JPWO2021099518A5

JPWO2021099518A5 -

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Publication number: JPWO2021099518A5
Application number: JP2022554964A
Authority: JP
Publication date: 2023-04-04

Description

方法Ｇ：１Ｈ－ピラゾールの合成
例示的な例：４－［３－（１，３－ベンゾジオキソール－５－イル）－１Ｈ－ピラゾール－５－イル］－３，６－ジクロロピリダジン化合物４８

ＤＣＭ（５ｍＬ）中の１－（１，３－ベンゾジオキソール－５－イル）エタノン（１３８ｍｇ、０．８４ｍｍｏｌ）、ＭｇＢｒ_２・Ｅｔ_２Ｏ（５４２ｍｇ、２．１ｍｍｏｌ）の混合物をＤＩＰＥＡ（３２３ｍｇ、４２６μＬ、２．５ｍｍｏｌ）で処理し、ＲＴで１０分間撹拌した。次に、乾燥ＤＣＭ（５ｍＬ）中の３，６－ジクロロピリダジン－４－カルボン酸（２０３ｍｇ、１．０５ｍｍｏｌ）、ベンゾトリアゾール（１２５ｍｇ、１．０５ｍｍｏｌ）およびＤＣＣ（２１６ｍｇ、１．０５ｍｍｏｌ）を２５℃で３時間撹拌することにより別に調製した１Ｈ－ベンゾトリアゾール－１－イル（３，６－ジクロロピリダジン－４－イル）メタノンの粗混合物を、５分間にわたって滴下添加した。得られた混合物を２５℃で１２時間撹拌し、次に水性０．５ＭＨＣｌ（２ｍＬ）で処理し、２５℃でさらに１０分間撹拌した。水（２０ｍＬ）の添加後、混合物をＤＣＭ（２^＊１５ｍＬ）で抽出した。合わせた有機画分を塩水で洗浄し、Ｎａ_２ＳＯ_４で乾燥し、真空濃縮した。粗生成物をカラムクロマトグラフィーにより精製して、中間体１－（１，３－ベンゾジオキソール－５－イル）－３－（３，６－ジクロロピリダジン－４－イル）プロパン－１，３－ジオン（１９０ｍｇ、６７％）をオレンジ色固体として得、これをさらに精製せずに次のステップで使用した。この中間体をＴＨＦ（４ｍＬ）に懸濁して、ヒドラジン一水和物（４０ｍｇ、０．８ｍｍｏｌ）を添加した。反応混合物を４０℃で一晩撹拌し、冷却し、真空濃縮した。粗生成物をカラムクロマトグラフィー（シリカゲル６３～１００、２０ｇ、クロロホルム／メタノール＝１００／１）により精製して、化合物４８（１００ｍｇ、２ステップにわたって３６％）を薄黄色固体として得た。 Method G: Synthesis of 1H-pyrazoles Illustrative Example: 4-[3-(1,3-benzodioxol-5-yl)-1H-pyrazol-5-yl]-3,6-dichloropyridazine Compound 48

A mixture of 1-(1,3-benzodioxol-5-yl)ethanone (138 mg, 0.84 mmol), MgBr ₂ .Et ₂ O (542 mg, 2.1 mmol) in DCM (5 mL) was treated with DIPEA (323 mg). , 426 μL, 2.5 mmol) and stirred at RT for 10 min. Then 3,6-dichloropyridazine-4-carboxylic acid (203 mg, 1.05 mmol), benzotriazole (125 mg, 1.05 mmol) and DCC (216 mg, 1.05 mmol) in dry DCM (5 mL) were added at 25°C. A crude mixture of 1H-benzotriazol-1-yl(3,6-dichloropyridazin-4-yl)methanone, prepared separately by stirring at rt for 3 hours, was added dropwise over 5 minutes. The resulting mixture was stirred at 25° C. for 12 hours, then treated with aqueous 0.5 M HCl (2 mL) and stirred at 25° C. for an additional 10 minutes. After addition of water (20 mL), the mixture was extracted with DCM (2 ^* 15 mL). The combined organic fractions were washed with brine, dried _over _Na2SO4 and concentrated in vacuo. The crude product is purified by column chromatography to give intermediate 1-(1,3-benzodioxol-5-yl)-3-(3,6-dichloropyridazin-4-yl)propane-1,3 -dione (190 mg, 67%) was obtained as an orange solid, which was used in the next step without further purification. This intermediate was suspended in THF (4 mL) and hydrazine monohydrate (40 mg, 0.8 mmol) was added. The reaction mixture was stirred at 40° C. overnight, cooled and concentrated in vacuo. The crude product was purified by column chromatography (silica gel 63-100, 20 g, chloroform/methanol=100/1) to give compound 48 (100 mg, 36% over two steps) as a pale yellow solid.

Claims

general formula Ia, Ib, IIa or IIb

(wherein X ¹ , X ² and X ³ are independently selected from CR ² , N and NR ¹ , provided that at least two of X ¹ , X ² and X ³ are N or NR ¹ and
Y ¹ , Y ² , Y ³ , Y ⁴ , Y ⁵ , Y ⁶ , Y ⁷ and Y ⁸ are independently selected from CR ³ and N with the proviso that Y ¹ , Y ² , Y ³ , Y ⁴ , Y at least one of ⁵ , Y ⁶ , Y ⁷ and Y ⁸ is N;
R ¹ is independently selected from hydrogen, C _1-4 alkyl and —(CH ₂ )—OP(═O)(OR)(OR), where C _1-4 alkyl is one or more optionally substituted with a halogen,
R ² is independently selected from hydrogen, halogen and C _1-4 alkyl, wherein C _1-4 alkyl can be optionally substituted with one or more halogens;
R is hydrogen or a cation;
R ³ is hydrogen, halogen, C _1-4 alkyl, OH and C _1-4 alkoxy, wherein C _1-4 alkyl and C _1-4 alkoxy can be optionally substituted with one or more halogens ,
R ⁴ and R ⁵ are independently selected from H and C _1-4 alkyl, wherein C _1-4 alkyl may be optionally substituted with one or more halogens, or R ⁴ and R ⁵ are , together with the nitrogen atom to which they are attached, form a 4- to 6-membered saturated heterocyclic ring, which in addition to the nitrogen atom to which R ⁴ and R ⁵ are attached, 1 selected from O and N optionally containing one or more heteroatoms, said 4- to 6-membered saturated heterocyclic ring may be optionally substituted with one or more R ⁶ ;
R ⁶ is independently selected from halogen, C _1-4 alkyl, OH and C _1-4 alkoxy, wherein C _1-4 alkyl and C _1-4 alkoxy are optionally substituted with one or more halogens can be
Hal is halogen)
or a prodrug, solvate or salt thereof.

but,

or

but,

and
2. A compound according to claim 1, wherein ^R1 and ^R2 are as defined in claim 1.

but,

or

but,

and
3. The compound of claim ² , wherein ^R1 and R2 are as defined in claim 1.

4. Any one of claims 1 to 3, wherein one, two or three of Y ¹ , Y ² , Y ³ , Y ⁴ , Y ⁵ , Y ⁶ , Y ⁷ and Y ⁸ are N. compound.

Y ¹ is N and at least one of Y ³ , Y ⁴ and Y ⁶ is N in Formula Ia or Ib, or Y ¹ is N and Y ³ , Y A compound according to any one of claims 1 to 4, wherein at least one of ⁴ , Y ⁵ , Y ⁶ , Y ⁷ and Y ⁸ is N.

Y ¹ is N, Y ² , Y ³ , Y ⁴ , Y ⁵ , Y ⁶ , Y ⁷ and Y ⁸ are CR ³ , preferably Y ¹ is N, Y ² , Y ³ , Y ⁴ , Y ⁵ , Y ⁶ , Y ⁷ and Y ⁸ are CH.

A compound according to any one of claims 1-6, wherein R ² is H.

8. Any one of claims 1-7, wherein at least one of R ⁴ and R ⁵ is C _1-4 alkyl, and the C _1-4 alkyl can be optionally substituted with one or more halogens. The compound according to the item.

R ⁴ and R ⁵ together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated heterocyclic ring which, in addition to the nitrogen atom to which R ⁴ and R ⁵ are attached, O and Claims 1-7, optionally containing one or more heteroatoms selected from N, wherein said 4-6 membered saturated heterocyclic ring can be optionally substituted with one or more R ⁶ A compound according to any one of

4-6 membered saturated heterocycle is selected from azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl, wherein azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl can be optionally substituted with one or more ^R6 Item 9. A compound according to item 9.

The compound is detectably labeled, preferably the compound is detectably labeled with ¹⁸ F, ¹¹ C, ¹²⁵ I, ¹²³ I, ¹³¹ I, ⁷⁷ Br and ⁷⁶ Br, more preferably the compound is detectably labeled with ¹⁸ F or a compound of any one of claims 1 to 10, or a prodrug, solvate or salt thereof, detectably labeled with ^11C .

A diagnostic composition comprising a compound according to any one of claims 1-11, or a solvate or salt thereof, and optionally a pharmaceutically acceptable carrier.

A pharmaceutical composition comprising a compound according to any one of claims 1-10, or a prodrug, solvate or salt thereof, and optionally a pharmaceutically acceptable carrier.

A compound according to any one of claims 1 to 11, or a prodrug, solvate or salt thereof, for use in the diagnosis of diseases associated with α-synuclein aggregation.

A compound according to any one of claims 1 to 10, or a prodrug, solvate or salt thereof, for use in the treatment of diseases associated with α-synuclein aggregation.

A compound for use according to claim 14 or 15, wherein the disease associated with α-synuclein aggregation is selected from Parkinson's disease, dementia with Lewy bodies and multiple system atrophy.

Use of a compound according to any one of claims 1 to 11, or a prodrug, solvate or salt thereof, for inhibiting α-synuclein aggregation in vitro or ex vivo.

A compound according to any one of claims 1 to 11, or a solvate or salt thereof, for use in imaging α-synuclein aggregation.

12. A kit for preparing a detectably labeled compound of claim 11, or solvate or salt thereof, wherein the compound of claim 11, or solvate or salt thereof, is formed in a reaction A kit comprising at least two precursor compounds to.