 2 HC1 / H20)
Calculated (%) C: 56.01 H: 7.59 N: 15.07
Found (%) C: 55.96 H: 7.85 N: 14.85
Positive ion FAB-MS m/z: 467 [M+H]+
Specific rotation [a]20 D =+71.08 (c =0.543 methanol)
Appearance: white powder
Example 130
4-{r(lS RV2-(3.4-dmydro-2H-pyrrol-5-ylaminokvclohexyl]amino}-N-isobutyl-6-memylq uinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C24H34N60 / 2 HC1 / 1.2 H20)
Calculated (%) C: 55.94 H: 7.47 N: 16.31
Found (%) C: 55.89 H: 7.64 N: 16.24
Positive ion FAB-MS m/z: 423 [M+H]+
Specific rotation [a]20 D =+93.53 (c =0.464 methanol)
Appearance: white powder
[0042]
Example 131
4-i[ iS.2RV2-(3,4-dihydro-2H-pyrrol-5-ylaminokyclohexyllaminol-N-('2-isopropoxyethyl -6-methylquinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C25H36N602 / 2 HC1 / 1.6 H20)
Calculated (%) C: 54.17 H: 7.49 N: 15.16
Found (%) C: 54.27 H: 7.39 N: 15.21
Positive ion FAB-MS m/z: 453 [M+H]+
Specific rotation [a]20 D =+95.25 (c =0.527 methanol)
Appearance: white powder
Example 132
4- ( [d S.2RV 2-(3 ,4-dihydro-2H-pyrrol-5 -ylamino cyclohexyl] amino 1 -6-methyl-N- [2-(meth ylthio ethyl]quinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C23H32N6OS / 2 HC1 / 1.3 H20)
Calculated (%) C: 51.45 H: 6.87 N: 15.65
Found (%) C: 51.52 H: 6.96 N: 15.47
Positive ion FAB-MS m/z: 441 [M+H]+
Specific rotation [a]20 D =+88.30 (c =0.530 methanol)
Appearance: white powder
Example 133
4-j[(lS.2RV2-(3.4-dihydro-2H-pyn:ol-5-ylaminote^
methylethylV6-methylquinazolin-2-carboxamide dihvdrochloride
Positive ion FAB-MS m/z: 453 [M+H]+
Specific rotation [a]20 D =+64.62 (c =0.489 methanol)
Appearance: white powder
Example 134
4- 1 [( 1 S.2RV 2-(3.4-dihydro-2H-pyrrol-5-ylamino)cyclohexyl] amino I -N- { [ 1 -fmethoxymeth yl cyclohexyl]methyl } -6-methylquinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C29H42N602 / 2 HC1 / 1.4 H20)
Calculated (%) C: 57.59 H: 7.80 N: 13.89
Found (%) C: 57.64 H: 7.79 N: 13.67
Positive ion FAB-MS m/z: 507 [M+H]+
Specific rotation [a]20 D =+54.23 (c =0.531 methanol)
Appearance: white powder
Example 135
4- { [( 1 S.2RV 2-(3.4-dihydro-2H-pyrrol-5 -ylamino cyclohexyl] amino } -6-methyl-N-(2-piperi din-1 -ylethyl quinazolin-2-carboxamide trihydrochloride
Elemental analysis value (as C27H39N70 / 3 HC1 / 2.1 H20)
Calculated (%) C: 51.90 H: 7.45 N: 15.69
Found (%) C: 52.10 H: 7.77 N: 15.40
Positive ion FAB-MS m/z: 478 [M+H]+
Specific rotation [a]20 D =+111.91 (c =0.470 methanol)
Appearance: white powder
Example 136
N-cyclopentyl-4-{[(lS.2R -2-(3,4-dihydro-2H-pyrrol-5-ylamino cvclohexyl]aminol-6-met
hylquinazolin-2-carboxamide dihvdrochloride
Elemental analysis value (as C25H34N60 / 2 HC1 / 2.4 H20)
Calculated (%) C: 54.52 H: 7.47 N: 15.26
Found (%) C: 54.64 H: 7.12 N: 15.07
Positive ion FAB-MS m/z: 435 [M+H]+
Specific rotation [a]20 D =+86.87 (c =0.541 methanol)
Appearance: white powder
Example 137
N-tert-butyl-4-([nS.2RV2-(3.4-dihydro-2H-pmol-5-ylaminokyclohexyl]aminol-6-methyl quinazolin-2 -carboxamide dihvdrochloride
Elemental analysis value (as C24H34N60 / 2 HC1 / 1.2 H20)
Calculated (%) C: 55.74 H: 7.48 N: 16.25
Found (%) C: 55.81 H: 7.68 N: 16.00
Positive ion FAB-MS m/z: 423 [M+H]+
Specific rotation [<x]20 D =+79.42 (c =0.491 methanol)
Appearance: white powder
Example 138
4- ( [( 1 S.2RV 2-(3.4-dihydro-2H-pyrrol-5 -ylamino cvclohexyl] amino I -N-(trans-4-methoxyc vclohexylV6-methylquinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C27H38N602 / 2 HC1 / 1.5 H20)
Calculated (%) C: 56.05 H: 7.49 N: 14.53
Found (%) C: 56.15 H: 7.56 N: 14.48
Positive ion FAB-MS m/z: 479 [M+H]+
Specific rotation [a] D =+77.12 (c =0.542 methanol)
Appearance: white powder
Example 139
4-([flS,2R 2-n^-dihvdro-2H-pyiTol-5-ylaminokvclohexyl]amino}-6-methyl-N-(tetrahvd
ro-2H-pyran-4-yl)quinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C25H34N602 / 2 HC1 / 1.4 H20)
Calculated (%) C: 54.72 H: 7.13 N: 15.32
Found (%) C: 55.01 H: 7.10 N: 14.93
Positive ion FAB-MS m/z: 451 [M+H]+
Specific rotation [a]20 D =+80.15 (c =0.519 methanol)
Appearance: white powder
Example 140
4- { [Π S,2R -2-(3 ,4-dihydro-2H-pyrrol-5 -ylamino cyclohexyl] amino } -N-isopropyl-6-methyl quinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C23H32N60 / 2 HC1 / 1.3 H20)
Calculated (%) C: 54.72 H: 7.31 N: 16.65
Found (%) C: 54.94 H: 7.45 N: 16.29
Positive ion FAB-MS m/z: 409 [M+H]+
Specific rotation [a]20 D =+96.16 (c =0.547 methanol)
Appearance: white powder
[0043]
Example 141
4-i[ iS.2RV2-(3.4-dihydro-2H-pyrrol-5-ylamino cyclohexyl]amino}-N- cis-4-methoxycyc lohexyl -6-methylquinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C27H38N602 / 2 HC1 / 2.5 H20)
Calculated (%) C: 54.36 H: 7.60 N: 14.09
Found (%) C: 54.39 H: 7.31 N: 13.99
Positive ion FAB-MS m/z: 479 [M+H]+
Specific rotation [a]20 D =+68.99 (c =0.516 methanol)
Appearance: white powder
Example 142
hexyl]aminol-6-methylquinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C28H39N702 / 2 HC1 / 2.2 H20)
Calculated (%) C: 54.40 H: 7.40 N: 15.86
Found (%) C: 54.73 H: 7.48 N: 15.48
Positive ion FAB-MS m/z: 506 [M+H]+
Specific rotation [a]20 D =+74.33 (c =0.487 methanol)
Appearance: white powder
Example 143
4-[rriS RV2-irr3RV3-hvdroxy-3^-dihvdro-2H-pyrrol-5-yl1aminolcvclohexyDamino1-N-i sobutyl-6-methylquinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C24H34N602 / 2 HC1 / 0.4 H20)
Calculated (%) C: 55.57 H: 7.15 N: 16.20
Found (%) C: 55.66 H: 7.39 N: 16.07
Positive ion FAB-MS m/z: 439 [M+H]+
Specific rotation [a]20 D =+109.62 (c =0.478 methanol)
Appearance: pale brown powder
Example 144
4-f (( 1 S .2RV2- ί Γ( 3 SV3 -hvdroxy-3.4-dihvdro-2H-pyrrol-5-yll amino } cvclohexynaminol -N-i sobutyl-6-methylquinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C24H34N602 / 2 HC1 / 0.9 H20)
Calculated (%) C: 54.63 H: 7.22 N: 15.93
Found (%) C: 54.90 H: 7.15 N: 15.61
Positive ion FAB-MS m/z: 439 [M+H]+
Specific rotation [a]20 D =+51.83 (c =0.710 methanol)
Appearance: pale brown powder
Example 145
6-chloro-N-cycloheptyl-4-((nS.2RV2-[('2-oxo-3.4-dihvdro-2H-pyrrol-5-vDamino]cycloh^ yl I amino quinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C26H33N602C1 / 2 HCl / 1.5 H20)
Calculated (%) C: 52.31 H: 6.42 N: 14.08
Found (%) C: 52.38 H: 6.51 N: 14.11
Positive ion FAB-MS m/z: 497 [M+H]+
Specific rotation [a]20 D =+133.62 (c =0.464 methanol)
Appearance: white powder
Example 146
N-(tert-butoxyV6-chloro-4-([nS.2RV2-n.4-dihydro-2H-pyrrol-5-ylamino cvclohexyl]ami no 1 quinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C23H31N602C1 / 2 HCl / H20)
Calculated (%) C: 50.23 H: 6.42 N: 15.28
Found (%) C: 49.97 H: 6.35 N: 14.99
Positive ion FAB-MS m/z: 459 [M+H]+
Specific rotation [a]20 D =+74.84 (c =0.473 methanol)
Appearance: white powder
Example 147
N-(cyclopentylmemyl -4-{[(lS.2R -2-n,4-dihydro-2H-pyrrol-5-ylamino cyclohexyl]am } -6-methylquinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C26H36N60 / 2 HCl / H20)
Calculated (%) C: 55.65 H: 7.62 N: 14.98
Found (%) C: 55.58 H: 7.24 N: 14.84
Positive ion FAB-MS m/z: 449 [M+H]+
Specific rotation [a]20 D =+51.66 (c =0.542 methanol)
Appearance: white powder
Example 148
4-([ilS.2RV2-G^-dihydro-2H-pyrrol-5-yla^
ylthiolpropyl] quinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C24H34N6OS / 2 HCl / H20)
Calculated (%) C: 52.84 H: 7.02 N: 15.40
Found (%) C: 52.83 H: 7.11 N: 15.33
Positive ion FAB-MS m/z: 455 [M+H]+
Specific rotation [a]20 D =+82.04 (c =0.529 methanol)
Appearance: white powder
Example 149
4-([aS.2RV2-i3.4-dihvdro-2H-pyiTol-5-ylam^
methylquinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C25H30N6O2 / 2 HCl / H20)
Calculated (%) C: 55.87 H: 6.38 N: 15.64
Found (%) C: 56.09 H: 6.66 N: 15.26
Positive ion FAB-MS m/z: 447 [M+H]+
Specific rotation [a]20 D =+89.45 (c =0.474 methanol)
Appearance: white powder
Example 150
N-(tert-butoxyV4- ( [Π S.2R -2-(3.4-dihydro-2H-pyrrol-5-ylamino)cyclohexyl]amino} -6-me thylquinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C24H34N602 / 2 HCl / 0.7 H20)
Calculated (%) C: 55.00 H: 7.19 N: 16.04
Found (%) C: 55.00 H: 7.15 N: 15.96
Positive ion FAB-MS m/z: 439 [M+H]+
Specific rotation [a]20 D =+85.48 (c =0.496 methanol)
Appearance: white powder
[0044]
Example 151
4-iraS.2R>2-G.4-dihvdro-2H-pmol-5-yl^
fluoroethynquinazolin-2-carboxamide dihvdrochloride
Elemental analysis value (as C22H27N6OF3 / 2 HC1 / 0.7 H20)
Calculated (%) C: 49.48 H: 5.74 N: 15.74
Found (%) C: 49.37 H: 5.72 N: 15.48
Positive ion FAB-MS m/z: 449 [M+H]+
Specific rotation [a]20 D =+104.62 (c =0.541 methanol)
Appearance: white powder
Example 152
4- ( [( 1 S,2R)-2-(3 ,4-dihydro-2H-pyrrol-5-ylaminofcyclohexyl]amino } -N-(trans-4-hvdroxycv clohexylV6-methylquinazolin-2-carboxamide dihvdrochloride
Positive ion FAB-MS m/z: 465 [M+H]+
Specific rotation [a]20 D =+72.65 (c =0.490 methanol)
Appearance: white powder
Example 153
N-(4-methoxyphenyl -6-memyl-4-|[nS.2RV2-(pyridin-2-ylamino cyclohexyl]amino}quina zolin-2 -carboxamide dihvdrochloride
Elemental analysis value (as C28H30N6O2 / 2 HC1 / H20)
Calculated (%) C: 58.64 H: 5.98 N: 14.65
Found (%) C: 58.44 H: 5.90 N: 14.67
Positive ion FAB-MS m/z: 482 [M+H]+
Appearance: pale brown powder
Example 154
N-isobutyl-6-methyl-4-{[(lS.2R)-2-(pyridin-2-ylamino)cyclohexyl]amino}quinazolin-2-car boxamide dihvdrochloride
Elemental analysis value (as C25H32N60 / 2 HC1 / 1.5 H20)
Calculated (%) C: 56.39 H: 7.00 N: 15.78
Found (%) C: 56.46 H: 6.74 N: 15.84
Positive ion FAB-MS m/z: 432 [M+H]+
Appearance: yellow powder
Example 155
6-chloro-4-|"(Y 1 S.2RV2- ( [imino(phenyOmethyl] amino I cvclohexyDamino] -N-[2-(4-methoxy ethyDethyl]quinazolin-2-carboxamide dihvdrochloride
Elemental analysis value (as C31H33N602C1 / 2 HC1 / 2.4 H20)
Calculated (%) C: 55.30 H: 5.96 N: 12.48
Found (%) C: 55.26 H: 5.72 N: 12.25
Positive ion FAB-MS m/z: 557 [M+H]+
Specific rotation [a]20 D =+78.95 (c =0.537 methanol)
Appearance: pale brown powder
Example 156
6-chloro-N-(cyclopentylmethyl -4- [(Y 1 S .2RV 2- { [imino(phenyl methyl] amino } cyclohexyOa mino] quinazolin-2 -carboxamide dihvdrochloride
Elemental analysis value (as C28H33N60C1 / 2 HC1 / 0.8 H20)
Calculated (%) C: 56.77 H: 6.23 N: 14.19
Found (%) C: 56.81 H: 6.14 N: 13.91
Positive ion FAB-MS m/z: 505 [M+H]+
Specific rotation [a]20 D =+94.71 (c =0.549 methanol)
Appearance: white powder
Example 157
6-chloro-N-(3 ,3 -dimethylbutylV4- [(( 1 S .2RV2- { [imino(phenv methyl] amino \ cvclohexyDa mino] quinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C28H35N60C1 / 2 HC1 / 0.8 H20)
Calculated (%) C: 56.58 H: 6.55 N: 14.14
Found (%) C: 56.47 H: 6.48 N: 14.26
Positive ion FAB-MS m/z: 507 [M+H]+
Specific rotation [a]20 D =+103.51 (c =0.398 methanol)
Appearance: white powder
Example 158
6-chloro-N- 3-fluorobenzylV4-[ iS.2RV2-i[imino phenvnmemyl]amino>cyclohexynamin olquinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C29H28N60C1F / 2 HC1 / 1.5 H20)
Calculated (%) C: 55.20 H: 5.28 N: 13.32
Found (%) C: 55.22 H: 5.21 N: 13.00
Positive ion FAB-MS m/z: 531 [M+H]+
Specific rotation [a]20 D =+91.81 (c =0.501 methanol)
Appearance: white powder
Example 159
4-[(nS,2RV2-([2-fuiYl(imino mem^
methylquinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C25H32N603 / 2 HC1 / 0.9 H20)
Calculated (%) C: 54.23 H: 6.52 N: 15.18
Found (%) C: 54.28 H: 6.50 N: 15.15
Positive ion FAB-MS m/z: 465 [M+H]+
Specific rotation [a]20 D =+76.07 (c =0.510 methanol)
Appearance: white powder
Example 160
4-[(( 1 S.2RV2- { [2-furyl(irnino methyl] amino } cyclohexyDamino] -N-C2-methoxyethyl - 6-me thylquinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C24H30N6O3 / 2 HC1 / 1.2 H20)
Calculated (%) C: 52.89 H: 6.36 N: 15.42
Found (%) C: 52.94 H: 6.28 N: 15.29
Positive ion FAB-MS m/z: 451 [M+H]+
Specific rotation [a]20 D =+104.31 (c =0.533 methanol)
Appearance: white powder
[0045]
Example 161
N-(cyclohexylmethylV4- [(( 1 S.2RV2- 1 [imino yridin-2-yDmethyll amino } cyclohexyOamin o]-6-methylquinazolin-2-carboxamide dihvdrochloride
Positive ion FAB-MS m/z: 476 [M+H]+
Specific rotation [a]20 D =+53.58 (c =0.530 methanol)
Appearance: white powder
Example 162
4-[((lS,2Ry2-j[imino(pyridin-2-yD^
lquinazolin-2-carboxamide dihydrochloride
Positive ion FAB-MS m/z: 446 [M+H]+
Specific rotation [a]20 D =+93.55 (c =0.543 methanol)
Appearance: white powder
Example 163
N- 2-emylbutylV4-[( iS.2RV2-{[2-furyl(imino methyl]amino|cyclohexyDami^^ quinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C27H36N602 / 2 HC1 / 1.5 H20)
Calculated (%) C: 56.25 H: 7.17 N: 14.58
Found (%) C: 56.21 H: 6.96 N: 14.43
Positive ion FAB-MS m/z: 477 [M+H]+
Specific rotation [a]20 D =+58.41 (c =0.517 methanol)
Appearance: white powder
Example 164
N-f 2-ethylbutyl>4- \(( 1 S.2RV2- ( [imino(pyridin-2-yPmethyl] amino ) cyclohexyOamino] -6- methylquinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C28H37N70 / 2 HCl / 1.2 H20)
Calculated (%) C: 57.77 H: 7.17 N: 16.84
Found (%) C: 57.88 H: 7.16 N: 16.54
Positive ion FAB-MS m/z: 488 [M+H]+
Specific rotation [a]20 D =+57.76 (c =0.554 methanol)
Appearance: white powder
Example 165
N-fcyclopropylmethyl>4-[(nS.2R>2-([2-fu^
methylquiriazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C25H30N6O2 / 2 HCl / 1.2 H20)
Calculated (%) C: 55.49 H: 6.41 N: 15.53
Found (%) C: 55.44 H: 6.34 N: 15.42
Positive ion FAB-MS m/z: 447 [M+H]+
Specific rotation [a] D =+72.26 (c =0.476 methanol)
Appearance: white powder
Example 166
4-[((lS.2RV2-([imino(pyridin-2-ynmethyl]amino}cyclohexyl amino]-N-('3-methoxypropyl V6-methylquinazolin-2-carboxamide dihydrochloride
Positive ion FAB-MS m/z: 476 [M+H]+
Specific rotation [a]20 D =+72.40 (c =0.511 methanol)
Appearance: white powder
Example 167
N-i2 -dimethylpropylV4-[(YlS.2RV2-([2-fu^
-methylquinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C26H34N602 / 2 HCl / 0.9 H20)
Calculated (%) C: 56.60 H: 6.91 N: 15.23
Found (%) C: 56.57 H: 6.74 N: 15.18
Positive ion FAB-MS m z: 463 [M+H]+
Specific rotation [a]20 D =+67.63 (c =0.482 methanol)
Appearance: white powder
Example 168
4-\(( 1 S .2RV2- 1 [2-furyl(imino methyl]amino } cyclohexynamino] -N-(3 -methoxy-2.2-dimeth ylpropyn-6-methylquinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C27H36N603 / 2 HC1 / 1.4 H20)
Calculated (%) C: 54.90 H: 6.96 N: 14.23
Found (%) C: 55.04 H: 6.90 N: 13.92
Positive ion FAB-MS m/z: 493 [M+H]+
Specific rotation [ct]20 D =+58.92 (c =0.482 methanol)
Appearance: white powder
Example 169
4-[((lS,2R)-2-([2-fi -yl(imino)m
lohexyl] -6-methylquinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C29H38N603 / 2 HC1 / 2 H20)
Calculated (%) C: 55.50 H: 7.07 N: 13.39
Found (%) C: 55.53 H: 6.81 N: 13.14
Positive ion FAB-MS m/z: 519 [M+H]+
Specific rotation [a]20 D =+77.88 (c =0.416 methanol)
Appearance: white powder
Example 170
N-ethyl-4- 1" (( 1 S .2RV2- 1 f 2-ruryl(imino rnethyl]amino } cyclohexy0amino]-6-methylquinazol in-2-carboxamide dihydrochloride
Elemental analysis value (as C23H28N602 / 2 HC1 / 2.7 H20)
Calculated (%) C: 50.96 H: 6.58 N: 15.50
Found (%) C: 50.98 H: 6.18 N: 15.15
Positive ion FAB-MS m/z: 421 [M+H]+
Specific rotation [a]20 D =+86.40 (c =0.537 methanol)
Appearance: white powder
[0046]
Example 171
4-[(Y 1 S .2RV2- 1 [iminofphenyDmethyl] amino ) cyclohexynamino] -N-(4-methoxyphenylV6- methylquinazolin-2 -carboxamide dihydrochloride
Elemental analysis value (as C30H32N6O2 / 2 HC1 / 2.6 H20)
Calculated (%) C: 57.34 H: 6.29 N: 13.37
Found (%) C: 57.34 H: 6.15 N: 13.47
Positive ion FAB-MS m/z: 509 [M+H]+
Specific rotation [a]20 D =+12.54 (c =0.606 methanol)
Appearance: pale yellow powder
Example 172
N-n-butyl-4- [(( 1 S,2R -2- { [iminoCphenvnmethyl] amino } cyclohexynamino] -6-methylquinaz olin-2-carboxamide dihydrochloride
Elemental analysis value (as C27H34N60 / 2 HC1 / 1.6 H20)
Calculated (%) C: 57.87 H: 7.05 N: 15.00
Found (%) C: 57.80 H: 7.02 N: 14.82
Positive ion FAB-MS m/z: 459 [M+H]+
Specific rotation [a]20 D =+75.63 (c =0.788 methanol)
Appearance: white powder
Example 173
N-n-butyl-6-methyl-4-[(Y 1 S.2RV2- 1 [(methylimino (phenyl methyl]amino } cvclohexyPamin o] quinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C28H36N60 / 2 HC1 / 1.2 H20)
Calculated (%) C: 59.30 H: 7.18 N: 14.82
Found (%) C: 59.22 H: 6.96 N: 14.94
Positive ion FAB-MS m/z: 473 [M+H]+
Specific rotation [a]20 D =+29.53 (c =0.684 methanol)
Appearance: white powder
Example 174
N-n-butyl-4- { [( 1 S.2RV 2-( 1 H-isoindol-3 -ylamino)cyclohexyl] amino } -6-methylquinazolin-2
-carboxamide dihydrochloride
Elemental analysis value (as C28H34N60 / 2 HC1 / 1.2 H20)
Calculated (%) C: 59.51 H: 6.85 N: 14.87
Found (%) C: 59.70 H: 6.76 N: 14.81
Positive ion FAB-MS m/z: 471 [M+H]+
Specific rotation [a]20 D =+46.63 (c =0.609 methanol)
Appearance: pale yellow powder
Example 175
N-n-butyl-4- [(( 1 S .2RV2- ( [ihydroxyiminoXphenyDmethyl] amino } cyclohexyl amino]-6-met hylquinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C27H34N602 / 2 HC1 / 0.8 H20)
Calculated (%) C: 57.71 H: 6.74 N: 14.96
Found (%) C: 57.77 H: 6.63 N: 15.03
Positive ion FAB-MS m/z: 475 [M+H]+
Specific rotation [a]20D =+3.13 (c =0.511 methanol)
Appearance: white powder
Example 176
4-[(Y 1 S.2RV2- ( [[2-(dimethylamino phenyll iimino methyl] amino } cvclohexyl)amino"l-N-(4- methoxyphenyl -6-methylquinazolin-2-carboxamide trihydrochloride
Elemental analysis value (as C32H37N702 / 3 HCl / H20)
Calculated (%) C: 56.60 H: 6.23 N: 14.44
Found (%) C: 56.78 H: 6.24 N: 14.35
Positive ion FAB-MS m/z: 552 [M+H]+
Specific rotation [a]20 D =+21.93 (c =0.547 methanol)
Appearance: pale yellow powder
Example 177
4-[(nS.2R>2-{[i3-fluorophenylXimino)m
henylV6-methylquinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C30H31FN6O2 / 2 HCl / 0.8 H20)
Calculated (%) C: 58.69 H: 5.68 N: 13.69
Found (%) C: 58.83 H: 5.55 N: 13.42
Positive ion FAB-MS m/z: 527 [M+H]+
Specific rotation [a]20 D =+12.78 (c =0.735 methanol)
Appearance: pale yellow powder
Example 178
4-[((lS.2RV2-([2-furyl(imino memy
methylquinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C28H30N6O3 / 2 HCl / 1.5 H20)
Calculated (%) C: 56.20 H: 5.89 N: 14.04
Found (%) C: 56.22 H: 5.83 N: 13.82
Positive ion FAB-MS m/z: 499 [M+H]+
Specific rotation [a]20 D =+1.86 (c =0.642 methanol)
Appearance: pale yellow powder
Example 179
N-n-butyl-6-cMoro-4-[((lS.2RV2-([immo(phenyl methyl]amino}cyclohexyl arninolquinaz olin-2-carboxamide dihydrochloride
Elemental analysis value (as C26H31C1N60 / 2 HCl / 0.5 H20)
Calculated (%) C: 55.67 H: 6.11 N: 14.98
Found (%) C: 55.68 H: 6.17 N: 14.86
Positive ion FAB-MS m/z: 479 [M+H]+
Specific rotation [a]20 D =+89.76 (c =0.684 methanol)
Appearance: white powder
Example 180
N-n-butyl-4-[( iS.2RV2-{[imino(phenyl methyllamino}cyclohexynamino1-6-methoxyquin azolin-2-carboxamide dihvdrochloride
Elemental analysis value (as C27H34N602 / 2 HCl / 1.25 H20)
Calculated (%) C: 56.89 H: 6.81 N: 14.74
Found (%) C: 56.82 H: 6.65 N: 14.64
Positive ion FAB-MS m/z: 475 [M+H]+
Specific rotation [a]20 D =+108.39 (c =0.679 methanol)
Appearance: white powder
[0047]
Example 181
4- [(( 1 S .2SV 2- { [iminofphenyDmethyl] amino I cyclohexyDamino] -N-(4-methoxyphenylV 6-m ethylquinazolin-2-carboxamide dihvdrochloride
Elemental analysis value (as C30H32N6O2 / 2 HCl / 1.2 H20)
Calculated (%) C: 59.74 H: 6.08 N: 13.93
Found (%) C: 59.73 H: 5.99 N: 13.94
Positive ion FAB-MS m/z: 509 [M+H]+
Specific rotation [a]20 D =+40.36 (c =0.654 methanol)
Appearance: pale yellow powder
Example 182
6-chloro-N-cvcloheptyl-4-[((lS.2R -2-([imino('phenyl methyl]aminolcyclohexyl)amino]qu
inazolin-2-carboxamide dihvdrochloride
Elemental analysis value (as C29H35CIN6O / 2 HCl / 1.2 H20)
Calculated (%) C: 56.76 H: 6.47 N: 13.70
Found (%) C: 56.84 H: 6.31 N: 13.66
Positive ion FAB-MS m/z: 519 [M+H]+
Specific rotation [a]20 D =+100.55 (c =0.537 methanol)
Appearance: white powder
Example 183
N-cycloheptyl-4-|"(Y 1 S.2RV2- { [imino(phenyOmethyl~| amino 1 cvclohexynamino] -6-methoxy quinazolin-2-carboxamide dihvdrochloride
Elemental analysis value (as C3oH38N602 / 2 HCl / 1.3 H20)
Calculated (%) C: 58.97 H: 7.03 N: 13.75
Found (%) C: 58.95 H: 6.85 N: 13.76
Positive ion FAB-MS m/z: 515 [M+H]+
Specific rotation [a]20 D =+109.66 (c =0.538 methanol)
Appearance: white powder
Example 184
N-cycloheptyl-4-[((lS.2RV2-i[imino^henynmemyllamino}cyclohexyl)amino]-6-methylq uinazolin-2-carboxamide dihvdrochloride
Elemental analysis value (as C30H38N6O / 2 HCl / 2 H20)
Calculated (%) C: 59.30 H: 7.30 N: 13.83
Found (%) C: 59.12 H: 7.03 N: 13.99
Positive ion FAB-MS m/z: 499 [M+H]+
Specific rotation [a]20 D =+85.09 (c =0.463 methanol)
Appearance: white powder
Example 185
6-chloro-N-cycloheptyl-4-[(YlS.2RV2-([2-fi^
inazolin-2-carboxamide dihvdrochloride
Elemental analysis value (as C27H33C1N602 / 2 HC1 / 2.2 H20)
Calculated (%) C: 52.17 H: 6.39 N: 13.52
Found (%) C: 52.17 H: 6.15 N: 13.70
Positive ion FAB-MS m/z: 509 [M+H]+
Specific rotation [a]20 D =+109.94 (c =0.573 methanol)
Appearance: white powder
Example 186
N-isobutyl-4- { [( 1 S.2R)-2-( 1 H-isoindol-3 -ylamino)cvclohexyl] amino } -6-methylquinazolin- 2-carboxamide dihvdrochloride
Elemental analysis value (as C28H34N60 / 2 HC1 / 1.5 H20)
Calculated (%) C: 58.94 H: 6.90 N: 14.73
Found (%) C: 59.14 H: 6.88 N: 14.60
Positive ion FAB-MS m/z: 471 [M+H]+
Specific rotation [a]20 D =+68.82 (c =0.555 methanol)
Appearance: white powder
Example 187
N-cycloheptyl-4- ([(IS .2RV 2-f 1 H-isoindol-3 -ylamino)cvclohexyl] amino } -6-methylquinazo lin-2-carboxamide dihvdrochloride
Elemental analysis value (as C31H38N60 / 2 HC1 / 2 H20)
Calculated (%) C: 60.09 H: 7.16 N: 13.56
Found (%) C: 59.88 H: 7.13 N: 13.58
Positive ion FAB-MS m/z: 511 [M+H]+
Specific rotation [a]20 D =+29.96 (c =0.534 methanol)
Appearance: pale yellow powder
Example 188
6-chloro-N-cvcloheptyl-4-[ ΠS R -2-([imino yridi -2-yl memyl]amino}cyclohexyl ami
nolquinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C28H34C1N70 / 2 HCl / 2.2 H20)
Calculated (%) C: 53.16 H: 6.44 N: 15.50
Found (%) C: 53.20 H: 6.59 N: 15.32
Positive ion FAB-MS m/z: 520 [M+H]+
Specific rotation [a]20 D =+93.92 (c =0.477 methanol)
Appearance: white powder
Example 189
N-n-butyl-4-[(nS.2RV2-{[imino(p id^
uinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C26H33N70 / 2 HCl / 2.5 H20)
Calculated (%) C: 54.07 H: 6.98 N: 16.98
Found (%) C: 53.87 H: 7.36 N: 16.73
Positive ion FAB-MS m/z: 460 [M+H]+
Specific rotation [a]20 D =+75.62 (c =0.521 methanol)
Appearance: white powder
Example 190
4-[((lS.2R -2-{[imino^yridin-2-ynmethyl]aminolcvclohexyl)amino]-N-(3-methoxy-2.2-di methylpropylV6-methylquinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C28H37N702 / 2 HCl / 1.6 H20)
Calculated (%) C: 55.55 H: 7.03 N: 16.20
Found (%) C: 55.76 H: 6.77 N: 15.95
Positive ion FAB-MS m/z: 504 [M+H]+
Specific rotation [a]20 D =+49.33 (c =0.454 methanol)
Appearance: white powder
[0048]
Example 191
N-ethyl-4- [(( 1 S .2RV2- ( [imino(pyridin-2-yl methyl] amino } cyclohexyDamino] -6-methylqui nazolin-2 -carboxamide dihydrochloride
Elemental analysis value (as C24H29N70 / 2 HC1 / 1.5 H20)
Calculated (%) C: 54.24 H: 6.45 N: 18.45
Found (%) C: 54.14 H: 6.49 N: 18.28
Positive ion FAB-MS m/z: 432 [M+H]+
Specific rotation [a]20 D =+93.78 (c =0.499 methanol)
Appearance: white powder
Example 192
4-|Yd S.2RV2- ( [imino(pyridin-2-yl')methyl]aminolcyclohexynaminol-N-(2-methoxy- 1.1 -di methylethylV6-methylquinazolin-2-carboxamide trihvdrochloride
Elemental analysis value (as C27H35N702 / 3 HC1 / 1.4 H20)
Calculated (%) C: 51.95 H: 6.59 N: 15.71
Found (%) C: 52.10 H: 6.62 N: 15.42
Positive ion FAB-MS m/z: 490 [M+H]+
Specific rotation [a]20 D =+88.29 (c =0.564 methanol)
Appearance: white powder
Example 193
4-[fnS.2R -2-([2-f iryl(imino memy
hexyl)-6-methylquinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C28H36N603 / 2 HC1 / H20)
Calculated (%) C: 56.47 H: 6.77 N: 14.11
Found (%) C: 56.46 H: 6.88 N: 14.11
Positive ion FAB-MS m/z: 505 [M+H]+
Specific rotation [a]20 D =+78.74 (c =0.508 methanol)
Appearance: white powder
Example 194
N-(2,2-dimethylpropyl -4-[f(lS,2R -2-{[imm^ mino] -6-methylquinazolin-2-carboxamide dihydrochloride Elemental analysis value (as C26H35N70 / 2 HCl / 0.75 H20) Calculated (%) C: 56.98 H: 7.08 N: 17.89
Found (%) C: 57.19 H: 6.85 N: 17.70
Positive ion FAB-MS m/z: 462 [M+H]+
Specific rotation [a]20 D =-25.62 (c =0.484 methanol)
Appearance: white powder
Example 195
6-fluoro-4-[(QS.2R>2-{[2-furyl(imino)me
oxycyclohexyDquinazolin-2-carboxamide dihydrochloride Elemental analysis value (as C27H33FN603 / 2 HCl / 1.8 H20) Calculated (%) C: 52.82 H: 6.34 N: 13.69
Found (%) C: 52.94 H: 6.23 N: 13.72
Positive ion FAB-MS m/z: 509 [M+H]+
Specific rotation [a]20 D =+36.36 (c =0.495 methanol) Appearance: white powder
Example 196
4-[inS,2R)-2-([3-fiuYl(imino)memyl^
hexyl -6-methylquinazolin-2-carboxamide dihydrochloride Elemental analysis value (as C28H36N603 / 2 HCl / 1.4 H20) Calculated (%) C: 55.79 H: 6.82 N: 13.94
Found (%) C: 55.94 H: 6.73 N: 13.69
Positive ion FAB-MS m/z: 505 [M+H]+
Specific rotation [a]20 D =+88.09 (c =0.563 methanol) Appearance: white powder
Example 197
N-(4.4-dif orocyclohexylV4-[(nS. R -2-([2-fury^
ol-6-methylquinazolin-2-carboxamide dihvdrochloride
Positive ion FAB-MS m/z: 511 [M+H]+
Specific rotation [<x]20 D =+79.24 (c =0.530 methanol)
Appearance: white powder
Example 198
4-[((lS.2R -2-j[imino(pyridin-2-v0memy
V6-methylquinazolin-2-carboxamide trihydrochloride
Positive ion FAB-MS m/z: 509 [M+H]+
Specific rotation [a]20 D =-4.42 (c =0.995 methanol)
Appearance: golden yellow powder
Example 199
4- [(( 1 S .2RV2- { [imino(pyridin-3 - vPmethyl] amino } cvclohexyDamino] -N-(4-methoxyphenyl
)-6-methylquinazolin-2-carboxamide trihydrochloride
Elemental analysis value (as C29H31N702 / 3 HC1 / 1.5 H20)
Calculated (%) C: 53.92 H: 5.77 N: 15.18
Found (%) C: 53.89 H: 5.80 N: 15.14
Positive ion FAB-MS m/z: 509 [M+H]+
Specific rotation [a]20 D =-23.50 (c =0.570 methanol)
Appearance: yellow powder
Example 200
4-[((lS. R -2-j[imino(pyridin-4-ynmem^
V6-methylquinazolin-2-carboxamide trihydrochloride
Elemental analysis value (as C29H31N702 / 3 HC1 / 0.3 H20)
Calculated (%) C: 55.78 H: 5.59 N: 15.70
Found (%) C: 55.76 H: 5.77 N: 15.74
Positive ion FAB-MS m/z: 509 [M+H]+
Specific rotation [a]20 D =-9.04 (c =1.105 methanol)
Appearance: yellow powder
[0049]
Example 201
6-chloro-N-cycloheptyl-4-j[(lS.2RV2-(quinazolm^
n-2-carboxamide dihydrochloride
Elemental analysis value (as C30H34N7OC1 / 2 HC1 / 0.8 H20)
Calculated (%) C: 57.07 H: 6.00 N: 15.53
Found (%) C: 57.06 H: 5.94 N: 15.32
Positive ion FAB-MS m/z: 544 [M+H]+
Specific rotation [a] D =+7.06 (c =0.764 methanol)
Appearance: white powder
Example 202
4- [( ( 1 S .2RV2- { [iminoCphenyPmethyl] amino } cyclohexyPamino] -N-isobutyl-6-methylquina zolin-2-carboxamide dihydrochloride
Elemental analysis value (as C27H34N60 / 2 HC1 / 2.2 H20)
Calculated (%) C: 56.78 H: 7.13 N: 14.71
Found (%) C: 56.71 H: 6.82 N: 14.62
Positive ion FAB-MS m/z: 459 [M+H]+
Specific rotation [a]20 D =+72.00 (c =0.500 methanol)
Appearance: white powder
Example 203
6-chloro-N-cycloheptyl-4-|Y( 1 S .2RV2- { [(3 -fluorophenyl¥imino1methyl] amino } cyclohexyH amino]quinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C29H34N60C1F / 2 HC1 / 2.5 H20)
Calculated (%) C: 53.18 H: 6.31 N: 12.83
Found (%) C: 53.40 H: 6.14 N: 12.70
Positive ion FAB-MS m/z: 537 [M+H]+
Specific rotation [a]20 D =+82.28 (c =0.559 methanol)
Appearance: white powder
Example 204
4-r(ilS R>2-([iminofoyridin-2-ynm
l -6-methylquinazolin-2-carboxamide dihvdrochloride
Positive ion FAB-MS m/z: 490 [M+H]+
Specific rotation [a]20 D =+107.86 (c =0.534 methanol)
Appearance: white powder
Example 205
4-[((lS.2R)-2-([imino yridin-2-yl memyl]amino>cvclohexyΠamino]-6-memyl-N-[2-(meth ylthiokthyl]quinazolin-2-carboxamide dihvdrochloride
Positive ion FAB-MS m/z: 478 [M+H]+
Specific rotation [a]20 D =+74.85 (c =0.521 methanol)
Appearance: white powder
Example 206
4-[((lS.2R)-2-j[immo(4-memoxyphenv0memyl^
ethylquinazolin-2-carboxamide dihvdrochloride
Elemental analysis value (as C28H36N602 / 2 HCl / H20)
Calculated (%) C: 58.03 H: 6.96 N: 14.50
Found (%) C: 58.05 H: 6.91 N: 14.59
Positive ion FAB-MS m z: 489 [M+H]+
Specific rotation [a]20 D =+55.88 (c =0.476 methanol)
Appearance: white powder
Example 207
4-[(Y 1 S.2RV2- { [imino(phenyl methyl] amino } cvclohexyPaminol -N-G -methoxypropyD-6-m ethylquinazolin-2-carboxamide dihvdrochloride
Elemental analysis value (as C27H34N602 / 2 HC1 / 2.5 H20)
Calculated (%) C: 54.73 H: 6.97 N: 14.18
Found (%) C: 54.71 H: 6.60 N: 14.21
Positive ion FAB-MS m/z: 475 [M+H]+
Specific rotation [a]20 D =+73.66 (c =0.505 methanol)
Appearance: pale brown powder
Example 208
4-[ iS.2RV2-{[amino(memoxyimino memyl]aminolcyclohexynaminol-N-(2-methoxyeth ylV6-methylquinazolin-2-carboxamide dihydrochloride
Step L 4-1 [Π S.2RV2-('cyanoamino cyclohexyl]aminol-
N-(2-methoxyethyn-6-methylquinazolin-2-carboxamide
In an argon atmosphere, to a solution of 3.30 g of 4- { [( 1 S,2R)-2-aminocyclohexyl]amino } -N-(2-methoxyethyl)-6-methylquinazolin-2-carbox amide in 80 ml of tetrahydrofuran, 1.54 ml of triethylamine and 978 mg of cyanogen bromide were sequentially added at -20°C, and the mixture was stirred at the same temperature for 0.5 hour. Water was added to the reaction solution, and the mixture was subjected to an extraction with ethyl acetate. The organic layer was washed with water and saturated brine and dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (chloroform : methanol = 50 : 1), whereby 1.96 g of a desired compound was obtained as a pale yellow crystal.
Step 2j 4-[((Ί S.2R -2-{ [amino(methoxyimino methyll aminolcvclohexyDamino]-N-(2-memoxyethylV6-methylquinazolin-2-carboxamide
To a solution of 1.96 g of 4-{[(lS,2R)-2- (cyanoamino)cyclohexyl]amino}-N-(2-methoxyethyl)-6-methylquinazolin-2-carboxamide and 8.56 g of methoxyamine hydrochloride in 80 ml of ethanol, 10.86 g of sodium carbonate was added and the mixture was heated at reflux for 1 hour. The reaction solution was added to 400 ml of ice water, and the deposited substance was collected by
filtration. After the collected deposited substance was washed with water, it was dried under reduced pressure. The obtained powder was washed with a mixed solution of (chloroform : diisopropyl alcohol = 1 : 1), whereby 1.71 g of a desired compound was obtained as a white powder.
Elemental analysis value (as C21H31N 03)
Calculated (%) C: 58.72 H: 7.27 N: 22.83
Found (%) C: 58.48 H: 7.17 N: 22.76
Positive ion FAB-MS m/z: 430 [M+H]+
Appearance: white powder
Step. 3j 4-ff (1 S.2RV2-I [aminoCmethoxyimino^methyll aminolcvclohexyl amino]-N-(2-methoxyethylV6-methylquinazolin-2-carboxamide dihvdrochloride
1.71 g of 4-[((lS,2R)-2-{[amino(methoxyimino) methyl]amino}cyclohexyl)amino]-N-(2-methoxyethyl)-6-methylquinazolin-2-carboxamide was suspended in 20 ml of ethyl acetate, and 5 ml of a 4 N hydrogen chloride-ethyl acetate solution was added thereto, and the mixture was stirred for 15 minutes. To the reaction solution, 40 ml of diethyl ether was added, and the resulting deposited substance was collected by filtration, washed with diethyl ether and dried under reduced pressure, whereby 2.01 g of a desired compound was obtained as a white powder.
Positive ion FAB-MS m/z: 430 [M+H]+
Specific rotation [a]20 D =+56.80 (c =0.500 methanol)
In the same manner as in Example 208, the following compounds of Examples 209 to 247, 249 and 250 were produced.
Example 209
4- [(( 1 S.2F -2- { [amino(methoxyimino)methyl] amino I cyclohexynamino] -N-(4-methoxyphe nylV6-methylquinazolin-2-carboxamide dihvdrochloride
Elemental analysis value (as C25H31N703 / 2 HC1 / 0.6 H20)
Calculated (%) C: 53.50 H: 6.14 N: 17.48
Found (%) C: 53.81 H: 6.11 N: 17.14
Positive ion FAB-MS m/z: 478 [M+H]+
Specific rotation [a]20 D =-20.23 (c =0.771 methanol)
Appearance: yellow powder
Example 210
4- [(( 1 S.2RV2- ( [amino(hydroxyimino methyl] amino } cyclohexynamino] -N-(4-methoxyphe nylV6-methylquinazolin-2-carboxamide dihvdrochloride
Elemental analysis value (as C24H29N703 / 2 HC1 / H20)
Calculated (%) C: 51.99 H: 6.00 N: 17.68
Found (%) C: 52.23 H: 6.07 N: 17.55
Positive ion FAB-MS m/z: 464 [M+H]+
Specific rotation [a]20 D =-34.15 (c =0.650 methanol)
Appearance: pale yellow powder
[0050]
Example 211
4- [((I S.2RV2- { [aminofmethoxyimino'lmethyll amino I cvclohexynamino] -N-isobutyl-6-met hylquinazolin-2-carboxamide dihvdrochloride
Elemental analysis value (as C22H33N702 / 2 HC1 / 2.5 H20)
Calculated (%) C: 48.44 H: 7.39 N: 17.97
Found (%) C: 48.59 H: 7.05 N: 17.88
Positive ion FAB-MS m/z: 428 [M+H]+
Specific rotation [a]20 D =+45.71 (c =0.525 methanol)
Appearance: white powder
Example 212
4-\(( 1 S ,2RV2- { [aminofhvdroxyimino methyl] amino ) cvclohexyDamino] -N-isobutyl-6-meth ylquinazolin-2-carboxamide dihvdrochloride
Positive ion FAB-MS m/z: 414 [M+H]+
Specific rotation [a]20 D =+33.55 (c =0.590 methanol)
Appearance: white powder
Example 213
4-[(( 1 S,2R>2- ( [amino(memoxyimino)memyl] amino } cyclohexynamino] -6-methyl-N-(n-pr opyl)quinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C21H31N702 / 2 HC1 / 1.8 H20)
Calculated (%) C: 48.61 H: 7.11 N: 18.90
Found (%) C: 48.32 H: 6.71 N: 18.60
Positive ion FAB-MS m/z: 414 [M+H]+
Specific rotation [a]20 D =+48.84 (c =0.520 methanol)
Appearance: white powder
Example 214
4- [(( 1 S .2RV2- { [aminof memoxyimino^methyl] amino } cyclohexyDamino] -N-(cyclopropylm ethyl -6-methylquinazolin-2-carboxamide dihydrochloride
Positive ion FAB-MS m/z: 426 [M+H]+
Specific rotation [a] D =+46.72 (c =0.535 methanol)
Appearance: white powder
Example 215
4-[(( 1 S.2RV2- { [amino(methoxyiminotoethyl] amino } cyclohexynamino] -N-(2-hydroxyethy lV6-methylquinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C20H29N7O3 / 2 HC1 / 3 H20)
Calculated (%) C: 44.28 H: 6.87 N: 18.07
Found (%) C: 44.59 H: 6.48 N: 18.14
Positive ion FAB-MS m/z: 416 [M+H]+
Specific rotation [a] D =+56.32 (c =0.625 methanol)
Appearance: white powder
Example 216
4-\(( 1 S.2RV2- ( [amino(memoxyimino memyl] amino } cvclohexyl)amino]-N-isopropyl-6-me thylquinazolin-2-carboxamide dihvdrochloride
Elemental analysis value (as C2iH3iN702 / 2 HC1 / 2 H20)
Calculated (%) C: 48.28 H: 7.14 N: 18.77
Found (%) C: 48.52 H: 6.79 N: 18.72
Positive ion FAB-MS m/z: 414 [M+H]+
Specific rotation [a]20 D =+43.61 (c =0.720 methanol)
Appearance: white powder
Example 217
4-f (( 1 S.2RV2- { [amino(methoxyimino methyl]amino I cyclohexyl)amino]-N-cyclopropyl-6- methylquinazolin-2-carboxamide dihydrochloride
Positive ion FAB-MS m/z: 412 [M+H]+
Specific rotation [a]20 D =+49.39 (c =0.575 methanol)
Appearance: white powder
Example 218
4-f (Y 1 S.2RV2- { [amino(methoxyimino methyl] amino } cvclohexyDamino] -N-cyclobutyl-6-m ethylquinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C22H31N702 / 2 HC1 / 1.6 H20)
Calculated (%) C: 50.11 H: 6.92 N: 18.59
Found (%) C: 50.19 H: 6.69 N: 18.55
Positive ion FAB-MS m/z: 426 [M+H]+
Specific rotation [a]20 D =+35.10 (c =0.490 methanol)
Appearance: white powder
Example 219
-trifluoroethyl quinazolin-2-carboxamide dihydrochloride
Positive ion FAB-MS m/z: 454 [M+H]+
Specific rotation [a]20 D =+56.92 (c =0.520 methanol)
Appearance: white powder
Example 220
4-[(Y 1 S .2RV2- { [aminof memoxyiminolmethyl] amino I cyclohexynamino] -N-ethyl-N.6-dime thylquinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C21H31N702 / 2 HC1 / 2.3 H20)
Calculated (%) C: 47.78 H: 7.18 N: 18.57
Found (%) C: 47.80 H: 6.74 N: 18.53
Positive ion FAB-MS m/z: 414 [M+H]+
Specific rotation [a]20 D =+37.14 (c =0.490 methanol)
Appearance: white powder
[0051]
Example 221
4- \(( 1 S,2R)-2- ( fiminoC 1 ,2-oxazinan-2-yl")methyl]amino } cyclohexy0amino]-N-( -methoxy phenylV6-methylquinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C28H35N703 / 2 HC1 / 0.8 H20)
Calculated (%) C: 55.59 H: 6.43 N: 16.21
Found (%) C: 55.89 H: 6.66 N: 15.87
Positive ion FAB-MS m/z: 518 [M+H]+
Specific rotation [a]20 D =-14.90 (c =0.510 methanol)
Appearance: yellow powder
Example 222
6-chloro-N-cycloheptyl-4-[ iS.2R -2-|[iminon.2-oxazinan-2-vnmethyl]amino}cyclohexy l~)amino]quinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C27H38N702C1 / 2 HC1 / 2.2 H20)
Calculated (%) C: 50.62 H: 6.99 N: 15.30
Found (%) C: 50.45 H: 6.59 N: 15.19
Positive ion FAB-MS m/z: 528 [M+H]+
Specific rotation [a]20 D =+57.73 (c =0.485 methanol)
Appearance: white powder
Example 223
4-\((l S .2RV2- { [iminoC 1.2-oxazinan-2-yQmethyl] amino I cvclohexynamino] -N-isobutyl-6- methylquinazolin-2 -carboxamide dihvdrochloride
Elemental analysis value (as C25H37N702 / 2 HC1 / H20)
Calculated (%) C: 53.76 H: 7.40 N: 17.55
Found (%) C: 53.51 H: 7.20 N: 17.26
Positive ion FAB-MS m/z: 468 [M+H]+
Specific rotation [a] D =+56.76 (c =0.532 methanol)
Appearance: white powder
Example 224
N-cvcloheptyl-4-l"(Yl S,2R -2-( [iminon .2-oxazinan-2-ynmethyl]amino}cyclohexynamino]-
6-methylquinazolin-2-carboxamide dihvdrochloride
Elemental analysis value (as C28H41N702 / 2 HC1 / 1.5 H20)
Calculated (%) C: 55.35 H: 7.63 N: 16.14
Found (%) C: 55.67 H: 7.73 N: 15.92
Positive ion FAB-MS m/z: 508 [M+H]+
Specific rotation [a]20 D =+52.47 (c =0.404 methanol)
Appearance: white powder
Example 225
6-chloro-N-cycloheptyl-4- [(Y 1 S .2RV2- 1 [imino(isoxazolidin-2- vDmethyl] amino } cyclohexyl )amino]quinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C26H36N702C1 / 2 HC1 / 2.5 H20)
Calculated (%) C: 49.41 H: 6.86 N: 15.51
Found (%) C: 49.18 H: 6.86 N: 15.41
Positive ion FAB-MS m/z: 514 [M+H]+
Specific rotation [a]20 D =+76.82 (c =0.492 methanol)
Appearance: white powder
Example 226
4- [id S .2RV 2 - ( [aminofmethoxyiminolmethy 1] amino } cyclohexyDamino] -6-chloro-N-cyclo heptylquinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C24H34N702C1 / 2 HC1 / H20)
Calculated (%) C: 49.79 H: 6.62 N: 16.93
Found (%) C: 49.66 H: 6.54 N: 17.12
Positive ion FAB-MS m/z: 488 [M+H]+
Specific rotation [a]20 D =+54.20 (c =0.424 methanol)
Appearance: white powder
Example 227
6-chloro-N-cycloheptyl-4-(|Y lS.2R)-2-r(imino[methoxyfmethyDamino]methyl}amino')cycl ohexyllamino>quinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C25H36N702C1 / 2 HC1 / 2.5 H20)
Calculated (%) C: 48.43 H: 6.99 N: 15.81
Found (%) C: 48.28 H: 6.60 N: 15.97
Positive ion FAB-MS m/z: 502 [M+H]+
Specific rotation [a]20 D =+78.83 (c =0.515 methanol)
Appearance: white powder
Example 228
N-f2.2-dimethylpropyiy4-[((lS,2R>2-([im^
amino] -6-methylquinazolin-2-carboxamide dihydrochloride
Positive ion FAB-MS m/z: 468 [M+H]+
Specific rotation [a]20 D =+50.28 (c =0.533 methanol)
Appearance: white powder
Example 229
4- |"(Y 1 S.2RV2- ( [imino(isoxazolidin-2-yl methyl] amino ) cyclohexyl amino] -6-methyl-N- [3 -( methylthiolpropyl] quinazolin-2-carboxamide dihvdrochloride
Elemental analysis value (as C24H35N702S / 2 HC1 / H20)
Calculated (%) C: 49.99 H: 6.82 N: 17.00
Found (%) C: 50.05 H: 6.72 N: 16.87
Positive ion FAB-MS m/z: 486 [M+H]+
Specific rotation [a]20 D =+56.42 (c =0.514 methanol)
Appearance: white powder
Example 230
4-[((lS.2R -2-([imino(isoxazolidin-2-y^
2.2-dimethylpropylV6-methylquinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C26H39N703 / 2 HC1 / H20)
Calculated (%) C: 53.06 H: 7.36 N: 16.66
Found (%) C: 53.44 H: 7.13 N: 16.52
Positive ion FAB-MS m/z: 498 [M+H]+
Specific rotation [a]20 D =+48.19 (c =0.527 methanol)
Appearance: pale yellow powder
[0052]
Example 231
4-[((lS,2R -2-{[imino(isoxazolidin-2-vnmethyl]amino}cvclohexynamino1-6-methyl-N-('tet rahydro-2H-pyran-4-y Dquinazolin-2 -carboxamide dihydrochloride
Elemental analysis value (as C25H35N703 / 2 HC1 / 2.4 H20)
Calculated (%) C: 50.23 H: 7.05 N: 16.40
Found (%) C: 50.29 H: 6.88 N: 16.39
Positive ion FAB-MS m/z: 482 [M+H]+
Specific rotation [a] D =+62.18 (c =0.550 methanol)
Appearance: white powder
Example 232
4-[(( 1 S,2R)-2- { [imino(isoxazolidin-2-yDmemyl]amino I cyclohexyDaminol -N-(trans-4-meth oxycyclohexylV6-methylquinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C27H39N703 / 2 HC1 / 2 H20)
Calculated (%) C: 52.42 H: 7.33 N: 15.85
Found (%) C: 52.13 H: 7.19 N: 15.69
Positive ion FAB-MS m/z: 510 [M+H]+
Specific rotation [a]20 D =+61.67 (c =0.548 methanol)
Appearance: white powder
Example 233
N-(2-emylbutylV4-[((lS,2R)-2-{[iminofo
]-6-methylquinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C26H39N702 / 2 HC1 / H20)
Calculated (%) C: 54.54 H: 7.57 N: 17.12
Found (%) C: 54.49 H: 7.38 N: 16.91
Positive ion FAB-MS m/z: 482 [M+H]+
9Ω
Specific rotation [a] D =+52.57 (c =0.563 methanol)
Appearance: white powder
Example 234
N-(2.2-dimethylpropylV4-([(lS,2R -2-(|imino[methoxy(methynamino]methyl}amino )cvcl ohexyl] amino )-6-methylquinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C24H37N702 / 2 HC1 / 0.5 H20)
Calculated (%) C: 53.63 H: 7.50 N: 18.24
Found (%) C: 53.63 H: 7.56 N: 17.89
Positive ion FAB-MS m/z: 456 [M+H]+
Specific rotation [a]20 D =+64.07 (c =0.518 methanol)
Appearance: white powder
Example 235
4- [(( 1 S .2RV2- ( [imino(isoxazolidin-2-ynmethyl] amino } cyclohexyPamino] -N-isobutyl-6-m ethylquinazolin-2 -carboxamide dihydrochloride
Elemental analysis value (as C24H35N702 / 2 HC1 / 1.2 H20)
Calculated (%) C: 52.59 H: 7.25 N: 17.89
Found (%) C: 52.55 H: 7.13 N: 17.59
Positive ion FAB-MS m/z: 454 [M+H]+
Specific rotation [a]20 D =+59.96 (c =0.507 methanol)
Appearance: white powder
Example 236
4- { [( 1 S .2RV2 -( { imino [methoxyfmethynamino] methyl } aminotevclohexy 1] amino I -N-isobut yl-6-methylquinazolin-2-carboxamide dihvdrochloride
Elemental analysis value (as C23H35N702 / 2 HC1 / 0.7 H20)
Calculated (%) C: 52.41 H: 7.34 N: 18.60
Found (%) C: 52.44 H: 7.22 N: 18.26
Positive ion FAB-MS m/z: 442 [M+H]+
Specific rotation [a]20 D =+73.00 (c =0.526 methanol)
Appearance: white powder
Example 237
4-{[(lS,2R -2-f(imino[memoxyimethy
-4-methoxycvclohexyn-6-methylquinazolin-2-carboxamide dihvdrochloride
Elemental analysis value (as C26H39N703 / 2 HC1 / H20)
Calculated (%) C: 53.06 H: 7.36 N: 16.66
Found (%) C: 53.34 H: 7.17 N: 16.40
Positive ion FAB-MS m/z: 498 [M+H]+
Specific rotation [a]20 D =+70.16 (c =0.496 methanol)
Appearance: white powder
Example 238
4- { [( 1 S,2R>2-( { imino [methoxy(methvDamino] methyl I aminoteyclohexy 1] amino } -N-(3 -me thoxypropyn-6-methylquinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C23H35N703 / 2 HC1 / 2 H20)
Calculated (%) C: 48.76 H: 7.29 N: 17.31
Found (%) C: 48.38 H: 6.89 N: 17.14
Positive ion FAB-MS m/z: 458 [M+H]+
Specific rotation [a]20 D =+66.80 (c =0.500 methanol)
Appearance: white powder
Example 239
4- [(( 1 S.2RV2- ( |"amino(methoxyimino methyl] amino } cyclohexynammo] -N-(3 -methoxypro pylV6-methylquinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C22H33N703 / 2 HC1 / 2.2 H20)
Calculated (%) C: 47.36 H: 7.15 N: 17.57
Found (%) C: 47.19 H: 6.76 N: 17.50
Positive ion FAB-MS m/z: 444 [M+H]+
Specific rotation [a]20 D =+47.45 (c =0.510 methanol)
Appearance: white powder
Example 240
4- [(( 1 S .2RV2- { [amino(hydroxyimino methyl]amino } cyclohexynammo] -N-(3 -methoxypro pyn-6-methylquinazolin-2-carboxamide dihydrochloride
Positive ion FAB-MS m/z: 430 [M+H]+
Specific rotation [a]20 D =+31.28 (c =0.505 methanol)
Appearance: white powder
[0053]
Example 241
-6-methylquinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C23H33N703 / 2 HC1 / 2 H20)
Calculated (%) C: 47.83 H: 7.11 N: 17.75
Found (%) C: 47.59 H: 6.94 N: 17.72
Positive ion FAB-MS m/z: 444 [M+H]+
Specific rotation [a]20 D =+57.20 (c =0.500 methanol)
Appearance: white powder
Example 242
4-[(Y 1 R.2S )-2- ( [aminofmethoxyimino^memyl] amino 1 cyclohexynamino]-N-(2-methoxyeth ylV6-methylquinazolin-2-carboxamide dihydrochloride
Positive ion FAB-MS m/z: 430 [M+H]+
Specific rotation [a]20 D =-53.09 (c =0.550 methanol)
Appearance: white powder
Example 243
4-[(nS,2RV2-([amino(emoxyimino^methyllaminolcvclohexynamino]-N-(2-methoxyethyn -6-methylquinazolin-2-carboxamide dihydrochloride
Positive ion FAB-MS m/z: 444 [M+H]+
Specific rotation [a]20 D =+55.04 (c =0.505 methanol)
Appearance: white powder
Example 244
4-[(Y 1 S.2RV2- { [amino(propoxyimino)methyl]amino 1 cyclohexynamino] -N- 2-methoxyethy l -6-methylquinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C23H35N703 / 2 HC1 / 3.3 H20)
Calculated (%) C: 49.23 H: 7.26 N: 17.47
Found (%) C: 48.97 H: 6.88 N: 17.48
Positive ion FAB-MS m/z: 458 [M+H]+
Specific rotation [a]20 D =+50.29 (c =0.505 methanol)
Appearance: white powder
Example 245
4-{[(lS.2Ry2-(jamino[(2-methoxyethoxy imin^
methoxyethylV6-methylquinazolin-2-carboxamide dihvdrochloride
Elemental analysis value (as C23H35N704 / 2 HC1 / 2.4 H20)
Calculated (%) C: 46.84 H: 7.14 N: 16.63
Found (%) C: 46.82 H: 6.82 N: 16.50
Positive ion FAB-MS m/z: 474 [M+H]+
Specific rotation [a]20 D =+48.40 (c =0.500 methanol)
Appearance: white powder
Example 246
4- ( [( 1 S.2R -2-( { amino [(2-fluoroethoxy imino]methyl \ amino)cyclohexyl] amino } -N-(2-met hoxyethyl -6-methylquinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C22H32N703F / 2 HC1 / 2 H20)
Calculated (%) C: 46.32 H: 6.71 N: 17.19
Found (%) C: 46.32 H: 6.36 N: 17.09
Positive ion FAB-MS m/z: 462 [M+H]+
Specific rotation [a]20 D =+47.76 (c =0.515 methanol)
Appearance: white powder
Example 247
4-( ( ( 1 S.2RV 2- [(amino I [2-(methylthio ethoxy]imino } methvDamino] cyclohexyl > aminoVN- (2-methoxyethyl -6-methylquinazolin-2-carboxamide dihvdrochloride
Elemental analysis value (as C23H35N703S / 2 HC1 / 2 H20)
Calculated (%) C: 46.15 H: 6.90 N: 16.38
Found (%) C: 46.05 H: 6.73 N: 16.26
Positive ion FAB-MS m/z: 490 [M+H]+
Specific rotation [a]20 D =+39.19 (c =0.500 methanol)
Appearance: white powder
Example 248
4-[( i S,2RV2-( amino(methoxyimino memyllamino}cvclohexyl')amino]-N-(2-methoxyeth yl -6-methylquinazolin-2-carboxamide 1/2 sulfate
300 mg of 4-[((lS,2R)-2-{[amino(methoxyimino) methyl]amino}cyclohexyl)amino]-N-(2-methoxyethyl)-6-methylquinazolin-2-carboxamide was suspended in 9 ml of methanol, and 35.4 mg of concentrated sulfuric acid was added thereto. After the mixture was stirred for 15 minutes, 75 ml of diisopropyl ether was added thereto. The deposited substance was collected by filtration, washed with diisopropyl ether and dried under reduced pressure, whereby 314 mg of a desired compound was obtained as a white powder.
Elemental analysis value (as C21H31N703 / 0.5 H2S04 / 1.5 H20)
Calculated (%) C: 49.89 H: 6.98 N: 19.39
Found (%) C: 49.78 H: 6.61 N: 19.18
Positive ion FAB-MS m/z: 430 [M+H]+
Specific rotation [a] D =-27.63 (c =0.550 methanol)
Example 249
4- [(Y 1 S .2RV2- { [amino(methoxyimino)memyl] amino } cyclohexyPamino] -6-methylquinazoli n-2-carboxamide dihydrochloride
Positive ion FAB-MS m/z: 372 [M+H]+
Specific rotation [a]20 D =+57.20 (c =0.465 methanol)
Appearance: white powder
Example 250
4- [(( 1 S.2RV2- ( [amino(methoxyimino methyl] amino I cyclohexyDamino] -N-methoxy-6-met hylquinazolin-2-carboxamide dihydrochloride
Elemental analysis value (as C19H27N703 / 2 HC1 / 0.8 H20)
Calculated (%) C: 46.69 H: 6.31 N: 20.06
Found (%) C: 46.95 H: 6.27 N: 19.87
Positive ion FAB-MS m/z: 402 [M+H]+
Specific rotation [a]20 D =+8.80 (c =0.500 methanol)
Appearance: white powder
[0054]
Test example 1 : NOP receptor binding assay
A cell membrane suspension obtained from a human NOP receptor-expressing cell was prepared so that it contained 5 to 10 pg/mL of the membrane protein in a Tris buffer [50 mM Tris-HCl (pH7.8), 5 mM MgC12, 1 mM EGTA, 0.1% BSA]. To this, [3H]nociceptin (diluted at the final concentration of 0.08 nM with the Tris buffer) and a tested substance were added and the mixture was incubated at 25°C for 60 minutes. Using a cell harvester and a washing solution [50 mM Tris-HCl (pH7.8), 4°C], the membrane was recovered onto a GF/B filter which had been pretreated with 0.3% PEI, which was then washed further 4 times. The filter was transferred to a vial, to which a scintillator was added, and the radioactivity was measured using a liquid scintillation counter. Noted that a non-specific binding was regarded as a binding in the presence of 10 pico mol (PM) nociceptin, and a specific binding was obtained by subtracting the non-specific binding from the total binding. From a ratio of binding inhibition in the presence of the tested substance, an IC50 value was obtained.
Table 1
Example No IC50 value(nM)
35 740.2
58 755.4
60 965.1
90 94.7
92 674.1
227 7.5
234 87.6
236 35.4
240 241.5
248 362.9
According to example 1 and Table 1, the inventive antagonists have an excellent NOP receptor binding ability. These results indicate that it can be used as a therapeutic agent for a troublesome disease such as pain, migraine, rheumatoid arthritis and neuralgia and as an agent for overcoming the resistance to morphine or the like.
[0055]
Preparation example 1
100 g of the inventive antagonist of Example 1, 292 g of D-mannitol, 120 g of corn starch and 28 g of low-substituted hydroxypropyl cellulose are placed in a fluidized bed granulation dryer (STREA; manufactured by PAUREC) and granulated with spraying a certain amount of an aqueous 5% hydroxypropyl cellulose solution. After drying and then milling with a grinding/milling machine (COMIL; manufactured by PAULEC), a certain amount of magnesium stearate is mixed therewith in a mixer (BOHRE container mixer Model MC20; manufactured by KOTOBUKI-GIKEN), and the mixture is molded into tablets with a diameter of 7 mm and a weight of 140 mg per tablet with a rotary tablet compacting machine (CORRECT 12HUK; manufactured by KIKUSUI), whereby a tablet containing 25 mg of the inventive antagonist is obtained.
Preparation example 2
75 g of the inventive antagonist of Example 1, 180 g of lactose, 75 g of corn starch and 18 g of carmellose calcium are placed in a stirring granulator (vertical granulator model VG-01), and a certain amount of an aqueous 5% hydroxypropylmethyl cellulose solution is
added thereto and the mixture is granulated and dried by a fluidized bed granulation dryer (STREA; manufactured by PAUREC) and then milled by a grinding/milling machine (COMIL; manufactured by PAULEC). 120 mg of the milled material is filled into a No. 3 capsule using a capsule filling machine (capsule filler; SHIONOGI QUALICAPS), whereby a capsule containing 25 mg of the inventive antagonist is obtained.
Preparation example 3
2.5 g of the inventive antagonist of Example 1 and 4.5 g of sodium chloride are weighed, and 450 ml of water for injection is added thereto and the mixture is stirred and dissolved, and then adjusted to pH 6.5 with 0.1 mol/1 hydrochloric acid or 0.1 mol/1 sodium hydroxide. Then water for injection is added to make the total volume 500 ml. The solution thus prepared is filtered under pressure through a membrane filter (pore size: 0.22 μπι). Then 5.3 ml of the filtrate is aseptically filled into a sterilized 5 ml brown ampoule, whereby an injection formulation containing 25 mg of the inventive antagonist is obtained. The procedure from the preparation through the filling is performed in an aseptic manner. Preparation example 4
99.75 g of WITEPSOL H-15 (manufactured by HIRTH) is dissolved at 45°C and 0.25 g of the inventive antagonist of Example 1 is added thereto and dispersed therein by stirring. The resulting dispersion is infused into a 1 g suppository mold while paying attention to preventing deposition at a high temperature, solidified and taken out from the mold, whereby a suppository containing 25 mg of the inventive antagonist is obtained. Preparation example 5
0.5 g of the inventive antagonist of Example 1, 5.2 g of sodium dihydrogen phosphate, 11.9 g of sodium monohydrogen phosphate, 2.5 g of sodium chloride and 0.3 g of benzalkonium chloride are weighed, and 950 ml of purified water is added thereto, and the mixture is stirred and dissolved. Then purified water is added to make the total volume 1000 ml. The solution thus prepared is filtered under pressure through a membrane filter (pore size: 0.2 μηι). Then, 5 ml of the filtrate is filled aseptically to a
sterilized 5 ml eye drop bottle, whereby an eye drop (5 ml) containing 0.5 mg/ml of the inventive antagonist is obtained. The procedure from the preparation through the filling is performed in an aseptic manner.
Preparation example 6
80 g of olive oil, 15 g of cetyl alcohol and 15 g of stearyl alcohol are weighed, and the mixture is stirred and dissolved while heating to 70°C on a water bath (oil phase). Separately, 1 g of the inventive antagonist of Example 1, 10 g of Polysolvate 80, 5 g of sodium lauryl sulfate, 0.25 g of methyl parahydroxybenzoate, 0.15 g of propyl parahydroxybenzoate and 880 g of purified water are weighed, and the mixture is stirred and dissolved while heating to 70°C on a water bath (aqueous phase). The oil phase and the aqueous phase are placed in a vacuum emulsifying apparatus and then the mixture is emulsified while stirring at a high speed in a homomixer at 70°C under vacuum. Then, the resulting emulsion is water-cooled to 35°C while stirring at a low speed. Then 50 ml of the resulting emulsion is filled into a 50 ml container for lotion, whereby a lotion (50 ml) containing 1.0 mg/ml of the inventive antagonist is obtained.
Preparation example 7
250 g of white petrolatum, 250 g of stearyl alcohol and 40 g of polyoxyethylene hydrogenated castor oil 60 are weighed, and the mixture is stirred and dissolved while heating to 70°C on a water bath (oil phase). Separately, 1 g of the inventive antagonist of Example 1, 120 g of propylene glycol, 0.25 g of methyl parahydroxybenzoate, 0.15 g of propyl parahydroxybenzoate and 340 g of purified water are weighed, and the mixture is stirred and dissolved while heating to 70°C on a water bath (aqueous phase). The oil phase and the aqueous phase are placed in a vacuum stirring and mixing apparatus and then the mixture is emulsified while stirring at 70°C under vacuum. An ointment obtained by cooling the resulting emulsion and slowly stirring until the emulsion is solidified is filled into a 10 g ointment bottle or a 10 g ointment tube, whereby an ointment containing 1.0 mg/g of the inventive antagonist is obtained.
Preparation example 8
110 g of gelatin, 25 g of polyvinyl alcohol and 10 g of methylcellulose are weighed and mixed to obtain a mixed powder. Then, 13 g of glycerin is added thereto, and the powder is dispersed therein using a small-sized mixer. Then, 100 g of purified water is added thereto, and the mixture is dissolved therein while heating to 60°C. Further, 85 g of kaolin is added thereto and dispersed therein at 60°C. A dispersion separately obtained by mixing 20 g of glycerin with 5 g of sodium polyacrylate is added thereto, and dissolved and dispersed therein at 60°C. Then 15 g of polybutene is added thereto and dispersed therein at 60°C. To the dispersion, 0.5 g of the inventive antagonist of Example 1 is added and dispersed therein at 50°C thereby obtaining a paste. Then, the paste is spread over a support (nonwoven fabric) (100 g/700 cm ), and then the coated support is covered with a liner made of a polyethylene film (50 μηι) and cut, whereby an adhesive preparation is obtained. The inventive antagonist is contained in an amount of 1 mg in 7 cm of the adhesive preparation.
INDUSTRIAL APPLICABILITY
[0056] Since the inventive antagonist has an excellent NOP receptor binding ability, it can be used for a prolonged period safely as a therapeutic agent against a dolorous disease such as a pain, migraine, rheumatoid arthritis and neuralgia and as an agent for overcoming the resistance to morphine or the like.
Claims
1. A non-opioid branch of the opioid peptide family of receptors antagonist which is a compound represented by the following general formulas [1], or a pharmaceutically acceptable salt thereof:
[Chemical Formula 1]
[1]
wherein R1 represents hydrogen or alkyl;
R represents hydrogen, alkoxy, tetrahydropyranyl, phenyl, cycloalkyl, (cycloalkyl)alkyl or alkyl, in which the alkoxy, tetrahydropyranyl, phenyl, cycloalkyl, (cycloalkyl)alkyl and alkyl may be substituted with 1 to 3 groups selected from the group consisting of (1) alkoxy, (2) halogen, (3) alkoxyalkyl, (4) hydroxy, (5) alkylthio, (6) a 5- to 10-membered aromatic heterocyclic group containing 1 to 3 heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, (7) a 5- to 7-membered saturated aliphatic heterocyclic group which may be substituted with acyl and contains 1 to 3 nitrogen atoms, and (8) phenyl which may be substituted with halogen or alkoxy;
R3 and R4 are the same or different and each represents hydrogen, alkyl, alkoxy or halogen;
R5 is combined with R6 to represent alkylene, or represents hydrogen, hydroxy, alkyl, phenyl or alkoxy, in which the alkylene may be substituted with hydroxy or oxo, and may be condensed with a benzene ring; the alkyl, phenyl and alkoxy represented by R5 may
be substituted with 1 to 3 groups selected from the group consisting of alkoxy, alkylthio and halogen; and
R6 represents (1) alkyl, (2) cycloalkyl, (3) phenyl, (4) a 5- to 10-membered aromatic heterocyclic group containing 1 to 3 heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom or (5) -N(R 61 )(R 62 ), in which the alkyl, cycloalkyl, phenyl and aromatic heterocyclic group may be substituted with 1 to 3 groups selected from the group consisting of (1) alkoxy, (2) hydroxy, (3) phenyl, (4) pyridyl, (5) furyl, (6) halogen and (7) N,N-dialkylamino; R61 is combined with R62 to represent -0-(CH2)n-, or represents hydrogen or alkyl; R represents hydrogen or alkoxy which may be substituted with 1 to 3 groups selected from the group consisting of alkoxy, alkylthio and halogen; n represents an integer of 3 to 5;
With the proviso that a compound wherein R5 is hydrogen and R6 is -NH2 is excluded.
2. The non-opioid branch of the opioid peptide family of receptors antagonist according to claim 1, wherein
R5 is combined with R6 to represent alkylene or is hydrogen, alkyl, phenyl or alkoxy, in which the alkylene may be substituted with hydroxy or oxo, and may be condensed with a benzene ring; and
R6 is (1) alkyl, (2) cycloalkyl, (3) phenyl, or (4) a 5- to 10-membered aromatic heterocyclic group containing 1 to 3 heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, in which the alkyl, cycloalkyl, phenyl and aromatic heterocyclic group may be substituted with 1 to 3 groups selected from the group consisting of (1) alkoxy, (2) hydroxy, (3) phenyl, (4) pyridyl, (5) furyl, (6) halogen and (7) N,N-dialkylamino.
3. The non-opioid branch of the opioid peptide family of receptors antagonist according to claim 1, wherein
R2 is hydrogen, tetrahydropyranyl, phenyl, cycloalkyl, (cycloalkyl)alkyl or alkyl, in which
the tetrahydropyranyl, phenyl, cycloalkyl, (cycloalkyl)alkyl and alkyl may be substituted with 1 to 3 groups selected from the group consisting of (1) alkoxy, (2) halogen, (3) hydroxy, and (4) alkylthio;
R3 and R4 are the same or different and each is hydrogen, alkyl or halogen;
R5 is hydrogen, hydroxy or alkoxy which may be substituted with 1 to 3 groups selected from the group consisting of alkoxy, alkylthio and halogen; and
R6 is -N(R61)(R62), in which R61 is combined with R62 to form -0-(CH2)„-, in which n represents an integer of 3 to 5, or is hydrogen or alkyl; R is hydrogen or alkoxy which may be substituted with 1 to 3 groups selected from the group consisting of alkoxy, alkylthio and halogen.
4. The non-opioid branch of the opioid peptide family of receptors antagonist according to claim 1, wherein
R is (1) hydrogen, (2) alkoxy, (3) tetrahydropyranyl, (4) phenyl which may be substituted with alkoxy, (5) cycloalkyl which may be substituted with 1 to 3 groups selected from the group consisting of halogen, alkoxy, alkoxyalkyl and hydroxy, (6) (cycloalkyl)alkyl which may be substituted with 1 to 3 groups selected from the group consisting of alkoxyalkyl and hydroxy or (7) alkyl;
R5 is combined with R6 to represent alkylene or is hydrogen, alkyl, phenyl or hydroxy, in which the alkylene may be substituted with hydroxy or oxo, and may be condensed with a benzene ring; and
R6 represents (1) alkyl which may be substituted with 1 to 3 groups selected from the group consisting of alkoxy, hydroxy, N,N-dialkylamino, phenyl, pyridyl and furyl, (2) cycloalkyl, (3) phenyl which may be substituted with 1 to 3 groups selected from the group consisting of alkoxy, halogen and Ν,Ν-dialkylamino or (4) a 5- to 10-membered aromatic heterocyclic group containing 1 to 3 heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom.
5. The non-opioid branch of the opioid peptide family of receptors antagonist
according to claim 1, wherein R2 is (1) hydrogen, (2) tetrahydropyranyl, (3) phenyl which may be substituted with alkoxy, (4) cycloalkyl which may be substituted with alkoxy, (5) (cycloalkyl)alkyl or (6) alkyl which may be substituted with 1 to 3 groups selected from the group consisting of halogen, hydroxy, alkoxy and alkylthio;
R3 and R4 are the same or different and each is hydrogen, alkyl or halogen;
R5 is (1) hydrogen, (2) hydroxy or (3) alkyl which may be substituted with 1 to 3 groups selected from the group consisting of alkoxy, alkylthio and halogen; and
R6 is -N(R61)(R62), in which R61 is combined with R62 to form -0-(CH2)„-, in which n is an integer of 3 to 5, or is hydrogen or alkyl; R is hydrogen or alkoxy.
6. The non-opioid branch of the opioid peptide family of receptors antagonist according to claim 1, which is selected from the group consisting of the following (1) to (15) compounds or a pharmaceutically acceptable salt thereof:
( 1 ) 4- { [(1 S,2R)-2-(ethanimidoylamino)cyclohexyl]amino } -N-(2-methoxyethyl)- 6-methylquinazolin-2-carboxamid,
(2) N-(2,2-dimethylpropyl)-4-({(l S,2R)-2-[(2-methoxy-2-methylpropanimidoyl)- amino]cyclohexyl}amino)-6-methylquinazolin-2-carboxamide,
(3) 4-( { ( 1 S,2R)-2- [(3 -methoxypropanimidoyl)amino] cyclohexyl } amino)-N-(3 - methoxypropyl)-6-methylquinazolin-2-carboxamide,
(4) 4-( { ( 1 S,2R)-2- [(3 -hydroxypropanimidoyl)amino] cyclohexyl } amino)-N- isopropyl-6-methylquinazolin-2-carboxamide,
(5) 4-({(lS ,2R)-2-[(3 -hydroxypropanimidoyl)amino] cyclohexyl } amino)-N-(3 - methoxypropyl)-6-methylquinazolin-2-carboxamide,
(6) 4-( { ( 1 S,2R)-2- [(2-hydroxy-2-methylpropanimidoyl)amino] cyclohexyl } amino)- N-isobutyl-6-methylquinazolin-2-carboxamide,
(7) N-(2-ethoxyethyl)-4-({(l S,2R)-2-[(3-hydroxypropanimidoyl)amino]- cyclohexyl}amino)-6-methylquinazolin-2-carboxamide,
(8) 4-({(lS,2R)-2-[(2-hydroxy-2-methylpropanimidoyl)amino]cyclohexyl}-
amino)-N-isopropyl-6-methylquinazolin-2-carboxamide,
(9) 4-({(lS,2R)-2-[(2-hydroxy-2-methylpropanimidoyl)amino]cyclohexyl}- amino)-N-(2-methoxyethyl)-6-methylquinazolin-2-carboxamide,
( 10) 4-( { ( 1 S,2R)-2- [(2-methoxyethanimidoyl)amino] cyclohexyl } amino)-N-(2- methoxyethyl)-6-methylquinazolin-2-carboxamide,
(11) 4-{[(lS,2R)-2-(ethanimidoylamino)cyclohexyl]amino}-N-(3-methoxypropyl)- 6-methylquinazolin-2-carboxamide,
( 12) 4-( { ( 1 S,2R)-2- [(2-methoxyethanimidoyl)amino] cyclohexyl } amino)-N-(3 - methoxypropyl)-6-methylquinazolin-2-carboxamide,
(13) 4- { [(1 S,2R)-2-(ethanimidoylamino)cyclohexyl]amino} -N-(2-ethoxyethyl)-6- methylquinazolin-2-carboxamide,
( 14) N-(2-ethoxyethyl)-4-( {(IS ,2R)-2- [(2-methoxyethanimidoyl)amino] - cyclohexyl }amino)-6-methylquinazolin-2-carboxamide, and
(15) 4- { [(1 S,2R)-2-(ethanimidoylamino)cyclohexyl] amino } -N-isopropyl-6- methylquinazolin-2-carboxamide.
7. The non-opioid branch of the opioid peptide family of receptors antagonist according to claim 1, which is selected from the group consisting of the following (1) to (13) compounds or a pharmaceutically acceptable salt thereof:
( 1 ) 4- [(( 1 S,2R)-2- { [amino(methoxyimino)methyl]amino } cyclohexyl)amino] -N-(2- methoxyethyl)-6-methylquinazolin-2-carboxamide,
(2) 4- [(( 1 S ,2R)-2- { [amino(methoxyimino)methyl] amino } cyclohexyl)amino] -N- isobutyl-6-methylquinazolin-2-carboxamide,
(3) 4-[((lS,2R)-2-{[amino(hydroxyimino)methyl]amino}cyclohexyl)amino]-N- isobutyl-6-methylquinazolin-2-carboxamide,
(4) 4-[(( 1 S,2R)-2- { [amino(methoxyimino)methyl]amino } cyclohexyl)amino]-N- (cyclopropylmethyl)-6-methylquinazolin-2-carboxamide,
(5) 4-[((lS,2R)-2-{[amino(methoxyimino)methyl]amino}cyclohexyl)amino]-N-
isopropyl-6-methylquinazolin-2-carboxamide,
(6) 4-{[(lS,2R)-2-({imino[methoxy(methyl)amino]methyl}amino)cyclohexyl]- amino } -N-isobutyl-6-methylquinazolin-2-carboxamide,
(7) 4- [(( 1 S,2R)-2- { [amino(methoxyimino)methyl]arnino } cyclohexyl)amino)-N-(3 - methoxypropyl)-6-methylquinazolin-2-carboxamide,
(8) 4- [(( 1 S ,2R)-2- { [amino(hydroxyimino)methyl] amino } cyclohexyl)amino] -N-(3 - methoxypropyl)-6-methylquinazolin-2-carboxamide,
(9) 4-[((lS,2R)-2-{[amino(methoxyimino)methyl]amino}cyclohexyl)amino]-N-(2- ethoxyethyl)-6-methylquinazolin-2-carboxamide,
(10) 4-[((l S,2R)-2- { [amino(ethoxyimino)methyl] amino } cyclohexyl)amino] -N-(2- methoxyethyl)-6-methylquinazolin-2-carboxamide,
(11) 4-{ [(1 S,2R)-2-({amino[(2-methoxyethoxy)imino]methyl}amino)cyclohexyl]- amino } -N-(2-methoxyethyl)-6-methylquinazolin-2-carboxamide,
(12) 4- { [( 1 S,2R)-2-( { amino[(2-fluoroethoxy)imino]methyl } amino)cyclohexyl] - amino } -N-(2-methoxyethyl)-6-methylquinazolin-2-carboxamide, and
(13) 4-( { ( 1 S ,2R)-2-[(amino { [2-(methylthio)ethoxy] imino } methyl)amino] - cyclohexyl}amino)-N-(2-methoxyethyl)-6-methylquinazolin-2-carboxamide.
8. The non-opioid branch of the opioid peptide family of receptors antagonist according to claim 1 , for the treatment of a mental disorder, neuropathy and physiological disorder, and particularly effective in ameliorating anxiety and stress disorder, depression, traumatic disorder, amnesia due to Alzheimer's disease or other dementia, symptoms of epilepsy and spasm, acute and/or chronic pain, drug abuse withdrawal symptoms, water balance control, Na+ excretion, arterial blood pressure disorder, and eating disorder such as an obesity.
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| WO2016105448A1 (en) * | 2014-12-22 | 2016-06-30 | Darryl Rideout | Imidazoline receptor type 1 ligands for use as therapeutics |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003091224A1 (en) * | 2002-04-26 | 2003-11-06 | Nippon Shinyaku Co., Ltd. | Quinazoline derivative and medicine |
| WO2007040231A1 (en) * | 2005-10-03 | 2007-04-12 | Nippon Shinyaku Co., Ltd. | Quinazoline derivative and pharmaceutical |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003091224A1 (en) * | 2002-04-26 | 2003-11-06 | Nippon Shinyaku Co., Ltd. | Quinazoline derivative and medicine |
| WO2007040231A1 (en) * | 2005-10-03 | 2007-04-12 | Nippon Shinyaku Co., Ltd. | Quinazoline derivative and pharmaceutical |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016105448A1 (en) * | 2014-12-22 | 2016-06-30 | Darryl Rideout | Imidazoline receptor type 1 ligands for use as therapeutics |
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