WO2010101128A1 - Composé amide - Google Patents

Composé amide Download PDF

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Publication number
WO2010101128A1
WO2010101128A1 PCT/JP2010/053282 JP2010053282W WO2010101128A1 WO 2010101128 A1 WO2010101128 A1 WO 2010101128A1 JP 2010053282 W JP2010053282 W JP 2010053282W WO 2010101128 A1 WO2010101128 A1 WO 2010101128A1
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Prior art keywords
piperidin
compound
carbonyl
methyl
pyrrolo
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PCT/JP2010/053282
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English (en)
Japanese (ja)
Inventor
英範 ▲薊▼
友亮 阿部
昭夫 掛札
祐明 平野
和志 渡邉
裕 近藤
晃雄 神川
規夫 関
実 安田
裕之 臼田
和美 菊池
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アステラス製薬株式会社
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Publication of WO2010101128A1 publication Critical patent/WO2010101128A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—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
    • C07D211/08—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present invention relates to an amide compound useful as an active ingredient of a pharmaceutical composition, for example, a pharmaceutical composition for treating prostatic hypertrophy or prostate cancer.
  • Benign prostatic hyperplasia is a disease with dysuria that occurs mainly in elderly men over 50 years of age, and the frequency of onset increases with age.
  • the number of BPH patients in Japan has been increasing in recent years with the rapid aging of the population structure.
  • BPH is a medically important disease because it significantly lowers the quality of life of elderly men due to its dysuria and is diagnosed and treated most frequently in urological practice.
  • the two causes of dysuria associated with BPH are direct urethral compression (mechanical obstruction) due to enlarged prostate and increased urethral pressure (functional obstruction) due to excessive contraction of prostate smooth muscle via sympathetic nerves. has been shown to be involved at the same time.
  • Drug therapy can cope with both mechanisms, and a 5 ⁇ reductase inhibitor is mainly used for mechanical occlusion, and an ⁇ 1 sympathetic blocker ( ⁇ 1 blocker) is mainly used for functional occlusion.
  • 5 ⁇ reductase inhibitors regress the prostate by an antiandrogenic action based on inhibition of the conversion of testosterone to 5 ⁇ dehydrotestosterone (DHT), a more powerful androgen, by 5 ⁇ reductase.
  • DHT dehydrotestosterone
  • ⁇ 1 blockers are first-line drugs for BPH treatment because they are effective immediately after administration and are excellent in safety.
  • DHT in the prostate has been thought to be produced by 5 ⁇ reductase from testosterone produced in the testis and endocrineally supplied to the prostate. Recently, however, it has been reported that about half of DHT and its precursor testosterone in the prostate are synthesized from the adrenal steroid dehydroepiandrosterone (DHEA) in prostate cells (Frontier in Neuroendocrinology). , 2001, 22, 185-212). Such a sex hormone production system in the cells of the sex hormone target organ is called intracrinology. With 5 ⁇ reductase inhibitors, it is difficult to inhibit testosterone synthesis in this prostate region (intracrine testosterone synthesis).
  • DHEA adrenal steroid dehydroepiandrosterone
  • the DHT concentration in the prostate decreased to about 20% before the administration, whereas the concentration of the prostatic testosterone in the prostate increased fourfold.
  • the 5 ⁇ reductase inhibitor has the effect of suppressing the DHT concentration in the prostate, but does not have the effect of suppressing the testosterone concentration in the prostate, and conversely increases the concentration.
  • testosterone has an androgen receptor binding activity that is about half that of DHT, this increase in testosterone concentration in the prostate region is also considered to contribute to the inadequate efficacy of finasteride on BPH.
  • Anti-androgen therapy with surgical castration and gonadotropin-releasing hormone agonist is also used in prostate cancer. It has been reported that these antiandrogen therapies are insufficient in the testosterone concentration suppressing effect in the prostate gland. For example, in prostate cancer patients who have undergone the above-described antiandrogen therapy, the blood testosterone concentration decreased to about 10% before treatment, whereas the DHT concentration in the prostate remained about half (The Journal of Clinical Endocrinology and Metabolism, 1995, 80, 1066-1071). This suggests that the testosterone concentration in the prostate is not sufficiently reduced.
  • prostate cancer Hamone Refractory Prostate Cancer
  • the androgen receptor is localized in the nucleus, and there is a significant difference between the testosterone concentration in relapsed prostate cancer tissue and that in normal prostate Was not seen (Clinical Cancer Research, 2004, 10, 440-448).
  • These reports indicate that the existing treatments are completely inadequate in reducing prostate testosterone concentration in the treatment of relapsed prostate cancer, and that the mechanism of prostate testosterone synthesis, i.e., suppression of prostate intracrine testosterone synthesis, is a new treatment for prostate cancer treatment. It strongly suggests that it can be a target.
  • the intracrine testosterone synthesis inhibitor of the prostate since the intracrine testosterone synthesis inhibitor of the prostate has an action to lower the testosterone concentration in the prostate and has no action to lower the blood testosterone concentration, (1) not only the testosterone concentration in the prostate but also DHT The concentration is also lowered, and (2) it is expected to be a very attractive BPH therapeutic agent and / or prostate cancer therapeutic agent capable of avoiding side effects due to suppression of testosterone-derived blood testosterone concentration.
  • 17 ⁇ -hydroxysteroid dehydrogenase In the biosynthesis of testosterone, 17 ⁇ -hydroxysteroid dehydrogenase (17 ⁇ HSD) is essential. Although 17 ⁇ HSD has several subtypes, 17 ⁇ HSD type 5 (17 ⁇ HSD type 5) is highly expressed in human prostate, and increased expression in prostate cancer and relapsed prostate cancer has also been reported (Steroids, 2004). , 69, 795-801; Cancer Research, 2006, 66, 2815-2825). On the other hand, almost all testosterone in the blood is produced in the testis by 17 ⁇ HSD type 3 (17 ⁇ HSD type 3), and 17 ⁇ HSD type 3 is hardly expressed in other tissues including the prostate (Nature Genetics, 1994). , 7, 34-39).
  • 17 ⁇ HSD typeH5 synthesis is thought to be responsible for prostate intracrine testosterone synthesis, and it is expected that 17 ⁇ HSD type 5 selective inhibitor will selectively suppress prostate intracrine testosterone synthesis.
  • 17 ⁇ HSD type 5 has been pointed out in estrogen-dependent tissues such as the mammary gland and is expected to be effective in estrogen-dependent diseases such as breast cancer (Endocrine Reviews, 2003, 24, 152-182).
  • AKR1C3 also known as 17 ⁇ HSD type 5
  • AKR aldo-keto reductase
  • ROS reactive oxygen species
  • SNP single nucleotide polymorphism
  • 17 ⁇ HSDHtype 5 inhibitors include steroid derivatives (Patent Document 1), NSAIDs (Non-steroidal Anti-InflammatorymmDrugs) such as flufenamic acid and indomethacin (Non-Patent Document 1), cinnamic acid derivatives (Non-Patent Document 2), N -Sulphonylindole derivatives (Patent Document 2), benzimidazolylbenzoic acid derivatives (Patent Document 3), and the like have been reported.
  • Patent Document 4 published after the priority date of the present application, an indol-2-ylcarbonylpiperidine derivative is disclosed.
  • An object of the present invention is to provide a compound useful as a therapeutic agent for a disease involving a pharmaceutical composition, for example, 17 ⁇ HSD type 5.
  • this invention relates to the pharmaceutical composition containing the compound or its salt of a formula (I), or its salt, and an excipient
  • Ring A is Which may be further substituted with 1 to 4 groups selected from Group G,
  • G group is R 0 , OR 0 , OH, halogen, halogeno lower alkyl, oxo, cycloalkyl, OR 00 -cycloalkyl, CO-R 0 , CO-cycloalkyl, CO-NH 2 , CO-NHR 0 , CO -N (R 0 ) 2 , CO-heterocycloalkyl, NH 2 , NHR 0 , N (R 0 ) 2 , R 00 -NH 2 , R 00 -NHR 0 , R 00 -N (R 0 ) 2 , OR 00 -NH 2 , OR 00 -NHR 0 , OR 00 -N (R 0 ) 2 , NH-CO-R 0 , NR 0 -CO-R 0 , R 00 -NH-CO-R 0 ,
  • the present invention also relates to a pharmaceutical composition for treating and / or preventing a disease involving 17 ⁇ HSD type 5 comprising a compound of formula (I) or a salt thereof.
  • This pharmaceutical composition includes a prophylactic or therapeutic agent for a disease involving 17 ⁇ HSD type 5 comprising a compound of formula (I) or a salt thereof.
  • the present invention also relates to the use of a compound of formula (I) or a salt thereof for producing a pharmaceutical composition for treating and / or preventing a disease involving 17 ⁇ HSD type 5.
  • the present invention also relates to a compound of formula (I) or a salt thereof used for treating and / or preventing diseases involving 17 ⁇ HSD type 5.
  • the present invention also relates to a method for treating and / or preventing a disease involving 17 ⁇ HSD type 5, which comprises administering an effective amount of a compound of formula (I) or a salt thereof to a subject.
  • the “subject” is a human or other animal that needs the prevention or treatment, and as a certain aspect, it is a human that needs the prevention or treatment.
  • the present invention also relates to an inhibitor of 17 ⁇ HSD type 5 containing a compound of formula (I) or a salt thereof.
  • the present invention also relates to the prevention or treatment of a disease associated with 17 ⁇ HSD type 5, comprising a step of mixing a compound of formula (I) or a salt thereof and a pharmaceutically acceptable carrier, solvent, or excipient.
  • the present invention relates to a method for producing a pharmaceutical composition.
  • the present invention also provides a pharmaceutical composition containing a compound of formula (I) or a salt thereof, and a compound of formula (I) or a salt thereof for treating and / or preventing a disease involving 17 ⁇ HSD type 5. It relates to a commercial package that contains a statement that it can or should be used.
  • the compound of the formula (I) has 17 ⁇ HSD type-5 inhibitory activity and can be used as an active ingredient of a pharmaceutical composition for prevention and / or treatment of diseases involving 17 ⁇ HSD type-5.
  • a pharmaceutical composition for preventing and / or treating diseases related to androgens.
  • alkyl and “alkylene” mean a linear or branched hydrocarbon chain unless otherwise specified.
  • “Lower alkyl” means linear or branched alkyl having 1 to 6 carbon atoms (hereinafter abbreviated as C 1-6 ), such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl and the like.
  • C 1-6 linear or branched alkyl having 1 to 6 carbon atoms
  • Another embodiment is C 1-4 alkyl
  • yet another embodiment is C 1-3 alkyl
  • yet another embodiment is methyl.
  • “Lower alkylene” means linear or branched C 1-6 alkylene such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, propylene, methylmethylene, ethylethylene, 1,2-dimethyl. Ethylene, 1,1,2,2-tetramethylethylene and the like.
  • Another embodiment is C 1-4 alkylene, yet another embodiment is methylene or ethylene, and yet another embodiment is methylene.
  • Halogen means F, Cl, Br, I.
  • Halogeno lower alkyl is C 1-6 alkyl substituted with one or more halogens. Another embodiment is lower alkyl substituted with 1 to 5 halogens, and yet another embodiment is C 1-3 alkyl substituted with 1 to 5 F, In an embodiment, it is trifluoromethyl.
  • Cycloalkyl is a C 3-10 saturated hydrocarbon ring group, which may have a bridge. For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl and the like.
  • Another embodiment is C 3-8 cycloalkyl, yet another embodiment is C 3-6 cycloalkyl, and still another embodiment is cyclopropyl, cyclopentyl, cyclohexyl.
  • the “aryl” is a C 6-14 monocyclic to tricyclic aromatic hydrocarbon ring group, and includes a cyclic group condensed with a C 5-8 cycloalkene at a double bond site thereof.
  • phenyl, naphthyl, tetrahydronaphthyl, and indanyl are used.
  • phenyl is used.
  • heterocycle examples include the following embodiments.
  • monocyclic saturated heterocycle (a) containing 1 to 4 nitrogen atoms, such as azepanyl, diazepanyl, aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, piperidyl, pyrazolidinyl, piperazinyl, azocanyl, etc .; (B) those containing 1 to 3 nitrogen atoms and 1 to 2 sulfur atoms and / or 1 to 2 oxygen atoms, such as thiomorpholinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, morpholinyl and the like; (C) those containing 1 to 2 sulfur atoms, such as tetrahydrothiopyranyl; (D) those containing 1 to 2 sulfur atoms and 1 to 2 oxygen atoms, such as oxathiolanyl; (E) those
  • (1) monocyclic unsaturated heterocyclic group (a) containing 1 to 4 nitrogen atoms, for example, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, dihydropyridyl, tetrahydropyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl , Triazolyl, tetrazolyl, triazinyl, dihydrotriazinyl, azepinyl and the like; (B) those containing 1 to 3 nitrogen atoms and 1 to 2 sulfur atoms and / or 1 to 2 oxygen atoms, for example thiazolyl, isothiazolyl, thiadiazolyl, dihydrothiazinyl, oxazolyl, isoxazolyl, oxadiazolyl, Oxazinyl and the like; (C) those containing 1 to 2 sulfur atoms, such as thienyl, thi
  • condensed polycyclic saturated heterocyclic group (a) containing 1 to 5 nitrogen atoms, such as quinuclidinyl, 7-azabicyclo [2.2.1] heptyl, 3-azabicyclo [3.2.2] nonanyl ; (B) those containing 1 to 4 nitrogen atoms, and 1 to 3 sulfur atoms and / or 1 to 3 oxygen atoms, such as trithiadiazaindenyl, dioxoleumidazolidinyl and the like; (C) those containing 1 to 3 sulfur atoms and / or 1 to 3 oxygen atoms, such as 2,6-dioxabicyclo [3.2.2] oct-7-yl;
  • condensed polycyclic unsaturated heterocyclic group (a) containing 1 to 5 nitrogen atoms for example, indolyl, isoindolyl, tetrahydroindolyl, indolinyl, indolizinyl, benzimidazolyl, dihydrobenzoimidazolyl, tetrahydolobenzoimidazolyl Quinolyl, tetrahydroquinolyl, isoquinolyl, tetrahydroisoquinolyl, benzopyrazolyl, tetrahydrobenzopyrazolyl, pyrrolopyridyl, indazolyl, imidazopyridyl, benzotriazolyl, tetrazolopyridazinyl, carbazolyl, acridinyl, quinoxalinyl, dihydroquinoxali Nyl, tetrahydroquinoxalinyl, phthalazinyl, dihydro
  • the “nitrogen-containing heterocycle” means that (1) (a), (1) (b), (2) (a), (2) (b), (3 ) A material containing at least one nitrogen atom, such as (a), (3) (b), (4) (a) and (4) (b).
  • “Heteroaryl” is a heterocyclic group having aromaticity among (2) and (4) of the above “heterocycle”, for example, pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl, Monocyclic heteroaryls such as triazolyl, triazinyl, tetrazolyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, thienyl, furyl, etc.
  • Heterocycloalkyl is a heterocyclic group in which the bond between ring atoms consists of only a single bond as in (1) and (3) of the above “heterocycle”.
  • heterocycle for example, pyrrolidinyl, piperidyl, Piperazinyl, morpholinyl, thiomorpholinyl, and in another embodiment, morpholinyl.
  • 17 ⁇ HSD type 5 inhibition is “17 ⁇ HSD type 5 selective inhibition”.
  • the "17 ⁇ HSD type 5 selectively inhibits” means that the inhibitory activity against 17 ⁇ HSD type 5 is stronger than the inhibitory activity against 17 ⁇ HSD type 3, as one aspect, three or more times in an IC 50 value, preferably 10 times or more Further, it means that there is a difference of 100 times or more.
  • “optionally substituted” means unsubstituted or substituted with 1 to 5 identical or different substituents. When there are a plurality of substituents, these substituents may be the same or different from each other.
  • An embodiment of ring A is a monocyclic group that may have a substituent
  • another embodiment is a bicyclic group that may have a substituent.
  • ring A is monocyclic
  • each of which may have 1 to 5 groups selected from group P on the ring, aryl, CO-aryl , CO-R 00 -aryl, OR 00 -aryl, heteroaryl, CO-heteroaryl, CO-R 00 -heteroaryl, and one group selected from OR 00 -heteroaryl
  • R A cyclic group which may have 1 to 3 groups selected from 0 , OR 0 , halogen, oxo, OR 00 -cycloalkyl, CO—R 0 and CO-cycloalkyl;
  • ring A examples include pyridyl, pyrrolyl, pyrazolyl, thienyl, and phenyl.
  • ring A may be (i) R 0 , OR 0 , OH, halogen, halogeno lower alkyl, oxo, OR 00 -cycloalkyl, CO—R 0 , CO— Cycloalkyl, NH 2 , NHR 0 , N (R 0 ) 2 , R 00 -NH 2 , R 00 -NHR 0 , R 00 -N (R 0 ) 2 , OR 00 -NH 2 , OR 00 -NHR 0 , OR 00 -N (R 0 ) 2 , and aryl, CH 2 CH 2 -aryl, CH ⁇ CH-aryl, each optionally having 1 to 5 groups selected from group P on the ring , CH 2 -
  • Examples of the ring A that is bicyclic include indolyl, tetrahydroindolyl, indolinyl, benzimidazolyl, isoquinolyl, tetrahydrobenzopyrazolyl, pyrrolopyridyl, furopyrrolyl, thienopyrrolyl, imidazolpyridinyl, and other embodiments include indolyl, benzimidazolyl. And pyrrolopyridyl, and in still another embodiment, benzoimidazolyl or pyrrolopyridyl.
  • Some embodiments of the P group include R 0 , halogen, halogeno lower alkyl, OR 0 , O-halogeno lower alkyl, S-halogeno lower alkyl, CN, N (R 0 ) 2 , cycloalkyl, heterocycloalkyl, O— CH 2 —O and O— (CH 2 ) 2 —O.
  • R 1 and R 2 are same or different from each other and H or R 0 , as another aspect, H or C 1-3 alkyl, and as another aspect, C 1-3 alkyl, and in yet another embodiment, is methyl or ethyl.
  • R 3 is H or C 1-3 alkyl, in a further embodiment, a H.
  • R 4 is C 1-3 alkyl, another embodiment is methyl or ethyl, and another embodiment is methyl.
  • m is 0-2, in another embodiment it is 0 or 1, and in another embodiment it is 0.
  • An embodiment of n is 2 to 4, another embodiment is 3, and another embodiment is 1.
  • the group having R 1 to R 3 is preferably substituted at the 4-position with respect to the N atom of the ring containing n, and when n is 1 or 2, the 3-position is substituted. Is preferably substituted.
  • the (6) a X embodiments, a methylene, ethylene or O-CH 2, In another embodiment, it is methylene or O-CH 2, methylene is yet another embodiment.
  • One embodiment of Y is a single bond, and another embodiment is —CH ⁇ CH—.
  • An embodiment of the compound of the formula (I) of the present invention is a compound comprising one or more combinations of the group embodiments described in the above (1) to (7), specifically, for example, the following combinations: Can be mentioned.
  • (8) A compound in which R 3 is H and Y is a single bond.
  • the compound according to (8), wherein n is 3 and X is ethylene.
  • (12) The part indicated by The compound according to any one of (10) to (11), (13) The compound according to (8) to (12), wherein m is 0 to 2, and R 4 is C 1-3 alkyl.
  • each ring A is a group selected from tetrahydroindolyl, indolinyl, benzimidazolyl, tetrahydrobenzopyrazolyl, pyrrolopyridyl, furopyrrolyl and thienopyrrolyl, each optionally having a substituent.
  • each ring A is a group selected from benzimidazolyl, pyrrolopyridyl, furopyrrolyl, and thienopyrrolyl, each optionally having a substituent.
  • each ring A is a group selected from benzimidazolyl and pyrrolopyridyl, each optionally having a substituent.
  • each ring A is a group selected from benzimidazolyl and pyrrolopyridyl, each optionally having a substituent.
  • R 1 and R 2 are methyl.
  • R 1 and R 2 are ethyl.
  • Examples of specific compounds included in the present invention include the following compounds.
  • Some of the compounds of formula (I) may exist as tautomers and geometric isomers depending on the type of substituent.
  • the compound of the formula (I) may be described in only one form of an isomer, but the present invention also includes other isomers, separated isomers, or those And mixtures thereof.
  • Some of the compounds of formula (I) may have asymmetric carbon atoms or axial asymmetry, and optical isomers based on these may exist.
  • the present invention also includes separated optical isomers of the compound of formula (I) or a mixture thereof.
  • the present invention includes a pharmaceutically acceptable prodrug of the compound represented by the formula (I).
  • a pharmaceutically acceptable prodrug is a compound having a group that can be converted to an amino group, a hydroxyl group, a carboxyl group, or the like by solvolysis or under physiological conditions.
  • groups that form prodrugs include those described in Prog. Med., 5, 2157-2161 (1985) and “Development of pharmaceuticals” (Yodogawa Shoten, 1990), Volume 7, Molecular Design 163-198. Is mentioned.
  • the salt of the compound of the formula (I) is a pharmaceutically acceptable salt of the compound of the formula (I), and may form an acid addition salt or a salt with a base depending on the type of substituent. is there.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid Acid addition with organic acids such as lactic acid, malic acid, mandelic acid, tartaric acid, dibenzoyl tartaric acid, ditoluoyl tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, glutamic acid Salts, salts with inorganic bases such as sodium, potassium, magnesium, calcium,
  • the present invention also includes hydrates and solvates of the compound of formula (I) and salts thereof, and polymorphic substances.
  • the present invention also includes compounds labeled with various radioactive or non-radioactive isotopes.
  • the compound of the formula (I) and a salt thereof can be produced by applying various known synthesis methods utilizing characteristics based on the basic structure or the type of substituent. At that time, depending on the type of functional group, it is effective in terms of production technology to protect the functional group with an appropriate protecting group (a group that can be easily converted into the functional group) at the stage from the raw material to the intermediate. There are cases. Examples of such protecting groups include protecting groups described in “Greene's Protective Groups in Organic Synthesis (4th edition, 2006)” by PGM Wuts and TW Greene. These may be appropriately selected according to the reaction conditions. In such a method, a desired compound can be produced by introducing the protecting group and carrying out the reaction, and then removing the protecting group as necessary.
  • the prodrug of the compound of the formula (I) introduces a specific group at the stage from the raw material to the intermediate as in the case of the protective group, or further reacts with the obtained compound of the formula (I).
  • the reaction can be carried out by applying a method known to those skilled in the art, such as ordinary esterification, amidation, dehydration and the like.
  • typical production methods of the compound of the formula (I) will be described. Each manufacturing method can also be performed with reference to the reference attached to the said description.
  • the manufacturing method of this invention is not limited to the example shown below.
  • the compound (I) of the present invention can be obtained by reacting the compound (1) with the compound (2).
  • the compound (1) and the compound (2) are used in an equivalent amount or in excess, and the mixture is preferably used in the presence of a condensing agent in a solvent inert to the reaction from cooling to heating. Is stirred at -20 ° C to 60 ° C, usually for 0.1 hour to 5 days.
  • the solvent used here are not particularly limited, but are aromatic hydrocarbons such as benzene, toluene or xylene, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane or chloroform, diethyl ether, tetrahydrofuran.
  • Ethers such as dioxane and dimethoxyethane, N, N-dimethylformamide, dimethyl sulfoxide, ethyl acetate, acetonitrile or water, and mixtures thereof.
  • condensing agents include, but are not limited to, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, dicyclohexylcarbodiimide, 1,1′-carbonyldiimidazole, diphenyl phosphate azide, and phosphorus oxychloride. Is not to be done. It may be preferred for the reaction to use an additive (eg 1-hydroxybenzotriazole).
  • Performing the reaction in the presence of an organic base such as triethylamine, N, N-diisopropylethylamine, or N-methylmorpholine, or an inorganic base such as potassium carbonate, sodium carbonate, or potassium hydroxide may facilitate the reaction. May be advantageous.
  • an organic base such as triethylamine, N, N-diisopropylethylamine, or N-methylmorpholine
  • an inorganic base such as potassium carbonate, sodium carbonate, or potassium hydroxide
  • the method of making it react with amine (2) after converting carboxylic acid (1) into a reactive derivative can also be used.
  • reactive derivatives of carboxylic acids include acid halides obtained by reacting with halogenating agents such as phosphorus oxychloride and thionyl chloride, mixed acid anhydrides obtained by reacting with isobutyl chloroformate, 1-hydroxy
  • active esters obtained by condensation with benzotriazole and the like include active esters obtained by condensation with
  • reaction of these reactive derivatives with the compound (2) is carried out in a solvent inert to the reaction such as halogenated hydrocarbons, aromatic hydrocarbons, ethers, etc., under cooling to heating, preferably ⁇ 20 It can be carried out at a temperature between 60 ° C and 60 ° C.
  • the compound (Ia) of the present invention in which R 3 is H can be obtained from the corresponding ester compound (3). That is, a compound in which R 1 and R 2 are H can be produced by reducing the ester compound (3), and a compound in which R 1 and R 2 are lower alkyl can be produced by subjecting the ester compound (3) to a Grignard reaction. .
  • a Grignard reaction an equal or excess amount of a reducing agent or Grignard reagent is used relative to compound (3), and the reaction is inert to the reaction, from cooling to heating, preferably from ⁇ 20 ° C. to room temperature, usually for 0.1 hour. Stir for ⁇ 5 days.
  • Examples of the solvent used here are not particularly limited, but include aromatic hydrocarbons, halogenated hydrocarbons, ethers, and mixtures thereof.
  • Examples of the reducing agent include, but are not limited to, lithium borohydride, sodium aluminum hydride, lithium aluminum hydride, lithium tri-tert-butoxyaluminum hydride, diisobutylaluminum hydride, and the like.
  • Examples of Grignard reagents include methylmagnesium bromide, ethylmagnesium bromide, propylmagnesium bromide and the like. For example, the method described in Synthesis 1983, 12, 1030-1031 can be applied.
  • Various compounds of the present invention (I) can be produced as appropriate using the compounds of the present invention (I) as raw materials using amidation, oxidation, reduction, hydrolysis, alkylation, condensation reaction, substitution reaction, etc., which are usually performed by those skilled in the art. can do.
  • a compound in which R 3 is R 0 can be produced by subjecting a compound in which R 3 is H to an O-alkylation reaction.
  • a compound having an alkoxycarbonyl group on ring A is subjected to hydrolysis to obtain a carboxylic acid compound, which is then subjected to an amidation reaction with various optionally substituted amino compounds to produce an amide compound.
  • an amide compound can be produced by subjecting a compound having an amino group on ring A to an amidation reaction with various carboxylic acid compounds.
  • the starting compound (1) can be easily produced by a known reaction.
  • the following reaction can be applied.
  • the raw material compound (1) having various substituents is a raw material compound in the following steps, for example, the compound (4), (7), (9), (10) or (11), and the desired substituent. Or it can manufacture by using the compound which has a group which can be converted into it.
  • the ester (6) of the compound (1a) can be obtained by condensing the compound (4) with diethyl oxalate or the like in the presence of a base such as potassium t-butoxide and reducing the nitro group of the obtained compound.
  • a base such as potassium t-butoxide
  • catalytic reduction in the presence of a catalyst such as Raney nickel or palladium carbon, or reduction using iron can be applied.
  • the ester (8) of the compound (1b) can be obtained by subjecting the compound (7) to a condensation reaction with ethyl azidoacetate or the like.
  • the compound (1c) can be obtained by condensing diethyl oxalate or the like with acetophenone (9), then hydrolyzing hydrated hydrazine and hydrolyzing the resulting ester.
  • Compound (1d) can be obtained by subjecting compound (10) to Heck reaction with pyruvic acid.
  • the compound (1e) can be obtained by subjecting the diamine compound (12) to an alkaline hydrolysis reaction after cyclization with trichloroacetimidate or the like.
  • diamine compounds having various substituents can be produced from the corresponding nitroanilines.
  • the raw material compound (3) can be produced by the reaction of the raw material compounds (13) and (1).
  • the reaction conditions can be carried out according to the first production method.
  • P 1 represents an amino-protecting group.
  • the starting compound (2a) can be obtained by reducing the compound (14) or deprotecting the compound (15) obtained by the Grignard reaction. In addition, compound (13) is obtained by deprotecting compound (14).
  • the compounds of formula (I) are isolated and purified as free compounds, their salts, hydrates, solvates or polymorphic substances.
  • the salt of the compound of formula (I) can also be produced by subjecting it to a conventional salt formation reaction. Isolation and purification are carried out by applying ordinary chemical operations such as extraction, fractional crystallization, and various fractional chromatography.
  • Various isomers can be produced by selecting an appropriate raw material compound, or can be separated by utilizing a difference in physicochemical properties between isomers.
  • optical isomers can be obtained by general optical resolution of racemates (for example, fractional crystallization leading to diastereomeric salts with optically active bases or acids, chromatography using chiral columns, etc.). Further, it can also be produced from a suitable optically active raw material compound.
  • Test Example The human 17 ⁇ HSD type 5 inhibitory activity and 17 ⁇ HSD type 3 inhibitory activity of the compounds of the present invention were confirmed by the test methods shown below. For detailed test procedures, Maniatis, T., et al., Molecular Cloning-A Laboratory Manual, Cold Spring Harbor Laboratory, NY (1982) and the like can be referred to. Further, the genes encoding human 17 ⁇ HSD type 5 and type 3 and 17 ⁇ HSD type 5 and type 3 described in 1 and 2 below can also be obtained by the method described in Molecular Endocrinology 1997, 11 (13), 1971-1984. it can.
  • the full-length cDNA encoding human 17 ⁇ HSD type 5 used in the pharmacological tests of the present invention is obtained by PCR using the cDNA derived from A549 cells of the human lung cancer-derived cell line as a template. did. The base sequence of the obtained cDNA was analyzed by the dideoxy terminator method, and a clone that matched the known human 17 ⁇ HSD type 5 sequence (GenBank accession No. NM_003739) was selected.
  • Escherichia coli BL21 was transformed with the plasmid containing these and cultured in large quantities, and the protein was purified using a GSTrapFF column (Amersham) and PreScissionProtease (Amersham). The purification method followed the instructions attached to the GSTrapFF column.
  • the collected cells are disrupted in a phosphate buffer containing 5% glycerol (500 ⁇ l of phosphate buffer containing 5% glycerol (pH 7.4, 200 mM) per 100 mm-dish) and centrifuged. After (16000 rpm, 5 min, 4 ° C.), the supernatant was used as an enzyme source.
  • a phosphate buffer containing 5% glycerol 500 ⁇ l of phosphate buffer containing 5% glycerol (pH 7.4, 200 mM) per 100 mm-dish
  • the amount of testosterone produced when no enzyme was added was 0%, the amount of testosterone produced when no compound was added was 100%, and the amount of testosterone produced when the compound was added was determined as a relative value.
  • IC 50 values were then calculated by the logistic regression method. Table 1 shows the IC 50 values of the inhibitory activity of human 17 ⁇ HSD type 5 of some Example compounds included in the compounds of the present invention. Ex represents an example compound number described later.
  • the enzyme activity can be measured using cells expressing human 17 ⁇ HSD type 5 or the like.
  • the cell growth inhibitory activity when the test compound was added was determined as a relative value, with the number of cells without addition of androstenedione as 0% proliferation, the number of cells when androstenedione was added, and when no test compound was added as 100%.
  • IC 50 values were then calculated by the logistic regression method. The IC 50 values of some example compounds in the above test are shown in Table 2.
  • CWR22R tumors were excised from CWR22R subcutaneous tumor-bearing nude mice. The excised tumor was subdivided into pieces of about 5 mm. The tumor pieces were washed twice with RPMI1640 medium containing 20% serum and then stirred for about 20 minutes in RPMI1640 medium containing 0.1% protease and 20% serum. The supernatant was collected and the cells were collected by centrifugation. This was repeated as necessary, and the collected cells were combined into a cell solution.
  • the cell solution was adjusted to 2 ⁇ 10 7 cells / mL. Further, the cell solution and Matrigel were mixed in an equal amount, and finally adjusted to 1 ⁇ 10 7 cells / mL.
  • the male nude mouse from which the testis was removed was transplanted by subcutaneous injection into the back of the cell matrigel mixed solution (0.1 mL) prepared by the above method.
  • the tumor volume became 100 mm 3 or more after transplantation, the following experiments were conducted after grouping based on the tumor volume.
  • the test substance was orally administered to CWR22R subcutaneous cancer-bearing mice. One hour later, ie one hour before dissection, androstenedione was administered into the tumor to give a 1 ng / 100 mm 3 tumor.
  • the composition of the androstenedione administration solution was 0.000075% DMF / 0.00005% polysorbate 80 / 9.9999875% saline / 90% Matrigel. After dissection, the tumor was removed, and after measuring the tumor weight, it was stored frozen. For measurement of the background value, tumors of mice that were orally administered only with the test substance administration solvent were excised, and an androstenedione administration solution was added under ice-cooling and rapidly frozen. 0.2 M Na-K phosphate buffer (pH 7.4) was added to the cryopreserved tumor sample, and a tumor homogenate was prepared with a homogenizer (polytron) under ice cooling.
  • a homogenizer polytron
  • Inhibition rate (%) 100 ⁇ (average value of testosterone concentration in test substance administration solvent administration group ⁇ average testosterone concentration in test substance administration group) / (average testosterone concentration in test substance administration solvent group ⁇ background testosterone concentration average value)
  • the compound of the formula (I) can be used as an active ingredient of a pharmaceutical composition for prevention and / or treatment of diseases involving 17 ⁇ HSD type 5.
  • a pharmaceutical composition for prevention and / or treatment of diseases involving 17 ⁇ HSD type 5 for prevention and / or treatment of diseases involving 17 ⁇ HSD type 5.
  • inhibition of 17 ⁇ HSD type 5 suppresses androgen synthesis and estrogen synthesis, and thus can be used as an active ingredient in a pharmaceutical composition for prevention and / or treatment of diseases involving androgen and estrogen.
  • 17 ⁇ HSD type 5 ie, androgen or estrogen-related diseases include, but are not limited to, prostate cancer, prostatic hypertrophy, acne, seborrhea, hirsutism, baldness, alopecia, precociousness, adrenal hypertrophy And polycystic ovary syndrome, breast cancer, endometriosis, leiomyoma and the like.
  • prostate cancer prostatic hypertrophy
  • prostatic hypertrophy such as lung cancer.
  • 17 ⁇ HSD type 5 is responsible for the intracrine androgen synthesis of the prostate, it is useful for the prevention and / or treatment of prostate cancer and prostate hypertrophy, which are diseases involving androgen, particularly in the prostate gland.
  • a compound having weak human 17 ⁇ HSD type 3 inhibitory activity which is an embodiment of the present invention does not affect the testosterone biosynthesis derived from human 17 ⁇ HSD type 3 in the testis, and has an inhibitory effect on the prostate due to the selective inhibitory action of 17 ⁇ HSD type 3. It can be expected to selectively suppress testosterone synthesis. That is, since the compound of formula (I) does not affect blood testosterone concentration, treatment and / or prevention of prostatic hypertrophy and prostate cancer without side effects such as sexual dysfunction due to suppression of blood testosterone concentration. Can be used for
  • a pharmaceutical composition containing one or more compounds of the formula (I) or a salt thereof as an active ingredient is an excipient usually used in the art, that is, a pharmaceutical excipient, a pharmaceutical carrier, etc. Can be prepared by a commonly used method. Administration is orally by tablets, pills, capsules, granules, powders, solutions, etc., or injections such as intra-articular, intravenous, intramuscular, suppositories, eye drops, ophthalmic ointments, transdermal solutions, Any form of parenteral administration such as an ointment, a transdermal patch, a transmucosal liquid, a transmucosal patch, and an inhalant may be used.
  • a solid composition for oral administration tablets, powders, granules and the like are used.
  • one or more active ingredients are mixed with at least one inert excipient.
  • the composition may contain an inert additive such as a lubricant, a disintegrant, a stabilizer and a solubilizing agent according to a conventional method. If necessary, tablets or pills may be coated with a sugar coating or a film of a gastric or enteric substance.
  • Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs and the like, and commonly used inert diluents such as purified water. Or ethanol.
  • the liquid composition may contain solubilizers, wetting agents, auxiliaries such as suspending agents, sweeteners, flavors, fragrances, and preservatives.
  • the injection for parenteral administration contains a sterile aqueous or non-aqueous solution, suspension or emulsion.
  • aqueous solvent include distilled water for injection or physiological saline.
  • Non-aqueous solvents include alcohols such as ethanol.
  • Such compositions may further contain isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, or solubilizing agents. These are sterilized by, for example, filtration through a bacteria-retaining filter, blending with a bactericide or irradiation. These can also be used by producing a sterile solid composition and dissolving or suspending it in sterile water or a sterile solvent for injection before use.
  • External preparations include ointments, plasters, creams, jellies, poultices, sprays, lotions, eye drops, eye ointments and the like.
  • ointment bases commonly used ointment bases, lotion bases, aqueous or non-aqueous solutions, suspensions, emulsions, and the like.
  • a transmucosal agent such as an inhalant or a nasal agent is used in a solid, liquid, or semi-solid state, and can be produced according to a conventionally known method.
  • known excipients, and further pH adjusters, preservatives, surfactants, lubricants, stabilizers, thickeners and the like may be appropriately added.
  • an appropriate device for inhalation or insufflation can be used.
  • a known device such as a metered dose inhalation device or a nebulizer
  • the compound is administered alone or as a powder in a formulated mixture or as a solution or suspension in combination with a pharmaceutically acceptable carrier. be able to.
  • the dry powder inhaler or the like may be for single or multiple administration, and a dry powder or a powder-containing capsule can be used. Alternatively, it may be in the form of a pressurized aerosol spray using a suitable propellant, for example, a suitable gas such as chlorofluoroalkane or carbon dioxide.
  • a suitable propellant for example, a suitable gas such as chlorofluoroalkane or carbon dioxide.
  • the appropriate daily dose is about 0.001 to 100 mg / kg, preferably 0.1 to 30 mg / kg, more preferably 0.1 to 10 mg / kg per body weight. Or in 2 to 4 divided doses.
  • the appropriate daily dose is about 0.0001 to 10 mg / kg per body weight, and is administered once to several times a day.
  • a transmucosal agent about 0.001 to 100 mg / kg per body weight is administered once to several times a day. The dose is appropriately determined according to individual cases in consideration of symptoms, age, sex, and the like.
  • the compound of the formula (I) can be used in combination with various therapeutic agents or preventive agents for diseases for which the compound of the formula (I) is considered to be effective.
  • the combination may be administered simultaneously, separately separately, or at desired time intervals.
  • a pharmaceutical preparation containing various therapeutic or prophylactic agents for the diseases for which the compound of formula (I) is considered to be effective, and a compound of formula (I), even if the coadministration preparation is formulated separately may be a composition.
  • the manufacturing method of the compound of Formula (I) is demonstrated in detail.
  • this invention is not limited to the compound as described in the following Example.
  • the production methods of the raw material compounds are shown in Production Examples, and the production of known compounds is shown in Reference Examples.
  • the production method of the compound of the formula (I) is not limited to the production methods of the specific examples shown below, and the compound of the formula (I) may be a combination of these production methods or a person skilled in the art. It can also be produced by methods that are self-evident.
  • the precipitate was collected by filtration, washed with hexane, and dried at room temperature to obtain 4.25 g of a brown solid.
  • the obtained solid was suspended in 177.45 ml of a mixed solvent of ethyl acetate and hexane (1:20), stirred at room temperature for 3 hours, and allowed to stand overnight.
  • the precipitate was collected by filtration, washed with hexane, and dried under reduced pressure to obtain 4.11 g of methyl 4-methyl-1H-pyrrolo [3,2-c] pyridine-2-carboxylate as a brown solid.
  • Production Example 15 Add 0.46 ml of pyruvic acid and 25.6 mg of palladium acetate to a solution of 427 mg of 2-bromo-5-methylpyridin-3-amine and 768 mg of 1,4-diazabicyclo [2.2.2] octane in 7 ml of DMF at room temperature under a nitrogen atmosphere. It was. The mixture was stirred at 125 ° C. for 3 hours under a nitrogen atmosphere, then cooled to room temperature and concentrated under reduced pressure. 10 ml of water was added to the residue, and the pH of the mixture was adjusted to 9-10 with 1 M sodium hydroxide solution, followed by filtration through celite.
  • the filtrate was washed with ethyl acetate, adjusted to pH 3-4 with 1 M hydrochloric acid, and washed again with ethyl acetate.
  • the residue obtained by concentrating the aqueous layer under reduced pressure was dissolved in 100 ml of MeOH, and 4 ml of thionyl chloride was added dropwise at room temperature. The mixture was heated at reflux for 4 hours and then concentrated. The residue was adjusted to pH 8 with aqueous sodium hydrogen carbonate solution and extracted with chloroform. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and insolubles were filtered off.
  • Production Example 19 Add 1 ml of trifluoroacetic acid to a mixture of 265 mg of 1-tert-butyl 2-methyl 4- (pyridin-3-yl) -1H-pyrrole-1,2-dicarboxylate and 10 ml of dichloromethane, and add 4 ml at room temperature. Stir for hours. Toluene was added to the reaction solution, and the solvent was distilled off under reduced pressure to obtain 359 mg of methyl 4- (pyridin-3-yl) -1H-pyrrole-2-carboxylate bis (trifluoroacetate) as a white solid.
  • Example 1 To a solution of 157 mg of 6-chloro-1H-benzimidazole-2-carboxylic acid and 138 mg of 2-methyl-1- (piperidin-4-yl) -2-propanol in 5 ml of DMF, 1-ethyl-3- (dimethyl Aminopropyl) carbodiimide hydrochloride 184 mg and 1-hydroxybenzotriazole 54 mg were added, and the mixture was stirred at room temperature for 2 hours. A saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added to the reaction solution, and the mixture was separated. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, and concentrated under reduced pressure.
  • 1-ethyl-3- (dimethyl Aminopropyl) carbodiimide hydrochloride 184 mg and 1-hydroxybenzotriazole 54 mg were added, and the mixture was stirred at room temperature for 2 hours.
  • Example 2 2-methyl-1- (piperidin-4-yl) -2-propanol 4.7 mg, 3- (3,4-dimethoxyphenyl) -1H-pyrazole-5-carboxylic acid 7.4 mg, triethylamine 0.0042 ml, and 1-hydroxy
  • PS-carbodiimide PS-Carbodiimide: Argonaute Technology
  • Example 3 To a solution of 29 mg of 3-acetylbenzonitrile and 44 mg of diethyl oxalate in 0.3 ml of DMF, 27 mg of potassium tert-butoxide was added and stirred at room temperature overnight. To the reaction solution was added 1 ml of 1M hydrochloric acid, and the mixture was concentrated under reduced pressure. To the obtained residue, hydrazine hydrate 0.015 ml and EtOH 0.5 ml were added and stirred at 60 ° C. for 5 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure.
  • Example 212 To a suspension of 65 mg of 1H-pyrrolo [2,3-c] pyridine-2-carboxylic acid in 3 ml of dichloromethane was added 0.088 ml of thionyl chloride and 0.001 ml of DMF under ice cooling, and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure. To the residue was added 3 ml of dichloromethane, and the solvent was distilled off under reduced pressure. The same operation was performed again on the obtained residue.
  • Example 213 Using 286 mg of 3,4-diamino-N, N-dimethylbenzamide, the same reaction as in Production Example 17 was carried out, and then the same treatment as in Example 1 was carried out to give 2- ⁇ [4- (2-hydroxy 104 mg of -2-methylpropyl) piperidin-1-yl] carbonyl ⁇ -N, N-dimethyl-1H-benzimidazole-5-carboxamide was obtained as colorless amorphous.
  • Example 214 (5-Amino-1H-benzimidazol-2-yl) [4- (2-hydroxy-2-methylpropyl) piperidin-1-yl] methanone
  • dichloromethane 37% formaldehyde Aqueous solution 177 ⁇ l, acetic acid 136 ⁇ l, and sodium triacetoxyborohydride 151 mg were sequentially added.
  • the mixture was stirred at room temperature for 1 day and then concentrated under reduced pressure.
  • Example 216 1- ⁇ 1-[(6-Bromo-1H-imidazo [4,5-b] pyridin-2-yl) carbonyl] piperidin-4-yl ⁇ -2-methylpropan-2-ol 133 mg
  • 53 mg of [4- (2-hydroxy-2-methylpropyl) piperidin-1-yl] (1H-imidazo [4,5-b] pyridin-2-yl) methanone was obtained as a white solid. It was.
  • Example 217 Using 234 mg of [4- (2-hydroxy-2-methylpropyl) piperidin-1-yl] (5-nitro-1H-benzimidazol-2-yl) methanone, (5- 223 mg of amino-1H-benzimidazol-2-yl) [4- (2-hydroxy-2-methylpropyl) piperidin-1-yl] methanone was obtained as a pale yellow amorphous.
  • Example 218 Methyl 7-chloro-1H-pyrrolo [3,2-b] pyridine-2-carboxylate 6.3 mg of THF 0.25 ml, EtOH 0.25 ml, and 1 M aqueous sodium hydroxide solution 0.5 ml were mixed at 50 ° C. overnight. did. To the reaction mixture was added 0.5 ml of 1M hydrochloric acid at room temperature, and the mixture was concentrated under reduced pressure. PS-Carbodiimide (Argonaute Technology Co., Ltd.) in a DMF 0.5 ml solution of the residue and 4.7 mg of 2-methyl-1-piperidin-4-ylpropan-2-ol and 4.1 mg of HOBt at room temperature 100 mg was added and stirred overnight.
  • PS-Carbodiimide ArArgonaute Technology Co., Ltd.
  • Example compounds shown in the table below were produced in the same manner as in the above Examples.
  • the structures, physicochemical data and production methods of the example compounds are shown in the table below.
  • the compound of the formula (I) has 17 ⁇ HSD type-5 inhibitory activity and can be used as an active ingredient of a pharmaceutical composition for prevention and / or treatment of diseases involving 17 ⁇ HSD type-5.
  • a pharmaceutical composition for preventing and / or treating diseases related to androgens.

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Abstract

Composé utile en tant que principe actif dans une préparation pharmaceutique destinée au traitement de maladies associées à 17βHSD type 5. Spécifiquement, l'invention concerne un agent pour le traitement de maladies associées à 17βHSD type 5, en particulier un composé amide comportant un groupe hydroxy alkyle sur un groupe aminocyclique, ledit composé amide présentant une activité inhibitrice puissante à l'encontre de 17βHSD type 5. Ce composé amide peut être utilisé comme principe actif d'une préparation pharmaceutique destinée à prévenir et/ou à traiter des maladies associées à 17βHSD type 5, telles qu'une hyperplasie prostatique et le cancer de la prostate.
PCT/JP2010/053282 2009-03-03 2010-03-02 Composé amide WO2010101128A1 (fr)

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CN112480005A (zh) * 2017-11-08 2021-03-12 北京嘉林药业股份有限公司 化合物及其治疗癌症的用途

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BR112012011793A2 (pt) 2009-11-18 2019-09-24 Fab Pharma Sas "acrilamidas heterocíclicas e seu uso como farmacêuticos"
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