WO2015030189A1 - 新規芳香族化合物およびその用途 - Google Patents
新規芳香族化合物およびその用途 Download PDFInfo
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- WO2015030189A1 WO2015030189A1 PCT/JP2014/072773 JP2014072773W WO2015030189A1 WO 2015030189 A1 WO2015030189 A1 WO 2015030189A1 JP 2014072773 W JP2014072773 W JP 2014072773W WO 2015030189 A1 WO2015030189 A1 WO 2015030189A1
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- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
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- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
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- C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/84—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
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- C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
- C07C237/40—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to a carbon atom of a six-membered aromatic ring
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- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/15—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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- C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D295/155—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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- C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/20—Oxygen atoms
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- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
Definitions
- the present invention is for the prevention or treatment of diseases related to bone metabolism, such as osteoporosis, fibrotic osteoarthritis (hyperparathyroidism), osteomalacia, Paget's disease, rheumatoid arthritis, osteoarthritis and the like.
- the present invention relates to a useful compound or a pharmacologically acceptable salt thereof.
- bone formation by osteoblasts and bone resorption by osteoclasts are repeatedly performed in the bone tissue, whereby old bone is constantly replaced with new bone, and the strength of the whole bone is maintained.
- bone mass and bone tissue deteriorate, resulting in osteoporosis, fibro-osteitis (hyperparathyroidism), osteomalacia, Paget's disease, rheumatoid arthritis, and deformation. It is thought to suffer from bone diseases such as osteoarthritis.
- Osteoporosis is particularly common among elderly people and women, and it is said that there are 11 million patients in Japan and more than 30 million patients in the United States. Symptoms include pains such as broken bones and low back pain, which may lead to bedridden, deformed bodies, or death depending on the fracture site such as an indirect hip fracture.
- As therapeutic agents for osteoporosis there are a bone resorption inhibitor that suppresses the activity of osteoclasts and a bone formation promoter that activates osteoblasts.
- calcitonin, bisphosphonates, estrogen receptor modulators and the like are used. However, these therapeutics prevent further bone loss but cannot reconstruct lost bone.
- human PTH (1-34) is used as an osteogenesis promoter and can be used for increasing bone mass and bone density and restructuring bone structure.
- the period of use is limited to one and a half to two years, and long-term subcutaneous injection is required, making it difficult for patients to comply with.
- Patent Documents 1 and 2 benzothiepine derivatives having alkaline phosphatase-inducing activity
- Patent Document 3 N-quinolylanthranilic acid derivatives
- Patent Document 4 triazolopyridazine derivatives
- Patent Document 5 thienopyridine derivatives
- Patent Document 5 [5,6] heterocyclic compounds
- an object of the present invention is to provide a novel low molecular weight compound that exhibits an osteogenesis promoting action (and / or bone resorption inhibiting action) and is highly safe and can be administered orally.
- the present inventors show a strong osteogenesis promoting action (and / or bone resorption suppressing action), and prevent or prevent diseases related to bone metabolism.
- the present inventors have found an excellent compound of the present invention that can be a therapeutic agent, and have completed the present invention.
- R 1 Cyano group, C1-6 alkylcarbonyl group, C1-6 alkylcarbonylamino group, nitro group, halogeno C1-6 alkyl group, C2-6 alkenyl group, halogeno C2-6 alkenyl group, carbamoyl group, or hydroxy C1-6 Alkyl group
- R 2 C1-6 alkoxy group, carbamoyl group, C1-6 alkylaminocarbonyl group, or C1-6 alkylcarbonyl group
- R 3 Hydrogen atom or halogen atom
- W —NH—, —O—, or —S— X: Single bond, -saturated heterocycle-, -CH 2- (
- R 1 Cyano group, C1-6 alkylcarbonyl group, C1-6 alkylcarbonylamino group, nitro group, halogeno C1-6 alkyl group, halogeno C2-6 alkenyl group, carbamoyl group, or hydroxy C1-6 alkyl group
- R 2 C1-6 alkoxy group, carbamoyl group, C1-6 alkylaminocarbonyl group, or C1-6 alkylcarbonyl group
- R 3 Hydrogen atom or halogen atom
- W —NH—, —O—, or —S— X: —Saturated heterocycle—, —CH 2 — (CH 2 ) n —,
- R 1 is cyano group, acetyl group, acetylamino group, nitro group, trifluoromethyl group, 1,1-difluoroethyl group, 1-fluoroethyl group, difluoromethyl group, carbamoyl group, or 1-hydroxyethyl group Or a pharmacologically acceptable salt thereof according to [1] or [1A].
- R 2 is a methoxy group, a carbamoyl group, a methylaminocarbonyl group or an acetyl group.
- [4] The compound or a pharmaceutically acceptable salt thereof according to any one of [1]-[3] and [1A], wherein S, T and U are all ⁇ CH—.
- the X is —saturated heterocycle— or —O— (CH 2 ) n —, wherein n is 2, [1]-[4] and any one selected from [1A] Or a pharmacologically acceptable salt thereof.
- [6] The compound or a pharmacologically acceptable salt thereof according to any one of [1]-[5] and [1A], wherein Y is a single bond or —O—.
- a pharmaceutical composition comprising the compound described in any one of [8] and [1A] or a pharmacologically acceptable salt thereof as an active ingredient.
- the pharmaceutical composition according to [9] which is used to promote bone formation.
- the pharmaceutical composition according to [9] which is used for preventing or treating a disease associated with bone metabolism.
- the pharmaceutical composition according to [12], wherein the disease relating to bone metabolism is osteoporosis.
- a method for improving bone metabolism comprising administering an effective amount of the pharmaceutical composition described in [9] to a mammal.
- a method for preventing or treating a disease associated with bone metabolism which comprises administering an effective amount of the pharmaceutical composition described in [9] to a mammal.
- a method for preventing or treating osteoporosis comprising administering an effective amount of the pharmaceutical composition described in [9] to a mammal.
- the compound of the present invention has low toxicity, shows favorable pharmacokinetics, has an action of promoting bone formation, and is used for metabolic bone diseases associated with decreased bone forming ability compared to bone resorbing ability. Useful for prevention or treatment. Examples of such metabolic bone diseases include osteoporosis, fibrotic osteoarthritis (hyperparathyroidism), osteomalacia, and Paget's disease that affects systemic bone metabolism parameters. It is particularly useful for senile osteoporosis with reduced bone forming ability.
- the pharmaceutical composition of the present invention containing the compound as an active ingredient is used as an osteogenesis promoting agent to promote healing of bone diseases such as fractures in the orthopedic region, bone defects and osteoarthritis, and teeth in the dental region. Applications can also be expected for treatment of periodontal disease and stabilization of artificial tooth roots.
- Halogen atom Fluorine atom, chlorine atom, bromine atom or iodine atom
- C1-C6 alkyl group A straight-chain or branched alkyl group having 1 to 6 carbon atoms, preferably a methyl group, an ethyl group, a propyl group, an isopropyl group, an isobutyl group or a tert-butyl group
- C1-C6 alkylcarbonyl group A group in which the C1-C6 alkyl group is bonded to a carbonyl group, and preferably an acetyl group, an ethylcarbonyl group, a propylcarbonyl group, an isopropylcarbonyl group, or a butylcarbonyl group, a C1-C6 alkoxy group: A group in which the C1-C6 alkoxy group: A group in which the C1-C6 alkoxy group: A group in which the C1-C6 al
- Propyl group C1-C6 alkylaminocarbonyl group A group in which the C1-C6 alkyl group is bonded to an aminocarbonyl group, preferably a methylaminocarbonyl group or an ethylaminocarbonyl group
- C2-6 alkenyl group A straight or branched alkenyl group having 2 to 6 carbon atoms, such as vinyl group, 1-propenyl (allyl) group, 2-propenyl group, isopropenyl group, 2-methyl-1-propenyl group, 1- Butenyl group, 2-butenyl group, 3-butenyl group, 2-buten-2-yl group, 3-methyl-2-butenyl group, 3-methyl-2-buten-2-yl group, 1-pentenyl group, 2 -Pentenyl group, 3-pentenyl group, 4-pentenyl group, 5-pentenyl group, 2-penten-2-yl group, 2-penten-3-yl group, 4-methyl-1-penten
- Saturated heterocyclic group Saturated 5-7 membered heterocyclic group containing 1-3 sulfur atom, oxygen atom and / or nitrogen atom, for example, tetrahydropyranyl group, tetrahydrofuranyl group, oxotetrahydrofuranyl group, morpholinyl group, thiomorpholinyl group, 1 -Oxothiomorpholinyl group, 1,1-dioxothiomorpholinyl group, pyrrolidinyl group, pyrrolinyl group, imidazolidinyl group, pyrazolidinyl group, piperidinyl group, piperazinyl group, oxazolidinyl group, isoxazolidinyl group, thiazolidinyl group 1,4-dioxanyl group and 1,1-dioxohexahydrothiopyranyl group.
- “—Saturated heterocycle—” refers to a divalent group derived from a saturated heterocycle, and examples of the saturated heterocycle include azetidine ring, tetrahydropyran ring, tetrahydrofuran ring, morpholine ring, thiomorpholine ring, 1- Examples include oxothiomorpholine ring, 1,1-dioxothiomorpholine ring, pyrrolidine ring, pyrroline ring, imidazolidine ring, pyrazolidine ring, piperidine ring, piperazine ring, oxazolidine ring, isoxazolidine ring, and thiazolidine ring.
- Optionally substituted means either unsubstituted or substituted 1-3. In the case of 2 or 3 substitution, each substituent may be the same or different.
- R 1 is a cyano group, a C1-6 alkylcarbonyl group, a C1-6 alkylcarbonylamino group, a nitro group, a halogeno C1-6 alkyl group, a C2-6 alkenyl group, a halogeno C2-6 alkenyl group, a carbamoyl group, or A hydroxy C1-6 alkyl group;
- R 1 is a cyano group, a C1-6 alkylcarbonyl group, a C1-6 alkylcarbonylamino group, a nitro group, a halogeno C1-6 alkyl group, a halogeno C2-6 alkenyl group, a carbamoyl group.
- the “C 1-6 alkylcarbonyl group” represented by R 1 is preferably a methylcarbonyl group (acetyl group).
- the “C 1-6 alkylcarbonylamino group” represented by R 1 is preferably a methylcarbonylamino group (acetylamino group), an ethylcarbonylamino group, or a propylcarbonylamino group.
- the “halogeno C 1-6 alkyl group” represented by R 1 is preferably a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a 1-fluoroethyl group, or a 1,1-difluoroethyl group.
- the “C2-6 alkenyl group” represented by R 1 is preferably a vinyl group.
- the “halogeno C2-6 alkenyl group” represented by R 1 is preferably a 1-fluorovinyl group.
- the “hydroxy C 1-6 alkyl group” represented by R 1 is preferably a hydroxymethyl group or a 1-hydroxyethyl group.
- R 1 is preferably cyano group, acetyl group, acetylamino group, ethylcarbonylamino group, propylcarbonylamino group, nitro group, fluoromethyl group, trifluoromethyl group, 1,1-difluoroethyl group, 1-fluoro.
- R 1 is preferably cyano group, acetyl group, acetylamino group, ethylcarbonylamino group, propylcarbonylamino group, nitro group, fluoromethyl group, trifluoromethyl group, 1, 1-difluoroethyl group, 1-fluoroethyl group, difluoromethyl group, 1-fluorovinyl group, carbamoyl group, hydroxymethyl group or 1-hydroxyethyl group, more preferably cyano group, acetyl group, acetyl group An amino group, a nitro group, a trifluoromethyl group, a 1,1-difluoroethyl group, a 1-fluoroethyl group, a difluoromethyl group, a carbamoyl group, or a 1-hydroxyethyl group.
- R 2 is, C1-6 alkoxy group, a carbamoyl group, C1-6 alkylaminocarbonyl group, or show a C1-6 alkylcarbonyl group.
- the “C1-6 alkoxy group” for R 2 is preferably a methoxy group.
- the “C 1-6 alkylaminocarbonyl group” represented by R 2 is preferably a methylaminocarbonyl group or an ethylaminocarbonyl group.
- the “C 1-6 alkylcarbonyl group” represented by R 2 is preferably a methylcarbonyl group (acetyl group).
- R 2 is preferably a methoxy group, a carbamoyl group, a methylaminocarbonyl group, an ethylaminocarbonyl group, or a methylcarbonyl group (acetyl group), more preferably a methoxy group, a carbamoyl group, a methylaminocarbonyl group, Or it is an acetyl group.
- R 3 represents a hydrogen atom or a halogen atom.
- the “halogen atom” represented by R 3 is preferably a fluorine atom.
- R 3 is preferably a hydrogen atom or a fluorine atom.
- W represents —NH—, —O—, or —S—. W is preferably —NH— or —O—.
- X represents a single bond, —saturated heterocycle—, —CH 2 — (CH 2 ) n —, —O— (CH 2 ) n —, — (CH 2 ) n —O—, or —CH ⁇ CH— (CH 2 ) n — [n represents an integer of any one selected from 1-4. ] Is shown.
- X is —saturated heterocycle—, —CH 2 — (CH 2 ) n —, —O— (CH 2 ) n —, — (CH 2 ) n —O—, or , —CH ⁇ CH— (CH 2 ) n — [n represents an integer of any one selected from 1-4.
- X is —CH 2 — (CH 2 ) n —
- n is preferably 1 or 2
- ie X is preferably —CH 2 —CH 2 — or —CH 2 —CH 2 —CH.
- 2- is azetidinediyl, piperidinediyl, and piperazinediyl.
- X is —CH 2 — (CH 2 ) n —
- n is preferably 1 or 2
- ie X is preferably —O—CH 2 — or —O—CH 2 —CH 2 —. is there.
- n is preferably 1, that is, X is preferably —CH 2 —O—.
- X is preferably —CH ⁇ CH— (CH 2 ) n —, n is preferably 1, ie, X is preferably —CH ⁇ CH—CH 2 —.
- - saturated heterocyclic - eg, Azechijinjiiru, piperidinediyl, piperazine Diyl
- Azetidinediyl piperidinediyl, piperazinediyl
- Y represents a single bond, —O—, or —CO—. Y is preferably a single bond or —O—.
- Z is substituted with a hydrogen atom, a saturated heterocyclic group which may be substituted with any group selected from substituent group ⁇ , or any group selected from substituent group ⁇
- the substituent group ⁇ includes a saturated heterocyclic group, a hydroxy C1-6 alkyl group, an aminosulfonylamino group, a carboxy group, a hydroxyl group, a C1-6 alkoxy group, and C1-6. It is an alkyl group.
- Z is selected from a hydrogen atom, a saturated heterocyclic group optionally substituted with any group selected from substituent group ⁇ , or substituent group ⁇ .
- a C1-6 alkyl group which may be substituted with any group, the substituent group ⁇ is a hydroxy C1-6 alkyl group, an aminosulfonylamino group, a carboxy group, a hydroxyl group, a C1-6 alkoxy group, and C1-6 alkyl group.
- the “saturated heterocyclic group” of the “saturated heterocyclic group optionally substituted with any group selected from the substituent group ⁇ ” represented by Z a tetrahydrofuranyl group, an oxotetrahydrofuranyl group, Tetrahydropyranyl group, morpholinyl group, piperidinyl group, piperazinyl group, 1,4-dioxanyl group and 1,1-dioxohexahydrothiopyranyl group are preferable.
- the group selected from the substituent group ⁇ is preferably a hydroxy C 1-6 alkyl group (eg, hydroxymethyl group) or a C 1-6 alkyl group (eg, methyl group).
- Examples of the “C1-6 alkyl group” of the “C1-6 alkyl group optionally substituted with any group selected from the substituent group ⁇ ” represented by Z include a methyl group, an ethyl group, a propyl group, Isopropyl group and isobutyl group are preferable.
- Examples of the group selected from the substituent group ⁇ include a saturated heterocyclic group (eg, tetrahydrofuranyl group, morpholinyl group), aminosulfonylamino group, carboxy group, hydroxyl group, or C 1-6 alkoxy group (eg, isopropoxy group). Group) is preferred.
- the group selected from the substituent group ⁇ is preferably an aminosulfonylamino group, a carboxy group, a hydroxyl group, or a C1-6 alkoxy group (eg, isopropoxy group).
- Z may preferably be substituted with any group selected from a hydrogen atom, a hydroxy C1-6 alkyl group (eg, hydroxymethyl group), and a C1-6 alkyl group (eg, methyl group).
- Good saturated heterocyclic group eg, tetrahydrofuranyl group, oxotetrahydrofuranyl group, tetrahydropyranyl group, morpholinyl group, piperidinyl group, piperazinyl group, 1,4-dioxanyl group, 1,1-dioxohexahydrothiopyranyl
- a saturated heterocyclic group eg, tetrahydrofuranyl group, morpholinyl group
- aminosulfonylamino group carboxy group, hydroxyl group, and C1-6 alkoxy group (eg, isopropoxy group).
- a C1-6 alkyl group which may be substituted with any of the above groups (eg, methyl group, ethyl group, propyl group, A C1-6 alkyl group substituted with a hydroxyl group (eg, methyl group, ethyl group, propyl group, isopropyl group, isobutyl group), tetrahydrofuranyl group, tetrahydropyranyl. Group, piperazinyl group or morpholinyl group.
- Z is preferably any one selected from a hydrogen atom, a hydroxy C1-6 alkyl group (eg, hydroxymethyl group), and a C1-6 alkyl group (eg, methyl group).
- a saturated heterocyclic group which may be substituted with such a group (eg, tetrahydrofuranyl group, oxotetrahydrofuranyl group, tetrahydropyranyl group, morpholinyl group, piperidinyl group, piperazinyl group, 1,4-dioxanyl group, 1, 1-dioxohexahydrothiopyranyl group) or any group selected from an aminosulfonylamino group, a carboxy group, a hydroxyl group, and a C1-6 alkoxy group (eg, isopropoxy group).
- a group eg, tetrahydrofuranyl group, oxotetrahydrofuranyl group, tetrahydropyranyl group, morpholinyl group, piperidinyl group, piperazinyl group, 1,4-dioxanyl group, 1, 1-dioxohexahydrothiopyranyl group
- An optionally substituted C 1-6 alkyl group (eg, methyl group, ethyl group, propyl group, isopropyl group, isobutyl group) More preferably, a C1-6 alkyl group substituted with a hydroxyl group (eg, methyl group, ethyl group, propyl group, isopropyl group, isobutyl group), tetrahydrofuranyl group, tetrahydropyranyl group, piperazinyl group, or morpholinyl group It is.
- Suitable compounds (I) include the following compounds.
- R 1 is a cyano group, acetyl group, acetylamino group, ethylcarbonylamino group, propylcarbonylamino group, nitro group, fluoromethyl group, trifluoromethyl group, 1,1-difluoroethyl group, 1-fluoroethyl group, A difluoromethyl group, a vinyl group, a 1-fluorovinyl group, a carbamoyl group, a hydroxymethyl group, or a 1-hydroxyethyl group;
- R 2 is a methoxy group, a carbamoyl group, a methylaminocarbonyl group, an ethylaminocarbonyl group, or a methylcarbonyl group (acetyl group);
- R 3 is a hydrogen atom or a fluorine atom;
- R 1 is cyano group, acetyl group, acetylamino group, nitro group, trifluoromethyl group, 1,1-difluoroethyl group, 1-fluoroethyl group, difluoromethyl group, carbamoyl group, or 1-hydroxyethyl group Is;
- R 2 is a methoxy group, a carbamoyl group, a methylaminocarbonyl group, or an acetyl group;
- W is —NH— or —O—;
- X is —saturated heterocycle— (eg, azetidinediyl, piperidinediyl, piperazinediyl) or —O—CH 2 —CH 2 —;
- Y is a single bond or —O—;
- Z is a C1-6 alkyl
- R 1 is an acetyl group, an acetylamino group, a nitro group, a trifluoromethyl group, a difluoromethyl group, a carbamoyl group, or a 1-hydroxyethyl group;
- R 2 is a methoxy group, a carbamoyl group, or an acetyl group;
- R 3 is a hydrogen atom or a fluorine atom;
- W is —NH— or —O—;
- X is —saturated heterocycle— (eg, azetidinediyl, piperidinediyl, piperazinediyl) or —O—CH 2 —CH 2 —;
- Y is a single bond or —O—;
- Z is a C1-6 alkyl group (eg, ethyl group, isobuty
- compound (I) include, for example, the compounds of Examples 1 to 99. Among them, (1) N- (4- ⁇ 4- [3- (2-hydroxyethoxy) azetidin-1-yl] phenylamino ⁇ -6-methoxypyridin-3-yl) acetamide, (2) 3- ⁇ 4- [3- (2-hydroxyethoxy) azetidin-1-yl] phenylamino ⁇ -4-nitrobenzamide, (3) 3- ⁇ 4- [4- (4-Fluoro-5-methoxy-2-nitrophenylamino) phenyl] piperazin-1-yl ⁇ -2,2-dimethylpropionic acid, (4) 4-acetyl-3- ⁇ 4- [2- (1,1-dioxohexahydro-1 ⁇ 6 -thiopyran-4-yloxy) ethoxy] phenylamino ⁇ benzamide; (5) 4-acetyl-3- ⁇ 4- [4- (2-hydroxy)
- “Treat” is to cure a disease or condition.
- the “pharmacologically acceptable salt” refers to a salt that can be used as a medicine. In the compound of this invention, when it has an acidic group or a basic group, since it can be made into a basic salt or an acidic salt by making it react with a base or an acid, the salt is shown.
- the pharmacologically acceptable “basic salt” of the compound of the present invention is preferably an alkali metal salt such as sodium salt, potassium salt or lithium salt; an alkaline earth metal salt such as magnesium salt or calcium salt.
- Organic base salts such as N-methylmorpholine salt, triethylamine salt, tributylamine salt, diisopropylethylamine salt, dicyclohexylamine salt, N-methylpiperidine salt, pyridine salt, 4-pyrrolidinopyridine salt, picoline salt or glycine salt; Amino acid salts such as lysine salts, arginine salts, ornithine salts, glutamates, and aspartates, and alkali metal salts are preferred.
- the pharmacologically acceptable “acid salt” of the compound of the present invention is preferably a hydrohalide salt such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide, Inorganic acid salts such as nitrates, perchlorates, sulfates, phosphates; lower alkane sulfonates such as methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate, p- Allyl sulfonates such as toluene sulfonate, organic acid salts such as acetate, malate, fumarate, succinate, citrate, ascorbate, tartrate, oxalate, maleate And amino acid salts such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamate salt and aspartate salt, most preferably hydrohalide salt (especially hydrochloride
- the compound of the present invention or a pharmacologically acceptable salt thereof may absorb moisture, adhere to adsorbed water, or become a hydrate when left in the air or by recrystallization.
- the present invention also includes such various hydrates, solvates and polymorphic compounds.
- the compound of the present invention may be a geometric isomer such as a cis isomer or a trans isomer, a tautomer or a d isomer, an l isomer, etc., depending on the type or combination of substituents.
- various isomers such as optical isomers may exist, the compound of the present invention is not particularly limited, all isomers, stereoisomers and any ratio of these isomers and stereoisomer mixtures Is also included.
- These optical isomers and a mixture of isomers can be isolated by a known resolution means.
- the isomer can also be produced by asymmetric synthesis.
- the compound of the present invention includes a label, that is, a compound in which one or more atoms of the compound of the present invention are substituted with an isotope (eg, 2 H, 3 H, 13 C, 14 C, 35 S, etc.) It is.
- a label that is, a compound in which one or more atoms of the compound of the present invention are substituted with an isotope (eg, 2 H, 3 H, 13 C, 14 C, 35 S, etc.) It is.
- the present invention also includes so-called prodrugs that are pharmacologically acceptable for the compounds of the present invention.
- a pharmacologically acceptable prodrug is a compound having a group that can be converted into an amino group, a hydroxyl group, a carboxy group, or the like of the compound of the present invention by hydrolysis or under physiological conditions.
- Drug-forming groups are described in Prog. Med., Vol. 5, pp. 217-1621, 1985, “Development of Drugs” (Yodogawa Shoten, 1990), Vol. 7, pp. 163-198, Molecular Design It is the basis of.
- the prodrug more specifically, when an amino group is present in the compound of the present invention, a compound in which the amino group is acylated, alkylated or phosphorylated (for example, the amino group is eicosanoylated).
- hydroxyl group is present in the compound of the present invention, a compound in which the hydroxyl group is acylated, alkylated, phosphorylated or borated (for example, The hydroxyl group is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated, dimethylated.
- a carboxy group is present in the compound of the present invention, a compound in which the carboxy group is esterified or amidated (for example, the carboxy group is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethyl Aminomethyl esterification, pivaloyloxymethyl esterification, 1-ethoxycarbonyloxyethyl esterification, 1-cyclohexyloxycarbonyloxyethyl esterification, amidation, or methylamidated compounds).
- the compound of the present invention can be produced by applying various known production methods utilizing characteristics based on the basic skeleton or the type of substituent.
- Known methods include, for example, the methods described in “ORGANIC FUNCTIONAL GROUP PREPARATIONS”, 2nd edition, ACADEMIC PRESS, INC., 1989, “Comprehensive Organic Transformations”, VCH Publishers Inc., 1989, and the like.
- it is effective in terms of production technology to protect the functional group with a suitable protecting group at the raw material or intermediate stage, or to replace it with a group that can be easily converted to the functional group. There are cases.
- Examples of such a functional group include an amino group, a hydroxyl group, and a carboxy group
- examples of protective groups thereof include, for example, “Protective Groups in Organic Synthesis (3rd edition, 1999)” by TW Greene and PG Wuts. May be appropriately selected depending on these reaction conditions.
- the desired compound can be obtained by removing the protective group or converting it to a desired group as necessary.
- the prodrug of the compound of the present invention is produced by introducing a specific group at the raw material or intermediate stage, or reacting with the obtained compound of the present invention, in the same manner as the above protecting group. it can.
- the reaction can be carried out by applying methods known to those skilled in the art, such as ordinary esterification, amidation, dehydration, hydrogenation and the like.
- the production method of the compound of the present invention is described below. However, the manufacturing method is not limited to the following method.
- the raw material compound in each reaction can obtain and use a commercially available thing easily, or can also manufacture it according to a method known per se, or a method according to it. .
- Method A is a method for producing compound (a-3) of the present invention by coupling compound (a-1) and compound (a-2).
- R 1 , R 2 , R 3 , S, T, U, W, X, Y and Z are as defined above, and Xa represents a leaving group such as a halogen atom or a trifluoromethanesulfonyloxy group.
- V represents —NH 2 , —OH, —SH.
- Step A is a reaction using a palladium catalyst, a metal halide such as NaH, an organic base such as i-Pr 2 NEt, or an inorganic base such as K 2 CO 3 and is inert.
- the compound (a-3) of the present invention is produced from the compound (a-1) and the compound (a-2) in a solvent.
- the amount of compound (a-2) to be used is generally 1 to 3 equivalents, preferably 1 to 1.5 equivalents, relative to compound (a-1).
- the amount of the palladium catalyst to be used is generally 0.01-0.2 equivalent, preferably 0.01-0.1 equivalent, relative to compound (a-1).
- the amount of metal halide to be used is generally 1 to 3 equivalents, preferably 1 to 1.5 equivalents, relative to compound (a-1).
- the amount of the organic base to be used is generally 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to compound (a-1).
- the amount of the inorganic base to be used is generally 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to compound (a-1).
- Inert solvents used are, for example, alcohols such as methanol, ethanol, propanol, 2-propanol or butanol; aromatic hydrocarbons such as benzene, toluene or xylene; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane Or ethers such as 1,2 dimethoxyethane; amides such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone or hexamethylphosphorotriamide; Or a halogen such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, o-dichlorobenzene, m-dichlorobenzene, fluorobenzene, trichloromethylbenzene or trifluoromethylbenzene. Hydrocarbons
- the reaction temperature varies depending on the raw material compound or the solvent used, but is usually 0 ° C. to the reflux temperature of the reaction mixture, preferably room temperature to the reflux temperature of the reaction mixture.
- the reaction time varies depending on the raw material compound, the solvent used, or the reaction temperature, but is usually 30 minutes to 96 hours, preferably 30 minutes to 24 hours.
- Method B is a method for producing compound (a-3) of the present invention by coupling compound (b-1) and compound (b-2).
- R 1 , R 2 , R 3 , S, T, U, V, X, Y, Z and Xa are as defined above.
- Step B This step is a nucleophilic substitution reaction using a palladium catalyst, a metal halide such as NaH, an organic base such as i-Pr 2 NEt, or an inorganic base such as K 2 CO 3.
- compound (a-3) is produced from b-1) and compound (b-2). This step can be performed under the same conditions as in Method A
- Method C is a method for producing the compound (c-4) of the present invention in which R 2 in the general formula (I) is a carbamoyl group or a C 1-6 alkylaminocarbonyl group.
- R 1 , R 3 , S, T, U, V, X, Y, Z and Xa are as defined above
- R 4 is a protecting group for a carboxyl group such as a C 1-6 alkyl group
- R 5 represents hydrogen or a C1-6 alkyl group.
- Step C1 This step is a nucleophilic substitution reaction using a palladium-catalyzed coupling reaction, a metal halide such as NaH, an organic base such as i-Pr 2 NEt, or an inorganic base such as K 2 CO 3 .
- compound (c-3) is produced from compound (c-1) and compound (c-2).
- This step can be performed under the same conditions as in Method A.
- Step C2 This step is a step to convert compound (c-3) to compound (c-4) by amidation reaction.
- This amidation step includes a method in which an ester group is directly converted to an amide group, or a method in which an ester group is hydrolyzed to a carboxyl group and then subjected to a condensation reaction with an amine for amidation.
- An amidation reaction for converting an ester group directly into an amide group is, for example, Chem. Rev., 1948, 45, 203, J. Am. Chem. Soc., 1950, 72, 1888, Org. Biol. Chem., 1962. , 84, 4457, J. Am. Chem. Soc., 1973, 95, 875, J. Am. Chem. Soc., 1981, 103, 7090 and the like.
- Method D is a method for producing the compound (d-2) of the present invention in which R 1 in the general formula (I) is a C1-6 alkylcarbonyl group and R 2 is a carbamoyl group or a C1-6 alkylaminocarbonyl group. is there.
- R 3 , R 5 , S, T, U, X, Y and Z are as defined above, and R 7 is a C 1-6 alkyl group.
- Step D Compound (d-1) has a carbonyl group protected with acetal, but this step is a step of deprotecting the protecting group.
- the method for deprotecting the acetal can be carried out in accordance with the method described in “Protective Groups Organic Synthesis ⁇ Synthesis (3rd edition, 1999)” by T.W. Greene and P.G. Wuts, for example.
- Method E is a method for producing the compound (e-3) of the present invention wherein R 1 and R 2 in the general formula (I) are different from each other and are a C 1-6 alkylcarbonyl group or a carbamoyl group.
- R 3 , R 7 , S, T, U, X, Y and Z are as defined above.
- Step E1 This step is a step for producing a compound (e-2) by subjecting the cyano group of the compound (e-1) to a hydrolysis reaction and converting it to a carbamoyl group.
- the hydrolysis reaction of the cyano group can be performed according to a known method.
- Step E2 This step is a step of producing compound (e-3) by deprotecting the acetal of compound (e-2). This step can be performed under the same conditions as in Method D.
- Method F is a method for producing the compound (f-4) of the present invention in which R 2 in the general formula (I) is a carbamoyl group.
- R 1 , R 3 , S, T, U, V, W, X, Y and Z are as defined above.
- Step F1 This step is a nucleophilic substitution reaction using a palladium catalyst, a metal halide such as NaH, an organic base such as i-Pr 2 NEt, an inorganic base such as K 2 CO 3 , and the compound ( In this step, compound (f-3) is produced from f-1) and compound (f-2). This step can be performed under the same conditions as in Method A.
- Step F2 This step is a hydrolysis reaction of cyano group, and is a step of producing compound (f-4) from compound (f-3). It can be performed under the same conditions as in Method E Step E2.
- Method G is a method for producing the compound (g-2) of the present invention in which R 1 in the general formula (I) is a C 1-6 alkylcarbonylamino group.
- R 2 , R 3 , S, T, U, W, X, Y, Z and R 7 are as defined above.
- Step G This step converts the nitro group to an amino group by catalytic hydrogenation using palladium on carbon or reduction reaction such as reaction in the presence of calcium chloride or zinc in ethanol aqueous solution under heating and reflux.
- compound (g-2) is produced.
- the reduction reaction can be performed according to a known method.
- the acylation can be performed according to a known method using the corresponding carboxylic acid (R 7 —COOH) or a derivative thereof.
- Method H is a method for producing the compound (h-2) of the present invention in which R 1 in the general formula (I) is a hydroxymethyl group.
- R 2 , R 3 , R 5 , S, T, U, W, X, Y and Z are as defined above.
- Step H This step is a step for producing compound (h-2) from compound (h-1), which is a reduction reaction.
- This step can be performed by reacting compound (h-1) in tetrahydrofuran in the presence of lithium aluminum hydride under ice cooling at room temperature.
- the amount of lithium aluminum hydride to be used is generally 1 to 3 equivalents relative to compound (h-1). While the reaction time varies depending on the raw material compounds, it is generally 30 minutes to 3 hours, preferably 30 minutes to 1 hour.
- Method I is a method for producing the compound (i-3) of the present invention in which R 1 in the general formula (I) is a halogeno C 1-6 alkyl group and R 2 is a carbamoyl group.
- R 3 , S, T, U, W, X, Y and Z are as defined above, and R 8 is a hydrogen atom or a C1-5 alkyl group.
- Step I1 This step is a step for producing compound (i-2) from compound (i-1), which is a reduction reaction.
- This step can be carried out by reacting compound (i-1) in methanol in the presence of sodium borohydride under ice cooling to room temperature.
- the amount of sodium borohydride to be used is generally 1-3 equivalents, preferably 1-2 equivalents, relative to compound (i-1). While the reaction time varies depending on the raw material compounds, it is generally 30 minutes to 3 hours, preferably 30 minutes to 1 hour.
- Step I2 This step is a step of producing compound (i-3) from compound (i-2), and is a halogenation reaction (in the above scheme, the fluorination reaction is described as an example). .
- This step is carried out by reacting compound (i-2) in chloroform in the presence of N, N-diethylaminosulfur trifluoride (DAST) as a halogenating agent (fluorinating agent) at room temperature from ice cooling.
- DAST N, N-diethylaminosulfur trifluoride
- the amount of N, N-diethylaminosulfur trifluoride to be used is generally 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to compound (i-2). While the reaction time varies depending on the raw material compounds, it is generally 30 minutes to 3 hours, preferably 30 minutes to 1 hour.
- Method J is a method for producing the compound (j-2) of the present invention in which R 1 in the general formula (I) is a carbamoyl group and R 2 is a C 1-6 alkylcarbonyl group.
- R 3 , R 7 , S, T, U, W, X, Y and Z are as defined above.
- Step J This step is a cyano group hydrolysis reaction, which is a step of producing compound (j-2) from compound (j-1). It can be performed under the same conditions as in Method E Step E2.
- Method K is a method for producing the compound (k-3) of the present invention in which R 1 in the general formula (I) is a halogeno C 1-6 alkyl group and R 2 is a carbamoyl group.
- R 3 , R 5 , S, T, U, W, X, Y and Z are as defined above.
- Step K1 This step is a step for producing compound (k-2) from compound (k-1), which is a reduction reaction.
- This step can be performed by heating compound (k-1) in tetrahydrofuran in the presence of lithium borohydride.
- the amount of lithium borohydride to be used is generally 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to compound (k-1). While the reaction time varies depending on the raw material compounds, it is generally 1 to 5 hours, preferably 1 to 3 hours.
- Step K2 This step is a step of producing compound (k-3) from compound (k-2), and is a halogenation reaction (in the above scheme, the fluorination reaction is described as an example). .
- This step can be performed by reacting compound (k-2) in chloroform in the presence of N, N-diethylaminosulfur trifluoride as a halogenating agent (fluorinating agent) at room temperature from ice cooling. .
- the amount of N, N-diethylaminosulfur trifluoride to be used is generally 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to compound (k-2). While the reaction time varies depending on the raw material compounds, it is generally 30 minutes to 3 hours, preferably 30 minutes to 1 hour.
- Step K3 This step is a step of producing compound (k-4) from compound (k-3), and is a hydrolysis reaction of cyano group. It can be performed under the same conditions as in Method E Step E2.
- Method L is a method for producing the compound (l-2) of the present invention in which R 1 in the general formula (I) is a halogeno C 1-6 alkyl group.
- R 2 , R 3 , R 8 , S, T, U, W, X, Y and Z are as defined above.
- Step L This step is a step for producing the compound (l-2) from the compound (l-1), and is a halogenation reaction (in the above scheme, the fluorination reaction is described as an example). .
- This step can be performed by heating compound (l-1) in chloroform in the presence of a fluorinating agent such as bis (2-methoxyethyl) aminosulfur trifluoride.
- a fluorinating agent such as bis (2-methoxyethyl) aminosulfur trifluoride.
- the amount of the fluorinating agent to be used is generally 1-5 equivalents, preferably 1-3 amounts, relative to compound (l-1). While the reaction time varies depending on the raw material compounds, it is generally 1 to 120 hours, preferably 1 to 72 hours.
- Method M is a method for producing the compound (m-2) of the present invention in which R 1 in the general formula (I) is a hydroxy C1-6 alkyl group.
- R 2 , R 3 , R 8 , S, T, U, W, X, Y and Z are as defined above.
- Step M This step is a step of producing compound (m-2) from compound (m-1), and is an asymmetric reduction reaction.
- This step can be performed according to the method described in, for example, J. Org. Chem., 1988, 53, 2861, Tetrahedron Asymmetry, 1992, 3, 1583, Tetrahedron Letters, 1994, 35, 2141.
- Method N is a method for producing the compound (a-3) of the present invention by deprotecting the protecting group of the compound (n-1) that can be produced from Method A according to Method M.
- R 1 , R 2 , R 3 , S, T, U, X, Y and Z are as defined above, and PG represents a protecting group for Z.
- Step N Compound -1 (n-1) is protected by a protecting group, but this step is a step of deprotecting the protecting group.
- the method for deprotecting each protecting group can be performed, for example, according to the method described in T.W. Greene and P.G. Wuts, "Protective Groups In Organic Synthesis (3rd edition, 1999)".
- the compound of the present invention produced by the above method can be isolated and purified by a known method such as extraction, precipitation, distillation, chromatography, fractional recrystallization, recrystallization and the like. Further, when the compound having the general formula (I) of the present invention or the intermediate of production has an asymmetric carbon, an optical isomer exists. These optical isomers can be isolated and purified by conventional methods such as fractional recrystallization (salt resolution) recrystallizing with an appropriate salt and column chromatography. The isomer can also be produced by asymmetric synthesis. As a reference for a method for resolving an optical isomer from a racemate, there can be mentioned “Enantiomers, Racemates and Resolution, John Wiley And Sons, Inc.” by J. Jacques et al.
- the compound of the present invention is highly safe, exhibits good pharmacokinetics, and has an excellent osteogenesis promoting action, prevention of diseases related to bone metabolism such as osteoporosis, Paget's disease of bone, osteoarthritis and the like. Or it is useful because it can be used for treatment (especially treatment).
- the compound of the present invention or a pharmacologically acceptable salt thereof is administered to a mammal (particularly human), it can be administered systemically or locally, orally or parenterally.
- the pharmaceutical composition of the present invention can be produced by selecting an appropriate form according to the administration method and preparing various preparations usually used.
- Examples of the form of the oral pharmaceutical composition include tablets, pills, powders, granules, capsules, solutions, suspensions, emulsions, syrups, elixirs and the like.
- the preparation of these forms of pharmaceuticals includes excipients, binders, disintegrants, lubricants, swelling agents, swelling aids, coating agents, plasticizers, stabilizers, antiseptics, antiseptics commonly used as additives.
- parenteral pharmaceutical compositions include injections, ointments, gels, creams, poultices, patches, sprays, inhalants, sprays, eye drops, nasal drops, suppositories, and inhalations. Agents and the like.
- the preparation of these forms of pharmaceuticals involves the use of stabilizers, preservatives, solubilizers, moisturizers, preservatives, antioxidants, flavoring agents, gelling agents, neutralizing agents, dissolution agents that are commonly used as additives.
- Adjuvant, buffer, isotonic agent, surfactant, colorant, buffer, thickener, wetting agent, filler, absorption enhancer, suspending agent, binder, etc. Can be carried out according to a conventional method.
- the dose of the compound having the general formula (I) or a pharmacologically acceptable salt thereof varies depending on the symptoms, age, body weight, the kind and dose of the drug to be administered in combination, but usually the general formula (I ) In the range of 0.001-1000 mg per adult (as a body weight of about 60 kg), monthly: once to several times, week: once to several times 1 time to several times, preferably once or several times, orally or parenterally or continuously administered intravenously in the range of 1-24 hours per day.
- the obtained oil (3.00 g, 8.16 mmol) was dissolved in dimethylformamide (30 mL), and 4-nitrofluorobenzene (1.04 mL, 9.79 mmol) and diisopropylethylamine (2.13 mL, 12.2 mmol) were added under nitrogen atmosphere. The mixture was stirred at 60 ° C. for 15 hours. The reaction mixture was allowed to cool to room temperature, water was added, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate.
- the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate, 4: 1 ⁇ 1: 1, V / V).
- the solvent of the target fraction was distilled off under reduced pressure to obtain the title target compound as a yellow oil (2.08 g, yield 79%).
- the residue was extracted with ethyl acetate (200 mL), and the organic layer was washed successively with 5% aqueous sodium thiosulfate and saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate, 4: 1 ⁇ 2: 1, V / V), and then the solvent of the target fraction was evaporated under reduced pressure. A yellow oily substance (10.34 g, yield 92%) of the target compound was obtained.
- Stir. 2- (2-Bromoethoxy) tetrahydropyran (30.9 g, 148 mmol) was added, and the mixture was stirred at 90 ° C. for 1 hr.
- Ethyl acetate was added to the reaction mixture, which was washed successively with water and then with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
- N- (6-methoxypyridin-3-yl) -2,2-dimethylpropionamide (25.2 g, 0.120 mol) prepared in Example 1 (1a) was dissolved in tetrahydrofuran (200 mL), and the temperature was -78 ° C. 1.7 M tert-butyllithium / pentane solution (200 mL, 0.34 mol) was added dropwise over 1 hour. After stirring at the same temperature for 30 minutes, a tetrahydrofuran solution (200 mL) of iodine (55.2 g, 0.220 mol) was added dropwise over 1 hour, followed by stirring at room temperature for 2 hours.
- Example 1 N- [6-methoxy-4- (4- ⁇ 3- [2- (tetrahydropyran-2-yloxy) ethoxy] azetidin-1-yl ⁇ phenylamino) pyridine-3-prepared in (1e) Il] acetamide (320 mg, 0.68 mmol) was dissolved in methanol (3 mL), 8.6 M hydrogen chloride / isopropanol solution (0.24 mL, 2.0 mmol) was added under ice cooling, and the mixture was stirred at the same temperature for 30 min.
- reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate, extracted twice with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the resulting powder was washed with isopropyl ether to give the title object compound as a white powder (150 mg, yield 59%).
- 1,4-Difluoro-2-methoxy-5-nitrobenzene (192 mg, 1.02 mmol) prepared in Example 2 (2a) was dissolved in dimethylformamide (3 mL) and prepared in Reference Example 1 (1c) 4 - ⁇ 3- [2- (Tetrahydropyran-2-yloxy) ethoxy] azetidin-1-yl ⁇ phenylamine (297 mg, 1.02 mmol) and diisopropylethylamine (0.27 mL, 1.5 mmol) were added and 15 hours at 80 ° C. Stir.
- reaction solution was neutralized with saturated aqueous sodium hydrogen carbonate, extracted twice with ethyl acetate, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the precipitated powder was collected by filtration with isopropyl ether to obtain a red powder (95 mg, yield 77%) of the title object compound.
- Example 3 4-Fluoro-5-methoxy-N 1- (4- ⁇ 3- [2- (tetrahydropyran-2-yloxy) ethoxy] azetidin-1-yl ⁇ phenyl) benzene-1 prepared in (3a) , 2-diamine (230 mg, 0.530 mmol) was dissolved in pyridine (2 mL), acetic anhydride (0.060 mL, 0.64 mmol) was added under ice cooling, and the mixture was stirred at the same temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate.
- the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate, 1: 1 ⁇ 0: 1, V / V).
- the solvent of the target fraction was distilled off under reduced pressure to obtain a blue oily substance (240 mg, yield 96%) of the title target compound.
- the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate, 3: 1 ⁇ 2: 1, V / V).
- the solvent of the target fraction was distilled off under reduced pressure to obtain the title target compound as a red oil (2.72 g, yield 89%).
- the organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
- the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate, 5: 1 ⁇ 3: 1 ⁇ 1: 1 ⁇ 1: 2 ⁇ 1: 4 ⁇ 0: 1, V / V).
- the solvent of the target fraction was distilled off under reduced pressure to obtain a dark red oily substance (1.70 g, 38% yield) of the title target compound.
- Acetic anhydride (20 mL) was added to 3-hydroxybenzoic acid (10.0 g, 72.4 mmol), and the mixture was stirred at 120 ° C. for 12 hours.
- the reaction mixture was poured into ice water and extracted twice with ethyl acetate.
- the organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
- the obtained residue was collected by filtration with isopropyl ether-hexane (1:10).
- Aluminum chloride (24.7 g, 185 mmol) was added to the obtained powder and stirred at 180 ° C. for 3 hours.
- the mixture was poured into ice and extracted twice with ethyl acetate.
- Ethyl 4-acetyl-3-trifluoromethanesulfonyloxybenzoate (500 mg, 1.47 mmol) prepared in Example 6 (6b) was dissolved in methylene chloride (10 mL), and ethylenedioxybis (trimethylsilane) was cooled with ice. (0.43 mL, 1.8 mmol) and trimethylsilyl trifluoromethanesulfonate (0.05 mL, 0.3 mmol) were added, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was washed with saturated aqueous sodium hydrogen carbonate and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
- the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate, 20: 1, V / V), and the solvent of the target fraction was evaporated under reduced pressure to give the title target compound as a pale yellow powder (490 mg Yield 87%).
- Example 6 Ethyl 4- (2-methyl- [1,3] dioxolan-2-yl) -3- (4- ⁇ 3- [2- (tetrahydropyran-2-yloxy) ethoxy] prepared in (6d) Azetidin-1-yl ⁇ phenylamino) benzoate (158 mg) was dissolved in tetrahydrofuran (3 mL), methanol (1 mL) and 1.0 M aqueous lithium hydroxide (0.86 mL, 0.86 mmol) were added, and 1 was added at room temperature. Stir for 4 hours at 40 ° C.
- the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate, 1: 1 ⁇ 1: 3 ⁇ 0: 1, V / V).
- the solvent of the target fraction was distilled off under reduced pressure to give the title target compound as a pale yellow powder (52 mg, yield 8.6%).
- Example 6 4- (2-Methyl- [1,3] dioxolan-2-yl) -3- (4- ⁇ 3- [2- (tetrahydropyran-2-yloxy) ethoxy] azetidine prepared in (6e) An orange powder (25 mg, 64% yield) of the title object compound was obtained in the same manner as in Example 4 (4e) using 1-yl ⁇ phenylamino) benzamide (52 mg, 0.105 mmol).
- Example 5-Bromo-2-methoxy-4-nitropyridine (80.4 g) prepared in (7b) was dissolved in acetic acid (250 mL), iron powder (67.4 g, 1.21 mol) ⁇ ⁇ was added, and the mixture was heated to 80. And stirred for 1 hour. After standing to cool, the insoluble material was filtered through Celite, and the solvent was distilled off under reduced pressure. To the residue was added 400 mL of water, adjusted to pH> 8 with potassium carbonate, ethyl acetate was added, and the mixture was filtered through Celite to separate the two layers of the filtrate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
- Example 7 5- (Acetyl) -2-methoxypyridin-4-ylamine (150 mg, 0.903 mmol) prepared in (7d) and 1- (4-iodophenyl) -3- [prepared in Reference Example 2 (2b) Using 2- (tetrahydropyran-2-yloxy) ethoxy] azetidine (436 mg, 1.08 ⁇ ⁇ ⁇ mmol) in the same manner as in Example 1 (1e) ⁇ , the title target compound was a yellow oil (52 mg, 13% yield) Got.
- Example 7 (5-acetyl-2-methoxypyridin-4-yl)-(4- ⁇ 3- [2- (tetrahydropyran-2-yloxy) ethoxy] azetidin-1-yl ⁇ phenyl prepared in (7e) ) Amine (52 mg, 0.12 mmol) was used to give the title compound as a yellow powder (24 mg, yield 56%) in the same manner as in Example 4 (4e).
- the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate, 2: 1, V / V), and the solvent of the target fraction was evaporated under reduced pressure to give the title target compound as a yellow oil (3.97 g Yield 66%).
- the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate, 4: 1, V / V), and the solvent of the target fraction was evaporated under reduced pressure to give the title target compound as an orange oil (3.61 g Yield 66%).
- the organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
- the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate, 2: 1 ⁇ 0: 1, V / V), and the solvent of the target fraction was distilled off under reduced pressure.
- the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
- the obtained residue was purified by silica gel column chromatography (chloroform: methanol, 100: 1, V / V).
- the solvent of the target fraction was distilled off under reduced pressure.
- the obtained residue was purified by basic silica gel column chromatography (chloroform: methanol, 50: 1, V / V).
- the solvent of the target fraction was distilled off under reduced pressure, and the resulting residue was dissolved in ethyl acetate, washed with water and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
- Example 9 Using 4- (1-benzhydrylazetidin-3-yl) morpholine (5.50 g, 17.8 mmol) prepared in Example 9 (9a), the title compound was prepared in the same manner as in Example 8 (8c). A yellow powder (3.10 g, 66% yield) was obtained.
- Example 9 Using 4- [1- (4-nitrophenyl) azetidin-3-yl] morpholine (1.66 g, 6.30 mmol) prepared in Example 9 (9b) in the same manner as in Example 8 (8e), the title purpose was obtained. A yellow powder (337 mg) of the compound was obtained.
- Example 9 (2-Methoxy-5-nitropyridin-4-yl)- ⁇ 4- [3- (morpholin-4-yl) azetidin-1-yl] phenyl ⁇ amine (0.34 g, prepared in (9c)) 0.87 mmol) was used in the same manner as in Example 8 (8f) to give the title object compound as a white powder (241 mg, yield 70%).
- N- ⁇ 6-methoxy-4- [4- (piperazin-1-yl) phenylamino] pyridin-3-yl ⁇ acetamide (100 mg, 0.293 mmol) prepared in Example 10 (10b) was dissolved in methylene chloride (2 To the mixture was added triethylamine (0.053 mL, 0.38 mmol) and 1.0 M acetoxyacetyl chloride / methylene chloride solution (0.29 mL, 0.29 mmol) under ice-cooling, and the mixture was stirred at the same temperature for 1 hour. The reaction solution was washed with water and saturated brine, and dried over anhydrous sodium sulfate.
- the solvent was distilled off under reduced pressure to obtain a light brown oil.
- the obtained oil was dissolved in methanol (2 mL), 5.0 M aqueous sodium hydroxide (0.29 mL, 1.5 mmol) was added at room temperature, and the mixture was stirred at the same temperature for 30 min.
- the reaction mixture was diluted with chloroform, washed with water and saturated brine, and dried over anhydrous sodium sulfate.
- the solvent was distilled off under reduced pressure, ethyl acetate was added, and the solvent was distilled off under reduced pressure.
- the precipitated powder was collected by filtration with ethyl acetate to give the title object compound as a white powder (75 mg, yield 64%).
- Example 12 1- ⁇ 4- [4- (4-Fluoro-5-methoxy-2-nitrophenylamino) phenyl] piperazin-1-yl ⁇ -2-hydroxyethanone (12a) tert-butyl 4- [4- (4-fluoro-5-methoxy-2-nitrophenylamino) phenyl] piperazine-1-carboxylate
- 1,4-Difluoro-2-methoxy-5-nitrobenzene (1.93 g) prepared in tert-butyl 4- (4-aminophenyl) piperazine-1-carboxylate (2.83 g, 10.2 mmol) and Example 2 (2a) , 10.2 mmol) was used in the same manner as in Example 2 (2b) to obtain a red powder (3.71 g, yield 82%) of the title object compound.
- Example 10 Using (4-fluoro-5-methoxy-2-nitrophenyl)-(4-piperazin-1-ylphenyl) amine (70 mg, 0.20 mmol) prepared in Example 12 (12b), Example 10 (10c ) was used to obtain a red powder (80 mg, 99% yield) of the title object compound.
- Example 12 (12b) (4-fluoro-5-methoxy-2-nitrophenyl)-(4-piperazin-1-ylphenyl) amine (156 mg, 0.450 mmol) and Example 11 (11a) Using the prepared methyl 2,2-dimethyl-3-oxopropionate (174 mg, 0.90 mmol) and using the same method as in Example 11 (11b), red powder (130 mg, yield) of the title target compound 63%).
- the obtained oil was dissolved in dimethylformamide (45 mL), 4-nitrophenol (1.77 g, 12.7 mmol) and potassium carbonate (2.93 g, 21.2 mmol) were added, and the mixture was stirred at 80 ° C. for 2 hr. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
- Example 14 4- [2- (Tetrahydrofuran-3-yloxy) ethoxy] phenylamine prepared in Example 14 (14b) (2.02 g, 9.05 mmol) and 4-chloro-2-methoxy-produced in Example 4 (4c) Using 5-nitropyridine (1.71 g, 9.05 mmol) and using the same method as in Example 4 (4d), a yellow powder (3.04 g, yield 90%) of the title object compound was obtained.
- Example 14 (2-Methoxy-5-nitropyridin-4-yl)- ⁇ 4- [2- (tetrahydrofuran-3-yloxy) ethoxy] phenyl ⁇ amine (3.04 g, 8.10 mmol) prepared in (14c) Using the same method as in Example 8 (8f), a pale purple powder (603 mg) of the title object compound was obtained.
- Example 8 (8a) and (8b) using 2- (4-nitrophenoxy) ethanol (1.00 g, 5.46 mmol) and N-methylpiperazine (1.21 mL, 10.9 mmol) prepared in Example 15 (15a) Using the same method as above, a yellow oil (763 mg, 53% yield) of the title object compound was obtained.
- 1 H-NMR (CDCl 3 , 400 MHz) ⁇ : 2.30 (3H, s), 2.47-2.62 (8H, m), 2.84.2.87 (2H, m), 4.18-4.20 (2H, m), 6.95-6.97 (2H, m), 8.90-8.92 (2H, m).
- Example 15 Using 1-methyl-4- [2- (4-nitrophenoxy) ethyl] piperazine (761 mg, 2.87 mmol) prepared in Example 15 (15b), the same procedure as in Example 14 (14b) was used. A yellow powder (684 mg, yield 100%) of the target compound was obtained.
- Example 15 4- [2- (4-Methylpiperazin-1-yl) ethoxy] phenylamine (222 mg, 0.942 mmol) prepared in Example 15 (15c) and N- (4- Using iodo-6-methoxypyridin-3-yl) acetamide (250 mg, 0.856 mmol) in the same manner as in Example 1 (1e), the title target compound was white powder (200 mg, yield 58%) Got.
- N- (4- ⁇ 4- [3- (2-hydroxyethoxy) azetidin-1-yl] phenylamino ⁇ -6-methoxypyridin-3-yl) acetamide (850 mg, prepared in Example 1 (1f) 2.28 mmol), N-tert-butoxycarbonylsulfamoylamine (0.67 g, 3.4 mmol) and triphenylphosphine (0.72 g, 2.7 mmol) were suspended in ethyl acetate: tetrahydrofuran (3: 1, 15 mL) Diethyl dicarboxylate (0.74 mL, 3.4 mmol) was added and stirred at room temperature for 20 hours.
- the solvent of the reaction solution was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform: methanol, 100: 0 ⁇ 100: 4, V / V).
- the solvent of the target fraction was distilled off under reduced pressure to obtain a pale yellow foam powder (1.05 g, yield 84%) of the title target compound.
- Example 17 4-acetyl-3- ⁇ 4- [2- (tetrahydropyran-4-yloxy) ethoxy] phenylamino ⁇ benzamide (17a) 4- [2- (4-Nitrophenoxy) ethoxy] tetrahydropyran
- Example 17 Ethyl 4- (2-methyl- [1,3] dioxolan-2-yl) -3- ⁇ 4- [2- (tetrahydropyran-4-yloxy) ethoxy] phenylamino ⁇ prepared in (17c) Benzoate (630 mg, 1.34 mmol) was dissolved in methanol (6 mL), 5.0 M aqueous sodium hydroxide (0.83 mL, 4.2 mmol) was added, and the mixture was stirred at 50 ° C. for 2 hr. Water (6 mL) was added to the reaction solution, methanol was distilled off under reduced pressure, and the residue was washed with toluene.
- the aqueous layer was neutralized with 6.0 M hydrochloric acid under ice cooling, extracted three times with chloroform, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain a light brown powder (366 mg, yield 62%) of the title object compound.
- the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate, 8: 1 ⁇ 2: 1, V / V).
- the solvent of the target fraction was evaporated under reduced pressure to give the title target compound as a pale yellow oil (3.54 g, yield 79%).
- Example 14 (14b) Using the method of Example 14 (14b) using 2- ⁇ 2- [2- (4-nitrophenoxy) ethoxy] ethoxy ⁇ tetrahydropyran prepared in Example 19 (19c), the title target compound was a brown oil. (3.21 g, yield 100%) was obtained.
- Example 19 4- (2-Methyl- [1,3] dioxolan-2-yl) -3- (4- ⁇ 2- [2- (tetrahydropyran-2-yloxy) ethoxy] ethoxy prepared in (19f) ⁇ Phenylamino) benzamide (1.41 g, 2.90 mmol) was used to give the title compound as a yellow powder (680 mg, 66% yield) in the same manner as in Example 17 (17f).
- the organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate.
- the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform: methanol, 98: 2 ⁇ 92: 8, V / V).
- the solvent of the target fraction was distilled off under reduced pressure to obtain the title target compound as a yellow oil (3.54 g, yield 90%).
- Example 14 Similar to Example 14 (14b), using 4- [2- (4-nitrophenoxy) ethoxy] tetrahydrothiopyran-1,1-dioxide (2.20 g, 6.98 mmol) prepared in Example 20 (20d) Using the method, a light brown powder (1.73 g, yield 87%) of the title object compound was obtained.
- the organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
- the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate 1: 1, V / V).
- the solvent of the target fraction was distilled off under reduced pressure to give the title target compound as a pale yellow oil (2.88 g, yield 26%).
- Example 4 The method used in Example 4 (4e) using 3- [2- (tetrahydropyran-2-yloxy) ethoxy] dihydrofuran-2-one (2.86 g, 12.4 mmol) prepared in Example 21 (21a) Gave a colorless oil (1.23 g, 68% yield) of the title compound.
- Example 21 Using 3- (4-hydroxyphenylamino) -4- (2-methyl- [1,3] dioxolan-2-yl) benzamide (500 mg, 1.59 mmol) prepared in Example 21 (21f) The yellowish orange powder (480 mg, yield 100%) of the title object compound was obtained by the method used in 17 (17f).
- the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate, 9: 1 ⁇ 8: 2, V / V), and the solvent of the target fraction was evaporated under reduced pressure to give the title target compound as a yellow oil. (7.06 g, 44% yield) was obtained.
- the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate, 85: 15 ⁇ 55: 45, V / V), and the solvent of the target fraction was evaporated under reduced pressure to give the title target compound as a yellow oil. (4.40 g, 77% yield) was obtained.
- Example 14 Using the same method as Example 14 (14b) using ethyl 4- [2- (4-nitrophenoxy) ethoxy] butyrate (4.40 g, 14.8 mmol) prepared in Example 22 (22f) A reddish brown oil (3.94 g, 99% yield) was obtained.
- Example 22 Ethyl 4- (2- ⁇ 4- [5-carbamoyl-2- (2-methyl- [1,3] dioxolan-2-yl) phenylamino] phenoxy ⁇ ethoxy) butyrate ( 640 mg, 1.35 mmol) was used to obtain the title compound orange powder (470 mg, 81% yield) by the method used in Example 17 (17f).
- Example 23 1- (4-Amino-3-bromophenyl) ethanone (15.8 g, 73.8 mmol) prepared in Example 23 (23a) was dissolved in acetic acid (265 mL), and concentrated sulfuric acid (12.5 mL) was added under ice cooling. In addition, the mixture was stirred at the same temperature for 10 minutes.
- Example 22 Using the 4-acetyl-2-bromobenzonitrile (1.40 g, 6.25 mmol) prepared in Example 22 (22b) and the method used in Example 6 (6c), the title target compound was pale reddish brown powder (1.36 g Yield 81%).
- Example 23 4- (2-Methyl- [1,3] dioxolan-2-yl) -2- ⁇ 4- [2- (tetrahydropyran-4-yloxy) ethoxy] phenylamino ⁇ benzoate prepared in (23d) Using the nitrile (50 mg, 0.12 mmol), a yellow oil (49 mg, 100% yield) of the title object compound was obtained by the method used in Example 17 (17f).
- Example 24 Using 4- [2- (4-nitrophenyl) ethyl] morpholine (5.75 g, 20.0 mmol) prepared in Example 24 (24a), the title target compound was prepared by the method used in Example 14 (14b). A yellow powder (1.50 g, 36% yield) was obtained.
- 3- (4-Nitrophenyl) prop-2-en-1-ol (1.50 g, 8.37 mmol) is dissolved in methylene chloride (15 mL), pyridine (5.1 mL, 63 mmol) is added, and then ice-cooled. Lower thionyl chloride (0.92 mL, 13 mmol) was added dropwise, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed successively with water, 1.0 M hydrochloric acid and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Morpholine (10 mL, 0.12 mol) was added to the resulting residue, and the mixture was stirred at room temperature for 30 minutes.
- the reaction mixture was diluted with diethyl ether, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
- the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate, 2: 1 ⁇ 0: 1, V / V).
- the solvent of the target fraction was distilled off under reduced pressure to obtain a brown powder (870 mg, yield 42%) of the title target compound.
- Example 22 Using methyl 4-cyano-2- ⁇ 4- [2- (tetrahydropyran-4-yloxy) ethoxy] phenylamino ⁇ benzoate (175 mg, 0.441 mmol) prepared in Example 26 (26b), Example 22 ( The pale yellow powder (190 mg, yield 100%) of the title object compound was obtained by the method used in 22i).
- Methyl 2- ⁇ 4- [2- (tetrahydropyran-4-yloxy) ethoxy] phenylamino ⁇ terephthalamate (190 mg, 0.441 mmol) prepared in Example 26 (26c) was dissolved in tetrahydrofuran (3 mL). , Lithium aluminum hydride (17 mg, 0.44 mmol) was added, and the mixture was stirred at room temperature for 0.5 hr. Diethyl ether (3 mL), 1 drop of water and 1 drop of 15% aqueous sodium hydroxide were added to the reaction mixture, and after stirring for 10 minutes, 3 drops of water were added and stirred for 0.5 hour.
- Example 29a Using 4-bromo-3-fluoro-N-methoxy-N-methylbenzamide (3.59 g, 13.7 mmol) prepared in Example 29 (29a), the title compound was prepared in the same manner as in Example 28 (28b). Of a yellow oil (2.49 g, 84% yield) was obtained.
- 1 H-NMR (CDCl 3 , 400 MHz) ⁇ : 2.59 (3H, s), 7.60 (1H, dd, J 8.2, 1.9 Hz), 7.64-7.73 (2H, m).
- Example 29b 1- (4-Bromo-3-fluorophenyl) ethanone (2.49 g, 11.5 mmol) prepared in Example 29 (29b) was dissolved in dimethylformamide (55 mL) and zinc cyanide (2.71 g, 23.0 mmol) was dissolved. And nitrogen gas was bubbled for 1 minute, tetrakistriphenylphosphine palladium (2.66 g, 2.30 mmol) was added, and the mixture was stirred at 80 ° C. for 1 hour in a nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate.
- Example 29e 4-acetyl-2- (4- ⁇ 3- [2- (tetrahydropyran-2-yloxy) ethoxy] azetidin-1-yl ⁇ phenoxy) benzamide (1.18 g, 2.60 mmol) prepared in Example 29 (29e) was used to give the title compound as a white crystal (301 mg, yield 31%) by the method used in Example 17 (17f).
- Example 30 4-acetyl-3- ⁇ 4- [4- (2-hydroxyethoxy) piperidin-1-yl] phenoxy ⁇ benzamide (30a) tert-butyl 4-tert-butoxycarbonylmethoxypiperidine-1-carboxylate
- Trifluoroacetic acid (12 mL) was added to tert-butyl 4- (2-hydroxyethoxy) piperidine-1-carboxylate (3.01 g, 12.3 mmol) prepared in Example 30 (30b) under ice-cooling, and the mixture was stirred for 1 hour. After stirring, the solvent was distilled off under reduced pressure. The residue was dissolved in tetrahydrofuran (14 mL), triethylamine (14 mL, 98 mmol) and tert-butyldimethylchlorosilane (3.71 g, 24.6 mmol) were added under ice cooling, and the mixture was stirred at room temperature for 50 minutes.
- Example 30 4-Benzyloxyphenyl) -4- [2- (tert-butyldimethylsilanyloxy) ethoxy] piperidine prepared in (30d) (500 mg, 1.13 mmol) was used to give the title object compound as a colorless oil (440 mg, yield 100%) in the same manner as in Example 14 (14b).
- Example 30 4- ⁇ 4- [2- (tert-dimethylsilanyloxy) ethoxy] piperidin-1-yl ⁇ phenol prepared in Example 30 (30e) (440 mg, 1.13 mmol) and 4-acetyl-3-fluorobenzonitrile (306 mg, 1.88 mmol) prepared in Example 28 (28b) were used in the same manner as in Example 28 (28c). A reddish brown powder of the compound (216 mg, 46% yield) was obtained.
- Example 22 Using 4-acetyl-3- ⁇ 4- [4- (2-hydroxyethoxy) piperidin-1-yl] phenoxy ⁇ benzonitrile (210 mg, 0.552 mmol) prepared in Example 30 (30f), Example 22 In the same manner as in (22i), a yellow powder (158 mg, yield 72%) of the title object compound was obtained.
- Example 31 4- (1,1-Difluoroethyl) -3- ⁇ 4- [4- (2-hydroxyethoxy) piperidin-1-yl] phenoxy ⁇ benzamide (31a) 4- (1,1-Difluoroethyl) -3-fluorobenzonitrile
- the reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
- the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate, 1: 1, V / V).
- the solvent of the target fraction was distilled off under reduced pressure to obtain the title target compound as a yellow powder (1.23 g, yield 39%).
- the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate, 2: 1, V / V).
- the solvent of the target fraction was distilled off under reduced pressure to give the title target compound as a tan powder (264 mg, 25%).
- Example 31 1- (4-benzyloxyphenyl) -4- [2- (tetrahydropyran-2-yloxy) ethoxy] piperidine (264 mg, 0.642 mmol) )
- a colorless oily product (212 mg, yield 100%) of the title object compound was obtained by the method used in IV.
- Example 31e 4- ⁇ 4- [2- (Tetrahydropyran-2-yloxy) ethoxy] piperidin-1-yl ⁇ phenol prepared in Example 31 (31e) (212 mg, 0.642 mmol) and prepared in Example 31 (31a) 4- (1,1-difluoroethyl) -3-fluorobenzonitrile (120 mg, 0.642 mmol) was used in the method used in Example 28 (28c) to give the title compound as a yellow oil (76 mg, Yield 24%).
- Example 31 4- (1,1-Difluoroethyl) -3- (4- ⁇ 4- [2- (tetrahydropyran-2-yloxy) ethoxy] piperidin-1-yl ⁇ phenoxy) benzoate prepared in (31f) Using a nitrile (70 mg, 0.14 mmol), a white powder (33 mg, 55% yield) of the title object compound was obtained in the same manner as in Example 22 (22i) and Example 4 (4e).
- Example 32a Using 4- [2- (4-benzyloxyphenoxy) ethoxy] tetrahydropyran (1.8 g, 5.5 mmol) prepared in Example 32 (32a), the title target compound was prepared by the method used in Example 14 (14b). Was obtained as a light brown oil (1.11 g, 85% yield).
- Cobalt (II) bromide (976 mg, 4.46 mmol) and zinc (4.96 g, 75.8 mmol) were suspended in acetonitrile (40 mL), and allyl chloride (1.10 mL, 13.4 mmol) and trifluoroacetic acid ( 0.205 mL, 2.68 mmol) was added, and after stirring for 10 minutes, methyl 4-bromo-3-fluorobenzoate (10.4 g, 44.6 mmol) and acetic anhydride (4.64 mL, 49.1 mmol) prepared in Example 32 (32c) Acetonitrile solution (60 mL) was added, and the mixture was stirred at room temperature for 18 hours.
- Example 33 4-acetyl-3- ⁇ 4- [2- (2-isopropoxyethoxy) ethoxy] phenoxy ⁇ benzamide (33a) 2- [2- (2-Chloroethoxy) ethoxy] propane
- Example 33 Using 4-benzyloxy- [2- (3-isopropoxyethoxy) ethoxy] benzene (1.95 g, 5.90 mmol) prepared in Example 33 (33b), the same procedure as used in Example 14 (14b) was used. A brown oily substance (1.36 g, yield 96%) of the target compound was obtained.
- 1 H-NMR (CDCl 3 , 400 MHz) ⁇ : 1.17 (6H, d, J 6.1 Hz), 3.59-3.65 (3H, m), 3.67-3.72 (2H, m), 3.79-3.85 (2H, m ), 4.00-4.06 (2H, m), 6.70-6.80 (4H, m).
- Example 33 4- [2- (2-Isopropoxyethoxy) ethoxy] phenol (1.36 g, 5.66 mol) prepared in Example 33 (33c) and 4-acetyl-3-fluorobenzonitrile prepared in Example 28 (28b) (1.02 g, 6.23 mmol) was used in the same manner as in Example 28 (28c) to give the title target compound as an orange oil (1.83 g, yield 84%).
- Example 22 Using 4-acetyl-3- ⁇ 4- [2- (2-isopropoxyethoxy) ethoxy] phenoxy ⁇ benzonitrile (1.83 g, 4.77 mmol) prepared in Example 33 (33d), Example 22 (22i) In the same manner, a white powder (1.53 g, yield 80%) of the title object compound was obtained.
- Example 34 4-acetyl-3- ⁇ 4- [3- (tetrahydropyran-4-yloxy) propenyl] phenoxy ⁇ benzamide (35a) 4-Iodophenyl acetate
- Example 34 (34a) 4-Iodophenyl acetate prepared in Example 34 (34a) (1.92 g, 7.33 mmol) and 1.04 g (7.31 mmol) of 4-allyloxytetrahydropyran prepared in Example 34 (34b) were dissolved in dimethylformamide (30 mL), palladium acetate (247 mg, 1.10 mmol), Triphenylphosphine (577 mg, 2.20 mmol) and silver acetate (3.67 g, 22.0 mmol) were added, and the mixture was stirred at 70 ° C. for 23 hours under a nitrogen atmosphere.
- reaction mixture was diluted with ethyl acetate, filtered through celite, the filtrate was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate.
- the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate, 5: 1, V / V), and then the solvent of the target fraction was distilled off under reduced pressure. A white powder of the compound (0.46 g, 23% yield) was obtained.
- the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate, 5: 1, V / V), and then the solvent of the target fraction was distilled off under reduced pressure to give the title target compound as a white powder (0.29 g, Yield 74%).
- Example 34 4- [3- (Tetrahydropyran-4-yloxy) propenyl] phenol (0.29 g, 1.1 mmol) prepared in Example 34 (34d) and 4-acetyl-3-fluorobenzoate prepared in Example 28 (28b) Using the nitrile (206 mg, 1.05 mmol), a yellow oil (396 mg, 100% yield) of the title object compound was obtained by the method used in Example 28 (28c).
- Example 22 Using 4-acetyl-3- ⁇ 4- [3- (tetrahydropyran-4-yloxy) propenyl] phenoxy ⁇ benzonitrile (390 mg, 1.03 mmol) prepared in Example 34 (34e), Example 22 (22i ) was used to obtain a white powder (300 mg, 73% yield) of the title object compound.
- Example 22 Using 4-difluoromethyl-3- ⁇ 4- [2- (tetrahydropyran-4-yloxy) ethoxy] phenoxy ⁇ benzonitrile (1.18 g, 3.28 mmol) prepared in Example 35 (35c), Example 22 ( The white powder (1.06 g, 86% yield) of the title object compound was obtained by the method used in 22i).
- Example 36 Using 3-fluoro-N-methoxy-N-methyl-4-trifluoromethylbenzamide (3.50 g, 13.9 mmol) prepared in Example 36 (36a), the title was prepared in the same manner as in Example 28 (28b). A colorless oil (3.05 g, 100%) of the target compound was obtained.
- Example 36 1- (3-Fluoro-4-trifluoromethylphenyl) ethanone (606 mg, 2.94 mmol) prepared in Example 36 (36b) and 4- [2- (tetrahydropyran--) prepared in Example 32 (32b) Using 4-yloxy) ethoxy] phenol (500 mg, 2.10 mmol) and the method used in Example 28 (28c), the title target compound was obtained as a pale yellow oil (162 mg, 18% yield).
- Example 37 Using 4-bromo-3-fluoro-N-methoxy-N-methylbenzamide (3.59 g, 13.7 mmol) prepared in Example 37 (37a) in the same manner as in Example 28 (28b), the title target compound Of a yellow oil (2.49 g, 84% yield) was obtained.
- 1 H-NMR (CDCl 3 , 400 MHz) ⁇ : 2.59 (3H, s), 7.60 (1H, dd, J 8.2, 1.9 Hz), 7.64-7.73 (2H, m).
- Example 37 Using 1- (4-bromo-3-fluorophenyl) ethanone (2.49 g, 11.5 mmol) prepared in Example 37 (37b), the title compound was pale yellow as described in Example 29 (29c). A powder (1.59 g, 85% yield) was obtained.
- 1 H-NMR (CDCl 3 , 400 MHz) ⁇ : 2.64 (3H, s), 7.73-7.80 (2H, m), 7.82 (1H, dd, J 7.8, 1.4 Hz).
- Example 32b 4-acetyl-2-fluorobenzonitrile (548 mg, 3.36 mmol) prepared in Example 37 (37c) and 4- [2- (tetrahydropyran-4-yloxy) ethoxy] prepared in Example 32 (32b)
- a pale yellow oil (710 mg, 55% yield) of the title object compound was obtained by the method used in Example 28 (28c) using phenol (800 mg, 3.36 mmol).
- the obtained residue was purified by silica gel column chromatography (chloroform: methanol, 100: 0 ⁇ 94: 6, V / V), and the solvent of the target fraction was distilled off under reduced pressure.
- the obtained residue was triturated with tert-butyl methyl ether and collected by filtration.
- the obtained powder was dissolved by heating in 4 mL of ethyl acetate: tert-butyl methyl ether (3: 1). The solution was stirred at room temperature for 30 minutes, and the precipitate was collected by filtration to give the title object compound as a white powder (30 mg, yield 60%).
- the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate, 1: 3 ⁇ 0: 1, V / V).
- the solvent of the target fraction was distilled off under reduced pressure to obtain the title target product (610 mg, yield 67%).
- 610 mg of the obtained powder was dissolved in tert-butyl methyl ether (3 mL) and ethyl acetate (1 mL) with heating, and then stirred for 30 minutes while returning to room temperature. The precipitate was collected by filtration to give the title object compound as a white powder (378 mg, yield 62%).
- Example 40 The same method as in Example 6 (6e), using methyl 4-acetyl-3- [4- (2-isopropoxyethoxymethyl) phenoxy] benzoate (810 mg, 2.10 mmol) prepared in Example 40 (40b) Gave a white powder (370 mg, 51% yield) of the title compound.
- the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate, 100: 1 ⁇ 1: 1, V / V).
- the solvent of the target fraction was distilled off under reduced pressure to obtain the title target compound as a colorless oil (3.95 g, yield 73%).
- Example 41 4- (4-Bromobenzyloxy) tetrahydropyran prepared in (41a) (3.95 g, 14.6 mmol) dissolved in 1,4-dioxane (50 mL) and bis (pinacolato) diboron (4.07 g, 16.0 mmol), bis (triphenylphosphine) palladium (II) dichloride (512 mg, 0.730 mmol) and potassium acetate (5.02 g, 51.1 mmol) were added, and the mixture was stirred at 100 ° C. for 1.5 hours under a nitrogen atmosphere.
- the reaction mixture was allowed to cool, ethyl acetate was added, the mixture was washed with water and saturated brine, and dried over anhydrous sodium sulfate.
- the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate, 9: 1 ⁇ 1: 1, V / V).
- the solvent of the target fraction was distilled off under reduced pressure to obtain the title target compound as a colorless oil (3.90 g, yield 84%).
- the reaction mixture was neutralized with 6.0 M hydrochloric acid, extracted twice with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
- the obtained residue was dissolved in dimethylformamide (5 mL), and 4-acetyl-3-fluorobenzonitrile (206 mg, 1.26 mmol) and potassium carbonate (348 mg, 2.52 mmol) prepared in Example 28 (28b) were prepared. And stirred at 100 ° C. for 2 hours.
- the reaction mixture was allowed to cool, ethyl acetate was added, the mixture was washed with water and saturated brine, and dried over anhydrous sodium sulfate.
- the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate, 4: 1 ⁇ 1: 1, V / V).
- the solvent of the target fraction was distilled off under reduced pressure to give the title target compound as a pale yellow powder (315 mg, 71% yield).
- Methyl 4-cyano-2- [4- (tetrahydropyran-4-yloxymethyl) phenoxy] benzoate (180 mg, 0.490 mmol) prepared in Example 42 (42b) was dissolved in tetrahydrofuran (2 mL) and nitrogen was added. Under an atmosphere and ice cooling, a 3.0 M lithium borohydride / tetrahydrofuran solution (0.24 mL, 0.72 mmol) was added, and the mixture was stirred at room temperature for 30 minutes and then heated to reflux for 1 hour. After allowing to cool, water was added and the mixture was extracted twice with ethyl acetate.
- the organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
- the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate, 9: 1 ⁇ 1: 4, V / V).
- the solvent of the target fraction was distilled off under reduced pressure to give the title target compound as a white powder (140 mg, 84% yield).
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Abstract
Description
骨形成と骨吸収のバランスが崩れると、骨量の低下や骨組織の劣化が生じ、骨粗鬆症、線維性骨炎(副甲状腺機能亢進症)、骨軟化症、ページェット病、慢性関節リューマチ、変形性関節炎などの骨疾患に罹患すると考えられている。特に骨粗鬆症は高齢者や女性に多く、日本国内で1100万人、アメリカ合衆国内で3000万人以上の患者が存在するといわれている。症状としては、骨折および腰痛等の疼痛があり、これがもとで寝たきりになったり、身体が変形したり、股間接骨折など骨折部位によっては死に至ることもある。
骨粗鬆症の治療薬としては破骨細胞の活性を抑える骨吸収抑制薬と骨芽細胞を活性化する骨形成促進薬がある。骨吸収抑制薬としては、カルシトニン、ビスホスホネート、エストロゲン受容体モジュレータなどが使用されている。しかしこれらの治療薬では、さらなる骨量の減少は防止されるが、失われた骨を再構築できない。一方、骨形成促進薬としてはヒトPTH(1-34)が用いられており、骨量および骨密度の上昇および骨構造の再構築に利用できる。しかしながら使用期間が1年半から2年に限定されており、また、長期にわたって皮下注射が必要で、患者がそれを遵守することは困難となる。
最近になって、アルカリホスファターゼ誘導活性を有するベンゾチエピン誘導体(特許文献1、2)、N-キノリルアントラニル酸誘導体(特許文献3)、トリアゾロピリダジン誘導体(特許文献4)、チエノピリジン誘導体(特許文献5)および[5,6]複素環化合物(特許文献6)が、骨形成促進や骨代謝に関連する疾患の治療に有用であることが報告されている。しかし、その臨床上の有用性は不明である。
[1]
一般式(I)を有する化合物又は薬理上許容される塩(以下、化合物(I)と略記することがある。):
R1:
シアノ基、C1-6アルキルカルボニル基、C1-6アルキルカルボニルアミノ基、ニトロ基、ハロゲノC1-6アルキル基、C2-6アルケニル基、ハロゲノC2-6アルケニル基、カルバモイル基、又は、ヒドロキシC1-6アルキル基
R2:
C1-6アルコキシ基、カルバモイル基、C1-6アルキルアミノカルボニル基、又は、C1-6アルキルカルボニル基
R3:
水素原子、又は、ハロゲン原子
S、T及びU:
S、T及びUのいずれかひとつが、=N-である場合、他は=CH-(但し、R3が置換している場合は、=C-);又は;
S、T及びUのすべてが=CH-(但し、R3が置換している場合は、=C-)
W:
-NH-、-O-、又は、-S-
X:
単結合、-飽和ヘテロ環-、-CH2-(CH2)n-、-O-(CH2)n-、-(CH2)n-O-、又は、-CH=CH-(CH2)n-
n:
1-4から選択されるいずれか1の整数
Y:
単結合、-O-、又は、-CO-
Z:
水素原子、置換基群αから選択されるいずれかの基で置換されていてもよい飽和へテロ環基、又は、置換基群αから選択されるいずれかの基で置換されていてもよいC1-6アルキル基
置換基群α:
飽和ヘテロ環基、ヒドロキシC1-6アルキル基、アミノスルホニルアミノ基、カルボキシ基、水酸基、C1-6アルコキシ基、C1-6アルキル基]。
一般式(I)を有する化合物又は薬理上許容される塩(以下、化合物(I)と略記することがある。):
R1:
シアノ基、C1-6アルキルカルボニル基、C1-6アルキルカルボニルアミノ基、ニトロ基、ハロゲノC1-6アルキル基、ハロゲノC2-6アルケニル基、カルバモイル基、又は、ヒドロキシC1-6アルキル基
R2:
C1-6アルコキシ基、カルバモイル基、C1-6アルキルアミノカルボニル基、又は、C1-6アルキルカルボニル基
R3:
水素原子、又は、ハロゲン原子
S、T及びU:
S、T及びUのいずれかひとつが、=N-である場合、他は=CH-(但し、R3が置換している場合は、=C-);又は;
S、T及びUのすべてが=CH-(但し、R3が置換している場合は、=C-)
W:
-NH-、-O-、又は、-S-
X:
-飽和ヘテロ環-、-CH2-(CH2)n-、-O-(CH2)n-、-(CH2)n-O-、又は、-CH=CH-(CH2)n-
n:
1-4から選択されるいずれか1の整数
Y:
単結合、-O-、又は、-CO-
Z:
水素原子、置換基群αから選択されるいずれかの基で置換されていてもよい飽和へテロ環基、又は、置換基群αから選択されるいずれかの基で置換されていてもよいC1-6アルキル基
置換基群α:
ヒドロキシC1-6アルキル基、アミノスルホニルアミノ基、カルボキシ基、水酸基、C1-6アルコキシ基、C1-6アルキル基]。
[2]
R1が、シアノ基、アセチル基、アセチルアミノ基、ニトロ基、トリフルオロメチル基、1,1-ジフルオロエチル基、1-フルオロエチル基、ジフルオロメチル基、カルバモイル基、又は、1-ヒドロキシエチル基である、[1]または[1A]に記載された化合物又はその薬理上許容される塩。
[3]
R2が、メトキシ基、カルバモイル基、メチルアミノカルボニル基、又は、アセチル基である、[1]、[1A]又は[2]に記載された化合物又はその薬理上許容される塩。
[4]
S、T及びUのすべてが=CH-である、[1]-[3]および[1A]から選択されるいずれか1項に記載された化合物又はその薬理上許容される塩。
[5]
Xが、-飽和ヘテロ環-、又は、-O-(CH2)n-であり、nが2である、[1]-[4]および[1A]から選択されるいずれか1項に記載された化合物又はその薬理上許容される塩。
[6]
Yが、単結合、又は、-O-である、[1]-[5]および[1A]から選択されるいずれか1項に記載された化合物又はその薬理上許容される塩。
[7]
Zが、水酸基で置換されているC1-6アルキル基、テトラヒドロフラニル基、テトラヒドロピラニル基、ピペラジニル基、又は、モルホリニル基である、[1]-[6]および[1A]から選択されるいずれか1項に記載された化合物又はその薬理上許容される塩。
[8]
以下に記載の化合物から選択されるいずれかの化合物又はその薬理上許容される塩:
(1)N-(4-{4-[3-(2-ヒドロキシエトキシ)アゼチジン-1-イル]フェニルアミノ}-6-メトキシピリジン-3-イル)アセタミド
[1]-[8]および[1A]から選択されるいずれか1項に記載された化合物又はその薬理上許容される塩を有効成分として含有する医薬組成物。
[10]
骨形成を促進するために用いられる、[9]に記載された医薬組成物。
[11]
骨代謝を改善するために用いられる、[9]に記載された医薬組成物。
[12]
骨代謝に関連する疾患を予防又は治療するために用いられる、[9]に記載された医薬組成物。
[13]
骨代謝に関連する疾患が、骨粗鬆症である、[12]に記載された医薬組成物。
[14]
哺乳動物に[9]に記載された医薬組成物の有効量を投与することを特徴とする骨代謝の改善方法。
[15]
哺乳動物に[9]に記載された医薬組成物の有効量を投与することを特徴とする、骨代謝に関連する疾患の予防方法又は治療方法。
[16]
哺乳動物に[9]に記載された医薬組成物の有効量を投与することを特徴とする、骨粗鬆症の予防方法又は治療方法。
本明細書中、化合物の標記に用いられる置換基等の用語の意味は以下の通りである。
ハロゲン原子:
フッ素原子、塩素原子、臭素原子又はヨウ素原子
C1-C6アルキル基:
炭素数1-6個の直鎖若しくは分枝鎖アルキル基であり、好適には、メチル基、エチル基、プロピル基、イソプロピル基、イソブチル基又はtert-ブチル基
C1-C6アルキルカルボニル基:
カルボニル基に上記C1-C6アルキル基が結合した基であり、好適には、アセチル基、エチルカルボニル基、プロピルカルボニル基、イソプロピルカルボニル基又はブチルカルボニル基
C1-C6アルコキシ基:
酸素原子に上記C1-C6アルキル基が結合した基であり、好適には、メトキシ基、エトキシ基、プロポキシ基、イソプロポキシ基又はt-ブトキシ基
C1-C6アルキルカルボニルアミノ基:
カルボニルアミノ基に上記C1-C6アルキル基が結合した基であり、好適には、アセチルアミノ基、エチルカルボニルアミノ基、プロピルカルボニルアミノ基、イソプロピルカルボニルアミノ基又はブチルカルボニルアミノ基
ハロゲノC1-C6アルキル基:
上記C1-C6アルキル基に1~9個(好ましくは1~6個、より好ましくは1~3個)のハロゲン原子が置換した基であり、例えば、フルオロメチル基、ジフルオロメチル基、トリフルオロメチル基、フルオロエチル基、ジフルオロエチル基、トリフルオロエチル基、フルオロプロピル基、ジフルオロプロピル基、トリフルオロプロピル基、フルオロブチル基、ジフルオロブチル基、トリフルオロブチル基、フルオロペンチル基、ジフルオロペンチル基、トリフルオロペンチル基、フルオロヘキシル基、ジフルオロヘキシル基、トリフルオロヘキシル基、ペンタフルオロエチル基、ヘキサフルオロプロピル基、ノナフルオロブチル基、クロロメチル基、ジクロロメチル基、トリクロロメチル基、クロロエチル基、ジクロロエチル基、トリクロロエチル基、クロロプロピル基、ジクロロプロピル基又はトリクロロプロピル基
ヒドロキシC1-C6アルキル基:
上記C1-C6アルキル基に1個のヒドロキシ基が結合した基であり、好適には、1-ヒドロキシメチル基、1-ヒドロキシエチル基、1-ヒドロキシプロピル基、2-ヒドロキシエチル基又は3-ヒドロキシプロピル基
C1-C6アルキルアミノカルボニル基:
アミノカルボニル基に上記C1-C6アルキル基が結合した基であり、好適には、メチルアミノカルボニル基又はエチルアミノカルボニル基
C2-6アルケニル基:
炭素数2~6個の直鎖若しくは分岐鎖アルケニル基であり、例えば、ビニル基、1-プロペニル(アリル)基、2-プロペニル基、イソプロペニル基、2-メチル-1-プロペニル基、1-ブテニル基、2-ブテニル基、3-ブテニル基、2-ブテン-2-イル基、3-メチル-2-ブテニル基、3-メチル-2-ブテン-2-イル基、1-ペンテニル基、2-ペンテニル基、3-ペンテニル基、4-ペンテニル基、5-ペンテニル基、2-ペンテン-2-イル基、2-ペンテン-3-イル基、4-メチル-1-ペンテニル基、1-ヘキセニル基、2-ヘキセニル基、3-ヘキセニル基
ハロゲノC2-C6アルケニル基:
炭素数2-6個の直鎖若しくは分岐鎖アルケニル基に1~5個(好ましくは1~3個、より好ましくは1又は2個)のハロゲン原子が置換した基であり、例えば1-フルオロビニル基、1-クロロビニル基、1-ブロモビニル基、トリフルオロビニル基、トリクロロビニル基又はトリブロモビニル基
硫黄原子、酸素原子又は/及び窒素原子を1-3個含む飽和5-7員複素環基であり、例えば、テトラヒドロピラニル基、テトラヒドロフラニル基、オキソテトラヒドロフラニル基、モルホリニル基、チオモルホリニル基、1-オキソチオモルホリニル基、1,1-ジオキソチオモルホリニル基、ピロリジニル基、ピロリニル基、イミダゾリジニル基、ピラゾリジニル基、ピペリジニル基、ピペラジニル基、オキサゾリジニル基、イソキサゾリジニル基、チアゾリジニル基、1,4-ジオキサニル基、1,1-ジオキソヘキサヒドロチオピラニル基である。
R1は、シアノ基、C1-6アルキルカルボニル基、C1-6アルキルカルボニルアミノ基、ニトロ基、ハロゲノC1-6アルキル基、C2-6アルケニル基、ハロゲノC2-6アルケニル基、カルバモイル基、又は、ヒドロキシC1-6アルキル基を示す。
本発明の別の実施態様では、R1は、シアノ基、C1-6アルキルカルボニル基、C1-6アルキルカルボニルアミノ基、ニトロ基、ハロゲノC1-6アルキル基、ハロゲノC2-6アルケニル基、カルバモイル基、又は、ヒドロキシC1-6アルキル基を示す。
R1で示される「C1-6アルキルカルボニル基」としては、メチルカルボニル基(アセチル基)が好ましい。
R1で示される「C1-6アルキルカルボニルアミノ基」としては、メチルカルボニルアミノ基(アセチルアミノ基)、エチルカルボニルアミノ基、プロピルカルボニルアミノ基が好ましい。
R1で示される「ハロゲノC1-6アルキル基」としては、フルオロメチル基、ジフルオロメチル基、トリフルオロメチル基、1-フルオロエチル基、1,1-ジフルオロエチル基が好ましい。
R1で示される「C2-6アルケニル基」としては、ビニル基が好ましい。
R1で示される「ハロゲノC2-6アルケニル基」としては、1-フルオロビニル基が好ましい。
R1で示される「ヒドロキシC1-6アルキル基」としては、ヒドロキシメチル基、1-ヒドロキシエチル基が好ましい。
本発明の別の実施態様では、R1は、好ましくは、シアノ基、アセチル基、アセチルアミノ基、エチルカルボニルアミノ基、プロピルカルボニルアミノ基、ニトロ基、フルオロメチル基、トリフルオロメチル基、1,1-ジフルオロエチル基、1-フルオロエチル基、ジフルオロメチル基、1-フルオロビニル基、カルバモイル基、ヒドロキシメチル基、又は、1-ヒドロキシエチル基であり、より好ましくは、シアノ基、アセチル基、アセチルアミノ基、ニトロ基、トリフルオロメチル基、1,1-ジフルオロエチル基、1-フルオロエチル基、ジフルオロメチル基、カルバモイル基、又は、1-ヒドロキシエチル基である。
R2で示される「C1-6アルコキシ基」としては、メトキシ基が好ましい。
R2で示される「C1-6アルキルアミノカルボニル基」としては、メチルアミノカルボニル基、エチルアミノカルボニル基が好ましい。
R2で示される「C1-6アルキルカルボニル基」としては、メチルカルボニル基(アセチル基)が好ましい。
R3で示される「ハロゲン原子」としては、フッ素原子が好ましい。
R3は、好ましくは、水素原子、又は、フッ素原子である。
S、T及びUとしては、好ましくは、Sが=N-であり、かつT及びUが=CH-であるか、又は、S、T及びUのすべてが=CH-であり、より好ましくは、S、T及びUのすべてが=CH-である。
Wは、好ましくは、-NH-、又は、-O-である。
本発明の別の実施態様では、Xは、-飽和ヘテロ環-、-CH2-(CH2)n-、-O-(CH2)n-、-(CH2)n-O-、又は、-CH=CH-(CH2)n-[nは、1-4から選択されるいずれか1の整数を示す。]を示す。
Xで示される「-飽和ヘテロ環-」としては、アゼチジンジイル、ピペリジンジイル、ピペラジンジイルが好ましい。
Xが-CH2-(CH2)n-である場合、nは好ましくは1又は2であり、すなわち、Xは、好ましくは、-CH2-CH2-又は-CH2-CH2-CH2-である。
Xが-O-(CH2)n-である場合、nは好ましくは1又は2であり、すなわち、Xは、好ましくは、-O-CH2-又は-O-CH2-CH2-である。
Xが-(CH2)n-O-である場合、nは好ましくは1であり、すなわち、Xは、好ましくは、-CH2-O-である。
Xが-CH=CH-(CH2)n-である場合、nは好ましくは1であり、すなわち、Xは、好ましくは、-CH=CH-CH2-である。
本発明の別の実施態様では、Xは、好ましくは、-飽和ヘテロ環-(例、アゼチジンジイル、ピペリジンジイル、ピペラジンジイル)、-CH2-CH2-、-CH2-CH2-CH2-、-O-CH2-、-O-CH2-CH2-、-CH2-O-、又は、-CH=CH-CH2-であり、より好ましくは、-飽和ヘテロ環-(例、アゼチジンジイル、ピペリジンジイル、ピペラジンジイル)、又は、-O-CH2-CH2-[-O-(CH2)n-であり、nが2である。]である。
Yは、好ましくは、単結合、又は、-O-である。
本発明の別の実施態様では、Zは、水素原子、置換基群αから選択されるいずれかの基で置換されていてもよい飽和へテロ環基、又は、置換基群αから選択されるいずれかの基で置換されていてもよいC1-6アルキル基を示し、置換基群αは、ヒドロキシC1-6アルキル基、アミノスルホニルアミノ基、カルボキシ基、水酸基、C1-6アルコキシ基、及び、C1-6アルキル基である。
置換基群αから選択される基としては、ヒドロキシC1-6アルキル基(例、ヒドロキシメチル基)、又は、C1-6アルキル基(例、メチル基)が好ましい。
置換基群αから選択される基としては、飽和へテロ環基(例、テトラヒドロフラニル基、モルホリニル基)、アミノスルホニルアミノ基、カルボキシ基、水酸基、又は、C1-6アルコキシ基(例、イソプロポキシ基)が好ましい。
本発明の別の実施態様では、置換基群αから選択される基としては、アミノスルホニルアミノ基、カルボキシ基、水酸基、又は、C1-6アルコキシ基(例、イソプロポキシ基)が好ましい。
本発明の別の実施態様では、Zは、好ましくは、水素原子、ヒドロキシC1-6アルキル基(例、ヒドロキシメチル基)、及び、C1-6アルキル基(例、メチル基)から選択されるいずれかの基で置換されていてもよい飽和へテロ環基(例、テトラヒドロフラニル基、オキソテトラヒドロフラニル基、テトラヒドロピラニル基、モルホリニル基、ピペリジニル基、ピペラジニル基、1,4-ジオキサニル基、1,1-ジオキソヘキサヒドロチオピラニル基)であるか、又は、アミノスルホニルアミノ基、カルボキシ基、水酸基、及び、C1-6アルコキシ基(例、イソプロポキシ基)から選択されるいずれかの基で置換されていてもよいC1-6アルキル基(例、メチル基、エチル基、プロピル基、イソプロピル基、イソブチル基)であり、より好ましくは、水酸基で置換されているC1-6アルキル基(例、メチル基、エチル基、プロピル基、イソプロピル基、イソブチル基)、テトラヒドロフラニル基、テトラヒドロピラニル基、ピペラジニル基、又は、モルホリニル基である。
[化合物I-1-1]
R1が、シアノ基、アセチル基、アセチルアミノ基、エチルカルボニルアミノ基、プロピルカルボニルアミノ基、ニトロ基、フルオロメチル基、トリフルオロメチル基、1,1-ジフルオロエチル基、1-フルオロエチル基、ジフルオロメチル基、ビニル基、1-フルオロビニル基、カルバモイル基、ヒドロキシメチル基、又は、1-ヒドロキシエチル基であり;
R2が、メトキシ基、カルバモイル基、メチルアミノカルボニル基、エチルアミノカルボニル基、又は、メチルカルボニル基(アセチル基)であり;
R3が、水素原子、又は、フッ素原子であり;
Sが=N-であり、かつT及びUが=CH-であるか、又は、S、T及びUのすべてが=CH-であり;
Wが、-NH-、-O-、又は、-S-であり;
Xが、単結合、-飽和ヘテロ環-(例、アゼチジンジイル、ピペリジンジイル、ピペラジンジイル)、-CH2-CH2-、-CH2-CH2-CH2-、-O-CH2-、-O-CH2-CH2-、-CH2-O-、又は、-CH=CH-CH2-であり;
Yが、単結合、-O-、又は、-CO-であり;
Zが、水素原子、ヒドロキシC1-6アルキル基(例、ヒドロキシメチル基)、及び、C1-6アルキル基(例、メチル基)から選択されるいずれかの基で置換されていてもよい飽和へテロ環基(例、テトラヒドロフラニル基、オキソテトラヒドロフラニル基、テトラヒドロピラニル基、モルホリニル基、ピペリジニル基、ピペラジニル基、1,4-ジオキサニル基、1,1-ジオキソヘキサヒドロチオピラニル基)であるか、又は、飽和へテロ環基(例、テトラヒドロフラニル基、モルホリニル基)、アミノスルホニルアミノ基、カルボキシ基、水酸基、及び、C1-6アルコキシ基(例、イソプロポキシ基)から選択されるいずれかの基で置換されていてもよいC1-6アルキル基(例、メチル基、エチル基、プロピル基、イソプロピル基、イソブチル基)である;
化合物(I)。
R1が、シアノ基、アセチル基、アセチルアミノ基、エチルカルボニルアミノ基、プロピルカルボニルアミノ基、ニトロ基、フルオロメチル基、トリフルオロメチル基、1,1-ジフルオロエチル基、1-フルオロエチル基、ジフルオロメチル基、1-フルオロビニル基、カルバモイル基、ヒドロキシメチル基、又は、1-ヒドロキシエチル基であり;
R2が、メトキシ基、カルバモイル基、メチルアミノカルボニル基、エチルアミノカルボニル基、又は、メチルカルボニル基(アセチル基)であり;
R3が、水素原子、又は、フッ素原子であり;
Sが=N-であり、かつT及びUが=CH-であるか、又は、S、T及びUのすべてが=CH-であり;
Wが、-NH-、-O-、又は、-S-であり;
Xが、-飽和ヘテロ環-(例、アゼチジンジイル、ピペリジンジイル、ピペラジンジイル)、-CH2-CH2-、-CH2-CH2-CH2-、-O-CH2-、-O-CH2-CH2-、-CH2-O-、又は、-CH=CH-CH2-であり;
Yが、単結合、-O-、又は、-CO-であり;
Zが、水素原子、ヒドロキシC1-6アルキル基(例、ヒドロキシメチル基)、及び、C1-6アルキル基(例、メチル基)から選択されるいずれかの基で置換されていてもよい飽和へテロ環基(例、テトラヒドロフラニル基、オキソテトラヒドロフラニル基、テトラヒドロピラニル基、モルホリニル基、ピペリジニル基、ピペラジニル基、1,4-ジオキサニル基、1,1-ジオキソヘキサヒドロチオピラニル基)であるか、又は、アミノスルホニルアミノ基、カルボキシ基、水酸基、及び、C1-6アルコキシ基(例、イソプロポキシ基)から選択されるいずれかの基で置換されていてもよいC1-6アルキル基(例、メチル基、エチル基、プロピル基、イソプロピル基、イソブチル基)である;
化合物(I)。
R1が、シアノ基、アセチル基、アセチルアミノ基、ニトロ基、トリフルオロメチル基、1,1-ジフルオロエチル基、1-フルオロエチル基、ジフルオロメチル基、カルバモイル基、又は、1-ヒドロキシエチル基であり;
R2が、メトキシ基、カルバモイル基、メチルアミノカルボニル基、又は、アセチル基であり;
R3が、水素原子、又は、フッ素原子であり;
S、T及びUのすべてが=CH-であり;
Wが、-NH-、又は、-O-であり;
Xが、-飽和ヘテロ環-(例、アゼチジンジイル、ピペリジンジイル、ピペラジンジイル)、又は、-O-CH2-CH2-であり;
Yが、単結合、又は、-O-であり;
Zが、水酸基で置換されているC1-6アルキル基(例、メチル基、エチル基、プロピル基、イソプロピル基、イソブチル基)、テトラヒドロフラニル基、テトラヒドロピラニル基、ピペラジニル基、又は、モルホリニル基である;
化合物(I)。
R1が、アセチル基、アセチルアミノ基、ニトロ基、トリフルオロメチル基、ジフルオロメチル基、カルバモイル基、又は、1-ヒドロキシエチル基であり;
R2が、メトキシ基、カルバモイル基、又は、アセチル基であり;
R3が、水素原子、又は、フッ素原子であり;
Sが=N-であり、かつT及びUが=CH-であるか、又は、S、T及びUのすべてが=CH-であり;
Wが、-NH-、又は、-O-であり;
Xが、-飽和ヘテロ環-(例、アゼチジンジイル、ピペリジンジイル、ピペラジンジイル)、又は、-O-CH2-CH2-であり;
Yが、単結合、又は、-O-であり;
Zが、カルボキシ基、水酸基、及び、C1-6アルコキシ基(例、イソプロポキシ基)から選択されるいずれかの基で置換されたC1-6アルキル基(例、エチル基、イソブチル基)、テトラヒドロフラニル基、テトラヒドロピラニル基、又は、1,1-ジオキソヘキサヒドロチオピラニル基である;
化合物(I)。
(1)N-(4-{4-[3-(2-ヒドロキシエトキシ)アゼチジン-1-イル]フェニルアミノ}-6-メトキシピリジン-3-イル)アセタミド、
(2)3-{4-[3-(2-ヒドロキシエトキシ)アゼチジン-1-イル]フェニルアミノ}-4-ニトロベンズアミド、
(3)3-{4-[4-(4-フルオロ-5-メトキシ-2-ニトロフェニルアミノ)フェニル]ピペラジン-1-イル}-2,2-ジメチルプロピオン酸、
(4)4-アセチル-3-{4-[2-(1,1-ジオキソヘキサヒドロ-1λ6-チオピラン-4-イルオキシ)エトキシ]フェニルアミノ}ベンズアミド、
(5)4-アセチル-3-{4-[4-(2-ヒドロキシエトキシ)ピペリジン-1-イル]フェノキシ}ベンズアミド、
(6)4-アセチル-3-{4-[2-(テトラヒドロピラン-4-イルオキシ)エトキシ]フェノキシ}ベンズアミド、
(7)4-アセチル-3-{4-[2-(2-イソプロポキシエトキシ)エトキシ]フェノキシ}ベンズアミド、
(8)4-ジフルオロメチル-3-{4-[2-(テトラヒドロピラン-4-イルオキシ)エトキシ]フェノキシ}ベンズアミド、
(9)4-(1-ヒドロキシエチル)-3-{4-[2-(テトラヒドロピラン-4-イルオキシ)エトキシ]フェノキシ}ベンズアミド、
(10)(R)-4-(1-ヒドロキシエチル)-3-{4-[2-(テトラヒドロピラン-4-イルオキシ)エトキシ]フェノキシ}ベンズアミド、
(11)4-ニトロ-3-{4-[2-(テトラヒドロピラン-4-イルオキシ)エトキシ]フェニルアミノ}ベンズアミド、
(12)4-アセチル-2-{4-[2-(1,1-ジオキソヘキサヒドロ-1λ6-チオピラン-4-イルオキシ)エトキシ]フェニルアミノ}ベンズアミド、
(13)3-{4-[3-(2-ヒドロキシエトキシ)アゼチジン-1-イル]フェノキシ}-4-トリフルオロメチルベンズアミド、
(14)4-アセチル-3-{4-[2-(テトラヒドロフラン-3-イルオキシ)エトキシ]フェノキシ}ベンズアミド、
(15)(S)-4-アセチル-3-{4-[2-(テトラヒドロフラン-3-イルオキシ)エトキシ]フェノキシ}ベンズアミド、
(16)(R)-4-アセチル-3-{4-[2-(テトラヒドロフラン-3-イルオキシ)エトキシ]フェノキシ}ベンズアミド、又は
(17)4-[(R)-1-ヒドロキシエチル]-3-(4-{2-[(S)-テトラヒドロフラン-3-イルオキシ]エトキシ}フェノキシ)ベンズアミドが好ましい。
「その薬理上許容される塩」とは、医薬として使用することができる塩を示す。本発明の化合物では、酸性基または塩基性基を有する場合に、塩基又は酸と反応させることにより、塩基性塩又は酸性塩にすることができるので、その塩を示す。
本発明の化合物の薬理上許容される「塩基性塩」としては、好適には、ナトリウム塩、カリウム塩、リチウム塩のようなアルカリ金属塩;マグネシウム塩、カルシウム塩のようなアルカリ土類金属塩;N-メチルモルホリン塩、トリエチルアミン塩、トリブチルアミン塩、ジイソプロピルエチルアミン塩、ジシクロヘキシルアミン塩、N-メチルピペリジン塩、ピリジン塩、4-ピロリジノピリジン塩、ピコリン塩のような有機塩基塩類又はグリシン塩、リジン塩、アルギニン塩、オルニチン塩、グルタミン酸塩、アスパラギン酸塩のようなアミノ酸塩であり、好適には、アルカリ金属塩である。
本発明の化合物は、ラベル体、すなわち、本発明の化合物の1又は2以上の原子を同位元素(例えば、2H、3H、13C、14C、35S等)で置換した化合物も含まれる。
本発明の化合物は、その基本骨格あるいは置換基の種類に基づく特徴を利用し、各種の公知の製造方法を適用して製造することができる。公知の方法としては、例えば、「ORGANIC FUNCTIONAL GROUP PREPARATIONS」、第2版、ACADEMIC PRESS,INC.、1989年、「Comprehensive Organic Transformations」、VCHPublishers Inc.、1989年等に記載された方法がある。
その際、官能基の種類によっては、当該官能基を原料ないし中間体の段階で適当な保護基で保護、又は当該官能基に容易に転化可能な基に置き換えておくことが製造技術上効果的な場合がある。
このような官能基としては、例えば、アミノ基、水酸基、カルボキシ基等があり、それらの保護基としては、例えば、T.W.Greene及びP.G. Wuts著、「Protective Groups in Organic Synthesis(第3版、1999年)」に記載の保護基があり、これらの反応条件に応じて適宜選択して用いればよい。このような方法によれば、当該置換基を導入して反応を行った後、必要に応じて保護基を除去、あるいは所望の基に転化することにより、所望の化合物を得ることができる。
また、本発明の化合物のプロドラッグは、上記保護基と同様に、原料ないし中間体の段階で特定の基を導入し、あるいは得られた本発明の化合物を用いて、反応を行うことで製造できる。反応は、通常のエステル化、アミド化、脱水、水素添加等、当業者により公知の方法を適用することにより行うことができる。
以下に本発明の化合物の製造方法について述べる。ただし、製造方法は、下記の方法に何ら限定されるものではない。
なお、各反応における原料化合物は、具体的製法を述べない場合、市販されているものを容易に入手して用いることができるか、または自体公知の方法、またはそれに準ずる方法に従って製造することもできる。
A法は化合物 (a-1)と化合物(a-2)とをカップリングさせて本発明の化合物 (a-3) を製造する方法である。
化合物(a-2)の使用量は、化合物(a-1)に対し、通常1~3当量、好ましくは1~1.5当量である。
パラジウム触媒の使用量は、化合物(a-1)に対し、通常0.01~0.2当量、好ましくは0.01~0.1当量である。
金属ハライドの使用量は、化合物(a-1)に対し、通常1~3当量、好ましくは1~1.5当量である。
有機塩基の使用量は、化合物(a-1)に対し、通常1~5当量、好ましくは1~3当量である。
無機塩基の使用量は、化合物(a-1)に対し、通常1~5当量、好ましくは1~3当量である。
B法はA法と同様に化合物 (b-1)と化合物(b-2)とをカップリングさせて本発明の化合物(a-3)を製造する方法である。
C法は一般式 (I) 中のR2がカルバモイル基又はC1-6アルキルアミノカルボニル基である本発明の化合物 (c-4)を製造する方法である。
Step C2 : 本工程は化合物 (c-3) をアミド化反応により、化合物 (c-4) に変換する工程である。本アミド化工程は、エステル基から直接アミド基に変換する方法、またはエステル基を加水分解してカルボキシル基とした後に、アミンとの縮合反応を行いアミド化する方法がある。エステル基から直接アミド基に変換するアミド化反応は、例えば、Chem. Rev., 1948, 45, 203、J. Am. Chem. Soc., 1950, 72, 1888、Org. Biol. Chem., 1962, 84, 4457、J. Am. Chem. Soc., 1973, 95, 875、J. Am. Chem. Soc., 1981, 103, 7090等に記載の方法に準じて行うことができる。
D法は一般式 (I) 中のR1がC1-6アルキルカルボニル基でありR2がカルバモイル基又はC1-6アルキルアミノカルボニル基である本発明の化合物 (d-2)を製造する方法である。
E法は一般式 (I) 中のR1及びR2がそれぞれ異なってC1-6アルキルカルボニル基またはカルバモイル基である本発明の化合物 (e-3)を製造する方法である。
Step E2 : 本工程は化合物 (e-2) のアセタールを脱保護し,化合物(e-3) を製造する工程である。本工程はD法と同様の条件で行うことができる。
F法は一般式 (I) 中のR2がカルバモイル基である本発明の化合物 (f-4)を製造する方法である。
Step F2 : 本工程はシアノ基の加水分解反応であり、化合物 (f-3)から化合物 (f-4)を製造する工程である。E法Step E2と同様の条件で行うことができる。
G法は一般式 (I) 中のR1がC1-6アルキルカルボニルアミノ基である本発明の化合物 (g-2)を製造する方法である。
還元反応は、公知の方法に準じて行うことができる。
アシル化は、対応するカルボン酸(R7-COOH)又はその誘導体を用いて、公知の方法に準じて行うことができる。
H法は一般式 (I) 中のR1がヒドロキシメチル基である本発明の化合物 (h-2)を製造する方法である。
水素化リチウムアルミニウムの使用量は、化合物(h-1)に対し、通常1~3当量である。
反応時間は原料化合物によって異なるが、通常30分乃至3時間であり、好適には30分乃至1時間である。
I法は一般式 (I) 中のR1がハロゲノC1-6アルキル基であり、R2がカルバモイル基である本発明の化合物 (i-3)を製造する方法である。
水素化ほう素ナトリウムの使用量は、化合物(i-1)に対し、通常1~3当量、好ましくは1~2当量である。
反応時間は原料化合物によって異なるが、通常30分乃至3時間であり、好適には30分乃至1時間である。
Step I2 : 本工程は化合物 (i-2) から化合物 (i-3) を製造する工程であり、ハロゲン化反応(なお、上記スキームでは、例示としてフッ素化反応を記載している。)である。本工程は、化合物 (i-2)をハロゲン化剤(フッ素化剤)としてのN,N-ジエチルアミノサルファートリフルオリド(DAST)存在下、クロロホルム中で氷冷下から室温にて反応させることによって行うことができる。
N,N-ジエチルアミノサルファートリフルオリドの使用量は、化合物(i-2)に対し、通常1~5当量、好ましくは1~3当量である。
反応時間は原料化合物によって異なるが、通常30分乃至3時間であり、好適には30分乃至1時間である。
J法は一般式 (I) 中のR1がカルバモイル基であり、R2がC1-6アルキルカルボニル基である本発明の化合物 (j-2)を製造する方法である。
K法は一般式 (I) 中のR1がハロゲノC1-6アルキル基であり、R2がカルバモイル基である本発明の化合物 (k-3)を製造する方法である。
水素化ほう素リチウムの使用量は、化合物(k-1)に対し、通常1~5当量、好ましくは1~3当量である。
反応時間は原料化合物によって異なるが、通常1乃至5時間であり、好適には1乃至3時間である。
Step K2 : 本工程は化合物 (k-2) から化合物 (k-3) を製造する工程であり、ハロゲン化反応(なお、上記スキームでは、例示としてフッ素化反応を記載している。)である。本工程は、化合物 (k-2)をハロゲン化剤(フッ素化剤)としてのN,N-ジエチルアミノサルファートリフルオリド存在下、クロロホルム中で氷冷下から室温にて反応させることによって行うことができる。
N,N-ジエチルアミノサルファートリフルオリドの使用量は、化合物(k-2)に対し、通常1~5当量、好ましくは1~3当量である。
反応時間は原料化合物によって異なるが、通常30分乃至3時間であり、好適には30分乃至1時間である。
Step K3 : 本工程は化合物 (k-3) から化合物 (k-4) を製造する工程であり、シアノ基の加水分解化反応である。E法Step E2と同様の条件で行うことができる。
L法は一般式 (I) 中のR1がハロゲノC1-6アルキル基である本発明の化合物 (l-2)を製造する方法である。
フッ素化剤の使用量は、化合物(l-1)に対し、通常1~5当量、好ましくは1~3量である。
反応時間は原料化合物によって異なるが、通常1乃至120時間であり、好適には1乃至72時間である。
M法は一般式 (I) 中のR1がヒドロキシC1-6アルキル基である本発明の化合物 (m-2)を製造する方法である。
N法はA法からM法に準じて製造することができる化合物 (n-1) の保護基を脱保護することによって、本発明の化合物 (a-3) を製造する方法である。
また、本発明の一般式(I)を有する化合物又は製造の中間体が不斉炭素を有する場合には光学異性体が存在する。これらの光学異性体は、適切な塩と再結晶する分別再結晶(塩分割)やカラムクロマトグラフィー等の常法によって、それぞれの異性体を単離、精製することができる。また、不斉合成によっても上記異性体を製造することができる。上記異性体をラセミ体から光学異性体を分割する方法の参考文献としては、J.Jacquesらの、「Enantiomers, Racemates and Resolution, John Wiley And Sons,Inc.」を挙げることができる。
経口用の医薬組成物の形態としては、錠剤、丸剤、散剤、顆粒剤、カプセル剤、水剤、懸濁剤、乳剤、シロップ剤、エリキシル剤等が挙げられる。これら形態の医薬の調製は、添加剤として通常用いられている賦形剤、結合剤、崩壊剤、滑沢剤、膨潤剤、膨潤補助剤、コーティング剤、可塑剤、安定剤、防腐剤、抗酸化剤、着色剤、溶解補助剤、懸濁化剤、乳化剤、甘味剤、保存剤、緩衝剤、希釈剤、湿潤剤等から必要に応じて適宜選択したものを用いて、常法に従って行うことができる。
4-{3-[2-(テトラヒドロピラン-2-イルオキシ)エトキシ]アゼチジン-1-イル}フェニルアミン
(1a) 1-ベンズヒドリル-3-[2-(テトラヒドロピラン-2-イルオキシ)エトキシ]アゼチジン
1H-NMR (CDCl3, 400 MHz) δ :1.40-1.85 (6H, m),2.88-2.95 (2H, m),3.45-3.58 (6H, m),3.75-3.85 (2H, m),4.15-4.22 (1H, m),4.36 (1H,s),4.55-4.62 (1H, m),7.12-7.19 (2H, m),7.20-7.28 (4H, m),7.35-7.40 (4H, m).
得られた油状物 (3.00 g、8.16 mmol) をジメチルホルムアミド (30 mL) に溶解し、4-ニトロフルオロベンゼン (1.04 mL、9.79 mmol)、ジイソプロピルエチルアミン (2.13 mL、12.2 mmol) を加え窒素雰囲気下、60℃ にて15時間撹拌した。反応液を室温に放冷後、水を加え酢酸エチルにて2回抽出した。有機層を水および飽和食塩水にて洗浄後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー (ヘキサン:酢酸エチル、4:1→1:1、V/V) にて精製した。目的分画の溶媒を減圧下留去し、標記目的化合物の黄色油状物 (2.08 g、収率79%) を得た。
1H-NMR (CDCl3, 400 MHz) δ :1.50-1.88 (6H, m),3.48-3.64 (2H, m),3.65-3.69 (2H, m),3.84-3.98 (4H, m),4.20-4.26 (2H, m),4.53-4.57 (1H,m),4.61-4.63 (1H, m),6.30-6.32 (2H, m),8.08-8.11 (2H, m).
1H-NMR (CDCl3, 400 MHz) δ :1.46-1.88 (6H, m),3.25-3.40 (2H, br),3.45-3.55 (1H, m),3.56-3.65 (5H, m),3.83-3.90 (2H, m),4.02-4.06 (2H, m),4.44-4.47 (1H,m),4.61-4.63 (1H, m),6.35-6.37 (2H, m),6.61-6.63 (2H, m).
1-(4-ヨードフェニル)-3-[2-(テトラヒドロピラン-2-イルオキシ)エトキシ]アゼチジン
(2a) 1-フェニル-3-[2-(テトラヒドロピラン-2-イルオキシ)エトキシ]アゼチジン
得られた残渣にヨードベンゼン (7.0 mL、63 mmol)、よう化銅(I) (918 mg、4.82 mmol)、L-プロリン (1.11 g、9.64 mmol)、炭酸カリウム (13.3 g、96.2 mmol) およびジメチルスルホキシド (24 mL)を加え、窒素を1分バブリング後、窒素雰囲気下、70℃ にて19時間撹拌した。放冷後、水(120 mL)に注加し、酢酸エチル (100 mL)にて2回抽出した。有機層を合わせ、水および飽和食塩水にて順次洗浄後、無水硫酸ナトリウムで乾燥し、減圧下溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー (ヘキサン:酢酸エチル、5:1→2:1、V/V) にて精製後、目的分画の溶媒を減圧下留去し、標記目的化合物の黄色油状物(7.8 g、収率55%) を得た。
1H-NMR (CDCl3, 400 MHz) δ:1.40-1.90 (6H, m),3.47-3.67 (4H, m),3.69-3.78 (2H, m),3.82-3.92 (2H, m),4.08-4.16 (2H, m),4.47-4.55 (1H, m),4.62-4.68 (1H, m),6.44-6.52 (2H, m),6.70-6.78 (1H, m),7.16-7.26 (2H, m).
1H-NMR (CDCl3, 400 MHz) δ:1.40-1.90 (6H, m),3.47-3.65 (4H, m),3.68-3.75 (2H, m),3.83-3.91 (2H, m),4.07 (2H, t, J=7.1 Hz),4.44-4.52 (1H, m),4.60-4.65 (1H, m),6.20-6.25 (2H, m),7.43-7.47 (2H, m).
2-(テトラヒドロフラン-3-イルオキシ)エタノール
(3a) 2-[2-(テトラヒドロフラン-3-イルオキシ)エトキシ]テトラヒドロピラン
1H-NMR (CDCl3, 400 MHz) δ:1.47-1.64 (4H, m),1.67-1.89 (2H, m),1.94-2.03 (2H, m),3.45-3.54 (1H, m),3.54-3.66 (3H, m),3.75-3.93 (6H, m),4.14-4.22 (1H, m),4.58-4.66 (1H, m).
1H-NMR (CDCl3, 400 MHz) δ:1.95-2.04 (2H, m),2.10-2.20 (1H, br),3.50-3.60 (2H, m),3.70-3.95 (6H, m),4.14-4.20 (1H, m).
2-(テトラヒドロピラン-4-イルオキシ)エタノール
(4a) 1-(テトラヒドロピラン-4-イルオキシ)-2-(テトラヒドロピラン-2-イルオキシ)エタン
1H-NMR (CDCl3, 400 MHz) δ:1.47-1.87 (8H, m),1.87-1.96 (2H, m),3.39-3.47 (2H, m),3.47-3.70 (5H, m),3.80-3.90 (2H, m),3.90-3.99 (2H, m),4.61-4.69 (1H, m).
1H-NMR (CDCl3, 400 MHz) δ:1.54-1.66 (2H, m),1.84 (1H, s),1.86-1.97 (2H, m),3.39-3.49 (2H, m),3.49-3.57 (1H, m),3.59 (2H, t, J=4.9 Hz),3.74 (2H, t, J=4.9 Hz),3.91-3.99 (2H, m).
4-{3-[2-(テトラヒドロピラン-2-イルオキシ)エトキシ]アゼチジン-1-イル}フェノール
(5a) 1-[4-(tert-ブチルジメチルシラニルオキシ)フェニル]-3-[2-(テトラヒドロピラン-2-イルオキシ)エトキシ]アゼチジン
1H-NMR (CDCl3, 400 MHz) δ: 0.15 (6H, s),0.96 (9H, s),1.51-1.87 (6H, m),3.48-3.52 (1H, m),3.57-3.67 (5H, m),3.84-3.89 (2H, m),4.05-4.08 (2H, m),4.44-4.49 (1H, m),4.62-4.63 (1H, m),6.35-6.37 (2H, m),6.69-6.72 (2H, m).
1H-NMR (CDCl3, 400 MHz) δ:1.50-1.88 (6H, m),3.47-3.53 (1H, m),3.58-3.65 (5H, m),3.85-3.91 (2H, m),4.04-4.07 (2H, m),4.43-4.49 (1H, m),4.62-4.64 (1H, m),4.68 (1H, s),6.36-6.39 (2H, m),6.70-6.72 (2H, m).
N-(4-{4-[3-(2-ヒドロキシエトキシ)アゼチジン-1-イル]フェニルアミノ}-6-メトキシピリジン-3-イル)アセタミド
(1a) N-(6-メトキシピリジン-3-イル)-2,2-ジメチルプロピオンアミド
1H-NMR (CDCl3, 400 MHz) δ:1.32 (9H, s),3.91 (3H, s),6.71 (1H, d, J=8.8 Hz),7.91 (1H, dd, J=8.8, 2.7 Hz),7.33-7.40 (1H, br),8.11 (1H, d, J=2.7 Hz).
1H-NMR (CDCl3, 400 MHz) δ:1.36 (9H, s),3.90 (3H, s),7.23 (1H, s),7.33-7.40 (1H, br),8.69 (1H, s).
1H-NMR (CDCl3, 400 MHz) δ :3.63-3.80 (2H, br),3.84 (3H, s),7.14 (1H, s),7.64 (1H, s).
1H-NMR (CDCl3, 400 MHz) δ : 2.24 (3H, s),3.91 (3H, s),6.96-7.10 (1H, br),7.24 (1H, s),8.59 (1H, s).
1H-NMR (CDCl3, 400 MHz) δ :1.50-1.80 (6H, m),1.96 (1H, s),2.24 (2H, s),3.46-3.92 (11H, m),4.05-4.20 (2H, m),4.45-4.55 (1H, m),4.60-4.70 (1H, m),6.07-6.30 (2H, m),6.40-6.54 (2H, m),6.95-7.10 (2H, m),7.76-7.84 (1H, s).
1H-NMR (CDCl3, 400 MHz) δ : 1.96 (1H, s),2.24 (2H, s),3.52-3.62 (2H, m),3.70-3.90 (7H, m),4.09-4.18 (2H, m),4.42-4.53 (1H, m),6.09-6.14 (1H, m),6.40-6.54 (3H, m),6.97-7.10 (3H, m),7.78-7.79 (1H, s).
MS (ESI) m/z : 373 (M+H)+.
2-{1-[4-(4-フルオロ-5-メトキシ-2-ニトロフェニルアミノ)フェニル]アゼチジン-3-イルオキシ}エタノール
(2a) 1,4-ジフルオロ-2-メトキシ-5-ニトロベンゼン
1H-NMR (CDCl3, 400 MHz) δ : 4.00 (3H, s),6.75-6.88 (1H, m),7.85-7.95 (1H, m).
1H-NMR (CDCl3, 400 MHz) δ :1.50-1.90 (6H, m),3.45-3.58 (1H, m),3.59-3.70 (3H, m),3.73 (3H, s),3.76-3.84 (2H, m),3.85-3.92 (2H, m),4.10-4.18 (2H, m),4.50-4.58 (1H, m),4.60-4.65 (1H, m),6.34 (1H, d, J=7.3 Hz),6.49-6.51 (2H, m),7.09-7.11 (2H, m),7.91 (1H, d, J=11.7 Hz),9.63 (1H, s).
1H-NMR (CDCl3, 400 MHz) δ :1.85-2.00 (1H, br),3.55-3.64 (2H, m),3.73 (3H, s),3.77-3.88 (4H, m),4.14-4.28 (2H, m),4.47-4.58 (1H, m),6.35 (1H, d, J=7.6 Hz),6.50-6.52 (2H, m),7.10-7.12 (2H, m),7.92 (1H, d, J=11.7 Hz),9.60-9.70 (1H, br).
MS (ESI) m/z : 373 (M+H)+.
N-(5-フルオロ-2-{4-[3-(2-ヒドロキシエトキシ)アゼチジン-1-イル]フェニルアミノ}-4-メトキシフェニル)アセタミド
(3a) 4-フルオロ-5-メトキシ-N1-(4-{3-[2-(テトラヒドロピラン-2-イルオキシ)エトキシ]アゼチジン-1-イル}フェニル)ベンゼン-1,2-ジアミン
1H-NMR (CDCl3, 400 MHz) δ :1.50-1.90 (6H, m),3.45-3.68 (6H, m),3.74 (3H, s),3.82-3.95 (2H, m),4.04-4.12 (2H, m),4.44-4.52 (1H, m),4.60-4.65 (1H, m),4.75-4.85 (2H, br),6.41-6.43 (2H, m),6.55 (1H, d, J=12.2 Hz),6.66-6.70 (3H, m).
1H-NMR (CDCl3, 400 MHz) δ :1.40-1.80 (6H, m),2.01 (3H, s),3.45-3.60 (6H, m),3.66 (3H, s),3.69-3.80 (2H, m),3.97-4.08 (2H, m),4.37-4.48 (1H, m),4.55-4.62 (1H, m),6.39-6.41 (2H, m),6.66 (1H, d, J=8.8 Hz),6.80-6.90 (3H, m),7.26 (1H, d, J=13.0 Hz),9.16 (1H, s).
1H-NMR (CD3CN, 400 MHz) δ : 2.07 (3H, m),2.75-2.85 (2H, m),3.49-3.55 (2H, m),3.60-3.68 (4H, m),3.72 (3H, s),4.35-4.55 (1H, m),7.30-7.63 (5H, m),8.50-8.80 (1H, m).
MS (ESI) m/z : 390 (M+H)+.
2-{1-[4-(2-メトキシ-5-ニトロピリジン-4-イルアミノ)フェニル]アゼチジン-3-イルオキシ}エタノール
(4a) 4-クロロ-3-ニトロピリジン
1H-NMR (CDCl3, 400 MHz) δ: 7.54 (1H, d, J=5.4 Hz),8.69 (1H, d, J=5.4 Hz),9.12 (1H, s).
1H-NMR (CDCl3, 400 MHz) δ : 6.69 (1H, s),8.71 (1H, s),12.80-13.05 (1H, br).
1H-NMR (CDCl3, 400 MHz) δ : 4.03 (3H, s),6.90 (1H, s),8.88 (1H, s).
1H-NMR (CDCl3, 400 MHz) δ :1.50-1.90 (6H, m),3.46-3.58 (1H, m),3.58-3.68 (3H, m),3.78-3.83 (2H, m),3.84-3.96 (5H, m),4.09-4.20 (2H, m),4.48-4.58 (1H, m),4.60-4.70 (1H, m),6.02 (1H, s),6.47-6.50 (2H, m),7.06-7.08 (2H, m),9.02 (1H, s),9.27 (1H, s).
1H-NMR (DMSO-d6, 400 MHz) δ : 1.93 (1H, t, J=6.1 Hz),3.54-3.62 (2H, m),3.72-3.84 (4H, m),3.90 (3H, s),4.12-4.20 (2H, m),4.45-4.58 (1H, m),6.02 (1H, s),6.48-6.50 (2H, m),7.07-7.09 (2H, m),9.02 (1H, s),9.26 (1H, br).
MS (ESI) m/z : 361 (M+H)+.
3-{4-[3-(2-ヒドロキシエトキシ)アゼチジン-1-イル]フェニルアミノ}-4-ニトロベンズアミド
(5a) 3-フルオロ-4-ニトロベンズアミド
1H-NMR (CDCl3, 400 MHz) δ:7.80-7.92 (2H, m),7.95-8.01 (1H, m),8.21-8.37 (2H, m).
1H-NMR (CDCl3, 400 MHz) δ:1.50-1.67 (4H, m),1.70-1.89 (2H, m),3.49-3.56 (1H, m),3.60-3.69 (3H, m),3.79 (2H, dd, J=8.0, 4.8 Hz),3.85-3.93 (2H, m),4.12-4.18 (2H, m),4.50-4.57 (1H, m),4.62-4.67 (1H, m),5.50-6.10 (2H, m),6.48-6.53 (2H, m),6.99 (1H, dd, J=8.8, 1.7 Hz),7.08-7.13 (2H, m),7.40 (1H, d, J=1.7 Hz),8.12 (1H, d, J=8.8 Hz),9.41 (1H, s).
1H-NMR (DMSO-d6, 400 MHz) δ :3.42-3.45 (2H, m),3.48-3.53 (2H, m),3.60-3.66 (2H, m),4.07-4.12 (2H, m),4.42-4.46 (1H, m),4.68 (1H, t, J=5.3 Hz),6.50-6.53 (2H, m),7.11-7.15 (3H, m),7.40 (1H, d, J=1.4 Hz),7.52-7.57 (1H, br),8.03-8.10 (1H, br),8.12 (1H, d, J=8.8 Hz),9.36 (1H, s).
MS (ESI) m/z : 373 (M+H)+.
4-アセチル-3-{4-[3-(2-ヒドロキシエトキシ)アゼチジン-1-イル]フェニルアミノ}ベンズアミド
(6a) エチル 4-アセチル-3-ヒドロキシベンゾエート
得られた粉末に塩化アルミニウム (24.7 g、185 mmol) を加え、180℃ にて3時間撹拌した。混合物を氷に注加し、酢酸エチルにて2 回抽出し、有機層を合わせ2.0 M 塩酸、飽和食塩水にて順次洗浄後、無水硫酸ナトリウムで乾燥し、減圧下溶媒を留去した。得られた残渣にエタノール (30 mL)および濃塩酸 (3 mL) を加え、12時間加熱還流した。反応液を減圧下濃縮後、水を加え、酢酸エチルにて2 回抽出し、有機層を合わせ飽和食塩水にて洗浄後、無水硫酸ナトリウムで乾燥し、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー (ヘキサン:酢酸エチル、9:1→4:1、V/V) にて精製後、目的分画の溶媒を減圧下留去し、標記目的化合物の淡黄色粉末 (916 mg,収率6.1%) を得た。
1H-NMR (CDCl3, 400 MHz) δ: 1.40 (3H, t, J=7.3 Hz),2.68 (3H, s),4.38 (2H, q, J=7.3 Hz),7.54 (1H, dd, J=8.3, 1.7 Hz),7.63 (1H, d, J=1.7 Hz),7.79 (1H, d, J=8.3 Hz),12.15 (1H, s).
1H-NMR (CDCl3, 400 MHz) δ: 1.43 (3H, t, J=7.3 Hz),2.67 (3H, s),4.43 (2H, q, J=7.3 Hz),7.85 (1H, d, J=8.1 Hz),7.97 (1H, d, J=1.4 Hz),8.13 (1H, dd, J=8.1, 1.4 Hz).
1H-NMR (CDCl3, 400 MHz) δ: 1.40 (3H, t, J=7.1 Hz),1.74 (3H, s),3.78-3.87 (2H, m),4.05-4.15 (2H, m),4.40 (2H, q, J=7.1 Hz),7.74 (1H, d, J=8.1 Hz),7.89 (1H, d, J=1.4 Hz),8.01 (1H, dd, J=8.1, 1.4 Hz).
得られた残渣 (70 mg)をジメチルホルムアミド (1 mL)に溶解し、1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド塩酸塩 (54 mg、0.28 mmol) および1-ヒドロキシベンゾトリアゾール (0.38 mg、0.28 mmol) を加え、室温にて10分撹拌し、14.8 M アンモニア水 (0.05 mL、0.7 mmol) を加え同温にて3時間撹拌後、1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド 塩酸塩 (54 mg、0.28 mmol) および1-ヒドロキシベンゾトリアゾール (0.38 mg、0.28 mmol)、14.8 M アンモニア水 (0.05 mL、0.7 mmol)を加え、さらに16時間撹拌した。反応液を酢酸エチルにて希釈し、水、飽和食塩水にて順次洗浄後、無水硫酸ナトリウムで乾燥し、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー (ヘキサン:酢酸エチル、1:1→1:3→0:1、V/V)にて精製した。目的分画の溶媒を減圧下留去し、標記目的化合物の淡黄色粉末 (52 mg、収率8.6%) を得た。
1H-NMR (CDCl3, 400 MHz) δ:1.47-1.92 (9H, m),3.46-3.66 (4H, m),3.69-3.78 (2H, m),3.84-3.94 (4H, m),4.06-4.16 (4H, m),4.46-4.54 (1H, m),4.61-4.66 (1H, m),5.27-5.58 (1H, br),5.70-6.02 (1H, br),6.44-6.50 (2H, m),6.98-7.06 (2H, m),7.12 (1H, dd, J=8.0, 1.7 Hz),7.22 (1H, s),7.36 (1H, d, J=1.7 Hz),7.46 (1H, d, J=8.0 Hz).
1H-NMR (CDCl3, 400 MHz) δ:1.96-2.07 (1H, br),2.65 (3H, s),3.57 (2H, t, J=4.4 Hz),3.72-3.82 (4H, m),4.11-4.17 (2H, m),4.45-4.52 (1H, m),5.45-5.75 (1H, br),5.75-6.10 (1H, br),6.45-6.51 (2H, m),6.97 (1H, dd, J=8.3, 1.4 Hz),7.05-7.12 (2H, m),7.30 (1H, d, J=1.4 Hz),7.82 (1H, d, J=8.3 Hz),10.33 (1H, s).
MS (ESI) m/z : 370 (M+H)+.
(5-アセチル-2-メトキシピリジン-4-イル)-{4-[3-(2-ヒドロキシエトキシ)アゼチジン-1-イル]フェニル}アミン
(7a) 5-ブロモ-2-メトキシピリジン-N-オキシド
1H-NMR (CDCl3, 400 MHz) δ : 4.07 (3H, s),6.78 (1H, d, J=9.0 Hz),7.38 (1H, d, J=9.0 Hz),8.38-8.42 (1H, m).
1H-NMR (CDCl3, 400 MHz) δ : 3.99 (3H, s),7.11 (1H, s),8.45 (1H, s).
1H-NMR (CDCl3, 400 MHz) δ: 2.55 (3H, s),3.93 (3H, s),5.84 (1H, s),6.00-7.20 (2H, br),8.58 (1H, s).
MS(ESI) m/z: 167 (M+H)+.
1H-NMR (CDCl3, 400 MHz) δ:1.90-2.00 (1H, m),2.60 (3H, s),3.54-3.60 (2H, m),3.72-3.82 (4H, m),3.88 (3H, s),4.10-4.19 (2H, m),4.45-4.54 (1H, m),6.02 (1H, s),6.44-6.50 (2H, m),7.02-7.08 (2H, m),8.62 (1H, s),10.25-10.35 (1H, br).
MS (ESI) m/z : 358 (M+H)+.
N-(4-{4-[3-(4-ヒドロキシメチルピペリジン-1-イル)アゼチジン-1-イル]フェニルアミノ}-6-メトキシピリジン-3-イル)アセタミド
(8a) 1-ベンズヒドリルアゼチジン-3-イル メタンスルホネート
1H-NMR (CDCl3, 400 MHz) δ: 2.99 (3H, s),3.15-3.23 (2H, m),3.59-3.68 (2H, m),4.39 (1H, s),5.10 (1H, quintet, J=5.8 Hz),7.16-7.22 (2H, m),7.24-7.30 (4H, m),7.36-7.41 (4H, m).
1H-NMR (CDCl3, 400 MHz) δ: 1.23 (3H, t,J=7.1 Hz),1.67-1.90 (6H, m),2.21-2.30 (1H, m),2.62-2.70 (2H, m),2.84-2.96 (3H, m),3.37-3.42 (2H, m),4.11 (2H, q, J=7.1 Hz),4.41 (1H, s),7.14-7.20 (2H, m),7.22-7.28 (4H, m),7.37-7.42 (4H, m).
得られた油状物 (3.88 g)をN-メチルピロリドン (20 mL)に溶解させ、p-フルオロニトロベンゼン(1.58 g、11.2 mmol) およびジイソプロピルエチルアミン (2.6 mL、15 mmol) を加え、70℃ にて7時間撹拌した。放冷後、水(100 mL)を加え、酢酸エチル (100 mL)にて2回抽出した。有機層を合わせ、水および飽和食塩水にて順次洗浄後、無水硫酸ナトリウムで乾燥し、減圧下溶媒を留去した。残渣をイソプロピルエーテル (30 mL)にて洗浄後、ろ取し、標記目的化合物の黄色粉末(2.48 g、収率73%) を得た。
1H-NMR (CDCl3, 400 MHz) δ: 1.23 (3H, t, J=7.1 Hz),1.73-1.84 (2H, m),1.93-2.06 (4H, m),2.30-2.39 (1H, m),2.78-2.85 (2H, m),3.30-3.38 (1H, m),3.88 (2H, dd, J=8.5, 5.4 Hz),4.06-4.12 (2H, m),4.15 (2H, q, J=7.1 Hz),6.28-6.33 (2H, m),8.07-8.13 (2H, m).
得られた残渣を塩化メチレン (80 mL) に溶解し、氷冷下、イミダゾール (1.37 g、20.1 mmol)、tert-ブチルジメチルシリルクロリド (2.42 g、16.1 mmol) を加え、室温にて12時間撹拌した。反応液に水を加え、酢酸エチルにて2回抽出した。有機層を飽和食塩水にて洗浄し、無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー (ヘキサン:酢酸エチル、4:1、V/V)にて精製後、目的分画の溶媒を減圧下留去し、標記目的化合物の橙色油状物(3.61 g、収率66%) を得た。
1H-NMR (CDCl3, 400 MHz) δ: 0.03 (6H, s),0.89 (9H, s),1.18-1.33 (2H, m),1.46-1.59 (1H, m),1.73-1.82 (2H, m),1.84-1.95 (2H, m),2.83-2.94 (2H, m),3.26-3.38 (1H, m),3.45 (2H, d, J=6.3 Hz),3.84-3.92 (2H, m),4.05-4.12 (2H, m),6.25-6.33 (2H, m),8.04-8.13 (2H, m).
得られた4-{3-[4-(tert-ブチルジメチルシラニルオキシメチル)ピペリジン-1-イル]アゼチジン-1-イル}フェニルアミン (2.81 g、7.48 mmol) および実施例4 (4c) で製造した4-クロロ-2-メトキシ-5-ニトロピリジン (1.41 g、7.48 mmol) を用い、実施例4 (4d)と同様な方法により標記目的化合物の赤褐色油状物(2.86 g、収率72%) を得た。
1H-NMR (CDCl3, 400 MHz) δ: 0.04 (6H, s),0.89 (9H, s),1.20-1.32 (2H, m),1.46-1.58 (1H, m),1.72-1.81 (2H, m),1.84-1.94 (2H, m),2.84-2.94 (2H, m),3.26-3.35 (1H, m),3.45 (2H, d, J=6.5 Hz),3.69-3.76 (2H, m),3.89 (3H, s),3.97-4.05 (2H, m),5.99 (1H, s),6.43-6.52 (2H, m),7.01-7.10 (2H, m),9.02 (1H, s),9.26 (1H, s).
得られたN4-(4-{3-[4-(tert-ブチルジメチルシラニルオキシメチル)ピペリジン-1-イル]アゼチジン-1-イル}フェニル)-6-メトキシピリジン-3,4-ジアミン (750 mg、1.51 mmol) をピリジン (8 mL)に溶解させ、氷冷下、無水酢酸 (0.14 mL、1.5 mmol) を加え、同温にて1時間撹拌した。反応液に水を加え、酢酸エチルにて2回抽出した。有機層を水、および飽和食塩水にて順次洗浄後、無水硫酸ナトリウムで乾燥し、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー (ヘキサン:酢酸エチル、2:1→0:1、V/V) にて精製し、目的分画の溶媒を減圧下留去した。
得られたN-[4-(4-{3-[4-(tert-ブチルジメチルシラニルオキシメチル)ピペリジン-1-イル]アゼチジン-1-イル}フェニルアミノ)-6-メトキシピリジン-3-イル]アセタミド (608 mg、1.13 mmol) をテトラヒドロフラン (6 mL)に溶解し、氷冷下、1.0 M テトラブチルアンモニウムフルオリド/テトラヒドロフラン溶液 (1.69 mL、1.7 mmol) を加え、室温にて4時間撹拌した。反応液に水を加え、クロロホルムにて2回抽出した。有機層を飽和食塩水にて洗浄後、無水硫酸ナトリウムで乾燥し、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー (クロロホルム:メタノール、100:1、V/V)にて精製した。目的分画の溶媒を減圧下留去した。得られた残渣を、塩基性シリカゲルカラムクロマトグラフィー (クロロホルム:メタノール、50:1、V/V) にて精製した。目的分画の溶媒を減圧下留去し、得られた残渣を酢酸エチルに溶解し、水にて洗浄後、無水硫酸ナトリウムで乾燥し、減圧下溶媒を留去した。得られた粉末をイソプロピルエーテル-ヘキサン(1:1) にて洗浄後、ろ取し、標記目的化合物の淡赤色粉末(104 mg、収率21%) を得た。
1H-NMR (CDCl3, 400 MHz) δ:1.24-1.37 (2H, m),1.50-1.70 (2H, m),1.75-1.84 (2H, m),1.86-1.96 (2H, m),1.96 (1H, s),2.24 (2H, s),2.87-2.96 (2H, m),3.26-3.35 (1H, m),3.51 (2H, d, J=6.3 Hz),3.64-3.74 (2H, m),3.82 (2H, s),3.84 (1H, s),3.94-4.03 (2H, m),6.07 (0.35H, s),6.08 (0.35H, s),6.12 (0.65H, s),6.26 (0.65H, s),6.40-6.47 (2H, m),6.50 (0.35H, s),6.96 (0.65H, s),6.98-7.04 (2H, m),7.77 (0.65H, s),7.79 (0.35H, s).
MS (ESI) m/z : 426 (M+H)+.
N-{6-メトキシ-4-[4-(3-モルホリン-4-イルアゼチジン-1-イル)フェニルアミノ]ピリジン-3-イル}アセタミド
(9a) 4-(1-ベンズヒドリルアゼチジン-3-イル)モルホリン
1H-NMR (CDCl3, 400 MHz) δ:2.26-2.33 (4H, m),2.87-3.02 (3H, m),3.36-3.43 (2H, m),3.68-3.73 (4H, m),4.41 (1H, s),7.16-7.43 (10H, m).
1H-NMR (CDCl3, 400 MHz) δ:2.41-2.52 (4H, m),3.35-3.41 (1H, m),3.72-3.81 (4H, m),3.86-3.92 (2H, m),4.07-4.11 (2H, m),6.29-6.33 (2H, m),8.08-8.12 (2H, m).
1H-NMR (CDCl3, 400 MHz) δ:2.40-2.52 (4H, m),3.30-3.41 (1H, m),3.70-3.80 (6H, m),3.90 (3H, s),3.97-4.05 (2H, m),6.00 (1H, s),6.44-6.53 (2H, m),7.03-7.11 (2H, m),9.02 (1H, s),9.26 (1H, s).
1H-NMR (CDCl3, 400 MHz) δ: 1.96 (1H, s),2.24 (2H, s),2.40-2.51 (4H, m),3.29-3.39 (1H, m),3.67-3.78 (6H, m),3.82 (1.8H, s),3.85 (1.2H, s),3.94-4.03 (2H, m),6.07 (0.4H, s),6.12 (0.6H, s),6.29-6.35 (0.6H, m),6.40-6.50 (2.4H, m),6.96-7.06 (3H, m),7.78 (0.6H, s),7.79 (0.4H, s).
MS (ESI) m/z : 398 (M+H)+.
N-(4-{4-[4-(2-ヒドロキシアセチル)ピペラジン-1-イル]フェニルアミノ}-6-メトキシピリジン-3-イル)アセタミド
(10a) tert-ブチル4-[4-(5-アセチルアミノ-2-メトキシピリジン-4-イルアミノ)フェニル]ピペラジン-1-カルボキシレート
1H-NMR (CDCl3, 400 MHz) δ : 1.49 (9H, s),1.96 (1H, s),2.25 (2H, s),3.05-3.20 (4H, m),3.52-3.68 (4H, m),3.83 (2H, s),3.86 (1H, s),6.15-6.20 (0.5H, m),6.26 (0.5H, s),6.44 (0.7H, s),6.50-6.53 (0.3H, m),6.87-6.95 (2H, m),7.01-7.14 (3H, m),7.77-7.82 (1H, m).
1H-NMR (DMSO-d6, 400 MHz) δ : 2.04 (3H, s),2.80-2.88 (4H, m),2.97-3.08 (4H, m),3.71 (3H, s),5.99 (1H, s),6.92-6.94 (2H, m),7.02-7.04 (2H, m),7.60 (1H, s),7.64 (1H, s),9.08 (1H, s).
得られた油状物をメタノール (2 mL)に溶解し、室温にて5.0 M水酸化ナトリウム水 (0.29 mL、1.5 mmol) を加え同温にて30分撹拌した。反応液をクロロホルムにて希釈後、水、飽和食塩水にて洗浄し、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去し、酢酸エチルを加えて減圧下溶媒を留去した。析出した粉末を酢酸エチルにてろ取し、標記目的化合物の白色粉末(75 mg、収率64%) を得た。
1H-NMR (DMSO-d6, 400 MHz) δ : 2.04 (3H, s),3.05-3.15 (4H, m),3.42-3.55 (2H, m),3.56-3.65 (2H, m),3.71 (3H, s),6.02 (1H, s),6.97-6.99 (2H, m),7.05-7.08 (2H, m),7.71 (1H, s),9.10-9.30 (1H, s).
MS (ESI) m/z : 400 (M+H)+.
3-{4-[4-(5-アセチルアミノ-2-メトキシピリジン-4-イルアミノ)フェニル]ピペラジン-1-イル}-2,2-ジメチルプロピオン酸
(11a) メチル 2,2-ジメチル-3-オキソプロピオネート
1H-NMR (CDCl3, 400 MHz) δ : 1.21 (6H, s),1.96 (1H, s),2.25 (2H, s),2.59 (2H, s),2.63-2.74 (4H, m),3.00-3.20 (4H, m),3.69 (3H, s),3.83 (2H, s),3.86 (1H, s),6.10 (0.3H, s),6.17 (0.3H, s),6.46 (0.4H, s),6.88-6.90 (2H, m),7.04-7.07 (2H, m),7.81 (1H, s).
1H-NMR (DMSO-d6, 400 MHz) δ : 1.11 (6H, s),2.03 (3H, s),2.53-2.58 (2H, br),2.63-2.74 (4H, m),3.05-3.15 (4H, m),3.70 (3H, s),5.99 (1H, s),6.92-6.95 (2H, m),7.02-7.04 (2H, m),9.14 (1H, s).
MS (ESI) m/z : 442 (M+H)+.
1-{4-[4-(4-フルオロ-5-メトキシ-2-ニトロフェニルアミノ)フェニル]ピペラジン-1-イル}-2-ヒドロキシエタノン
(12a) tert-ブチル4-[4-(4-フルオロ-5-メトキシ-2-ニトロフェニルアミノ)フェニル]ピペラジン-1-カルボキシレート
1H-NMR (CDCl3, 400 MHz) δ : 1.49 (9H, s),3.12-3.30 (4H, m),3.57-3.70 (4H, m),3.74 (3H, s),6.44 (1H, d, J=8.3 Hz),6.97-6.99 (2H, m),7.17-7.19 (2H, m),7.93 (1H, d, J=11.7 Hz),9.66 (1H, s).
1H-NMR (DMSO-d6, 400 MHz) δ : 2.82-2.88 (4H, m),3.06-3.14 (4H, m),3.74 (3H, s),6.53 (1H, d, J=7.8 Hz),6.97-7.00 (2H, m),7.23-7.25 (2H, m),7.94 (1H, d, J=12.0 Hz),9.66 (1H, s).
1H-NMR (DMSO-d6, 400 MHz) δ :3.12-3.24 (4H, m),3.46-3.54 (2H, m),3.59-3.66 (2H, m),3.74 (3H, s),4.10-4.14 (2H, m),4.58-4.68 (1H, br),6.55 (1H, d, J=7.6 Hz),7.02-7.04 (2H, m),7.26-7.28 (2H, m),7.95 (1H, d, J=12.0 Hz),9.66 (1H, s).
MS (ESI) m/z : 405 (M+H)+.
3-{4-[4-(4-フルオロ-5-メトキシ-2-ニトロフェニルアミノ)フェニル]ピペラジン-1-イル}-2,2-ジメチルプロピオン酸
(13a) メチル 3-{4-[4-(4-フルオロ-5-メトキシ-2-ニトロフェニルアミノ)フェニル]ピペラジン-1-イル}-2,2-ジメチルプロピオネート
1H-NMR (CDCl3, 400 MHz) δ : 1.20 (6H, s),2.57 (2H, s),2.65-2.74 (4H, m),3.13-3.20 (4H, m),3.68 (3H, s),3.73 (3H, s),6.41 (1H, d, J=7.6 Hz),6.93-6.95 (2H, m),7.13-7.16 (2H, m),7.92 (1H, d, J=11.7 Hz),9.65 (1H, s).
1H-NMR (DMSO-d6, 400 MHz) δ : 1.10 (6H, s),2.45-2.55 (2H, m),2.59-2.64 (4H, m),3.07-3.18 (4H, m),3.73 (3H, s),6.52 (1H, d, J=7.6 Hz),6.97-6.99 (2H, m),7.22-7.25 (2H, m),7.94 (1H, d, J=12.0 Hz),9.66 (1H, s).
MS (ESI) m/z : 447 (M+H)+.
N-(6-メトキシ-4-{4-[2-(テトラヒドロフラン-3-イルオキシ]フェニルアミノ}ピリジン-3-イル)アセタミド
(14a) 3-[2-(4-ニトロフェノキシ)エトキシ]テトラヒドロフラン
得られた油状物をジメチルホルムアミド (45 mL) に溶解し、4-ニトロフェノール (1.77 g、12.7 mmol) および炭酸カリウム (2.93 g、21.2 mmol) を加え、80℃ にて 2時間撹拌した。反応液に水を加え、酢酸エチルにて2回抽出した。有機層を水、飽和食塩水にて順次洗浄し、無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー (ヘキサン:酢酸エチル、1:1→1:1、V/V) にて精製後、目的分画の溶媒を減圧下留去し、標記目的化合物の黄色油状物(2.33 g、収率87%) を得た。
1H-NMR (CDCl3, 400 MHz) δ:1.99-2.07 (2H, m),3.76-3.96 (6H, m),4.18-4.26 (3H, m),6.93-7.04 (2H, m),8.15-8.25 (2H, m).
1H-NMR (CDCl3, 400 MHz) δ:1.95-2.07 (2H, m),3.38-3.49 (2H, br),3.69-3.95 (6H, m),4.03 (2H, t, J=4.8 Hz),4.19-4.25 (1H, m),6.60-6.66 (2H, m),6.70-6.79 (2H, m).
1H-NMR (CDCl3, 400 MHz) δ:2.01-2.09 (2H, m),3.76-3.98 (6H, m),3.91 (3H, s),4.08-4.17 (2H, m),4.20-4.29 (1H, m),6.04 (1H, s),6.92-7.02 (2H, m),7.12-7.21 (2H, m),9.04 (1H, s),9.31 (1H, s).
1H-NMR (CDCl3, 400 MHz) δ: 1.96 (1H, s),1.97-2.09 (2H, m),2.25 (2H, s),3.74-3.96 (6H, m),3.82 (3H, s),4.08-4.14 (2H, m),4.20-4.27 (1H, m),6.15 (0.3H, s),6.20 (1H, s),6.56 (0.3H, s),6.67 (0.7H, s),6.85-6.96 (2H, m),7.05-7.14 (2H, m),7.35 (0.7H, s),7.82 (1H, s).
MS (ESI) m/z : 388 (M+H)+.
N-(6-メトキシ-4-{4-[2-(4-メチルピペラジン-1-イル)エトキシ]フェニルアミノ}ピリジン-3-イル)アセタミド
(15a) 2-(4-ニトロフェノキシ)エタノール
1H-NMR (CDCl3, 400 MHz) δ:1.24-1.28 (1H, m),4.01-4.05 (2H, m),4.18-4.20 (2H, m),6.98-7.00 (2H, m),8.20-8.22 (2H, m).
1H-NMR (CDCl3, 400 MHz) δ: 2.30 (3H, s),2.47-2.62 (8H, m),2.84-2.87 (2H, m),4.18-4.20 (2H, m),6.95-6.97 (2H, m),8.90-8.92 (2H, m).
1H-NMR (DMSO-d6, 400 MHz) δ: 2.29 (3H, s),2.45-2.58 (8H, m),2.63-2.66 (2H, m),3.90-3.93 (2H, m),6.47-6.49 (2H, m),6.62-6.64 (2H, m).
1H-NMR (DMSO-d6, 400 MHz) δ : 2.04 (3H, s),2.14 (3H, s),2.26-2.39 (4H, m),2.47-2.54 (4H, m),2.66-2.69 (2H, m),3.71 (3H, s),4.04-4.07 (2H, m),6.00 (1H, s),6.94-6.97 (2H, m),6.94-6.97 (2H, m),7.08-7.10 (1H, s),7.71 (1H, s),9.10 (1H, s).
MS (ESI) m/z : 400 (M+H)+.
N-(4-{4-[3-(2-スルファモイルアミノエトキシ)アゼチジン-1-イル]フェニルアミノ}-6-メトキシピリジン-3-イル)アセタミド
(16a) N-(4-{4-[3-(2-tert-ブトキシカルボニルスルファモイルアミノエトキシ)アゼチジン-1-イル]フェニルアミノ}-6-メトキシピリジン-3-イル)アセタミド
1H-NMR (CDCl3, 400 MHz) δ : 1.55 (9H, s), 1.96 (1H, s),2.24 (2H, s),3.61 (2H, t,J=5.3 Hz),3.66-3.74 (2H, m),3.82 (2H, s),3.85 (1H, s),3.98 (2H, t,J=5.3 Hz),4.00-4.08 (2H, m),4.38-4.46 (1H, m),5.44-5.55 (2H, br),6.10 (0.35H, s),6.12 (0.35H, s),6.15 (0.65H, s),6.34 (0.65H, s),6.41-6.50 (2H, m),6.54 (0.65H, s),6.98-7.07 (2.35H, m),7.78 (0.65H, s),7.79 (0.35H, s).
1H-NMR (DMSO-d6, 400 MHz) δ : 2.03 (3H, s),3.04 (2H, q, J=6.1 Hz),3.49 (2H, t, J=6.1 Hz),3.57-3.64 (2H, m),3.69 (3H, s),4.01-4.10 (2H, m),4.38-4.46 (1H, m),5.89 (1H, s),6.43-6.50 (2H, m),6.51-6.60 (3H, m),6.95-7.05 (2H, m),7.54 (1H, s),7.67 (1H, s),9.05 (1H, s).
MS (ESI) m/z : 451 (M+H)+.
4-アセチル-3-{4-[2-(テトラヒドロピラン-4-イルオキシ)エトキシ]フェニルアミノ}ベンズアミド
(17a) 4-[2-(4-ニトロフェノキシ)エトキシ]テトラヒドロピラン
1H-NMR (CDCl3, 400 MHz) δ:1.57-1.69 (2H, m),1.88-1.98 (2H, m),3.40-3.50 (2H, m),3.54-3.65 (1H, m),3.83-3.90 (2H, m),3.91-4.00 (2H, m),4.20-4.25 (2H, m),6.95-7.02 (2H, m),8.16-8.24 (2H, m).
1H-NMR (CDCl3, 400 MHz) δ:1.55-1.72 (2H, m),1.85-1.98 (2H, m),3.37-3.50 (4H, m),3.53-3.64 (1H, m),3.75-3.83 (2H, m),3.90-3.99 (2H, m),4.00-4.08 (2H, m),6.60-6.67 (2H, m),6.72-6.80 (2H, m).
1H-NMR (DMSO-d6, 400 MHz) δ :1.55-1.70 (2H, m),1.73 (3H, s),1.88-1.98 (2H, m),3.42-3.68 (3H, m),3.82-4.01 (6H, m),4.07-4.20 (4H, m),6.88-6.90 (2H, m),7.04-7.06 (2H, m),7.30 (1H, s),7.45-7.51 (2H, m),7.76 (1H, s).
1H-NMR (DMSO-d6, 400 MHz) δ :1.55-1.70 (2H, m),1.73 (3H, s),1.90-1.98 (2H, m),3.42-3.49 (2H, m),3.57-3.66 (1H, m),3.82-3.88 (4H, m),3.92-4.00 (2H, m),4.09-4.20 (4H, m),5.40-5.60 (1H, br),5.80-6.05 (1H, br),6.89-6.91 (2H, m),7.05-7.07 (2H, m),7.14 (1H, dd, J=8.1, 1.7 Hz),7.31 (1H, s),7.48-7.50 (2H, m).
1H-NMR (DMSO-d6, 400 MHz) δ :1.60-1.70 (2H, m),1.90-1.98 (2H, m),2.66 (3H, s),3.42-3.52 (2H, m),3.57-3.66 (1H, m),3.82-3.88 (2H, m),3.92-4.02 (2H, m),4.10-4.16 (2H, m),5.40-5.60 (1H, br),5.80-6.00 (1H, br),6.93-6.95 (2H, m),7.00 (1H, dd, J=8.3, 1.7 Hz),7.15-7.17 (2H, m),7.36 (1H, d, J=1.7 Hz),7.84 (1H, d, J=8.3 Hz),10.39 (1H, s).
MS (ESI) m/z : 399 (M+H)+.
4-(1,1-ジフルオロエチル)-3-{4-[2-(テトラヒドロピラン-4-イルオキシ)エトキシ]フェニルアミノ}ベンズアミド
(18a) メチル 4-アセチル-3-ブロモベンゾエート
1H-NMR (CDCl3, 400 MHz) δ : 2.64 (3H, s),3.94 (3H, s),7.47 (1H, d, J=8.0 Hz),8.01 (1H, dd, J=8.0, 1.4 Hz),8.27 (1H, d, J=1.4 Hz).
1H-NMR (CDCl3, 400 MHz) δ : 2.06 (3H, t, J=18.3 Hz),4.43 (3H, s),7.68 (1H, d, J=8.3 Hz),8.01 (1H, dd, J=8.3, 0.5 Hz),8.30 (1H, d, J=0.5 Hz).
1H-NMR (CDCl3, 400 MHz) δ:1.59-1.71 (2H, m),1.90-2.00 (2H, m),2.03 (3H, t, J=18.6 Hz),3.42-3.50 (2H, m),3.57-3.68 (1H, m),3.80-3.89 (5H, m),3.92-4.01 (2H, m),4.10-4.16 (2H, m),6.10-6.18 (1H, m),6.90-6.97 (2H, m),7.04-7.09 (2H, m),7.46-7.51 (2H, m),7.67-7.71 (1H, m).
1H-NMR (CDCl3, 400 MHz) δ:1.59-1.70 (2H, m),1.90-2.00 (2H, m),2.04 (3H, t, J=18.6 Hz),3.41-3.52 (2H, m),3.57-3.66 (1H, m),3.80-3.88 (2H, m),3.94-4.01 (2H, m),4.10-4.16 (2H, m),5.40-6.05 (1H, m),6.14-6.22 (1H, m),6.89-6.96 (2H, m),7.03-7.10 (2H, m),7.17-7.22 (1H, m),7.43-7.48 (2H, m).
MS (ESI) m/z : 421 (M+H)+.
4-アセチル-3-{4-[2-(2-ヒドロキシエトキシ)エトキシ]フェニルアミノ}ベンズアミド
(19a) メチル 3-ブロモ-4-(2-メチル-[1,3]ジオキソラン-2-イル)ベンゾエート
1H-NMR (CDCl3, 400 MHz) δ : 1.80 (3H, s),3.70-3.81 (2H, m),3.91 (3H, s),4.04-4.11 (2H, m),7.73 (1H, d, J=8.0 Hz),7.92 (1H, dd, J=8.0, 1.4 Hz),8.25 (1H, d, J=1.4 Hz).
1H-NMR (CDCl3, 400 MHz) δ:1.47-1.68 (4H, m),1.69-1.91 (2H, m),3.47-3.55 (1H, m),3.58-3.67 (3H, m),3.68-3.74 (2H, m),3.75-3.82 (2H, m, THP C6-H, -OCH2CH2OTHP),3.83-3.93 (2H, m),4.61-4.68 (1H, m).
1H-NMR (CDCl3, 400 MHz) δ:1.46-1.65 (4H, m),1.68-1.90 (2H, m),3.46-3.56 (1H, m),3.59-3.68 (1H, m),3.72-3.80 (2H, m),3.83-3.96 (4H, m),4.20-4.29 (2H, m),4.60-4.68 (1H, m),6.94-7.03 (2H, m),8.15-8.24 (2H, m).
1H-NMR (CDCl3, 400 MHz) δ:1.45-1.65 (4H, m),1.67-1.91 (2H, m),3.36-3.46 (2H, br),3.47-3.56 (1H, m),3.59-3.68 (1H, m),3.70-3.78 (2H, m),3.80-3.93 (4H, m),4.01-4.09 (2H, m),4.60-4.68 (1H, m),6.58-6.66 (2H, m),6.72-6.80 (2H, m).
1H-NMR (CDCl3, 400 MHz) δ :1.47-1.63 (4H, m),1.69-1.78 (1H, m),1.72 (3H, s),1.79-1.90 (1H, m),3.46-3.56 (1H, m),3.61-3.70 (1H, m),3.74-3.80 (2H, m),3.82-3.95 (6H, m),3.83 (3H, s),4.07-4.17 (4H, m),4.62-4.68 (1H, m),6.86-6.94 (2H, m),7.01-7.08 (2H, m),7.27 (1H, s),7.41 (1H, dd, J=8.0, 1.4 Hz),7.48 (1H, d, J=8.0 Hz),7.71 (1H, d, J=1.4 Hz).
1H-NMR (CDCl3, 400 MHz) δ :1.47-1.68 (4H, m),1.69-1.89 (2H, m),1.72 (3H, s),3.47-3.56 (1H, m),3.61-3.70 (1H, m),3.74-3.80 (2H, m),3.84-3.95 (6H, m),4.08-4.17 (4H, m),4.62-4.68 (1H, m),5.42-5.66 (1H, br),5.84-6.06 (1H, br),6.86-6.93 (2H, m),7.01-7.09 (2H, m),7.15 (1H, dd, J=8.0, 1.7 Hz),7.29 (1H, s),7.46 (1H, d, J=1.7 Hz),7.48 (1H, d, J=8.0 Hz).
1H-NMR (CDCl3, 400 MHz) δ:2.06-2.30 (1H, br),2.66 (3H, s),3.64-3.71 (2H, m),3.72-3.78 (2H, m),3.85-3.94 (2H, m),4.16-4.24 (2H, m),5.60-5.80 (1H, br),6.04-6.28 (1H, br),6.92-7.00 (2H, m),7.03 (1H, dd, J=8.3, 1.4 Hz),7.12-7.21 (2H, m),7.33 (1H, d, J=1.4 Hz),7.84 (1H, d, J=8.3 Hz),10.37 (1H, s).
MS (ESI) m/z : 357 (M-H)-.
4-アセチル-3-{4-[2-(1,1-ジオキソヘキサヒドロ-1λ6-チオピラン-4-イルオキシ)エトキシ]フェニルアミノ}ベンズアミド
(20a) 1,4-ジオキサ-8-チアスピロ[4.5]デカン
1H-NMR (CDCl3, 400 MHz) δ :1.87-1.95 (4H, m),2.71-2.78 (4H, m),3.94 (4H, s).
1H-NMR (CDCl3, 400 MHz) δ :1.76-1.88 (2H, m),2.08-2.19 (2H, m),2.48-2.58 (2H, m),2.75-2.86 (2H, m),3.32-3.42 (1H, m),3.53-3.60 (2H, m),3.68-3.77 (2H, m).
1H-NMR (CDCl3, 400 MHz) δ :1.77-1.92 (2H, m),2.09-2.20 (2H, m),2.46-2.58 (2H, m),2.76-2.89 (2H, m),3.38-3.48 (1H, m),3.80-3.88 (2H, m),4.18-4.25 (2H, m),6.94-7.02 (2H, m),8.16-8.24 (2H, m).
1H-NMR (CDCl3, 400 MHz) δ :2.18-2.30 (2H, m),2.31-2.42 (2H, m),2.83-2.95 (2H, m),3.25-3.38 (2H, m),3.74-3.81 (1H, m),3.83-3.91 (2H, m),4.19-4.26 (2H, m),6.93-7.02 (2H, m),8.17-8.26 (2H, m).
1H-NMR (CDCl3, 400 MHz) δ :2.13-2.26 (2H, m),2.28-2.39 (2H, m),2.79-2.89 (2H, m),3.26-3.38 (2H, m),3.71-3.80 (3H, m),4.01-4.08 (2H, m),6.60-6.66 (2H, m), 6.70-6.77 (2H, m).
1H-NMR (CDCl3, 400 MHz) δ (ppm) : 1.72 (3H, s),2.17-2.30 (2H, m),2.31-2.43 (2H, m),2.82-2.94 (2H, m),3.30-3.43 (2H, m),3.75-3.80 (1H, m),3.80-3.91 (4H, m),3.84 (3H, s),4.07-4.17 (4H, m),6.84-6.92 (2H, m),7.03-7.11 (2H, m),7.29 (1H, s),7.42 (1H, dd, J=8.0, 1.4 Hz),7.49 (1H, d, J=8.0 Hz),7.73 (1H, d, J=1.4 Hz).
1H-NMR (CDCl3, 400 MHz) δ : 1.72 (3H, s),2.15-2.27 (2H, m),2.30-2.42 (2H, m), 2.80-2.92 (2H, m),3.24-3.40 (2H, m),3.73-3.79 (1H, m),3.79-3.95 (4H, m),4.07-4.20 (4H, m),5.35-5.60 (1H, br),5.90-6.15 (1H, br),6.85-6.91 (2H, m),7.04-7.10 (2H, m),7.16 (1H, dd, J=7.8, 1.6 Hz),7.30 (1H, s),7.49 (1H, d, J=7.8 Hz),7.51 (1H, d, J=1.6 Hz).
1H-NMR (CDCl3, 400 MHz) δ:2.15-2.27 (2H, m),2.31-2.41 (2H, m),2.66 (3H, s),2.80-2.90 (2H, m),3.24-3.37 (2H, m),3.72-3.79 (1H, m),3.80-3.86 (2H, m),4.14-4.20 (2H, m),5.55-5.75 (1H, br),6.05-6.20 (1H, br),6.89-6.95 (2H, m),7.02 (1H, dd, J=8.3, 1.7 Hz),7.14-7.20 (2H, m),7.40 (1H, d, J=1.7 Hz),7.84 (1H, d, J=8.3 Hz),10.40 (1H, s).
MS (ESI) m/z : 447 (M+H)+.
4-アセチル-3-{4-[2-(2-オキソテトラヒドロフラン-3-イルオキシ)エトキシ]フェニルアミノ}ベンズアミド
(21a) 3-[2-(テトラヒドロピラン-2-イルオキシ)エトキシ]ジヒドロフラン-2-オン
1H-NMR (CDCl3, 400 MHz) δ:1.48-1.88 (6H, m),2.25-2.36 (1H, m),2.48-2.57 (1H, m),3.46-3.54 (1H, m),3.60-3.68 (1H, m),3.78-3.94 (3H, m),4.02-4.11 (1H, m),4.18-4.27 (2H, m),4.37-4.45 (1H, m),4.60-4.66 (1H, m).
1H-NMR (CDCl3, 400 MHz) δ:2.25-2.40 (1H, m),2.53-2.64 (1H, m),3.70-3.85 (3H, m),3.89-4.00 (1H, m),4.02-4.11 (1H, m),4.19-4.30 (1H, m),4.39-4.50 (1H, m).
1H-NMR (CDCl3, 400 MHz) δ:2.25-2.36 (1H, m),2.53-2.64 (1H, m),3.07 (3H, s),3.87-3.96 (1H, m),4.17-4.30 (3H, m),4.37-4.47 (3H, m).
1H-NMR (CDCl3, 400 MHz) δ: 0.15 (6H, s),0.96 (9H, s),3.10-3.70 (2H, br),6.54-6.60 (2H, m),6.62-6.68 (2H, m).
1H-NMR (CDCl3, 400 MHz) δ: 0.21 (6H, s),1.00 (9H, s),1.72 (3H, s),3.83 (3H, s),3.84-3.89 (2H, m),4.07-4.12 (2H, m),6.76-6.83 (2H, m),6.96-7.02 (2H, m),7.23-7.30 (1H, br),7.41 (1H, dd, J=8.0, 1.5 Hz),7.48 (1H, d, J=8.0 Hz),7.73 (1H, d, J=1.5 Hz).
1H-NMR (DMSO-d6, 400 MHz) δ: 1.62 (3H, s),3.75-3.84 (2H, m),4.00-4.11 (2H, m),6.71-6.78 (2H, m),6.92-6.98 (2H, m),7.16-7.23 (3H, m),7.33 (1H, d, J=8.0 Hz),7.38 (1H, d, J=1.7 Hz),7.72-7.80 (1H, br),9.15 (1H, s).
1H-NMR (DMSO-d6, 400 MHz) δ: 2.63 (3H, s),6.77-6.83 (2H, m),7.03-7.13 (3H, m),7.33-7.35 (1H, m),7.42 (1H, s),7.92-7.98 (2H, m),9.41 (1H, s),10.19 (1H, s).
1H-NMR (CDCl3, 400 MHz) δ:2.30-2.40 (1H, m),2.53-2.62 (1H, m),2.66 (3H, s),3.98-4.06 (1H, m),4.10-4.33 (5H, m),4.40-4.46 (1H, m),5.45-5.70 (1H, br),5.80-6.10 (1H, br),6.91-6.97 (2H, m),7.01 (1H, dd, J=8.0, 1.7 Hz),7.13-7.19 (2H, m),7.36 (1H, d, J=1.7 Hz),7.84 (1H, d, J=8.0 Hz),10.38 (1H, s).
MS (ESI) m/z : 397 (M-H)-.
4-{2-[4-(2-アセチル-5-カルバモイルフェニルアミノ)フェノキシ]エトキシ}酪酸
(22a) 4-アセチル-3-ヒドロキシベンゾニトリル
1H-NMR (CDCl3, 400 MHz) δ : 2.68 (3H, s),7.17 (1H, dd, J=8.0, 1.4 Hz),7.28 (1H, d, J=1.4 Hz),7.83 (1H, d, J=8.0 Hz),12.26 (1H, s).
1H-NMR (CDCl3, 400 MHz) δ : 2.67 (3H, s),7.64 (1H, d, J=1.2 Hz),7.79 (1H, dd, J=8.0, 1.2 Hz),7.89 (1H, d, J=8.0 Hz).
1H-NMR (CDCl3, 400 MHz) δ : 1.72 (3H, s),3.77-3.88 (2H, m),4.06-4.17 (2H, m),7.53 (1H, d, J=1.4 Hz),7.66 (1H, dd, J=8.0, 1.4 Hz),7.81 (1H, d, J=8.0 Hz).
1H-NMR (CDCl3, 400 MHz) δ:1.81-2.15 (1H, br),3.67-3.71 (2H, m),3.75-3.80 (2H, m),3.89-3.94 (2H, m),4.12-4.27 (2H, m),6.96-7.01 (2H, m),8.11-8.22 (2H, m).
マロン酸ジエチル (9.77 mL、64.7 mmol) をジメチルホルムアミド (120 mL)に溶解させ、氷冷下水素化ナトリウム (P=60%) (2.59 g、64.7 mmol) を加え、同温にて30分撹拌後、先に得られた残渣のジメチルホルムアミド溶液 (30 mL)を加え、80℃ にて18時間撹拌した。反応液に水を加え、酢酸エチルにて2回抽出した。有機層を水、飽和食塩水にて順次洗浄後、無水硫酸ナトリウムで乾燥し、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー (ヘキサン:酢酸エチル、9:1→8:2、V/V) にて精製後、目的分画の溶媒を減圧下留去し、標記目的化合物の黄色油状物 (7.06 g、収率44%) を得た。
1H-NMR (CDCl3, 400 MHz) δ: 1.25 (6H, t, J=7.1 Hz),2.17-2.26 (2H, m),3.54 (1H, t, J=7.5 Hz),3.58-3.63 (2H, m),3.78-3.84 (2H, m),4.10-4.24 (6H, m),6.95-7.00 (2H, m),8.17-8.21 (2H, m).
1H-NMR (CDCl3, 400 MHz) δ: 1.25 (3H, t, J=7.1 Hz),1.89-1.97 (2H, m),2.40 (2H, t, J=7.3 Hz),3.55-3.61 (2H, m),3.79-3.84 (2H, m),4.12 (2H, q, J=7.1 Hz),4.17-4.23 (2H, m),6.95-7.02 (2H, m),8.17-8.23 (2H, m).
1H-NMR (CDCl3, 400 MHz) δ: 1.25 (3H, t, J=7.1 Hz),1.89-1.97 (2H, m),2.41 (2H, t, J=7.3 Hz),3.35-3.48 (2H, br),3.54-3.59 (2H, m),3.71-3.77 (2H, m),4.00-4.06 (2H, m),4.12 (2H, q, J=7.1 Hz),6.60-6.67 (2H, m),6.72-6.78 (2H, m).
1H-NMR (CDCl3, 400 MHz) δ : 1.25 (3H, t, J=7.1 Hz),1.72 (3H, s),1.90-2.00 (2H, m),2.42 (2H, t, J=7.3 Hz),3.59 (2H, t, J=6.1 Hz),3.77-3.82 (2H, m),3.82-3.88 (2H, m),4.08-4.17 (6H, m),6.90-6.95 (2H, m),6.99 (1H, dd, J=7.8, 1.4 Hz),7.01-7.07 (2H, m),7.18 (1H, d, J=1.4 Hz),7.35 (1H, s),7.48 (1H, d, J=7.8 Hz).
1H-NMR (CDCl3, 400 MHz) δ : 1.25 (3H, t, J=7.1 Hz),1.73 (3H, s),1.89-1.99 (2H, m),2.41 (2H, t, J=7.3 Hz),3.58 (2H, t, J=6.1 Hz),3.74-3.81 (2H, m),3.83-3.90 (2H, m),4.07-4.16 (6H, m),5.40-5.60 (1H, br),5.80-6.00 (1H, br),6.86-6.93 (2H, m),7.01-7.08 (2H, m),7.15 (1H, dd, J=8.0, 1.7 Hz),7.29 (1H, s),7.46 (1H, d, J=1.7 Hz),7.48 (1H, d, J=8.0 Hz).
1H-NMR (CDCl3, 400 MHz) δ: 1.24 (3H, t, J=7.1 Hz),1.90-1.99 (2H, m),2.41 (2H, t, J=7.3 Hz),2.66 (3H, s),3.58 (2H, t, J=6.1 Hz),3.76-3.84 (2H, m),4.08-4.17 (4H, m),5.45-5.65 (1H, br),5.85-6.05 (1H, br),6.90-6.98 (2H, m),7.01 (1H, dd, J=8.6, 1.7 Hz),7.12-7.20 (2H, m),7.35 (1H, d, J=1.7 Hz),7.84 (1H, d, J=8.6 Hz),10.38 (1H, s).
1H-NMR (CDCl3, 400 MHz) δ:1.87-2.00 (2H, m),2.46 (2H, t, J=7.1 Hz),2.65 (3H, s),3.60 (2H, t, J=6.1 Hz),3.76-3.87 (2H, m),4.10-4.20 (2H, m),6.06-6.22 (1H, br),6.40-6.56 (1H, br),6.92-7.02 (3H, m),7.10-7.18 (2H, m),7.31-7.37 (1H, m),7.82 (1H, d, J=8.0 Hz),10.35 (1H, s).
MS (ESI) m/z : 399 (M-H)-.
4-アセチル-2-{4-[2-(テトラヒドロピラン-4-イルオキシ)エトキシ]フェニルアミノ}ベンゾニトリル
(23a) 1-(4-アミノ-3-ブロモフェニル)エタノン
1H-NMR (CDCl3, 400 MHz) δ: 2.49 (3H, s),4.52-4.70 (2H, br),6.73 (1H, d, J=8.5 Hz),7.73 (1H, dd, J=8.5, 1.9 Hz),8.05 (1H, d, J=1.9 Hz).
1H-NMR (CDCl3, 400 MHz) δ: 2.63 (3H, s),7.77 (1H, d, J=8.0 Hz),7.95 (1H, dd, J=8.0, 1.7 Hz),8.22 (1H, d, J=1.7 Hz).
1H-NMR (CDCl3, 400 MHz) δ: 1.62 (3H, s),3.70-3.82 (2H, m),4.01-4.12 (2H, m),7.53 (1H, dd, J=7.8, 1.4 Hz),7.63 (1H, d, J=7.8 Hz),7.81 (1H, d, J=1.4 Hz).
1H-NMR (CDCl3, 400 MHz) δ : 1.55 (3H, s),1.60-1.71 (2H, m),1.91-2.00 (2H, m), 3.41-3.51 (2H, m),3.57-3.67 (1H, m),3.68-3.73 (2H, m),3.80-3.88 (2H, m),3.94-4.02 (4H, m),3.80-3.88 (2H, m),6.20 (1H, s),6.88 (1H, dd, J=8.0, 1.4 Hz),6.91-6.98 (2H, m),7.05 (1H, d, J=1.4 Hz),7.09-7.15 (2H, m),7.63 (1H, d, J=8.0 Hz).
1H-NMR (CDCl3, 400 MHz) δ:1.61-1.73 (2H, m),1.91-2.02 (2H, m),2.49 (3H, s),3.41-3.53 (2H, m),3.58-3.67 (1H, m),3.83-3.91 (2H, m),3.93-4.03 (2H, m),4.11-4.22 (2H, m),6.30 (1H, s),6.92-7.02 (2H, m),7.10-7.20 (2H, m),7.24-7.29 (1H, m),7.40-7.44 (1H, m),7.55 (1H, d, J=8.0 Hz).
MS (ESI) m/z : 379 (M-H)-.
4-アセチル-3-[4-(2-モルホリン-4-イルエチル)フェニルアミノ]ベンズアミド
(24a) 4-[2-(4-ニトロフェニル)エチル]モルホリン
1H-NMR (CDCl3, 400 MHz) δ:2.48-2.55 (4H, m),2.60-2.67 (2H, m),2.87-2.94 (2H, m),3.70-3.75 (4H, m),7.34-7.40 (2H, m),8.12-8.18 (2H, m).
1H-NMR (DMSO-d6, 400 MHz) δ: 2.87-3.50 (10H, m),3.70-4.05 (4H, br),6.69-6.75 (2H, m),6.98-7.04 (2H, m).
1H-NMR (CDCl3, 400 MHz) δ: 1.70 (3H, s),2.52-2.68 (6H, m),2.76-2.88 (2H, m),3.73-3.83 (4H, m),3.84-3.92 (2H, m),4.09-4.16 (2H, m),7.00-7.09 (3H, m),7.15-7.24 (2H, m),7.41 (1H, d, J=1.5 Hz),7.47 (1H, s),7.51 (1H, d, J=7.8 Hz).
1H-NMR (CDCl3, 400 MHz) δ: 1.71 (3H, s),2.50-2.64 (6H, m),2.74-2.81 (2H, m),3.73-3.80 (4H, m),3.82-3.92 (2H, m),4.05-4.16 (2H, m),5.40-6.10 (2H, br),7.02-7.07 (2H, m),7.10-7.16 (2H, m),7.17-7.22 (1H, m),7.42 (1H, s),7.49-7.54 (1H, m),7.69-7.72 (1H, m).
1H-NMR (CDCl3, 400 MHz) δ:2.52-2.68 (9H, m),2.78-2.88 (2H, m),3.75-3.82 (4H, m),5.70-6.20 (2H, br),7.02 (1H, d, J=1.7, 8.3 Hz),7.16-7.24 (4H, m),7.58 (1H, d, J=1.7 Hz),7.85 (1H, d, J=8.3 Hz),10.49 (1H, s).
MS (ESI) m/z : 368 (M+H)+.
(E)-4-アセチル-3-[4-(3-モルホリン-4-イルプロペニル)フェニルアミノ]ベンズアミド
(25a) (E)-4-[3-(4-ニトロフェニル)アリル]モルホリン
1H-NMR (CDCl3, 400 MHz) δ:2.48-2.55 (4H, m),3.20 (2H, dd, J=6.6, 1.3 Hz),3.71-3.78 (4H, m),6.45 (1H, dt, J=15.8, 6.6 Hz),6.58-6.65 (1H, m),7.46-7.52 (2H, m),8.14-8.20 (2H, m).
1H-NMR (CDCl3, 400 MHz) δ:2.44-2.53 (4H, m),3.11 (2H, dd, J=6.8, 1.2 Hz),3.60-3.76 (6H, m),6.04 (1H, dt, J=15.9, 6.8 Hz),6.37-6.45 (1H, m),6.59-6.65 (2H, m),7.15-7.21 (2H, m).
1H-NMR (CDCl3, 400 MHz) δ: 1.68 (3H, s),2.45-2.55 (4H, m),3.15 (2H, d, J=6.8 Hz),3.72-3.77 (4H, m),3.84-3.89 (2H, m),3.86 (3H, s),4.07-4.12 (2H, m),6.13 (1H, dt, J=15.8, 6.8 Hz),6.52 (1H, d, J=15.8 Hz),7.01-7.07 (2H, m),7.28-7.34 (2H, m),7.46-7.55 (3H, m),7.98 (1H, s).
1H-NMR (CDCl3, 400 MHz) δ: 1.69 (3H, s),2.46-2.55 (4H, m),3.14 (2H, d, J=6.8 Hz),3.72-3.77 (4H, m),3.83-3.89 (2H, m),4.07-4.13 (2H, m),5.40-5.70 (1H, br),5.75-6.10 (1H, br),6.13 (1H, dt, J=15.9, 6.8 Hz),6.48 (1H, d, J=15.9 Hz),7.02-7.07 (2H, m),7.24 (1H, dd, J=8.0, 1.7 Hz),7.27-7.33 (2H, m),7.53 (1H, d, J=8.0 Hz),7.76 (1H, d, J=1.7 Hz),8.01 (1H, s).
1H-NMR (DMSO-d6, 400 MHz) δ:2.34-2.43 (4H, m),2.65 (3H, s),3.08 (2H, d, J=6.4 Hz),3.54-3.62 (4H, m),6.22 (1H, dt, J=15.8, 6.4 Hz),6.52 (1H, d, J=15.8 Hz),7.18-7.27 (3H, m),7.42-7.53 (3H, m),7.69 (1H, d, J=1.2 Hz),8.00 (1H, d, J=8.3 Hz),8.02-8.09 (1H, br),10.35 (1H, s).
MS (ESI) m/z : 378 (M-H)-.
4-ヒドロキシメチル-3-{4-[2-(テトラヒドロピラン-4-イルオキシ)エトキシ]フェニルアミノ}ベンズアミド
(26a) メチル 4-シアノ-2-フルオロベンゾエート
1H-NMR (CDCl3, 400 MHz) δ: 3.97 (3H, s),7.44-7.48 (1H, m),7.50-7.55 (1H, m),8.02-8.08 (1H, m).
1H-NMR (CDCl3, 400 MHz) δ:1.59-1.72 (2H, m),1.90-2.00 (2H, m),3.44-3.52 (2H, m),3.58-3.68 (1H, m),3.80-3.89 (2H, m),3.92-4.01 (5H, m),4.12-4.18 (2H, m),6.85 (1H, dd, J= 8.3, 1.5 Hz),6.84-7.00 (2H, m),7.10-7.17 (3H, m),7.98 (1H, d, J=8.3 Hz),9.35 (1H, s).
1H-NMR (CDCl3, 400 MHz) δ:1.56-1.72 (2H, m),1.90-2.00 (2H, m),3.42-3.50 (2H, m),3.57-3.66 (1H, m),3.83-3.89 (2H, m),3.92-4.01 (5H, m),4.12-4.17 (2H, m),5.45-5.75 (1H, br),5.85-6.10 (1H, br),6.91-6.97 (2H, m),6.98 (1H, dd, J=8.0, 1.7 Hz),7.13-7.19 (2H, m),7.36 (1H, d, J=1.7 Hz),7.99 (1H, d, J=8.3 Hz),9.33 (1H, s).
1H-NMR (CDCl3, 400 MHz) δ:1.58-1.72 (2H, m),1.90-1.98 (2H, m),2.30-2.40 (1H, br),3.41-3.50 (2H, m),3.55-3.65 (1H, m),3.80-3.86 (2H, m),3.91-3.99 (2H, m),4.05-4.12 (2H, m),4.73 (2H, d, J=2.9 Hz),5.50-6.20 (2H, br),6.77 (1H, s),6.84-6.90 (2H, m),7.00-7.06 (2H, m),7.12 (1H, dd, J=7.8, 1.4 Hz),7.16 (1H, d, J=7.8 Hz),7.47 (1H, d, J=1.4 Hz).
MS (ESI) m/z : 387 (M+H)+.
N-(4-{4-[3-(2-ヒドロキシエトキシ)アゼチジン-1-イル]フェノキシ}-6-メトキシピリジン-3-イル)アセタミド
(27a) 2-メトキシ-5-ニトロ-4-(4-{3-[2-(テトラヒドロピラン-2-イルオキシ)エトキシ]アゼチジン-1-イル}フェノキシ)ピリジン
1H-NMR (CDCl3, 400 MHz) δ :1.50-1.90 (6H, m),3.47-3.56 (1H, m),3.59-3.68 (3H, m),3.72-3.80 (2H, m),3.85-3.92 (2H, m),3.93 (3H, s),4.08-4.20 (2H, m),4.47-4.58 (1H, m),4.60-4.70 (1H, m),6.00 (1H, s),6.46-6.49 (2H, m),6.95-6.97 (2H, m),8.85 (1H, s).
1H-NMR (CDCl3, 400 MHz) δ :1.50-1.90 (6H, m),2.23 (3H, s),3.47-3.57 (1H, m),3.58-3.68 (4H, m),3.70-3.80 (2H, m),3.84 (3H, s),3.85-3.94 (2H, m),4.08-4.18 (2H, m),4.46-4.58 (1H, m),4.60-4.70 (1H, m),5.92 (1H, s),6.46-6.48 (2H, m),6.92-6.94 (2H, m),7.40-7.48 (1H, br),8.98 (1H, s).
1H-NMR (DMSO-d6, 400 MHz) δ : 2.06 (3H, s),3.38-3.43 (2H, m),3.49-3.56 (2H, m),3.59-3.66 (2H, m),3.74 (3H, s),4.03-4.13 (2H, m),4.39-4.48 (1H, m),5.78 (1H, s),6.49-6.51 (2H, m),6.97-6.99 (2H, m),8.36 (1H, s),9.44 (1H, br).
MS (ESI) m/z : 374 (M+H)+.
4-アセチル-3-{4-[3-(2-ヒドロキシエトキシ)アゼチジン-1-イル]フェノキシ}ベンズアミド
(28a) 4-シアノ-2-フルオロ-N-メトキシ-N-メチルベンズアミド
1H-NMR (CDCl3, 400 MHz) δ:3.38 (3H, s),3.52 (3H, s),7.39-7.46 (1H, m),7.48-7.60 (2H, m).
1H-NMR (CDCl3, 400 MHz) δ: 2.68 (3H, d, J=4.8 Hz),7.47 (1H, dd, J=10.2, 1.4 Hz),7.53 (1H, dd, J=8.0, 1.4 Hz),7.93-8.01 (1H, m).
1H-NMR (CDCl3, 400 MHz) δ:1.47-1.66 (4H, m),1.69-1.89 (2H, m),2.72 (3H, s),3.46-3.56 (1H, m),3.59-3.68 (1H, m),3.66 (2H, t, J=6.8 Hz),3.75-3.81 (2H, m),3.85-3.93 (2H, m),4.15 (2H, t, J=6.8 Hz),4.49-4.56 (1H, m),4.61-4.66 (1H, m),6.47-6.53 (2H, m),6.90-6.96 (2H, m),7.00 (1H, d, J=1.2 Hz),7.31 (1H, dd, J=8.1, 1.2 Hz),7.82 (1H, d, J=8.1 Hz).
1H-NMR (CDCl3, 400 MHz) δ:1.48-1.68 (4H, m),1.69-1.91 (2H, m),2.70 (3H, s),3.47-3.55 (1H, m),3.58-3.69 (3H, m),3.73-3.79 (2H, m),3.84-3.92 (2H, m),4.13 (2H, t, J=6.8 Hz),4.47-4.55 (1H, m),4.61-4.66 (1H, m),6.45-6.51 (2H, m),6.90-6.96 (2H, m),7.23 (1H, d, J=1.7 Hz),7.41 (1H, dd, J=8.0, 1.7 Hz),7.82 (1H, d, J=8.0 Hz).
1H-NMR (CDCl3, 400 MHz) δ:2.06-2.17 (1H, br),2.70 (3H, s),3.54-3.61 (2H, m),3.70-3.83 (4H, m),4.13 (2H, t, J=6.9 Hz),4.44-4.52 (1H, m),5.60-6.30 (2H, br),6.45-6.52 (2H, m),6.90-6.97 (2H, m),7.23-7.27 (1H, m),7.37-7.43 (1H, m),7.82 (1H, d, J=8.1 Hz).
MS (ESI) m/z : 371 (M+H)+.
4-アセチル-2-{4-[3-(2-ヒドロキシエトキシ)アゼチジン-1-イル]フェノキシ}ベンズアミド
(29a) 4-ブロモ-3-フルオロ-N-メトキシ-N-メチルベンズアミド
1H-NMR (CDCl3, 400 MHz) δ: 3.36 (3H, s),3.54 (3H, s),7.40 (1H, dd, J=8.2, 1.9 Hz),7.49 (1H, dd, J=9.0, 1.9 Hz),7.59 (1H, dd, J=8.2, 6.8 Hz).
1H-NMR (CDCl3, 400 MHz) δ: 2.59 (3H, s),7.60 (1H, dd, J=8.2, 1.9 Hz),7.64-7.73 (2H, m).
1H-NMR (CDCl3, 400 MHz) δ: 2.64 (3H, s),7.73-7.80 (2H, m),7.82 (1H, dd, J=7.8, 1.4 Hz).
1H-NMR (CDCl3, 400 MHz) δ: 1.47-1.67 (4H, m),1.71-1.91 (2H, m),2.50 (3H, s),3.46-3.56 (1H, m),3.59-3.68 (1H, m),3.66 (2H, t, J=7.1 Hz),3.75-3.81 (2H, m),3.85-3.93 (2H, m),4.14 (2H, t, J=7.1Hz),4.49-4.56 (1H, m),4.61-4.66 (1H, m),6.46-6.52 (2H, m),6.93-6.99 (2H, m),7.28 (1H, d, J=1.9 Hz),7.58 (1H, dd, J=8.1, 1.9 Hz),7.71 (1H, d, J=8.1 Hz).
1H-NMR (CDCl3, 400 MHz) δ:1.48-1.68 (4H, m),1.69-1.90 (2H, m),2.51 (3H, s),3.47-3.55 (1H, m),3.58-3.69 (3H, m),3.74-3.81 (2H, m),3.85-3.93 (2H, m),4.14 (2H, t, J=7.1 Hz),4.49-4.56 (1H, m),4.61-4.66 (1H, m),6.01-6.12 (1H, br),6.45-6.51 (2H, m),6.93-6.98 (2H, m),7.31 (1H, d, J=1.4 Hz),7.37 (1H, dd, J=8.0, 1.4 Hz),7.75-7.86 (1H, br),8.33 (1H, d, J=8.0 Hz).
1H-NMR (CDCl3, 400 MHz) δ: 1.93 (1H, t, J=6.1 Hz),2.52 (3H, s),3.56-3.61 (2H, m),3.75-3.83 (4H, m),4.15 (2H, t, J=7.1 Hz),4.44-4.55 (1H, m),5.76-5.89 (1H, br),6.46-6.53 (2H, m),6.93-6.99 (2H, m),7.31 (1H, J=1.5 Hz),7.64 (1H, J=8.0, 1.5 Hz),7.73-7.86 (1H, br),8.34 (1H, d, J=8.0 Hz).
MS (ESI) m/z : 371 (M+H)+.
4-アセチル-3-{4-[4-(2-ヒドロキシエトキシ)ピペリジン-1-イル]フェノキシ}ベンズアミド
(30a) tert-ブチル4-tert-ブトキシカルボニルメトキシピペリジン-1-カルボキシレート
1H-NMR (CDCl3, 400 MHz) δ: 1.50 (9H, s),1.52 (9H, s),1.56-1.65 (2H, m),1.84-1.94 (2H, m),3.08-3.17 (2H, m),3.54-3.64 (1H, m),3.76-3.86 (2H, m),4.04 (2H, s).
1H-NMR (CDCl3, 400 MHz) δ:1.46-1.62 (11H, m),1.84-1.94 (2H, m),2.02 (1H, t, J=6.1 Hz),3.08-3.17 (2H, m),3.50-3.58 (1H, m),3.60-3.65 (2H, m),3.74-3.85 (4H, m).
残渣をテトラヒドロフラン (14 mL)に溶解させ、氷冷下、トリエチルアミン (14 mL、98 mmol) およびtert-ブチルジメチルクロロシラン (3.71 g、24.6 mmol) を加え、室温にて50分撹拌した。減圧下溶媒を留去し、飽和重曹水(20 mL)を加え、酢酸エチル (50 mL)にて2回抽出した。有機層を合わせ、飽和重曹水および飽和食塩水にて順次洗浄、無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー (酢酸エチル→クロロホルム:メタノール、5:1、V/V) にて精製した。目的分画の溶媒を減圧下留去し、標記目的化合物の褐色油状物(3.46 g、100%)を得た。
1H-NMR (CDCl3, 400 MHz) δ: 0.07 (6H,s),0.90 (9H, s),1.46-1.56 (2H, m),1.88-1.98 (2H, m),2.20-2.45 (1H,br),2.64-2.72 (2H, m),3.12 (2H, dt, J=13.2, 4.6 Hz),3.41-3.48 (1H, m),3.53 (2H, t, J=5.6 Hz),3.75 (2H, t, J=5.6 Hz).
1H-NMR (CDCl3, 400 MHz) δ : 0.07 (6H, s),0.90 (9H, s),1.68-1.80 (2H, m),1.95-2.06 (2H, m),2.76-2.85 (2H, m),3.33-3.41 (2H, m),3.43-3.51 (1H, m),3.55 (2H, t, J=5.6 Hz),3.76 (2H, t, J=5.6 Hz),5.01 (2H, s),6.87-6.91 (4H, m),7.27-7.45 (5H, m).
1H-NMR (CDCl3, 400 MHz) δ:1.73-1.83 (2H, m),1.97-2.10 (3H, m),2.71 (3H, s),2.94-3.03 (2H, m),3.47-3.58 (3H, m),3.60-3.65 (2H, m),3.73-3.78 (2H, m),6.94-7.01 (4H, m),7.03 (1H, d, J=1.5 Hz),7.32 (1H, dd, J=7.8, 1.5 Hz),7.83 (1H, d, J=7.8 Hz).
1H-NMR (CDCl3, 400 MHz) δ:1.70-1.84 (2H, m),1.97-2.03 (2H, m),2.88-3.02 (2H, m),2.69 (3H, s),2.88-3.00 (2H, m),3.43-3.57 (3H, m),3.62 (2H, t, J=4.4 Hz),3.73-3.79 (2H, m),6.92-7.00 (4H, m),7.30 (1H, d, J=1.2 Hz),7.42 (1H, dd, J=8.0, 1.2 Hz),7.83 (1H, d, J=8.0 Hz).
MS (ESI) m/z : 399 (M+H)+.
4-(1,1-ジフルオロエチル)-3-{4-[4-(2-ヒドロキシエトキシ)ピペリジン-1-イル]フェノキシ}ベンズアミド
(31a) 4-(1,1-ジフルオロエチル)-3-フルオロベンゾニトリル
1H-NMR (CDCl3, 400 MHz) δ: 2.01 (3H, t, J=18.6 Hz),7.41-7.47 (1H, m),7.50-7.55 (1H, m),7.65-7.71 (1H, m).
1H-NMR (CDCl3, 400 MHz) δ: 5.03 (2H, s),6.72-6.77 (2H, m),7.50-7.55 (5H, m),7.51-7.58 (2H, m).
1H-NMR (CDCl3, 400 MHz) δ:1.40-1.50 (1H, br),1.66-1.77 (2H, m),1.97-2.06 (2H, m),2.77-2.86 (2H, m),3.36-3.45 (2H, m),3.76-3.86 (1H, m),5.01 (2H, s),6.88-6.91 (4H, m),7.28-7.44 (5H, m).
1H-NMR (CDCl3, 400 MHz) δ:1.47-1.65 (4H, m),1.68-1.90 (4H, m),1.97-2.06 (2H, m),2.76-2.86 (2H, m),3.37-3.43 (2H, m),3.45-3.55 (2H, m),3.65-3.71 (2H, m),3.83-3.93 (2H, m),4.61-4.67 (1H, m),5.01 (2H, s),6.87-6.90 (4H, m),7.28-7.44 (5H, m).
1H-NMR (CDCl3, 400 MHz) δ:1.47-1.65 (4H, m),1.68-1.90 (2H, m),1.97-2.10 (2H, m),2.09 (3H, t, J=18.8 Hz),2.90-3.00 (2H, m),3.47-3.72 (6H, m),3.83-3.94 (2H, m),4.61-4.67 (4H, m),5.01 (2H, s),6.90-6.99 (4H, m),6.99-7.03 (1H, m),7.33 (1H, dd, J=8.0, 1.8 Hz),7.67 (1H, d, J=8.0 Hz).
1H-NMR (CDCl3, 400 MHz) δ: 1.70-1.82 (2H, m),1.99-2.07 (3H, m),2.69 (3H, t, J=18.8 Hz),2.88-2.98 (2H, m),3.42-3.56 (3H, m),3.62 (2H, t, J=4.4 Hz),3.73-3.79 (2H, m),6.91-6.94 (4H, m),7.24-7.28 (1H, br),7.41-7.47 (1H, m),7.66 (1H, d, J=8.0 Hz).
MS (ESI) m/z : 421 (M+H)+.
4-アセチル-3-{4-[2-(テトラヒドロピラン-4-イルオキシ)エトキシ]フェノキシ}ベンズアミド
(32a) 4-[2-(4-ベンジルオキシフェノキシ)エトキシ]テトラヒドロピラン
1H-NMR (CDCl3, 400 MHz) δ:1.57-1.68 (2H, m),1.88-1.97 (2H, m),3.41-3.49 (2H, m),3.54-3.63 (1H, m),3.80 (2H, t, J=5.1 Hz),3.91-3.99 (2H, m),4.07 (2H, t, J=5.1 Hz),5.00 (2H, s),6.82-6.92 (4H, m),7.28-7.43 (5H, m).
1H-NMR (CDCl3, 400 MHz) δ:1.59-1.68 (2H, m),1.89-1.97 (2H, m),3.40-3.48 (2H, m),3.55-3.64 (1H, m),3.80 (2H, t, J=5.1 Hz),3.92-3.99 (2H, m),4.06 (2H, t, J=5.1 Hz),4.68-4.73 (1H, br),6.70-6.82 (4H, m).
1H-NMR (CDCl3, 400 MH) δ: 3.93 (3H, s),7.60-7.80 (3H, m).
1H-NMR (CDCl3, 400 MH) δ: 2.68 (3H, d, J=4.6 Hz),3.96 (3H, s),7.77-7.95 (3H, m).
1H-NMR (CDCl3, 400 MHz) δ:1.60-1.70 (2H, m),1.90-2.00 (2H, m),2.69 (3H, s),3.41-3.50 (2H, m),3.57-3.65 (1H, m),3.83-3.87 (5H, m),3.93-4.00 (2H, m),4.11-4.18 (2H, m),6.93-7.00 (4H, m),7.45 (1H, d, J=1.5 Hz),7.73 (1H, dd, J=8.4, 1.5 Hz),7.81 (1H, d, J=8.4 Hz).
1H-NMR (CDCl3, 400 MHz) δ:1.61-1.70 (2H, m),1.90-2.00 (2H, m),2.70 (3H, s),3.42-3.51 (2H, m),3.57-3.67 (1H, m),3.82-3.88 (2H, m),3.92-3.89 (2H, m),4.11-4.18 (2H, m),5.50-5.80 (1H, br),5.90-6.13 (1H, br),6.93-7.02 (4H, m),7.27-7.30 (1H, m),7.41-7.46 (1H, m),7.82-7.86 (1H, m).
MS (ESI) m/z : 400 (M+H)+.
4-アセチル-3-{4-[2-(2-イソプロポキシエトキシ)エトキシ]フェノキシ}ベンズアミド
(33a) 2-[2-(2-クロロエトキシ)エトキシ]プロパン
窒素雰囲気下、無水イソプロパノール (132 g、2.20 mol) にナトリウム (12.6 g、0.550 mol) を分割添加し、3時間加熱還流後、先に得られた油状物を滴下し、15時間加熱還流した。放冷後、10% クエン酸水を加え酢酸エチルにて2回抽出した。有機層を水および飽和食塩水にて順次洗浄、無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去した。得られた残渣を蒸留 (20 mmHg) し、62℃から73℃の留分をシリカゲルカラムクロマトグラフィー (ヘキサン:酢酸エチル10:1、V/V) にて精製した。目的分画の溶媒を減圧下留去し、標記目的化合物の無色油状物(20.9 g、収率23%) を得た。
1H-NMR (DMSO-d6, 400 MHz) δ: 1.17 (6H, d, J=6.1 Hz),3.57-3.67 (7H, m),3.75-3.80 (2H, m).
1H-NMR (CDCl3, 400 MHz) δ: 1.16 (6H, d, J=6.1 Hz),3.56-3.63 (3H, m),3.66-3.71 (2H, m),3.80-3.86 (2H, m),4.05-4.10 (2H, m),5.00 (2H, s),6.81-6.92 (4H, m),7.27-7.45 (5H, m).
1H-NMR (CDCl3, 400 MHz) δ: 1.17 (6H, d, J=6.1 Hz),3.59-3.65 (3H, m),3.67-3.72 (2H, m),3.79-3.85 (2H, m),4.00-4.06 (2H, m),6.70-6.80 (4H, m).
1H-NMR (CDCl3, 400 MHz) δ: 1.17 (6H, d, J=6.1 Hz),2.70 (3H, s),3.58-3.66 (3H, m),3.69-3.75 (2H, m),3.86-3.93 (2H, m),4.13-4.19 (2H, m),6.98 (4H, m),7.01 (1H, s),7.34 (1H, dd, J=7.8, 1.2 Hz),7.83 (1H, d, J=7.8 Hz).
1H-NMR (DMSO-d6, 400 MHz) δ: 1.06 (6H, d, J=6.1 Hz),2.58 (3H, s),3.45-3.60 (5H, m),3.70-3.78 (2H, m),4.05-4.13 (2H, m),6.96-7.10 (4H, m),7.28 (1H, d, J=1.5 Hz),7.45-7.55 (1H, br),7.62 (1H, dd, J=8.0, 1.5 Hz),7.71 (1H, d, J=8.0 Hz),8.00-8.10 (1H, br).
MS (ESI) m/z : 400 (M-H)-.
4-アセチル-3-{4-[3-(テトラヒドロピラン-4-イルオキシ)プロペニル]フェノキシ}ベンズアミド
(35a) 4-ヨードフェニル アセテート
1H-NMR (CDCl3, 400 MHz) δ: 2.29 (3H, s),6.83-6.88 (2H, m),7.65-7.70 (2H, m).
1H-NMR (CDCl3, 400 MHz) δ:1.56-1.66 (2H, m),1.85-1.95 (2H, m),3.39-3.48 (2H, m),3.49-3.57 (1H, m),3.91-3.99 (2H, m),4.00-4.06 (2H, m),5.14-5.21 (1H, m),5.25-5.33 (1H, m),5.87-5.99 (1H, m).
1H-NMR (CDCl3, 400 MHz) δ:1.58-1.68 (2H, m),1.88-1.98 (2H, m),2.29 (3H, s),3.40-3.49 (2H, m),3.54-3.63 (1H, m),3.92-4.00 (2H, m),4.16-4.21 (2H, m),6.25 (1H, dt, J=15.9, 5.8 Hz),6.59 (1H, d, J=15.9 Hz),7.01-7.07 (2H, m),7.35-7.42 (2H, m).
1H-NMR (CDCl3, 400 MHz) δ:1.60-1.70 (2H, m),1.90-1.98 (2H, m),3.42-3.51 (2H, m),3.57-3.65 (1H, m),3.95-4.02 (2H, m),4.15-4.19 (2H, m),6.14 (1H, dt, J=15.6, 6.3 Hz),6.53 (1H, d, J=15.6 Hz),6.74-6.79 (2H, m),7.23-7.28 (2H, m).
1H-NMR (CDCl3, 400 MHz) δ:1.60-1.71 (2H, m),1.90-1.99 (2H, m),2.68 (3H, s),3.42-3.50 (2H, m),3.56-3.65 (1H, m),3.94-4.02 (2H, m),4.19-4.24 (2H, m),6.29 (1H, dt, J=15.9, 5.8 Hz),6.63 (1H, d, J=15.9 Hz),6.97-7.03 (2H, m),7.11 (1H, d, J=1.4 Hz),7.41 (1H, dd, J=8.0, 1.4 Hz),7.43-7.48 (2H, m),7.86 (1H, d, J=8.0 Hz).
1H-NMR (CDCl3, 400 MHz) δ: 1.62-1.71 (2H, m),1.90-1.99 (2H, m),2.66 (3H, s),3.42-3.51 (2H, m),3.56-3.65 (1H, m),3.94-4.02 (2H, m),4.18-4.23 (2H, m),5.60-6.20 (2H, br),6.25 (1H, dt, J=16.1, 5.8 Hz),6.63 (1H, d, J=16.1 Hz),6.95-7.01 (2H, m),7.38 (1H, d, J=1.5 Hz),7.38-7.43 (2H, m),7.49 (1H, dd, J=8.0, 1.5 Hz),7.87 (1H, d, J=8.0 Hz).
MS (ESI) m/z : 394 (M-H)-.
4-ジフルオロメチル-3-{4-[2-(テトラヒドロピラン-4-イルオキシ)エトキシ]フェノキシ}ベンズアミド
(35a) 3-フルオロ-4-ホルミルベンゾニトリル
1H-NMR (CDCl3, 400 MHz) δ: 7.53 (1H, dd, J=9.5, 1.0 Hz),7.57-7.61 (1H, m),8.00 (1H, dd, J=8.1, 6.8 Hz),10.40 (1H, s).
1H-NMR (CDCl3, 400 MHz) δ: 6.91 (1H, t, J=54.4 Hz),7.46 (1H, dd, J=9.3, 1.2 Hz),7.58 (1H, d, J=8.0 Hz),7.72-7.77 (1H, m).
1H-NMR (CDCl3, 400 MHz) δ:1.58-2.04 (2H, m),1.92-1.99 (2H, m),3.42-3.49 (2H, m),3.57-3.64 (1H, m),3.83-3.87 (2H, m),3.93-4.00 (2H, m),4.10-4.17 (2H, m),6.92-7.22 (6H, m),7.38-7.42 (1H, m),7.72-7.76 (1H, m).
1H-NMR (DMSO-d6, 400 MHz) δ:1.34-1.45 (2H, m),1.81-1.90 (2H, m),2.99-3.36 (2H, m),3.52-3.60 (1H, m),3.72-3.84 (4H, m),4.07-4.13 (2H, m),6.98-7.07 (4H, m),7.11-7.41 (2H, m),7.48-7.56 (1H, br),7.64-7.72 (2H, m),8.03-8.12 (1H, br).
MS (ESI) m/z : 408 (M+H)+.
1-(3-{4-[2-(テトラヒドロピラン-4-イルオキシ)エトキシ]フェノキシ}-4-トリフルオロメチルフェニル)エタノン
(36a) 3-フルオロ-N-メトキシ-N-メチル-4-トリフルオロメチルベンズアミド
1H-NMR (CDCl3, 400 MHz) δ: 3.38 (3H, s),3.55 (3H, s),7.50-7.59 (2H, m),7.63-7.68 (1H, m).
1H-NMR (CDCl3, 400 MHz) δ: 2.64 (3H, s),7.70-7.78 (2H, m),7.79-7.83 (1H, m).
1H-NMR (DMSO-d6, 400 MHz) δ:1.36-1.47 (2H, m),1.83-1.90 (2H, m),2.55 (3H, s),3.29-3.37 (2H, m),3.52-3.60 (1H, m),3.75-3.84 (4H, m),4.09-4.13 (2H, m),7.01-7.09 (4H, m),7.27 (1H, s),7.83 (1H, d, J=8.3 Hz),7.93 (1H, d, J=8.3 Hz).
MS (ESI) m/z : 425 (M+H)+.
4-アセチル-2-{4-[2-(テトラヒドロピラン-4-イルオキシ)エトキシ]フェノキシ}ベンゾニトリル
(37a) 4-ブロモ-3-フルオロ-N-メトキシ-N-メチルベンズアミド
1H-NMR (CDCl3, 400 MHz) δ: 3.36 (3H, s),3.54 (3H, s),7.40 (1H, dd, J=8.2, 1.9 Hz),7.49 (1H, dd, J=9.0, 1.9 Hz),7.59 (1H, dd, J=8.2, 6.8 Hz).
1H-NMR (CDCl3, 400 MHz) δ: 2.59 (3H, s),7.60 (1H, dd, J=8.2, 1.9 Hz),7.64-7.73 (2H, m).
1H-NMR (CDCl3, 400 MHz) δ: 2.64 (3H, s),7.73-7.80 (2H, m),7.82 (1H, dd, J=7.8, 1.4 Hz).
1H-NMR (DMSO-d6, 400 MHz) δ:1.36-1.47 (2H, m),1.82-1.91 (2H, m),2.54 (3H, s),3.28-3.38 (2H, m),3.52-3.61 (1H, m),3.74-3.84 (4H, m),4.09-4.16 (2H, m),7.02-7.09 (2H, m),7.12-7.20 (3H, m),7.77-7.83 (1H, m),8.06 (1H, d, J=8.0 Hz).
MS (ESI) m/z : 382 (M+H)+.
4-(1-ヒドロキシエチル)-3-{4-[2-(テトラヒドロピラン-4-イルオキシ)エトキシ]フェノキシ}ベンズアミド
1H-NMR (DMSO-d6, 400 MHz) δ: 1.32 (3H, d, J=6.4 Hz),1.35-1.46 (2H, m),1.81-1.90 (2H, m),3.31-3.37 (2H, m),3.51-3.60 (1H, m),3.72-3.85 (4H, m),4.03-4.11 (2H, m),5.01-5.10 (1H, m),5.25 (1H, d, J=4.4 Hz),6.90-7.01 (4H, m),7.16-7.21 (1H, m),7.27-7.35 (1H, br),7.57-7.64 (2H, m),7.87-7.94 (1H, br).
MS (ESI) m/z : 402 (M+H)+.
4-(1-フルオロエチル)-3-{4-[2-(テトラヒドロピラン-4-イルオキシ)エトキシ]フェノキシ}ベンズアミド
得られた粉末 610 mg をtert-ブチルメチルエーテル (3 mL)および酢酸エチル (1 mL)に加熱溶解後、室温に戻しながら、30分撹拌した。析出物をろ取し標記目的化合物の白色粉末 (378 mg、収率62%) を得た。
1H-NMR (DMSO-d6, 400 MHz) δ:1.34-1.46 (2H, m),1.62 (3H, dd, J=24, 6.3 Hz),1.82-1.91 (2H, m),3.30-3.37 (2H, m),3.52-3.60 (1H, m),3.75 (2H, t, J=4.4 Hz),3.77-3.84 (2H, m),4.08 (2H, t, J=4.4 Hz),5.92-6.11 (1H, m),6.98-7.02 (4H, m),7.19-7.23 (1H, m),7.36-7.45 (1H, br),7.52-7.57 (1H, m),7.62-7.68 (1H, m),7.94-8.02 (1H, br).
MS (ESI) m/z : 404 (M+H)+.
4-アセチル-3-[4-(2-イソプロポキシエトキシメチル)フェノキシ]ベンズアミド
(40a) 4-(2-イソプロポキシエトキシメチル)フェノール
1H-NMR (CDCl3, 400 MHz) δ :1.15-1.21 (6H, m),3.58-3.68 (5H, m),4.47 (2H, s),5.48-5.55 (1H, br),6.75-6.77 (2H, m),7.17-7.19 (2H, m).
1H-NMR (CDCl3, 400 MHz) δ : 1.18 (6H, d, J=6.1 Hz),2.66 (3H, s),3.56-3.75 (5H, m),3.87 (3H, s),4.58 (2H, s),6.99-7.01 (2H, m),7.36-7.39 (2H, m),7.56 (1H, d, J=8.5 Hz),7.78-7.89 (2H, m).
1H-NMR (CDCl3, 400 MHz) δ : 1.18 (6H, d, J=6.1 Hz),2.67 (3H, s),3.60-3.72 (5H, m),4.57 (2H, s),5.45-6.25 (2H, br),6.99-7.01 (2H, m),7.37-7.39 (3H, m),7.50 (1H, d, J=8.0 Hz),7.87 (1H, d, J=8.0 Hz).
MS (ESI) m/z : 370 (M-H)-.
4-アセチル-3-[4-(テトラヒドロピラン-4-イルオキシメチル)フェノキシ]ベンズアミド
(41a) 4-(4-ブロモベンジルオキシ)テトラヒドロピラン
1H-NMR (CDCl3, 400 MHz) δ:1.59-1.72 (2H, m),1.89-1.99 (2H, m),3.40-3.50 (2H, m),3.53-3.63 (1H, m),3.92-4.01 (2H, m),4.51 (2H, s),7.20-7.26 (2H, m),7.44-7.50 (2H, m).
得られた残渣をジメチルホルムアミド (5 mL) に溶解し、実施例28 (28b) で製造した4-アセチル-3-フルオロベンゾニトリル (206 mg、1.26 mmol) および炭酸カリウム (348 mg、2.52 mmol) を加え、100℃ にて2時間撹拌した。反応液を放冷後、酢酸エチルを加え、水および飽和食塩水にて洗浄後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去し、シリカゲルカラムクロマトグラフィー (ヘキサン:酢酸エチル、4:1→1:1、V/V)にて精製した。目的分画の溶媒を減圧下留去し、標記目的化合物の微黄色粉末 (315 mg、収率71%) を得た。
1H-NMR (CDCl3, 400 MH) δ: 1.62-1.75 (2H, m),1.93-2.02 (2H, m),2.69 (3H, s),3.42-3.52 (2H, m),3.59-3.69 (1H, m),3.94-4.04 (2H, m),4.58 (2H, s),7.01-7.06 (2H, m),7.10 (1H, d, J=1.2 Hz),7.39 (1H, dd, J=1.2, 8.0 Hz),7.40-7.46 (2H, m),7.86 (1H, d, J=8.0 Hz).
1H-NMR (DMSO-d6, 400 MHz) δ:1.42-1.55 (2H, m),1.85-1.95 (2H, m),2.57 (3H, s),3.30-3.38 (2H, m),3.54-3.64 (1H, m),3.77-3.87 (2H, m),4.52 (2H, s),7.03-7.09 (2H, m),7.35-7.42 (3H, m),7.55 (1H, s),7.67-7.74 (1H, m),7.77 (1H, d, J=8.0 Hz),8.10 (1H, s).
MS (ESI) m/z : 392 (M+Na)+.
4-フルオロメチル-3-[4-(テトラヒドロピラン-4-イルオキシメチル)フェノキシ]ベンズアミド
(42a) メチル 4-シアノ-2-フルオロベンゾエート
1H-NMR (CHCl3, 400 MHz) δ: 3.97 (3H, s),7.48 (1H, dd, J=9.8, 1.5 Hz),7.52 (1H, dd, J=8.1, 1.5 Hz),8.05 (1H, dd, J=8.1, 7.3 Hz).
1H-NMR (CHCl3, 400 MHz) δ:1.62-1.78 (2H, m),1.90-2.03 (2H, m),3.42-3.56 (2H, m),3.58-3.68 (1H, m),3.89 (3H, s),3.92-4.05 (2H, m),4.57 (2H, s),6.98-7.00 (2H, m),7.13 (1H, s),7.38-7.41 (3H, m),7.94 (1H, d, J=8.1 Hz).
1H-NMR (CHCl3, 400 MHz) δ:1.63-1.76 (2H, m),1.90-2.03 (2H, m),2.20-2.40 (1H, br),3.42-3.52 (2H, m),3.59-3.68 (1H, m),3.92-4.03 (2H, m),4.56 (2H, s),4.84 (2H, d, J=4.4 Hz),6.97-7.00 (3H, m),7.37-7.39 (3H, m),7.61 (1H, d, J=7.8 Hz).
1H-NMR (CHCl3, 400 MHz) δ:1.61-1.75 (2H, m),1.91-2.03 (2H, m),3.43-3.53 (2H, m),3.58-3.68 (1H, m),3.92-4.05 (2H, m),4.57 (2H, s),5.59 (2H, d, J=47 Hz),6.98-7.01 (3H, m),7.39-7.42 (3H, m),7.60 (1H, d, J=7.8 Hz).
1H-NMR (DMSO-d6, 400 MHz) δ:1.39-1.50 (2H, m),1.82-1.93 (2H, m),3.29-3.35 (2H, m),3.52-3.62 (1H, m),3.75-3.85 (2H, m),4.50 (2H, s),5.51 (2H, d, J=47 Hz),6.98-7.00 (2H, m),7.33-7.38 (3H, m),7.40-7.46 (1H, br),7.59 (1H, d, J=8.0 Hz),7.68 (1H, d, J=8.0 Hz),8.00-8.05 (1H, br).
MS (ESI) m/z : 358 (M-H)-.
(R)-4-(1-ヒドロキシエチル)-3-{4-[2-(テトラヒドロピラン-4-イルオキシ)エトキシ]フェノキシ}ベンズアミド
1H-NMR (DMSO-d6, 400 MHz) δ: 1.32 (3H, d, J=6.4 Hz),1.35-1.46 (2H, m),1.81-1.90 (2H, m),3.31-3.37 (2H, m),3.51-3.60 (1H, m),3.72-3.85 (4H, m),4.03-4.11 (2H, m),5.01-5.10 (1H, m),5.25 (1H, d, J=4.4 Hz),6.90-7.01 (4H, m),7.16-7.21 (1H, m),7.27-7.35 (1H, br),7.57-7.64 (2H, m),7.87-7.94 (1H, br).
MS (ESI) m/z : 402 (M+H)+.
本発明の化合物 5g、乳糖 895gおよびトウモロコシデンプン 100gをブレンダーで混合することにより、散剤を得ることができる。
本発明の化合物5g、乳糖 865gおよび低置換度ヒドロキシプロピルセルロース 100gを混合した後、10%ヒドロキシプロピルセルロース水溶液 300gを加えて練合する。これを押し出し造粒機を用いて造粒し、乾燥すると顆粒剤が得られる。
本発明の化合物5g、乳糖 90g、トウモロコシデンプン 34g、結晶セルロース 20gおよびステアリン酸マグネシウム 1gをブレンダーで混合した後、錠剤機で打錠することにより、錠剤が得られる。
(試験例1)骨芽細胞分化試験
マウス骨髄由来間葉系細胞株ST2細胞(入手先:理化学研究所)を96 well plateにおいて、10%牛胎児血清を含むα-MEM培地(入手先:GIBCO BRL Cat.No.12000-022)中、4×103cells/0.1 mL/wellの細胞密度で播種し、37℃、5%CO2条件下で24h培養した。次いで、各試験化合物を終濃度0.001~10 μMになるように添加し、コントロールには最終濃度0.1%(v/v)のDMSOを添加した。さらに4日間培養後、アルカリホスファターゼ(ALP)活性を以下の方法で測定を行った。
培養した96 well plateの培地を除去した後、PBSバッファー(KCl 0.2 g/L,KH2PO4 0.2 g/L,Na2HPO4・12H2O 2.9 g/L,NaCl 8 g/L)100 μL/well で洗浄し、細胞溶解液 (10 mM MgCl2、2%(v/v)TritonX-100) 50 μL/wellを添加し、室温で3分撹拌した。基質溶液(50 mMジエタノールアミン(和光純薬 Cat.No.099-03112)、20 mM p-ニトロフェニルホスファイト(ナカライテスクCat.No.25019-81)) 50 μL/wellを添加し、室温で9分間静置後、1 N NaOH 50 μL/wellを加えて反応を停止し、マイクロプレートリーダー(大日本製薬社)を用いて405nmの吸光度を測定した。
コントロールの吸光度を100%とした際の試験化合物の吸光度の増加率(%)を算出し、骨芽細胞の分化度を評価した。
本試験において、実施例1、2、5、6、8、9、13、16、17、18、20、28、29、30、32、33、34、35、38、39、40、41、43、45、47、48、50、53、57、58、62、63、64、65、66、67、68、69、70、74、77、82、83、85、88、89、90、91、92、94、95、96、97の化合物は、0.1μg/mLで、200%以上のアルカリホスファターゼ活性を示した。
12週齢雌性F344ラット(SLC)は麻酔下で卵巣摘出又は偽手術を施した。手術翌々日より試験化合物を0.5%メチルセルロース溶液 (和光純薬Cat.No.133-14255) に懸濁し、一日一回、週6あるいは7日経口投与した。なお、対照群には0.5%メチルセルロース溶液を経口投与した。投与8週後、麻酔下で腹部大動脈より全採血して安楽死させ、左右大腿骨を摘出した。
摘出した大腿骨は、軟部組織を除去した後、DXA装置DCS-600R(アロカ株式会社)を用いて骨密度を測定した。骨密度は、大腿骨全体、並びに、全体を三等分して近位端、骨幹部及び遠位端部分に分けて評価した。
本試験において、実施例1、32、38、43、67、77の化合物は10 mg/kg以下で有意に骨密度を増加させた。
Claims (16)
- 一般式(I)を有する化合物又は薬理上許容される塩:
R1:
シアノ基、C1-6アルキルカルボニル基、C1-6アルキルカルボニルアミノ基、ニトロ基、ハロゲノC1-6アルキル基、C2-6アルケニル基、ハロゲノC2-6アルケニル基、カルバモイル基、又は、ヒドロキシC1-6アルキル基
R2:
C1-6アルコキシ基、カルバモイル基、C1-6アルキルアミノカルボニル基、又は、C1-6アルキルカルボニル基
R3:
水素原子、又は、ハロゲン原子
S、T及びU:
S、T及びUのいずれかひとつが、=N-である場合、他は=CH-(但し、R3が置換している場合は、=C-);又は;
S、T及びUのすべてが=CH-(但し、R3が置換している場合は、=C-)
W:
-NH-、-O-、又は、-S-
X:
単結合、-飽和ヘテロ環-、-CH2-(CH2)n-、-O-(CH2)n-、-(CH2)n-O-、又は、-CH=CH-(CH2)n-
n:
1-4から選択されるいずれか1の整数
Y:
単結合、-O-、又は、-CO-
Z:
水素原子、置換基群αから選択されるいずれかの基で置換されていてもよい飽和へテロ環基、又は、置換基群αから選択されるいずれかの基で置換されていてもよいC1-6アルキル基
置換基群α:
飽和へテロ環基、ヒドロキシC1-6アルキル基、アミノスルホニルアミノ基、カルボキシ基、水酸基、C1-6アルコキシ基、C1-6アルキル基]。 - R1が、シアノ基、アセチル基、アセチルアミノ基、ニトロ基、トリフルオロメチル基、1,1-ジフルオロエチル基、1-フルオロエチル基、ジフルオロメチル基、カルバモイル基、又は、1-ヒドロキシエチル基である、請求項1に記載された化合物又はその薬理上許容される塩。
- R2が、メトキシ基、カルバモイル基、メチルアミノカルボニル基、又は、アセチル基である、請求項1又は2に記載された化合物又はその薬理上許容される塩。
- S、T及びUのすべてが=CH-である、請求項1-3から選択されるいずれか1項に記載された化合物又はその薬理上許容される塩。
- Xが、-飽和ヘテロ環-、又は、-O-(CH2)n-であり、nが2である、請求項1-4から選択されるいずれか1項に記載された化合物又はその薬理上許容される塩。
- Yが、単結合、又は、-O-である、請求項1-5から選択されるいずれか1項に記載された化合物又はその薬理上許容される塩。
- Zが、水酸基で置換されているC1-6アルキル基、テトラヒドロフラニル基、テトラヒドロピラニル基、ピペラジニル基、又は、モルホリニル基である、請求項1-6から選択されるいずれか1項に記載された化合物又はその薬理上許容される塩。
- 以下に記載の化合物から選択されるいずれかの化合物又はその薬理上許容される塩:
(1)N-(4-{4-[3-(2-ヒドロキシエトキシ)アゼチジン-1-イル]フェニルアミノ}-6-メトキシピリジン-3-イル)アセタミド
- 請求項1-8から選択されるいずれか1項に記載された化合物又はその薬理上許容される塩を有効成分として含有する医薬組成物。
- 骨形成を促進するために用いられる、請求項9に記載された医薬組成物。
- 骨代謝を改善するために用いられる、請求項9に記載された医薬組成物。
- 骨代謝に関連する疾患を予防又は治療するために用いられる、請求項9に記載された医薬組成物。
- 骨代謝に関連する疾患が、骨粗鬆症である、請求項12に記載された医薬組成物。
- 哺乳動物に請求項9に記載された医薬組成物の有効量を投与することを特徴とする骨代謝の改善方法。
- 哺乳動物に請求項9に記載された医薬組成物の有効量を投与することを特徴とする、骨代謝に関連する疾患の予防方法又は治療方法。
- 哺乳動物に請求項9に記載された医薬組成物の有効量を投与することを特徴とする、骨粗鬆症の予防方法又は治療方法。
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WO2018186366A1 (ja) | 2017-04-03 | 2018-10-11 | 京都薬品工業株式会社 | 新規サイクリン依存性キナーゼ8及び/又は19阻害剤 |
JPWO2018186366A1 (ja) * | 2017-04-03 | 2020-02-20 | 京都薬品工業株式会社 | 新規サイクリン依存性キナーゼ8及び/又は19阻害剤 |
US11013728B2 (en) | 2017-04-03 | 2021-05-25 | Kyoto Pharmaceutical Industries, Ltd. | Cyclin-dependent kinase 8 and/or 19 inhibitor |
JP7152784B2 (ja) | 2017-04-03 | 2022-10-13 | 京都薬品工業株式会社 | 新規サイクリン依存性キナーゼ8及び/又は19阻害剤 |
JP2022505987A (ja) * | 2018-10-22 | 2022-01-14 | エスカー セラピューティクス,インコーポレイテッド | Tyk2阻害剤およびその使用 |
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US10059663B2 (en) | 2018-08-28 |
ES2704232T3 (es) | 2019-03-15 |
JPWO2015030189A1 (ja) | 2017-03-02 |
EP3040329A4 (en) | 2017-01-25 |
EP3040329A1 (en) | 2016-07-06 |
PL3040329T3 (pl) | 2019-04-30 |
AU2014312756A1 (en) | 2016-04-07 |
CA2922716C (en) | 2021-10-12 |
AU2014312756B2 (en) | 2018-11-22 |
EP3040329B1 (en) | 2018-10-10 |
HUE041418T2 (hu) | 2019-05-28 |
DK3040329T3 (en) | 2019-01-28 |
JP6484555B2 (ja) | 2019-03-13 |
CA2922716A1 (en) | 2015-03-05 |
US20160207883A1 (en) | 2016-07-21 |
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