US20050096322A1 - Nitrogen-containing heterocyclic compound - Google Patents

Nitrogen-containing heterocyclic compound Download PDF

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US20050096322A1
US20050096322A1 US10/505,939 US50593904A US2005096322A1 US 20050096322 A1 US20050096322 A1 US 20050096322A1 US 50593904 A US50593904 A US 50593904A US 2005096322 A1 US2005096322 A1 US 2005096322A1
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group
lower alkyl
triazolo
substituents selected
pyridazine
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Susumu Igarashi
Ryo Naito
Yoshinori Okamoto
Noriyuki Kawano
Issei Tsukamoto
Ippei Sato
Makoto Takeuchi
Hiroyuki Kanoh
Masato Kobori
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Astellas Pharma Inc
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Astellas Pharma Inc
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Priority to US11/190,859 priority Critical patent/US7173033B2/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings

Definitions

  • the present invention relates to a nitrogen-containing heterocyclic compound having an ability of stimulating bone formation in an osteoblast or a pharmaceutically acceptable salt thereof.
  • a normal bone metabolism involves an equilibrium between the level of bone resorption by osteoclasts and the level of bone formation by osteoblasts, by which a homeostasis is maintained.
  • a metabolic bone disease is considered to be developed once such a balance between the bone resorption and the bone formation is lost.
  • This disease includes osteoporosis, osteitis fibrosa (hyperparathyroidism), osteomalacia and Paget's disease which affects the parameters of systemic bone metabolism.
  • the osteoporosis is observed frequently in postmenoposal women or old men, and causes a pain such as a lumbar pain and a bone fracture, and is seriously problematic especially in older patients whose bone fracture readily leads to a systemic weakness and a dementia.
  • a calcium preparation, active vitamin D 3 preparation, calcitonin preparation and estrogen preparation are employed.
  • a bone-forming agent is highly desired especially in a senile osteoporosis which was reported to be caused mainly by a reduction in the bone formation due to a reduction in the bone turnover (New Eng. J. Med. 314, P1676, (1986)).
  • a triazolopyridazine derivative having a bronchodilating effect which is a compound wherein Ra and Rb are taken together with an adjacent N atom to form a 4-methyl-1-piperazinyl, E is a single bond, and R is an unsubstituted phenyl, p-methylphenyl, m-methylphenyl, p-methoxyphenyl, m-chlorophenyl, p-chlorophenyl or m-nitrophenyl, disclosed in German Patent 2,444,322 and JP-A-50-58092.
  • R is an optionally substituted imidazolyl disclosed in German Patents 2,261,693, 2,254,873 and 2,215,999; an antibacterial compound wherein R is 5-nitro-2-furyl or 5-nitro-2-thienyl disclosed in German Patent publications 2,161,586, 2,161,587 and 2,113,438.
  • a nitrogen-containing heterocyclic compound shown below exhibits a potent bone formation-stimulating effect on the osteoblast and thus can serve as an excellent prophylactic or therapeutic agent against a metabolic bone disease, whereby establishing the invention.
  • the invention relates to a nitrogen-containing heterocyclic compound represented by the formula (I): or a pharmaceutically acceptable salt thereof, wherein
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a nitrogen-containing heterocyclic compound represented by the formula (I) shown above or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, especially to a bone-forming agent.
  • the invention encompasses use of a nitrogen-containing heterocyclic compound represented by the formula (I) or a pharmaceutically acceptable salt thereof for manufacturing a bone-forming agent for a mammalian animal as well as a method for stimulating bone formation in a mammalian animal comprising administering an effective amount of a nitrogen-containing heterocyclic compound represented by the formula (I) or a pharmaceutically acceptable salt thereof to the mammalian animal.
  • a “lower” means, unless otherwise specified, a straight or branched carbon chain having 1 to 6 carbon atoms.
  • a “lower alkyl” is preferably methyl, ethyl and propyl group.
  • Alk is an abbreviation of “lower alkyl”.
  • aryl is preferably a C 6-14 monocyclic to tricyclic aryl group. More preferably, it is a phenyl or naphthyl group, particularly, a phenyl group. It is also possible that a phenyl group is fused with a C 5-8 cycloalkyl group to form, for example, an indanyl or tetrahydronaphthyl group.
  • a “cycloalkyl” is preferably a C 3-14 cycloalkyl group, which may have bridge(s). More preferably, it is a C 3-10 cycloalkyl group, particularly, a cyclopentyl, cyclohexyl and cycloheptyl group.
  • a “cycloalkenyl” is a group having 1 to 2 double bonds in the above-mentioned “cycloalkyl” ring.
  • a “4- to 8-membered monocyclic saturated or partially unsaturated heterocyclic ring” is a 4- to 8-membered monocyclic saturated heterocyclic ring having 1 to 4 heteroatoms selected from N, S and O, which may have bridge(s) and may partially have an unsaturated bond.
  • it is tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, 1,2,3,6-tetrahydropyridyl, homopiperidinyl, piperazinyl, homopiperazinyl, quinucridinyl and morpholinyl group.
  • heteroaryl is a 5- to 6-membered monocyclic heteroaryl group having 1 to 4 heteroatoms selected from N, S and O, which may be fused with a benzene ring or a 5- to 6-membered monocyclic heteroaryl to form a bi- to tri-cyclic heteroaryl group, which may be saturated partially.
  • Such a 5- to 6-membered heteroaryl is preferably a furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl and triazinyl group, while a bi- to tri-cyclic heteroaryl is preferably a benzofuranyl, benzothienyl, benzothiadiazolyl, benzothiazolyl, benzoxazolyl, benzoxadiazolyl, benzoimidazolyl, indolyl, isoindolyl, indazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinox
  • a partially saturated heteroaryl may for example be 1,2,3,4-tetrahydroquinolyl group. More preferably, it is a pyridyl, pyrimidinyl, furyl, thienyl, thiazolyl, quinolyl, benzofuranyl, benzothienyl, indolyl, imidazopyridyl and naphthylidinyl group, especially a pyridyl group.
  • a substituent on an “optionally substituted aryl”, and “optionally substituted heteroaryl”, “optionally substituted cycloalkyl”, “optionally substituted cycloalkenyl”, “optionally substituted 4- to 8-membered monocyclic saturated or partially unsaturated heterocyclic ring” is preferably the same or different 1 to 5 substituents selected from Group B shown below, more preferably groups selected from Group B1, especially a halogen, OAlk and SAlk.
  • Group B An Alk which may have 1 to 4 substituents selected from Group G, halogen, NR 1 R 2 , NR 1 CO-Alk, NO 2 , CN, OR 1 , —O-(Alk having 1 to 4 substituents selected from Group G), SR 1 , —S-halogeno-Alk, —O—CO-Alk, COOR 1 , COR 1 , CONR 1 R 2 , SOAlk, SO 2 Alk, SO 2 NR 1 R 2 , P( ⁇ O) (OR 1 ) 2 , —O—CH 2 —O—, —O—(CH 2 ) 2 —O—, aryl which may have 1 to 4 substituents selected from Group D, heteroaryl which may have 1 to 4 substituents selected from Group D, —O-(aryl which may have 1 to 4 substituents selected from Group D), 4- to 8-membered monocyclic saturated or partially unsaturated heterocyclic ring which may have 1 to 4
  • R 1 and R 2 are as defined above; “Group D” consists of Alk, halogen, halogeno-Alk, NR 1 R 2 , NO 2 , CN, OR 1 and SR 1 ; “Group G” consists of halogen, NR 1 R 2 , CN, COOR 1 , OR 1 , SR 1 , 4- to 8-membered monocyclic saturated or partially unsaturated heterocyclic ring which may have 1 to 4 substituents selected from Group D, aryl which may have 1 to 4 substituents selected from Group D and heteroaryl which may have 1 to 4 substituents selected from Group D; a “halogen” is I, Br, F and Cl; and a “halogeno-Alk” is a lower alkyl substituted by 1 or more halogen atoms (especially CF 3 ). The same applies analogously to the followings.
  • Group B1 Alk, halogen, halogeno-Alk, NR R 2 , NO 2 , CN, OR 1 , —O-halogeno-Alk, SR 1 , COOR 1 , CONR 1 R 2 , SO 2 Alk, 4- to 8-membered monocyclic saturated or partially unsaturated heterocyclic ring, phenyl and phenoxy group.
  • a “4- to 8-membered saturated or partially unsaturated heterocyclic ring” which may be formed from Ra and Rb taken together with an adjacent N atom may for example be a 4- to 8-membered monocyclic saturated or partially unsaturated heterocyclic ring having 1 to 2 N atoms as ring atoms with the rest of the ring atoms being C atoms.
  • Such a heterocyclic ring may form a fused ring together with a benzene ring or a C 5-8 cycloalkyl ring, may have bridge(s), and may form a Spiro ring.
  • it is pyrrolydinyl, piperidinyl, homopiperidinyl, piperazinyl, pyrazolidinyl, imidazolidinyl, homopiperazinyl, perhydroazocinyl, pyrrolinyl, imidazolinyl, pyrazolinyl, 1,2,3,6-tetrahydropyridyl, 1,2-dihydropyridyl, tetrahydropyridazinyl, tetrahydropyrazinyl, 1,4,5,6-tetrahydropyrimidinyl, indolinyl, isoindolinyl, 1,2,3,4-tetrahydroquinolyl, 1,2,3,4-tetrahydroisoquinolyl, 3-azabicyclo[3.2.1]octyl, 8-azabicyclo[3.2.1]octyl, 3-azabicyclo[3.2.2]nonyl, 3-azabicyclo[3.3.1
  • a piperidyl group is especially preferred.
  • Such a heterocyclic ring may have substituent(s), and such a substituent is preferably 1 to 5 substituents selected from Group B listed above. More preferably, it is 1 to 5 substituents selected from (Alk which may have substituent(s) selected from COOR 1 , OR 1 and phenyl), halogen, NR 1 R 2 , CN, OR 1 , —O-(Alk which may have substituent(s) selected from COOR 1 , OR and phenyl), SR COOR 1 , CONR 1 R 2 and phenyl, especially 1 to 2 substituents selected from Alk, halogen, OR 1 and COOR 1 .
  • An especially preferred compound in the invention is nitrogen-containing heterocyclic compounds listed below and their pharmaceutically acceptable salts.
  • Some of the invention substituents may allow geometric isomers or tautomers to exist, and the invention encompasses all these isomers as being separated or in a mixture.
  • An invention compound may have an asymmetric carbon atom, based on which an optical isomer may exist.
  • the invention encompasses all of these optical isomers as mixtures or individually separated forms.
  • An invention compound (I) may form an acid addition salt or a salt with a base depending on the type of the substituent.
  • a salt is a pharmaceutically acceptable salt, preferably an acid addition salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid and the like and with an organic acid such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, aspartic acid, glutamic acid and the like, a salt with an inorganic base including a metal such as sodium, potassium, magnesium, calcium, aluminum and the like, and with an organic base such as methylamine, ethylamine, ethanolamine, lysine, ornithine and the like, as well as an am
  • the invention includes various hydrates or solvates of an invention compound (I) or its salt, as well as the forms of polymorphic crystals.
  • An invention compound and a pharmaceutically acceptable salt thereof can be produced by utilizing the characteristics based on its skeleton and the types of the substituents and applying various known synthetic methods.
  • a certain functional group in a starting material or an intermediate is substituted by a suitable protective group, i.e., a group which can readily be converted back to this certain functional group.
  • the protective group is removed if necessary to obtain an intended compound.
  • a functional group may for example be a hydroxyl group or carboxyl group, and its protective group may be those listed for example in Greene and Wuts, Protective Groups in Organic Synthesis, 2nd Ed., and can be used appropriately depending on the reaction conditions.
  • An invention compound (I) can be obtained by a standard N-alkylation method, for example by reacting an amine derivative (III) and a compound (II) having an ordinary leaving group such as a halogen atom or an organic sulfonate in the presence or absence of a base such as potassium carbonate, triethylamine, sodium hydride and the like, in an inert solvent such as N,N-dimethylformamide (DMF), toluene, tetrahydrofuran (THF), acetonitrile and the like or without using any solvent with cooling or under reflux.
  • a base such as potassium carbonate, triethylamine, sodium hydride and the like
  • a compound obtained in the first preparation method described above can further be subjected to a standard substituent-modifying reaction, for example, reduction from a nitro group to an amino group, amidation, sulfonamidation, N-alkylation, esterification, ester hydrolysis, hydroxyl group etherification, thioether sulfonation, halogenation, olefin-derivatization, and the like to obtain an invention compound having a desired substituent.
  • a standard substituent-modifying reaction for example, reduction from a nitro group to an amino group, amidation, sulfonamidation, N-alkylation, esterification, ester hydrolysis, hydroxyl group etherification, thioether sulfonation, halogenation, olefin-derivatization, and the like to obtain an invention compound having a desired substituent.
  • Any of these reactions can readily be conducted in accordance with a method described for example in ORGANIC FUNCTIONAL GROUP PREPARAQ
  • the starting material (II) of the present application can be prepared by subjecting a hydrazine compound (IV) and a carboxylic acid compound (V) to a dehydration condensation reaction to form a hydrazide compound (VI) followed by a cyclization.
  • the dehydration condensation reaction in the first step can be conducted by a standard method, for example by using a free carboxylic acid and a coupling agent such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (WSCD) or a carboxylic acid-activating agent such as 1,1′-carbonyldiimidazole, or using a reactive derivative of a carboxylic acid (for example, acid halide such as acid chloride and acid bromide; acid azides; active esters prepared from methanol, ethanol, benzyl alcohol, optionally substituted phenol, N-hydroxysuccinimide and the like; symmetric acid anhydrides; mixed acid anhydrides with alkylcarbonates, p-toluenesulfonic acid and the like).
  • a coupling agent such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (WSCD) or a carboxylic acid-activating agent such as
  • the reaction is conducted using equimolar amounts or an excessive amount of any one of the reactants, in an organic solvent which is inert to the reaction, such as pyridine, THF, methylene chloride, DMF, acetonitrile and the like.
  • organic solvent which is inert to the reaction
  • the reaction temperature is selected appropriately depending on the type of the reactive derivative. In a case of a certain reactive derivative, it may be advantageous to add a base such as 4-dimetylaminopyridine for promoting the reaction.
  • the cyclization in the second step can be conducted by a reaction in the presence or absence of an acid such as acetic acid, p-toluenesulfonic acid, hydrochloric acid and the like, in a solvent such as xylene, ethylene glycol and the like, or without using any solvent.
  • This reaction can be conducted at room temperature or with heating under reflux.
  • An starting material (IX) of the present application can be produced by coupling a compound (IV) with an isocyanate compound (VII) in a solvent inert to the reaction such as acetonitrile to form a compound (VIII) followed by adding 1,2-dibromo-1,1,2,2-tetrachloroethane and triphenylphosphine in the presence of a base such as triethylamine whereby effecting a cyclization.
  • the reaction can be conducted appropriately by a standard method at room temperature or with heating under reflux.
  • a reaction product obtained by each preparation method described above can be isolated and purified as a free base, free acid, its salt, hydrate or any of various solvates.
  • a salt can be produced by an ordinary salt formation reaction.
  • the isolation and the purification can be conducted by applying ordinary chemical procedures such as extraction, concentration, distillation, crystallization, filtration, recrystallization, various chromatographies and the like.
  • Each isomer can be isolated utilizing a physicochemical difference between isomers.
  • an optical isomer can be separated by an ordinary optical resolution method, for example, fractional crystallization or chromatography.
  • An optical isomer can be synthesized from a suitable optically active starting compound.
  • An invention compound has an ability of stimulating the bone formation by osteoblasts, and is useful in preventing or treating a metabolic bone disease associated with a lower bone formation ability relative to the bone resorption ability.
  • a metabolic bone disease includes osteoporosis, osteitis fibrosa (hyperparathyroidism), osteomalacia and Paget's disease which affects the parameters of systemic bone metabolism. It is useful especially in a senile osteoporosis associated with a reduced bone formation ability.
  • An invention bone-forming agent may also be useful in promoting a cure from a bone disease in the field of orthopedics such as bone fracture, bone loss and osteoarthritis, as well as in the field of dentistry for treating a periodontitis or stabilizing an artificial dental root.
  • a phenotypic trait of osteoblasts includes an alkaline phosphatase (ALP) activity, production of bone matrix proteins (collagen, osteocalcin, osteonectin, osteopontin and the like), presence of an active vitamin D3 receptor, parathyroid hormone receptor, estrogen receptor, androgen receptor (Molecular Medicine, Vol. 30, No. 10, 1232 (1993)).
  • ALP alkaline phosphatase
  • the ALP is increased at an early stage of the onset of the osteoblast functions (Journal of Cellular Physiology, Vol. 143, 420 (1990)).
  • the role of the ALP for the bone formation by the osteoblast is believed to be to increase the phosphate ion level at a site of the bone formation and to decompose pyrophosphoric acid which is an inhibitor of calcification (“SAIBO KOGAKU”, Vol.13, No. 12, 1062 (1994)). It was also reported that a subcutaneous implantation of the ALP bound covalently to a collagen sheet caused the calcification (J. Clin. Invest., 89, 1974 (1992)). Accordingly, the osteoblast-induced ALP activity elevation can be regarded as an index of the bone formation.
  • FIG. 1 shows the osteoid thickness in an invention compound treatment group and a control group in Experimental Example 2.
  • FIG. 2 shows the bone formation rate in an invention compound treatment group and a control group in Experimental Example 2.
  • a mouse osteoblast cell line MC3T3-E1 was seeded at the density of 3000 cells/well in 96-well plates in 5% fetal bovine serum (FBS)-supplemented ⁇ -minimum essential medium (MEM) and incubated for 4 to 6 hours.
  • FBS fetal bovine serum
  • MEM ⁇ -minimum essential medium
  • DMSO dimethyl sulfoxide
  • the reaction was stopped by adding 0.5M sodium hydroxide, and the absorbance at a wavelength of 405 nm (correction wavelength: 492 nm) was measured and represented by a % value based on the value in the control group being regarded as 100%, from which the ALP activity was calculated.
  • the measurement described above was in accordance with the method by Lowry et al (Journal of Biological Chemistry, Vol. 207, page 19, (1954)).
  • each rat was treated only with 0.1 ml of the mineral oil once a day for successive 10 days. On the 11th day of the treatment, the drug was discontinued and on the 18th day each rat was sacrificed to remove the calvaria.
  • tetracyclin 25 mg/kg was given on the 10th day of the treatment and then calcein (20 mg/kg) was given subcutaneously to the dorsal area on the 16th day for labeling the bone.
  • the calvaria thus obtained was fixed in 70% ethanol, and coronal sections were made according to a standard procedure and subjected to a bone morphometric measurements. Osteoids thickness and bone formation rate in an invention compound treatment group and a control group are shown in FIG. 1 and FIG. 2 .
  • a pharmaceutical composition containing an invention compound (I) or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier can be prepared by an ordinary method using one or more of a compound represented by the formula (I) or pharmaceutically acceptable salt thereof together with a pharmaceutical carrier, excipient and other additives employed usually in a formulation.
  • the administration can be conducted in various dosage forms orally as a tablet, pill, capsule, granule, powder, liquid, inhalation formulation and the like, or parenterally as an injection formulation such as an intravenous injection, intramuscular injection and the like, as well as a suppositories, percutaneous liquid formulations, ointments, percutaneous patches and the like.
  • a solid composition for an invention oral administration may be a tablet, powder, granule and the like.
  • one or more active substance is mixed with at least one inert diluent such as lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, magnesium aluminate metasilicate and the like.
  • the composition may contain additives other than the inert diluent as customary in the art, including a lubricant such as magnesium stearate, a disintegrant such as calcium fibrinoglycolate, a stabilizer, a dissolution aid such as glutamic acid or aspartic acid.
  • a tablet or pill may be sugar-coated if necessary with sucrose, gelatin, hydroxypropyl cellulose, hydroxypropylmethyl cellulose phthalate and the like or covered with a gastric or enteric film coating.
  • a liquid composition for an oral administration contains a pharmaceutically acceptable emulsifier, solubilizer, suspending agent, syrup, elixir and the like, together with an ordinarily employed inert diluent such as a purified water and ethanol.
  • Such a composition may contain, in addition to an inert diluent, other auxiliary agents such as a humectant, suspending agent, as well as a sweetener, flavor, fragrance and preservative.
  • An injection formulation for a parenteral administration includes an aseptic aqueous or non-aqueous solution, suspension and emulsion.
  • Such an aqueous solution and suspension may contain a distilled water for injection or a physiological saline.
  • a non-aqueous solution and suspension may contain propylene glycol, polyethylene glycol, a vegetable oil such as an olive oil, an alcohol such as ethanol, as well as Polysorbate 80 (trade name) and the like.
  • Such a composition may also contain auxiliary agents such as a preservative, humectant, emulsifier, dispersing agent, dissolution aid (for example, glutamic acid, aspartic acid) and the like.
  • Any of these materials can be made aseptic by filtration through a filter retaining bacteria, incorporation of a sterilizing agent or irradiation. Any of these material can be formulated as an aseptic solid composition which is to be reconstituted just before use with an aseptic water or aseptic solvent for injection.
  • the daily dose is about 0.001 to 10 mg/kg body weight, preferably 0.01 to 5 mg/kg, which may be given at once, or twice to four times in portions.
  • the daily dose is about 0.0001 to 1 mg/kg body weight, which may be given at once, or several times in portions.
  • the dosage may vary depending on the symptom, age, sex and the like of each individual patient.
  • N-cyclopentyl-3-(3-methoxyphenyl)-1,2,4-triazolo[4,3-b]pyridazine-6-amine 300 mg
  • 60% sodium hydride 44 mg
  • the reaction mixture was combined with water, and extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure.
  • reaction solution was combined with water, chloroform and 2-propanol, and insoluble materials were filtered off.
  • the resultant organic phase was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • the resultant crude crystals were washed with ethanol, and stirred with heating under reflux in piperidine (10 ml) for 3 hours.
  • the resultant colorless solids were combined with ethanol (40 ml) and 10% palladium-carbon (150 mg), and stirred under hydrogen atmosphere at room temperature for 6 hours, and then the catalyst was filtered off.
  • the resultant filtrate was concentrated under reduced pressure to obtain 6-piperidin-1-yl-3-piperidin-3-yl-1,2,4-triazolo[4,3-b]pyridazine (1.18 g) as a colorless amorphous.
  • reaction solution was combined with water, and the precipitate was collected by filtration, and washed with water and diethyl ether, combined with acetic acid (30 ml), heated under reflux, and then the reaction solution was concentrated under reduced pressure.
  • the residue was combined with saturated aqueous solution of sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • 6-hydrazino-N-methyl-N-phenylpyridazine-3-amine (1.14 g) in methylene chloride (10 ml)
  • 6-chloropicolic acid (0.83 g)
  • WSCD hydrochloride (1.22 g) were added, and the mixture was stirred at room temperature overnight.
  • the reaction solution was purified by silica gel column chromatography (eluent: chloroform) to obtain 6-chloro-N′- ⁇ 6-[methyl(phenyl)amino]pyridazin-3-yl ⁇ pyridine-2-carbohydrazide (0.57 g). This compound (0.56 g) was stirred at 150° C.
  • Example 2 By proceeding similarly to Example 1 optionally with conducting an ordinary salt formation using 4M hydrogen chloride-ethyl acetate, the compounds of Examples 20 to 170 were obtained.
  • the compound of Example 108 was obtained similarly to Example 2, the compound of Example 109 similarly to Example 3, the compounds of Examples 110 and 111 similarly to Example 4, the compounds of Examples 112 to 114 similarly to Example 8, the compound of Example 115 similarly to Example 10, the compounds of Examples 116 to 118 similarly to Example 12, the compounds of Examples 119 and 120 similarly to Example 13, the compound of Example 121 similarly to Example 18, and the compounds of Example 122 to 123 similarly to Example 19.

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US20070203136A1 (en) * 2005-12-21 2007-08-30 Tianbao Lu Triazolopyridazines as kinase modulators
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WO2003074525A1 (fr) 2003-09-12
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EP1481977A1 (en) 2004-12-01
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CA2476757A1 (en) 2003-09-12
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US7173033B2 (en) 2007-02-06

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