WO1999033798A1 - Derives heterocycliques azotes - Google Patents

Derives heterocycliques azotes Download PDF

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Publication number
WO1999033798A1
WO1999033798A1 PCT/JP1998/005849 JP9805849W WO9933798A1 WO 1999033798 A1 WO1999033798 A1 WO 1999033798A1 JP 9805849 W JP9805849 W JP 9805849W WO 9933798 A1 WO9933798 A1 WO 9933798A1
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Prior art keywords
lower alkyl
substituent
optionally
alkylene
aryl
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PCT/JP1998/005849
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English (en)
Japanese (ja)
Inventor
Seijiro Akamatsu
Eiji Kawaminami
Shinya Nagashima
Souichirou Kawazoe
Tetsuro Ogami
Ken-Ichi Suzuki
Yuzo Matsumoto
Minoru Okada
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Yamanouchi Pharmaceutical Co., Ltd.
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Priority to AU16876/99A priority Critical patent/AU1687699A/en
Publication of WO1999033798A1 publication Critical patent/WO1999033798A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a drug, particularly to a nitrogen-containing heterocyclic derivative having an ⁇ 3 integrin inhibitory action.
  • Integrin is a membrane glycoprotein composed of a heavy chain and a / 3 chain heterodimer, is widely found in many cells, and is known to be a superfamily gene involved in various physiological phenomena . In particular, it is involved in binding to extracellular matrix adhesion factors as a receptor on the cell membrane in cell adhesion, and transmits extracellular information into cells. In recent years, it has also been shown that intracellular information is transmitted outside the cell, and integrins are considered to be one of the important molecules in physiological phenomena.
  • ⁇ 3 Integrin (hereafter av ⁇ 3), a member of the integrin superfamily, is expressed on endothelial cells, smooth muscle cells, osteoclasts, melanoma cells, etc., and is involved in cell-extracellular matrix adhesion.
  • ⁇ 3 was identified as a vitronectin receptor on cells, but it was shown that fibrinogen, fibronectin, etc. also bind as ligands in addition to vitronectin. It is known that ⁇ 3 and extracellular matrix bind via the Arg-Gly-Asp (RGD) sequence of the adhesion factor.
  • the RGD sequence was identified as the minimal sequence required for fibronectin cell adhesion.
  • the RGD sequence is also present in fibrinogen, von Willebrand factor, vitronectin and other adhesion factors, and binds to cells via that sequence. It is also known that integrins that recognize the RGD sequence include ⁇ 5 ⁇ 1, allbp3, ⁇ 5, ⁇ , etc. in addition to ⁇ 3.
  • vascular endothelial cells migrate on the extracellular matrix, and the binding of integrin to the extracellular matrix is important. Playing a role.
  • ⁇ 3 is highly expressed in vascular endothelial cells at the wound site, and ⁇ 3 is actually highly expressed in neovascular vessels at tumor or inflamed sites compared to normal blood vessels (Brooks et al., Science. 264, 569-571). , 1994).
  • ⁇ 3 inhibitory antibodies and RGD-containing peptides that inhibit ⁇ 3 inhibit angiogenesis of the chicken allantois membrane, and its action is thought to be due to the inhibition of ⁇ 3 causing apoptosis of endothelial cells (Brook et al, Cell, 79 (1994), 1157-1164). Inhibition of ⁇ 3 inhibits angiogenesis and reduces tumor size (Brook et al, Cell, 79 (1994), 1157-1164), and ⁇ 3 inhibitory antibody has shown a tumor growth inhibitory effect in tumor-bearing nude mice (Brooks et al., J. Clin. Invest. 96, 1815-1822,
  • ⁇ 3 inhibitors are expected to be used as therapeutic agents for diseases involving angiogenesis in their pathology, such as cancer, arthritis, rheumatism, retinopathy, and psoriasis.
  • ⁇ 3 is involved in metastasis of cancer cells (Firaldo et al., J. Cell. Biol. 130, 441-450, 1995), ⁇ 3 inhibitors have the potential to become cancer metastasis inhibitors.
  • ⁇ 3 is also induced in osteoclasts, and it has been reported that ⁇ 3 inhibitory antibodies inhibit the binding of osteoclasts to bone and inhibit bone resorption (Ross et al., J. Biol. Chei , 268, 9901-9907, 1993). Also, RGD-containing peptides that inhibit ⁇ 3 inhibited osteoclast adhesion (Wong et al., Mol. Pharmacol. 50, 529-537, 1996). ⁇ 3 inhibitory antibody and RGD-containing peptide inhibited bone resorption in a PTHrP-induced hypercalcemia model in thyroid- and parathyroidectomy rats (Clippes et al., Endocrnology. 137, 918-924, 1996).
  • ⁇ 3 is highly expressed in the intima of atherosclerotic lesions (Hoshiga et al., Circ. Res. 77, 1129-1135, 1995), and inhibition of ⁇ 3 inhibits smooth muscle cell migration (Bilato et al. , J. Clin. Invest. 100, 693-704, 1997). Further, in vascular injury model by balloon catheter, RGD-containing peptides that inhibit the alpha Nyubeta3 is inhibited intimal thickening (Choi et. Al, J. Vase . Surg. 19, 125-134, 1994).
  • alpha Nyubeta3 inhibitors impair inhibitory migration of smooth muscle cells, intimal hyperplasia of a blood vessel, is expected as restenosis preventive agent after PTCA.
  • ⁇ 3 also acts as a receptor for bacteria and viruses to enter cells (Current Biology, Vol. 3 (9), 596-599, 1993) .Therefore, ⁇ 3 inhibitors are used as antiviral agents. could be useful.
  • a benzoic acid derivative disclosed in W097 / 08145 is known.
  • the present inventors have conducted intensive studies on compounds that antagonize the ⁇ 3 integrin.
  • a novel nitrogen-containing heterocyclic derivative characterized by having a nitrogen-containing heterocyclic ring as a basic skeleton, such as indoline has been reported to be a good derivative.
  • the present invention has been found to have ⁇ 3 integrin inhibitory activity and to be useful as a prophylactic or therapeutic agent for diseases involving ⁇ 3 integrin, and has completed the present invention.
  • the present invention relates to a nitrogen-containing heterocyclic derivative represented by the following general formula (I) or a salt thereof.
  • Ra —H or —lower alkyl
  • Rb, Rc same or different, —H, monohalogen, —lower alkyl optionally having substituent (s), lower alkenyl optionally having substituent (s), —having substituent (s) Lower alkynyl, --cycloalkyl, --aryl which may have a substituent, --heteroaryl which may have a monosubstituent, --lower alkyl which may have a CO--substituent —CO—aryl which may have a substituent, —CO—heteroaryl which may have a substituent, —NHSO 2 —lower alkyl which may have a substituent, —NH S ⁇ 2 - which may have a substituent Ariru, or - NHS0 2 _ to which may have a substituent heteroaryl,
  • Rd 100H or -0-lower alkyl
  • R f same or different, —H, 100H or —lower alkyl
  • Rg — H, lower alkyl, lower alkenyl, lower alkynyl, lower cycloalkyl, lower alkylene, cycloalkyl, optionally substituted aryl, — optionally substituted Heteroaryl, —Aryl optionally having lower alkylene mono-substituent, —Lower alkylene—Heteroaryl optionally having substituent, one COO-lower alkyl, one COO-cycloalkyl, —COO— An aryl having an optional substituent, a heteroaryl optionally having a CO-monosubstituent, an alkyl having a COO-lower alkylene-cycloalkyl group, a COO-a lower alkylene-substituent Aryl, —COO—lower alkylene—optionally substituted heteroaryl, —NH—lower alkyl, one NH—cycloalkyl, one NH—substituted Optionally, —NH
  • Rh —H, —lower alkyl, one COO—lower alkyl, or integral with Rg And it became one (c 2 _ 6 alkylene) one,
  • RR 2 same or different, lower alkyl, —lower alkenyl, —lower alkynyl, monohalogen, —lower alkyl substituted with halogen, _N ⁇ 2 , —CN, -OH, —SH, —O—lower Alkyl, —S—lower alkyl, one CO ⁇ H, one COO—lower alkyl, —CO—lower alkyl, —C —NH 2 , _NH 2 , —NH_lower alkyl and —N (lower alkyl) 2
  • R 3 , R 4 same or different, —H, —lower alkyl, lower alkyl substituted with monohalogen or monohalogen, and
  • Rb is —H; lower alkyl; lower alkenyl; lower alkynyl; —cycloalkyl; —lower alkyl, —halogen, lower alkyl substituted with monohalogen, —aryl, —NO 2 , —CN, — OH, — 0_lower alkyl, —SH, —S—lower alkyl, —O—lower alkylene—O—, —C OO—lower alkyl and —COOH having one or more substituents Or a heteroaryl containing one or two heteroatoms selected from ⁇ , S and N, which may have one or more substituents selected from lower alkyl and halogen. ,
  • R c is - a ⁇ Li Ichiru, - H, or, or - NHS 0 2
  • Rg is —H, one lower alkyl, one lower alkenyl, one lower alkynyl, —cycloalkyl, one lower alkylene-cycloalkyl, —aryl, one lower alkylene-aryl, one O, S and N
  • p is 0, q is 0 or an integer of 1 to 2
  • R 2 is —lower alkyl
  • R 3 R 4 are the same or different and are _H, —lower alkyl or monohalogen;
  • aryl which may have one or more substituents selected from pyridyl, quinolyl, or —halogen, 1 O—lower alkylene—O—, and 1 CO OH; Is,
  • R f and Re is -H
  • R f and Re is -H
  • the R h one together with R g - a (C 2 6 alkylene) one or
  • a medicine particularly an ⁇ 3 integrin inhibitor, comprising the above-mentioned nitrogen-containing heterocyclic derivative or a salt thereof.
  • the compound of the general formula (I) is further described as follows.
  • lower refers to a straight or branched hydrocarbon chain having 1 to 6 carbon atoms.
  • the “lower alkyl” is preferably an alkyl group having 1 to 3 carbon atoms, particularly preferably methyl and ethyl.
  • “Lower alkenyl” is preferably vinyl, aryl, 1-probenyl, isopropenyl, 1-butenyl, 2-butenyl and 3-butenyl.
  • “Lower alkynyl J is preferably ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl and 1-methyl-2-propynyl.”
  • Cycloalkyl is preferably carbon atoms 3 to 8 cycloalkyls.
  • the number two to six lower alk Killen atoms include ethylene, trimethylene and 2, 2_ dimethyl trimethylene is preferred.
  • “One 0—lower alkylene—O—” includes methylenediyl, Ethylenediyl is preferred.
  • Aryl means an aromatic hydrocarbon ring group, preferably an aryl having 6 to 14 carbon atoms, and particularly preferably phenyl, naphthyl and fluorenyl.
  • heteroaryl refers to a heteroaryl fused with a 5- to 6-membered monocyclic or benzene ring containing 1 to 4 (preferably 1 to 2) heteroatoms selected from 0, S and N.
  • the monocyclic heteroaryl is preferably furyl, cyenyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, and is a heteroaryl fused with a benzene ring.
  • Halogen includes F, CI, Br and I.
  • the “lower alkyl substituted with halogen” one CF 3 is preferable.
  • Examples of the substituent in the “lower alkyl optionally having a substituent”, the “lower alkenyl optionally having a substituent” and the “lower alkynyl optionally having a substituent” include: Although there is no particular limitation, it is preferably 1 to 4 substituents selected from the following group A.
  • Group A one halogen, one N ⁇ 2 , — CN, — ⁇ H, _ ⁇ —lower alkyl, —SH, one S—lower alkyl, — C ⁇ OH, _COO—lower alkyl, one CO—lower alkyl, —CO—substituted aryl group which may have a substituent group, one CO NH 2 , one NH 2 , one NH-lower alkyl group, —N (lower alkyl) 2 , —substituent group B Aryl which may have — cycloalkyl and heteroaryl optionally having substituents of the following group B.
  • the substituent in the "aryl which may have a substituent” and the “heteroaryl which may have a substituent” is not particularly limited, but is preferably 1 to 4 selected from the following group B Is a substituent of
  • Group B one lower alkyl, one lower alkenyl, —lower alkynyl, —cycloalkyl, one halogen, lower alkyl substituted with one halogen, aryl, one N ⁇ 2 , one CN, -OH, —O—lower alkyl, _ SH, I S—Lower Arch Le, -O- lower alkylene one O-, _ C_ ⁇ _OH one COO- lower alkyl, - CO- lower alkyl, - CO- Ariru, - C_ ⁇ _NH 2, _ NH 2, One NH one lower alkyl and - N (lower alkyl) 2 .
  • the compound of the present invention may have a geometric variant or a tautomer depending on the type of the substituent, but the present invention includes a separated form or a mixture of these isomers. Further, the compound of the present invention may have an asymmetric carbon atom, and may have an isomer based on the asymmetric carbon atom. The present invention includes a mixture of these optical isomers and an isolated one.
  • the compound of the present invention may form a salt.
  • the acid addition salt include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid and phosphoric acid. , 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, etc.
  • the salt with an acid include an acid addition salt with an organic acid.
  • the salt with a base examples include inorganic bases containing metals such as sodium, potassium, magnesium, calcium, and aluminum, or methylamine, ethylamine, ethanolamine, lysine, orditin. And the like, salts with organic bases such as and the like, and ammonium salts. Furthermore, the present invention also includes various hydrates, solvates, and polymorphic substances of the compound (I) of the present invention and salts thereof.
  • the compound of the present invention and a pharmaceutically acceptable salt thereof can be produced by applying various known synthetic methods, utilizing characteristics based on the basic skeleton or the types of substituents.
  • an appropriate protecting group that is, a group that can be easily converted to the functional group at the intermediate stage, without using the raw material.
  • the desired compound can be obtained by removing the protecting group, if necessary.
  • Such functional groups include, for example, amino group, hydroxyl group, carbonyl group and the like.
  • protecting groups are, for example, rprotective Groups in Organi, by Green (Greene) and Wuts (Wuts).
  • c Synthes is '' 2nd edition These may be appropriately used according to the reaction conditions. A typical production method of the compound of the present invention will be described below.
  • the compound (I) of the present invention can be produced by reacting a carboxylic acid represented by the general formula (II) or a reactive derivative thereof with an amino derivative ( ⁇ ) and, if desired, subjecting it to a deesterification reaction. it can.
  • reactive derivatives of carboxylic acids include acid halides (acid chloride, acid bromide, etc.), acid anhydrides (ethyl ethyl chloroformate, benzyl chloroformate, phenyl chloroformate, mixed acid with isovaleric acid, etc.).
  • Anhydrides include active esters (p-i-trophenyl ester, succinimide ester, pentafluorophenyl ester, benzotriazolyl ester, etc.), lower alkyl esters, aralkyl esters, acid azides and the like.
  • Such a reactive derivative of a carboxylic acid can be easily obtained from the corresponding carboxylic acid according to a commonly used general method.
  • the amidation reaction can be performed by a conventional method.
  • a base an inorganic base such as sodium hydroxide or an organic base such as triethylamine (TEA), diisopropylethylamine, pyridine, N-methylmorpholine
  • TAA triethylamine
  • a condensing agent dicyclohexyl carpoimide (DCC), 1-ethyl-3- (3-dimethylaminopropyl) carpoimide (W SC), 1,1'-Luponylbis-1H-imidazole (CDI), etc.
  • additives such as N-hydroxysuccinimide (HONSu) and 1-hydroxybenzotriazole (H ⁇ B t) may be added.
  • Solvents include aromatic hydrocarbon solvents such as benzene and toluene; ether solvents such as tetrahydrofuran (THF) and 1,4-dioxane; halogenated hydrocarbon solvents such as dichloromethane and chloroform; N, N Amide solvents such as dimethylformamide (DMF) and N, N-dimethylacetamide; and basic solvents such as pyridin.
  • an alcohol solvent may be further used. These solvents are used alone or in combination of two or more. The solvent should be appropriately selected according to the type of the starting compound and the like.
  • ester compound can be subjected to a deesterification reaction to obtain a carboxylic acid compound.
  • Deesterification can be performed by an ordinary method using an acid or an alkali.
  • the compound (la) of the present invention can be obtained by reacting an amino compound (IV) with an isocyanate or an isothiocyanate compound (V) or by reacting a carbamate (VI).
  • It can be produced by reacting with various amines or hydrazines via I) and subjecting it to a deesterification reaction according to a conventional method, if desired.
  • the reaction is usually suitably performed in the presence of a solvent.
  • the solvent used is not particularly limited as long as it does not affect the reaction, and examples thereof include the above-mentioned halogenated hydrocarbon solvents, aromatic hydrocarbon solvents, ether solvents, amide solvents, or hexane, acetonitrile, Dimethyl sulfoxide and the like. These solvents may be used as a mixture. If necessary, the same base as in the first production method may be added.
  • the reaction is carried out under cooling or heating.
  • the reaction time varies depending on the reaction reagent, reaction temperature, solvent and the like, but is usually several minutes to several tens of hours.
  • Ri represents 1 C ⁇ O—lower alkyl
  • ha 1 represents halogen
  • R j represents a lower alkyl group. The same applies hereinafter.
  • the compound (lb) of the present invention is synthesized from an amino compound (IV) and a thioperia compound (IX) according to the method of, for example, Yaw Fui Yong et al., J. Org. Chei., 1997, 62, 1540.
  • the thiourea compound (la ′) obtained by the second production method is converted to an S-alkyl compound (XI) by a conventional method, and then a known nucleophilic substitution reaction is performed using various amines 01). And then removing the protecting group by a conventional method and, if desired, subjecting it to a deesterification reaction.
  • a k denotes the C 2 _ 6 alkylene.
  • the compound (Ic) of the present invention can be produced by reacting the S-alkyl compound (XI) obtained by the third production method with various alkyldiamines and, if desired, subjecting it to a deesterification reaction according to a conventional method.
  • a reaction solvent an alcohol-based solvent, an amide-based solvent, or a solvent capable of dissolving the compound (XI), such as dimethylsulfoxide, is suitably used.
  • the reaction is carried out at room temperature or under heating.
  • the reaction time varies depending on the reaction reagent, reaction temperature, solvent and the like, but is usually several hours to several days.
  • the compound of the present invention may be produced through a known N-alkylation reaction / substitution reaction, depending on the type of the substituent.
  • the starting compound of the compound of the present invention can be produced by a conventional method using, for example, a known reaction shown in the following synthesis scheme. Each reaction can be carried out in the same manner as in the above-mentioned method for producing the compound of the present invention, or by applying ordinary reaction conditions used in the art.
  • the starting compound (I la) in which X is NR h is prepared according to the method described in B. Drake et al., Synthes is, 1994, (6), 579. I can do it.
  • reaction products obtained by each of the above methods are isolated and purified as various solvates such as free compounds, their salts or hydrates.
  • the salt can be produced by subjecting it to a usual salt formation reaction.
  • Isolation and purification are performed by applying ordinary chemical operations such as extraction, concentration, evaporation, crystallization, filtration, recrystallization, and various types of chromatography.
  • Various isomers can be isolated by a conventional method utilizing the physicochemical difference between the isomers.
  • optical isomers can be separated by common optical resolution methods, such as fractional crystallization or chromatography.
  • the compounds of the present invention are useful as active ingredients in pharmaceutical preparations.
  • it has ⁇ 3 intedarin inhibitory activity, and ⁇ 3 integrin is involved in its pathology, diseases involving angiogenesis, bone resorption by osteoclasts, migration of smooth muscle cells, entry of bacteria and viruses, for example, It is useful as a prophylactic / therapeutic agent for cancer, cancer metastasis (including bone metastasis of cancer), retinopathy, rheumatoid arthritis, psoriasis, osteoporosis, hypercalcemia, restenosis after PTCA, and viral infection.
  • the ⁇ 3 integrin inhibitory effect of the compound of the present invention was confirmed by the following pharmacological test (1).
  • the usefulness of the compound of the present invention for diseases involving ⁇ 3 integrin is confirmed by a pharmacological test using a known disease model such as the pharmacological tests (2) and (3) described below.
  • ⁇ 3 integrin was obtained from a fraction obtained by solubilizing human placenta with 50 mM n-octyl-b-thioglucoside. , J. Biochem. 116, 778-786, 1994).
  • vitronectin was biotinylated using NHS-Biotin (Pierce).
  • a streptavidin-pyotinylated horseradish peroxidase complex (Amersham) diluted 1000-fold with TBS was added in increments of 1 ⁇ m, and allowed to react at room temperature for 1 hour, followed by washing 3 times with TBS.
  • the compound of the present invention well inhibits the binding of vitronectin to ⁇ 3 integrin, and the IC 5 of the compounds of Examples lb, 2b, 3, 8, 12, 13, 14, 20, 21, 45, 46 and 47 was obtained. . All values were less than 10 nM.
  • angiogenesis inhibitory effect of the compound of the present invention is confirmed using the method described in the literature (Sato et al. FEBS-Lett., 322 (2), 155-158, 1993).
  • a pharmaceutical composition comprising the compound (I) of the present invention or a salt thereof and a pharmaceutically acceptable carrier comprises one or more of the compound represented by the general formula (I) or a salt thereof, It can be prepared by a commonly used method using pharmaceutical carriers, excipients, and other additives usually used for formulation.
  • Administration can be in the form of tablets, pills, capsules, granules, powders, liquids, etc., orally, or intravenous, intramuscular, etc., injections, suppositories, transdermal, etc. It is good.
  • the one or more active substances comprise at least one inert diluent, such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, metasilicate. It is mixed with magnesium acid aluminate.
  • the composition may contain additives other than inert diluents, such as lubricants such as magnesium stearate, disintegrants such as calcium cellulose glycolate, stabilizers such as lactose, Glutamic acid or aspartic acid May be contained.
  • tablets or pills may be coated with sugar coating such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate or the like, or with a film of gastric or enteric substance.
  • Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, and the like, and are commonly used inert diluents, such as purified Contains water and ethanol.
  • the composition may contain, in addition to the inert diluent, adjuvants such as wetting agents and suspending agents, sweetening agents, flavoring agents, flavoring agents and preservatives.
  • Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions.
  • Aqueous solutions and suspensions include, for example, distilled water for injection and physiological saline. Examples of water-insoluble solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and polysorbate.
  • compositions may further comprise adjuvants such as preservatives, wetting agents, emulsifiers, dispersants, stabilizers (eg, lactose), solubilizing agents (eg, glutamic acid, aspartic acid).
  • adjuvants such as preservatives, wetting agents, emulsifiers, dispersants, stabilizers (eg, lactose), solubilizing agents (eg, glutamic acid, aspartic acid).
  • solubilizing agents eg, glutamic acid, aspartic acid.
  • Transmucosal preparations such as nasal preparations are solid, liquid, and semi-solid preparations, and can be manufactured according to methods known per se. For example, known pH adjusters, preservatives, thickeners, and excipients are appropriately added to form a solid, liquid, or semi-solid.
  • Nasal drugs are administered using conventional spraying equipment, nasal drops, tubes, nasal inserts, and the like.
  • the daily dose is about 0.001 to 1 Omg Z kg per body weight, preferably 0.001 to 1 mg Z kg. Alternatively, it is administered in 2 to 4 divided doses.
  • the daily dose is preferably about 0.001 to 1 mg / kg of body weight, administered once daily or in divided doses.
  • the daily dose should be The appropriate dose is about 0.001 to 1 Omg Z kg per weight, given once a day or in multiple doses. The dose is determined as appropriate for each individual case, taking into account symptoms, age, gender, etc. BEST MODE FOR CARRYING OUT THE INVENTION
  • 6-Nitroindoline was dissolved in 1,2-dichloroethane, and TEA and ethylmalonyl chloride were added thereto under ice-cooling and reacted at room temperature.
  • the product was purified to give ethyl 3- (6-dinitroindolin) -3-oxopropionate as a yellow solid.
  • Ethyl 3- (6-aminoindoline-tolyl) -3-oxopropionate is dissolved in dichloromethane, and ⁇ , ⁇ '-bis-tert-butoxycarbonylthiodiarea, TEA, and iodide 2- The reaction mixture was stirred overnight at room temperature under an argon gas atmosphere. The product was purified to give ethyl 3- ⁇ 6- [ ⁇ , ⁇ '-bis (ie-butoxycarbonyl) guanidino] indoline-triethyl 3- oxopropionate as a white solid.
  • a 1N aqueous sodium hydroxide solution and the same amount of purified water were added to a THF solution containing the compound obtained in Reference Example 7, and the mixture was stirred at room temperature for about 2 hours.
  • the solvent was concentrated under reduced pressure, made acidic solution (PH 4) with 0.5N hydrochloric acid under ice-cooling, extracted with ethyl acetate, purified by a conventional method, and purified with 3- ⁇ 6- [ ⁇ , ⁇ '- Bis ( ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ) guanidino] indrin-1-yl ⁇ -3-oxopropionic acid was obtained.
  • Table 1 shows the physicochemical properties of the compounds of Reference Examples 1 to 15 and 17 and Table 2 shows the structures and physicochemical properties of the compounds of Reference Examples 18 to 27.
  • the chemical properties are shown in Tables 3-9.
  • Tables 10 and 11 specifically show other compounds included in the present invention. These compounds can be easily prepared in a manner analogous to that described in the above examples or in the preparation method, or by applying a few thousand modifications obvious to those skilled in the art.

Abstract

Cette invention concerne des dérivés hétérocycliques azotés qui correspondent à la formule générale (I). Ces dérivés possèdent une action inhibitrice d'intégrine αvβ3, et sont utiles afin d'inhiber la néo-vascularisation et de prévenir la resténose post-PTCA. Cette invention concerne également des sels de ces dérivés ainsi qu'une composition thérapeutique les contenant.
PCT/JP1998/005849 1997-12-25 1998-12-24 Derives heterocycliques azotes WO1999033798A1 (fr)

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WO2001000576A1 (fr) * 1999-06-29 2001-01-04 Ortho-Mcneil Pharmaceutical, Inc. Uree-peptoides de type indole et indazole utilises en tant qu'antagonistes du recepteur de thrombine
WO2001058893A2 (fr) * 2000-02-11 2001-08-16 Merck Patent Gmbh Derives d'indol-3-yl
WO2001087834A1 (fr) * 2000-05-16 2001-11-22 Takeda Chemical Industries, Ltd. Antagoniste de l'hormone de concentration de la melanine
US6630451B1 (en) 1999-06-29 2003-10-07 Orthomcneil Pharmaceutical, Inc. Benzimidazolone peptidometics as thrombin receptor antagonist
US6849639B2 (en) 1999-12-14 2005-02-01 Amgen Inc. Integrin inhibitors and their methods of use
US6858577B1 (en) 1999-06-29 2005-02-22 Ortho-Mcneil Pharmaceutical, Inc. Indole peptidomimetics as thrombin receptor antagonists
WO2005120477A2 (fr) 2004-06-07 2005-12-22 Merck & Co., Inc. N- (2-benzyl) -2-phenylbutanamides modulant le recepteur d'androgene
US7049297B2 (en) 1999-06-29 2006-05-23 Ortho-Mcneil Pharmaceutical, Inc. Indazole peptidomimetics as thrombin receptor antagonists
EP2017263A1 (fr) * 2006-05-09 2009-01-21 Daiichi Sankyo Company, Limited Derive acide carboxylique inferieur d'heteroarylamide
WO2014146494A1 (fr) * 2013-03-20 2014-09-25 中国科学院上海药物研究所 Composé β-aminocarbonyle, procédé de préparation, composition pharmaceutique et utilisation correspondants
WO2015181676A1 (fr) 2014-05-30 2015-12-03 Pfizer Inc. Dérivés carbonitriles en tant que modulateurs sélectifs du récepteur des androgènes
US9388161B2 (en) 2013-11-18 2016-07-12 Forma Therapeutics, Inc. Tetrahydroquinoline compositions as BET bromodomain inhibitors
US10377769B2 (en) 2013-11-18 2019-08-13 Forma Therapeutics, Inc. Benzopiperazine compositions as BET bromodomain inhibitors
WO2023275715A1 (fr) 2021-06-30 2023-01-05 Pfizer Inc. Métabolites de modulateurs sélectifs du récepteur des androgènes

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US6858577B1 (en) 1999-06-29 2005-02-22 Ortho-Mcneil Pharmaceutical, Inc. Indole peptidomimetics as thrombin receptor antagonists
US6630451B1 (en) 1999-06-29 2003-10-07 Orthomcneil Pharmaceutical, Inc. Benzimidazolone peptidometics as thrombin receptor antagonist
US7183252B2 (en) 1999-06-29 2007-02-27 Ortho-Mcneil Pharmaceutical, Inc. Indole peptidomimetics as thrombin receptor antagonists
US7049297B2 (en) 1999-06-29 2006-05-23 Ortho-Mcneil Pharmaceutical, Inc. Indazole peptidomimetics as thrombin receptor antagonists
US6365617B1 (en) 1999-06-29 2002-04-02 Ortho-Mcneil Pharmaceutical, Inc. Indole and indazole urea-peptoids as thrombin receptor antagonists
WO2001000576A1 (fr) * 1999-06-29 2001-01-04 Ortho-Mcneil Pharmaceutical, Inc. Uree-peptoides de type indole et indazole utilises en tant qu'antagonistes du recepteur de thrombine
US6943149B2 (en) 1999-06-29 2005-09-13 Ortho Mcneil Pharmaceutical, Inc. Benzimidazolone peptidomimetics as thrombin receptor antagonists
US6849639B2 (en) 1999-12-14 2005-02-01 Amgen Inc. Integrin inhibitors and their methods of use
US6743810B2 (en) 2000-02-11 2004-06-01 Merck Patent Gmbh Indol-3-yl derivatives
WO2001058893A2 (fr) * 2000-02-11 2001-08-16 Merck Patent Gmbh Derives d'indol-3-yl
WO2001058893A3 (fr) * 2000-02-11 2002-04-18 Merck Patent Gmbh Derives d'indol-3-yl
DE10006139A1 (de) * 2000-02-11 2001-08-16 Merck Patent Gmbh Indol-3-yl-Derivate
WO2001087834A1 (fr) * 2000-05-16 2001-11-22 Takeda Chemical Industries, Ltd. Antagoniste de l'hormone de concentration de la melanine
WO2005120477A2 (fr) 2004-06-07 2005-12-22 Merck & Co., Inc. N- (2-benzyl) -2-phenylbutanamides modulant le recepteur d'androgene
EP2017263A1 (fr) * 2006-05-09 2009-01-21 Daiichi Sankyo Company, Limited Derive acide carboxylique inferieur d'heteroarylamide
EP2017263A4 (fr) * 2006-05-09 2011-11-30 Daiichi Sankyo Co Ltd Derive acide carboxylique inferieur d'heteroarylamide
WO2014146494A1 (fr) * 2013-03-20 2014-09-25 中国科学院上海药物研究所 Composé β-aminocarbonyle, procédé de préparation, composition pharmaceutique et utilisation correspondants
CN105051046A (zh) * 2013-03-20 2015-11-11 中国科学院上海药物研究所 β-氨基羰基类化合物、其制备方法、药物组合物及其用途
US10703764B2 (en) 2013-11-18 2020-07-07 Forma Therapeutics, Inc. Benzopiperazine compositions as BET bromodomain inhibitors
US9388161B2 (en) 2013-11-18 2016-07-12 Forma Therapeutics, Inc. Tetrahydroquinoline compositions as BET bromodomain inhibitors
US10336722B2 (en) 2013-11-18 2019-07-02 Forma Therapeutics, Inc. Tetrahydroquinoline compositions as BET bromodomain inhibitors
US10377769B2 (en) 2013-11-18 2019-08-13 Forma Therapeutics, Inc. Benzopiperazine compositions as BET bromodomain inhibitors
US10611750B2 (en) 2013-11-18 2020-04-07 Forma Therapeutics, Inc. Tetrahydroquinoline compositions as bet bromodomain inhibitors
US11084831B1 (en) 2013-11-18 2021-08-10 Forma Therapeutics, Inc. Benzopiperazine compositions as BET bromodomain inhibitors
US11111229B2 (en) 2013-11-18 2021-09-07 Forma Therapeutics, Inc. Tetrahydroquinoline compositions as BET bromodomain inhibitors
US10328082B2 (en) 2014-05-30 2019-06-25 Pfizer Inc. Methods of use and combinations
WO2015181676A1 (fr) 2014-05-30 2015-12-03 Pfizer Inc. Dérivés carbonitriles en tant que modulateurs sélectifs du récepteur des androgènes
WO2023275715A1 (fr) 2021-06-30 2023-01-05 Pfizer Inc. Métabolites de modulateurs sélectifs du récepteur des androgènes

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