JP2022507013A - H4アンタゴニスト化合物としてのピラゾール誘導体 - Google Patents
H4アンタゴニスト化合物としてのピラゾール誘導体 Download PDFInfo
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- JP2022507013A JP2022507013A JP2021521390A JP2021521390A JP2022507013A JP 2022507013 A JP2022507013 A JP 2022507013A JP 2021521390 A JP2021521390 A JP 2021521390A JP 2021521390 A JP2021521390 A JP 2021521390A JP 2022507013 A JP2022507013 A JP 2022507013A
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- ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 description 1
- SBMSLRMNBSMKQC-UHFFFAOYSA-N pyrrolidin-1-amine Chemical compound NN1CCCC1 SBMSLRMNBSMKQC-UHFFFAOYSA-N 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000002777 redistribution assay Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000034225 regulation of ventricular cardiomyocyte membrane depolarization Effects 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 208000037851 severe atopic dermatitis Diseases 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- MRTAVLDNYYEJHK-UHFFFAOYSA-M sodium;2-chloro-2,2-difluoroacetate Chemical compound [Na+].[O-]C(=O)C(F)(F)Cl MRTAVLDNYYEJHK-UHFFFAOYSA-M 0.000 description 1
- GGCZERPQGJTIQP-UHFFFAOYSA-N sodium;9,10-dioxoanthracene-2-sulfonic acid Chemical compound [Na+].C1=CC=C2C(=O)C3=CC(S(=O)(=O)O)=CC=C3C(=O)C2=C1 GGCZERPQGJTIQP-UHFFFAOYSA-N 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000006190 sub-lingual tablet Substances 0.000 description 1
- 238000003883 substance clean up Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 230000006794 tachycardia Effects 0.000 description 1
- 235000015523 tannic acid Nutrition 0.000 description 1
- 229940033123 tannic acid Drugs 0.000 description 1
- 229920002258 tannic acid Polymers 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000006068 taste-masking agent Substances 0.000 description 1
- LGEWGFOMLJQHLL-UHFFFAOYSA-N tert-butyl 2,3,4,4a,5,6,7,7a-octahydropyrrolo[3,4-b]pyridine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCC2CNCC12 LGEWGFOMLJQHLL-UHFFFAOYSA-N 0.000 description 1
- HMLOVTCREDBBMH-UHFFFAOYSA-N tert-butyl 3-(4-bromopyrazol-1-yl)piperidine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC1N1N=CC(Br)=C1 HMLOVTCREDBBMH-UHFFFAOYSA-N 0.000 description 1
- KYRWEDDXBNZACB-UHFFFAOYSA-N tert-butyl 3-amino-3-methylpyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(C)(N)C1 KYRWEDDXBNZACB-UHFFFAOYSA-N 0.000 description 1
- RIFXIGDBUBXKEI-UHFFFAOYSA-N tert-butyl 3-oxopiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCC(=O)C1 RIFXIGDBUBXKEI-UHFFFAOYSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- MCZDHTKJGDCTAE-UHFFFAOYSA-M tetrabutylazanium;acetate Chemical compound CC([O-])=O.CCCC[N+](CCCC)(CCCC)CCCC MCZDHTKJGDCTAE-UHFFFAOYSA-M 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000010474 transient expression Effects 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 229910052722 tritium Chemical class 0.000 description 1
- 238000000825 ultraviolet detection Methods 0.000 description 1
- 229940116269 uric acid Drugs 0.000 description 1
- 229940005605 valeric acid Drugs 0.000 description 1
- 208000003663 ventricular fibrillation Diseases 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 238000002424 x-ray crystallography Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/04—Antipruritics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- 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
- 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
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- Orthopedic Medicine & Surgery (AREA)
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Abstract
Description
本発明は、H4受容体アンタゴニストとしての活性を有する化合物を提供する。より詳細には、本発明は、H4受容体拮抗作用と低いhERG活性とを合わせ持つ化合物を提供する。
Xは、CHまたはNであり;
nは、1または2であり;
R1は、HまたはC1~3アルキルから選択され、C1~3アルキル基は、NHR1が結合した環へと戻るように環化されて、第2の環を形成していてもよく;
R2は、Hまたはメチルであり;
Aは、置換されていてもよいピラゾール環を表す)
を提供する。
から選択される環を表してもよい。
Xは、CHまたはNであり;
nは、1または2であり;
R1は、HまたはC1~3アルキルから選択され、C1~3アルキル基は、NHR1が結合した環へと戻るように環化されて、第2の環を形成していてもよく;
R2は、Hまたはメチルであり;
Aは、炭素-炭素結合によってXを含有する環に連結した、置換されていてもよいピラゾール環を表す)
を含む。
から選択される環を表してもよい。
R1は、HまたはC1~3アルキルから選択され、C1~3アルキル基は、NHR1が結合した環へと戻るように環化されて、第2の環を形成していてもよく;
R2は、Hまたはメチルである)
を含み得る。
式(1)の化合物の調製のための方法
式(1)の化合物は、当業者に周知の合成法、および本明細書に記載されている合成法に準拠して調製され得る。
(A)SNAr条件もしくは遷移金属触媒カップリング条件下、式(10)の化合物:
(B)遷移金属触媒カップリング条件もしくはSNAr条件下、式(12)の化合物:
A-M
(13)
(式中、A、R1、R2、Xおよびnは、上の式(1)で定義されている通りであり、LGは、好適な脱離基を表し、Mは、存在してもしなくてもよく、好適な置換金属または非金属を表す)との反応;または
(C)式(1)の1つの化合物の、式(1)の別の化合物への変換
を含む方法を提供する。
医薬製剤
活性化合物は、単独で投与することが可能であるが、医薬組成物(例えば、製剤)として供給されることが好ましい。
下の表1に示されている実施例1-1~18-1の化合物を調製した。それらの化合物のNMRおよびLCMS特性、ならびにそれらを調製するために使用した方法を表3に記載する。実施例のそれぞれに関する出発原料を、表2に列挙する。
調製経路が含まれていない場合、関連する中間体は市販されている。市販試薬は、さらに精製することなく利用した。室温(rt)は、約20~27℃を指す。1H NMRスペクトルは、BrukerまたはJeol機器のいずれかで、400MHzで記録した。ケミカルシフト値は、百万分率(ppm)、すなわち(δ)値で表す。NMRシグナルの多重度について、以下の略称を使用する:s=シングレット、br=ブロード、d=ダブレット、t=トリプレット、q=カルテット、quint=クインテット、td=ダブレットのトリプレット、tt=トリプレットのトリプレット、qd=ダブレットのカルテット、ddd=ダブレットのダブレットのダブレット、ddt=トリプレットのダブレットのダブレット、m=マルチプレット。カップリング定数は、Hzで測定したJ値として列挙する。NMRおよび質量分光法の結果は、バックグラウンドピークを考慮して補正した。クロマトグラフィーとは、60~120メッシュのシリカゲルを使用して実施し、窒素加圧下(フラッシュクロマトグラフィー)条件下で実行したカラムクロマトグラフィーを指す。「塩基性シリカ」を使用して実施されるカラムクロマトグラフィーは、Biotage(登録商標)KP-NHシリカゲルの使用を指す。「C18シリカ」を使用して逆相条件下で実施されるカラムクロマトグラフィーは、Biotage(登録商標)KP-C18シリカゲルの使用を指す。反応をモニタリングするためのTLCは、指定した移動相、および固定相としてMerck製のシリカゲルF254を使用して実施したTLCを指す。マイクロ波を媒介とする反応は、Biotage開始剤またはCEM Discoverマイクロ波用反応器で実施した。
LCMS分析
化合物のLCMS分析は、下の表に示されている機器および方法を使用したエレクトロスプレー条件下で実施した:
化合物精製
化合物の最終精製を、以下に詳述する機器および方法を使用して分取逆相HPLC、キラルHPLCまたはキラルSFCによって実施した。データは、以下の形式で示される:精製技法:[相(カラムの説明、カラム長×内径、粒径)、溶媒流速、グラジエント - 移動相A中の移動相Bの%(経時)として示す、移動相(A)、移動相(B)]。
分取HPLC精製:
SPD-20A UV検出器を備えるShimadzu LC-20APバイナリーシステム
321ポンプを備えるGilson半分取HPLCシステム、GX-271リキッドハンドラーおよびGilson Trilutionソフトウェアにより制御されるGilson 171 DAD
キラルHPLC精製:
SPD-20A UV検出器を備えるShimadzu LC-20APバイナリーシステム
キラルSFC精製:
Waters SFC200
精製方法A
分取HPLC:[逆相(X-BRIDGE C-18、250×19mm、5μm)、15mL/分、グラジエント0%~50%(18分間)、100%(2分間)、100%~0%(3分間)、移動相(A):水中の5mM炭酸水素アンモニウム+0.1%アンモニア、(B):アセトニトリル:メタノール(50:50)]。
精製方法B
分取HPLC:[逆相(X-BRIDGE C-18、150×19mm、5μm)、15mL/分、グラジエント0%~15%(21分間)、15%~15%(3分間)、100%(2分間)、100%~0%(2分間)、移動相(A):水中の5mM炭酸水素アンモニウム+0.1%アンモニア、(B):100%アセトニトリル]。
精製方法C
分取HPLC:[逆相(Gemini-NX C-18、100×30mm、5μm)、30mL/分、グラジエント40%~60%(8.7分間)、60%(0.5分間)、60%~100%(0.2分間)、100%(1分間)、100%~40%(0.2分間)、40%(0.9分間)、移動相(A):2.5Lの水+水中の5mLの28%アンモニア溶液、(B):100%アセトニトリル]。
精製方法D
分取HPLC:[逆相(X-BRIDGE C-18、250×50mm、5μm)、65mL/分、グラジエント0%~25%(30分間)、25%~25%(1分間)、100%(2分間)、100%~0%(5分間)、移動相(A):水中の5mM炭酸水素アンモニウム+0.1%アンモニア、(B):100%アセトニトリル]。
精製方法E
分取HPLC:[逆相(Gemini-NX C-18、100×30mm、5μm)、30mL/分、グラジエント60%~100%(8.7分間)、100%(1.7分間)、100%~60%(0.2分間)、60%(0.9分間)、移動相(A):2.5Lの水+水中の5mLの28%アンモニア溶液、(B):100%アセトニトリル]。
精製方法F
分取HPLC:[逆相(Kromasil eternity C-18、250×21.2mm、5μm)、15mL/分、グラジエント7%~20%(27分間)、100%(2分間)、100%~7%(3分間)、移動相(A):水中の0.1%トリフルオロ酢酸、(B):100%アセトニトリル]。
精製方法G
分取HPLC:[逆相(X-BRIDGE C-8、150×19mm、5μm)、16mL/分、グラジエント0%~25%(20分間)、25%~25%(3分間)、100%(2分間)、100%~0%(5分間)、移動相(A):水中の5mM炭酸水素アンモニウム+0.1%アンモニア、(B):100%アセトニトリル]。
精製方法H
分取HPLC:[逆相(Gemini-NX C-18、100×30mm、5μm)、30mL/分、グラジエント40%~70%(8.7分間)、70%(0.5分間)、70%~100%(0.2分間)、100%(1分間)、100%~40%(0.2分間)、40%(0.9分間)、移動相(A):2.5Lの水+水中の5mLの28%アンモニア溶液、(B):100%アセトニトリル]。
精製方法I
分取HPLC:[逆相(Gemini-NX C-18、100×30mm、5μm)、30mL/分、グラジエント5%~95%(8.7分間)、95%(0.5分間)、95%~100%(0.2分間)、100%(1分間)、100%~5%(0.2分間)、5%(0.9分間)、移動相(A):2.5Lの水+水中の5mLの28%アンモニア溶液、(B):100%アセトニトリル]。
精製方法J
分取HPLC:[逆相(Gemini-NX C-18、100×30mm、5μm)、30mL/分、グラジエント5%~35%(8.7分間)、35%(0.5分間)、35%~100%(0.2分間)、100%(1分間)、100%~5%(0.2分間)、5%(0.9分間)、移動相(A):2.5Lの水+水中の5mLの28%アンモニア溶液、(B):100%アセトニトリル]。
精製方法K
分取HPLC:[逆相(Gemini-NX C-18、100×30mm、5μm)、30mL/分、グラジエント60%~100%(8.7分間)、100%(1.7分間)、100%~60%(0.2分間)、60%(0.9分間)、移動相(A):2.5Lの水+水中の5mLの28%アンモニア溶液、(B):100%アセトニトリル]。
精製方法L
分取HPLC:[逆相(X-BRIDGE C-18、250×19mm、5μm)、10mL/分、グラジエント0%~20%(30分間)、20%~20%(9分間)、100%(3分間)、100%~0%(8分間)、移動相(A):水中の5mM炭酸水素アンモニウム+0.1%アンモニア、(B):100%アセトニトリル]。
精製方法M
分取HPLC:[逆相(X-BRIDGE C-18、150×19mm、5μm)、13mL/分、グラジエント0%~35%(18分間)、100%(3分間)、100%~0%(4分間)、移動相(A):水中の5mM炭酸水素アンモニウム+0.1%アンモニア、(B):100%アセトニトリル]。
精製方法N
キラルHPLC:[順相(CHIRALPAK IG、250×21mm、5μm)、18mL/分、均一溶媒(A:B)70:30(40分間)、移動相(A):ヘキサン中の0.1%ジエチルアミン、(B):イソプロパノール:メタノール(50:50)中の0.1%ジエチルアミン]。
精製方法O
分取HPLC:[逆相(X-BRIDGE C-18、150×19mm、5μm)、15mL/分、グラジエント10%~35%(20分間)、35%(3分間)、100%(2分間)、100%~10%(3分間)、移動相(A):水中の5mM炭酸水素アンモニウム+0.1%アンモニア、(B):アセトニトリル:メタノール(1:1)]。
精製方法P
SFC:[(CHIRALPAK IC、250×21mm、5μm)、80mL/分、均一溶媒(A:B)65:35(23分間)、移動相(A):100%液体CO2、(B):イソプロパノール:アセトニトリル(50:50)中の0.1%ジエチルアミン]。
精製方法Q
分取HPLC:[逆相(Gemini-NX C-18、100×30mm、5μm)、30mL/分、グラジエント30%~60%(8.7分間)、60%(0.5分間)、60%~100%(0.2分間)、100%(1分間)、100%~30%(0.2分間)、30%(0.9分間)、移動相(A):2.5Lの水+水中の5mLの28%アンモニア溶液、(B):100%アセトニトリル]。
略称
CDI = カルボニルジイミダゾール
DAST = ジエチルアミノ硫黄トリフルオリド
DCM = ジクロロメタン
DIPEA = N,N-ジイソプロピルエチルアミン
ESI = エレクトロスプレーイオン化
EtOAc = 酢酸エチル
h = 時間
H2O = 水
HCl = 塩化水素、塩酸
HPLC = 高速液体クロマトグラフィー
IPA = プロパン-2-ol
Lc = 液体クロマトグラフィー
MeCN = アセトニトリル
MeOH = メタノール
min(s) = 分間
MS = 質量分析法
nm = ナノメートル
NMR = 核磁気共鳴
POCl3 = 塩化ホスホリル
RT = 室温
sat. = 飽和
SFC = 超臨界流体クロマトグラフィー
TEA = トリエチルアミン
TFA = トリフルオロ酢酸
THF = テトラヒドロフラン
TLC = 薄層クロマトグラフィー
中間体の合成:
経路1
中間体12である5-ブロモ-3-(ジフルオロメチル)-1-((2-(トリメチルシリル)エトキシ)メチル)-1H-ピラゾールの調製によって例示される、ピラゾールの調製の典型的な手順
経路2
中間体15である3-(トリフルオロメチル)-1H-ピラゾール-5-カルボン酸の調製によって例示される、ピラゾールの調製の典型的な手順
経路3
中間体22である4-エチル-1-((2-(トリメチルシリル)エトキシ)メチル)-1H-ピラゾールの調製によって例示される、ピラゾールの調製の典型的な手順
中間体22に関するデータは表2にある。
経路4
中間体26であるtert-ブチル(R)-(1-(6-クロロ-2-(2,5-ジメチル-1H-ピロール-1-イル)ピリミジン-4-イル)ピロリジン-3-イル)(メチル)カルバメートの調製によって例示される、ピリミジンの調製の典型的な手順
1H NMR (400 MHz, クロロホルム-d) δ 7.19 (s, 1H), 5.91 (s, 2H), 2.42 (s, 6H).
DCM(20mL)に溶解した4,6-ジクロロ-2-(2,5-ジメチル-1H-ピロール-1-イル)ピリミジン(3.0g、12.4mmol)の溶液に、N,N-ジイソプロピルエチルアミン(6.48mL、37.2mmol)、続いてDCM(20mL)中のtert-ブチル(R)-メチル(ピロリジン-3-イル)カルバメート(中間体3)(2.61g、13.0mmol)を添加した。反応混合物を室温で20時間撹拌し、次いで、水性HCl(1M)の添加によってクエンチし、DCM(×2)を使用して抽出した。合わせた有機相を、相分離器を通してろ過し、減圧下で濃縮した。次いで、残渣を、カラムクロマトグラフィー(シリカ、石油エーテル中の0~25%酢酸エチル)を使用して精製して、tert-ブチル(R)-(1-(6-クロロ-2-(2,5-ジメチル-1H-ピロール-1-イル)ピリミジン-4-イル)ピロリジン-3-イル)(メチル)カルバメート(中間体26)(3.87g、77%)を得た。
経路5
中間体31である1,5-ジメチル-1H-ピラゾール-3-カルボン酸の調製によって例示される、ピラゾールの調製の典型的な手順
LCMS(システム1、方法B):m/z 169(M+H)+(ESI+ve)、1.42分、230nm。
経路6
中間体36である1-(ジフルオロメチル)-4-メチル-1H-ピラゾール-3-カルボン酸の調製によって例示される、ピラゾールの調製の典型的な手順
LCMS(システム3、方法D):m/z 205(M+H)+(ESI+ve)、3.77分、202nm。
経路7
中間体63であるエチル3-(4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)-1H-ピラゾール-1-イル)ピペリジン-1-カルボキシレートの調製によって例示されるピラゾールの調製の典型的な手順
LCMS(システム1、方法B):m/z 202(M+H)+(ESI+ve)、1.50分、202nm。
LCMS(システム1、方法B):m/z 280(M+H)+(ESI+ve)、1.61分、202nm。
LCMS(システム1、方法B):m/z 274/276(M-56+H)+(ESI+ve)、1.82分、230nm。
LCMS(システム2、方法E):m/z 230/232(M+H)+(ESI+ve)、2.54分、230nm。
LCMS(システム1、方法B):m/z 302/304(M+H)+(ESI+ve)、1.67分、233nm。
経路8
中間体71である4-ブロモ-3-エチル-1-(テトラヒドロ-2H-ピラン-2-イル)-1H-ピラゾールの調製によって例示される、ピラゾールの調製の典型的な手順
経路9
中間体88であるベンジルメチル(3-メチルピロリジン-3-イル)カルバメート塩酸塩の調製によって例示される、ピロリジンの調製の典型的な手順
LCMS(システム3、方法D):m/z 333(M-H)-(ESI-ve)、4.68分、202nm。
LCMS(システム3、方法D):m/z 349(M+H)+(ESI+ve)、5.05分、202nm。
経路10
中間体111である4-(ジフルオロメチル)-1-(4-メトキシベンジル)-1H-ピラゾール-3-カルボン酸の調製によって例示される、ピラゾールの調製の典型的な手順
LCMS(システム1、方法B):m/z 289(M+H)+(ESI+ve)、1.61分、275nm。
LCMS(システム1、方法B):m/z 311(M+H)+(ESI+ve)、1.71分、230nm。
経路11
中間体118であるtert-ブチル(R)-(1-(2-アミノ-6-(4-フルオロ-1-((2-(トリメチルシリル)エトキシ)メチル)-1H-ピラゾール-5-イル)ピリミジン-4-イル)ピロリジン-3-イル)(メチル)カルバメートの調製によって例示される、ピリミジンの部分的脱保護の典型的な手順
経路12
中間体121である4-(メチルチオ)-1H-ピラゾール-3-カルボン酸の調製によって例示される、ピラゾールの調製の典型的な手順
LCMS(システム1、方法B):m/z 187(M+H)+(ESI+ve)、1.39分、230nm。
経路13
中間体127である4-メトキシ-5-メチル-1-(テトラヒドロ-2H-ピラン-2-イル)-1H-ピラゾール-3-カルボン酸の調製によって例示される、ピラゾールの調製の典型的な手順。
LCMS(システム1、方法B):m/z 281(M+H)+(ESI+ve)、1.49分、229nm。
LCMS(システム1、方法B):m/z 365(M+H)+(ESI+ve)、1.73分、235nm。
一般合成手順:
経路A
実施例1-1である(R)-4-(3-(メチルアミノ)ピロリジン-1-イル)-6-(1H-ピラゾール-5-イル)ピリミジン-2-アミンの調製によって例示される、ピリミジンの調製の典型的な手順
LCMS(システム1、方法B):m/z 196(M+H)+(ESI+ve)、1.38分、240nm。
LCMS(システム1、方法B):m/z 360(M+H)+(ESI+ve)、1.44分、220nm。
経路B
実施例1-2である(R)-4-(1-メチル-1H-ピラゾール-5-イル)-6-(3-(メチルアミノ)ピロリジン-1-イル)ピリミジン-2-アミン二塩酸塩の調製によって例示される、ピリミジンの調製の典型的な手順
LCMS(システム1、方法A):m/z 374(M+H)+(ESI+ve)、1.40分、296nm。
経路C
実施例2-1である(R)-4-(1-メチル-1H-ピラゾール-3-イル)-6-(3-(メチルアミノ)ピロリジン-1-イル)ピリミジン-2-アミンの調製によって例示される、ピリミジンの調製の典型的な手順
LCMS(システム2、方法E):m/z 374(M+H)+(ESI+ve)、3.31分、254nm。
経路D
実施例2-2である(R)-4-(1-(ジフルオロメチル)-1H-ピラゾール-3-イル)-6-(3-(メチルアミノ)ピロリジン-1-イル)ピリミジン-2-アミン二塩酸塩の調製によって例示される、ピリミジンの調製の典型的な手順
LCMS(システム4、方法F):m/z 245(M+H)+(ESI+ve)、0.14分、254nm。
LCMS(システム4、方法F):m/z 410(M+H)+(ESI+ve)、2.06分、254nm。
経路E
実施例3-1である(R)-4-(3-メチル-1H-ピラゾール-5-イル)-6-(3-(メチルアミノ)ピロリジン-1-イル)ピリミジン-2-アミンの調製によって例示される、ピリミジンの調製の典型的な手順
LCMS(システム2、方法E):m/z 458(M+H)+(ESI+ve)、3.96分、313nm。
経路F
実施例3-3である(R)-4-(3-(ジフルオロメチル)-1H-ピラゾール-5-イル)-6-(3-(メチルアミノ)ピロリジン-1-イル)ピリミジン-2-アミンの調製によって例示される、ピリミジンの調製の典型的な手順
LCMS(システム4、方法F):m/z 540(M+H)+(ESI+ve)、2.70分、254nm。
経路G
実施例3-4である(R)-4-(3-(ジフルオロメチル)-1H-ピラゾール-5-イル)-6-(3-(メチルアミノ)ピロリジン-1-イル)ピリミジン-2-アミンジトリフルオロアセテートの調製によって例示される、ピリミジンの調製の典型的な手順
LCMS(システム2、方法E):m/z 249(M-H)-(ESI-ve)、4.47分、241nm。
LCMS(システム2、方法E):m/z 246(M+H)+(ESI+ve)、3.47分、237nm。
LCMS(システム2、方法E):m/z 230/266(M+H)+(ESI+ve)、4.57分、239nm。
LCMS(システム2、方法E):m/z 428(M+H)+(ESI+ve)、4.13分、243nm。
経路H
実施例4-1である(R)-4-(4-メチル-1H-ピラゾール-5-イル)-6-(3-(メチルアミノ)ピロリジン-1-イル)ピリミジン-2-アミンの調製によって例示される、ピリミジンの調製の典型的な手順
LCMS(システム2、方法E):m/z 294(M+H)+(ESI+ve)、3.53分、234nm。
LCMS(システム2、方法E):m/z 458(M+H)+(ESI+ve)、3.98分、278nm。
経路I
実施例4-2である(R)-4-(4-エチル-1H-ピラゾール-5-イル)-6-(3-(メチルアミノ)ピロリジン-1-イル)ピリミジン-2-アミンの調製によって例示される、ピリミジンの調製の典型的な手順
LCMS(システム4、方法F):m/z 518(M+H)+(ESI+ve)、2.58分、254nm。
経路J
実施例4-3である(R)-4-(4-クロロ-1H-ピラゾール-5-イル)-6-(3-(メチルアミノ)ピロリジン-1-イル)ピリミジン-2-アミンの調製によって例示される、ピリミジンの調製の典型的な手順
LCMS(システム4、方法F):m/z 602/604(M+H)+(ESI+ve)、3.13分、254nm。
経路K
実施例4-4である(R)-4-(4-メトキシ-1H-ピラゾール-5-イル)-6-(3-(メチルアミノ)ピロリジン-1-イル)ピリミジン-2-アミンの調製によって例示される、ピリミジンの調製の典型的な手順
LCMS(システム5、方法H):m/z 598(M+H)+(ESI+ve)、2.21分、205nm。
経路L
実施例7-1である(R)-4-(3,4-ジメチル-1H-ピラゾール-5-イル)-6-(3-(メチルアミノ)ピロリジン-1-イル)ピリミジン-2-アミン二塩酸塩の調製によって例示される、ピリミジンの調製の典型的な手順
LCMS(システム4、方法F):m/z 252(ボロン酸-18)+(ES+)、2.72分、254nm。
LCMS(システム4、方法F):m/z 518(M+H)+(ES+)、2.55分、254nm。
経路M
実施例11-1である((R)-4-(1,3-ジメチル-1H-ピラゾール-4-イル)-6-(3-(メチルアミノ)ピロリジン-1-イル)ピリミジン-2-アミンの調製によって例示される、ピリミジンの調製の典型的な手順
LCMS(システム3、方法D):m/z 388(M+H)+(ESI+ve)、3.53分、202nm。
経路N
実施例11-7である4-(1,3-ジメチル-1H-ピラゾール-4-イル)-6-(3-メチル-3-(メチルアミノ)ピロリジン-1-イル)ピリミジン-2-アミンの調製によって例示される、ピリミジンの調製の典型的な手順
LCMS(システム3、方法E):m/z 436(M+H)+(ESI+ve)、3.83分、247nm。
経路O
実施例11-8である4-(1,3-ジメチル-1H-ピラゾール-4-イル)-6-(オクタヒドロ-6H-ピロロ[3,4-b]ピリジン-6-イル)ピリミジン-2-アミンの調製によって例示される、ピリミジンの調製の典型的な手順
LCMS(システム3、方法D):m/z 414(M+H)+(ESI+ve)、3.75分、254nm。
経路P
実施例14-1である(R)-6-(1,5-ジメチル-1H-ピラゾール-4-イル)-4-(3-(メチルアミノ)ピロリジン-1-イル)ピリジン-2-アミン二塩酸塩の調製によって例示される、ピリジンの調製の典型的な手順
LCMS(システム4、方法F):m/z 387(M+H)+(ES+)、2.07分、254nm。
実施例A
H4アンタゴニスト機能性cAMP Giアッセイ
HEKf細胞を、ヒトH4受容体を発現するバキュロウイルスを使用して終夜感染させ、次いで、1,200rpmで5分間遠心分離し、細胞凍結培地(Sigma-Aldrich, Inc.)で凍結させ、-150℃で保存した。アッセイの当日、細胞を融解し、500nM IBMXを含むHBSSに再懸濁して1,500個の細胞/ウェルの密度を実現した。H4リガンドをDMSO中で調製し、低体積プレートに25nLでLabCyte ECHO音響分注によってスタンプした(stamped)。1ウェル当たり10μLの細胞を、1μMホルスコリンの存在下でプレーティングし、1,200rpmで1分間遠心分離にかけ、30分間インキュベートした後、総体積20μL/ウェルまでCisbio cAMP検出試薬を添加した。アンタゴニストアッセイについて、細胞をH4アンタゴニストリガンドと30分間予備インキュベートした後、EC80濃度のヒスタミンを添加し、さらに30分間インキュベートした。検出試薬を添加し、室温で60分間振とうした後、cAMP蓄積を、PheraStarプレートリーダーでHTRFを使用して測定した。4パラメーターロジスティックフィットの式を使用してアゴニスト効力を定量化してEC50値を生成した。アンタゴニストアッセイデータを使用し、Cheng-Prusoffの等式を使用してpKb値を計算して機能的アンタゴニスト親和性値を生成した。
H4アンタゴニスト機能的動的質量再分布アッセイ
HEKf細胞を、ヒトH4受容体を発現するバキュロウイルスを使用して感染させ、フィブロネクチンでコーティングしたEPICプレートに10,000個の細胞/ウェルの密度でプレーティングし、37℃で終夜インキュベートした。細胞の培地をウェル当たり20mM HEPESを含む30μL HBSSに交換し、LabCyte ECHO音響分注によってウェル当たり30nL DMSOを添加した。室温で2時間平衡化した後、DMSO中で調製した30nLのH4リガンドをLabCyte ECHO音響分注によって、播種したEPICプレートにスタンプし、細胞動的質量再分布を、Corning EPICプレートリーダーを使用してモニタリングした。45分間の測定後、30nL/ウェルのヒスタミンEC80を添加し、モニタリングしてアンタゴニストアッセイデータを得た。最大ベースライン較正応答(pm)を使用して、濃度応答曲線を生成した。4パラメーターロジスティックフィットの式を使用してアゴニスト効力を定量化してEC50値を生成した。アンタゴニストアッセイデータを使用し、Cheng-Prusoffの等式を使用してpKb値を計算して機能的アンタゴニスト親和性値を生成した。
hERGアッセイ
hERGアッセイデータを、以下に詳述する実験プロトコルを使用してMetrion Biosciences、Cambridge、UKによって測定した。
i)単一濃度アッセイの場合、2分間隔で試験濃度毎に5ボーラス添加として単一濃度の試験サンプルを30μMで適用し;または
ii)pIC50アッセイの場合、2分間隔で試験濃度毎に2ボーラス添加として4つの濃度の試験サンプルを1μM~30μMで適用し、
次いで、hERGテール電流振幅への影響を、4分間の記録時間中に測定した。各掃引電圧プロトコルについて、個々の細胞の膜電流およびパッシブ特性をQPatchアッセイソフトウェア(バージョン5.0)によって記録した。初期プレパルスステップから-40mVまでの間に測定した即時漏洩電流に対して試験パルスから-40mVまでの間に誘発されるピーク外向きテール電流振幅を測定した。QC目的で、アッセイに関する最小電流振幅は、ビヒクル時間の終了時に測定して、200pA超のピーク外向き電流である。QPatch分析ソフトウェアにより、各濃度の適用時間の終了時点での最後の3掃引についての平均ピーク電流を計算し、データは、Pipeline Pilot(Biovia、米国)で実行する開発されたバイオインフォマティクススイートを使用してExcelにエクスポートし調査する。テンプレートにより、各試験濃度適用時間に関するパーセント阻害を、対照(すなわちビヒクル)時間の終了時点に測定した値に対する平均ピーク電流または電荷の低下として計算する。各細胞からのパーセント阻害値を使用して、0および100%阻害レベルをそれぞれ非常に低濃度および非常に高濃度で固定し、自由Hill勾配係数を用いる4パラメーターロジスティックフィットを用いる濃度応答曲線を構築する。次いで、Hill勾配が0.5>nH<2.0以内である細胞からのデータのみを含めて、IC50(50%阻害濃度)およびHill係数を測定する。以下に報告されるIC50データは、少なくとも3つの別個の細胞の平均(N≧3)を表す。慣例では、最高濃度で40%超の遮断を実現できなかった試験サンプルは、不十分なまたは制約のないフィットに起因して曖昧なIC50値をもたらすことになる。この場合、試験された最高濃度より0.5 log単位大きい任意のIC50値が戻される。例えば、サンプルが、30μMの最高濃度で40%超の遮断の平均阻害を実証しない場合、100μMのIC50値、すなわち、pIC50≦4.0が報告される。
Claims (23)
- XがNである、請求項1に記載の化合物。
- R1が、Hまたはメチルである、請求項1または請求項2に記載の化合物。
- R2がHである、請求項1から3のいずれか一項に記載の化合物。
- Aが、
から選択される置換されていてもよいピラゾール環である、請求項1から7のいずれか一項に記載の化合物。 - R3が、H、メチル、CF3、CF2H、エチル、シクロプロピル、シクロブチル、CH2CF3、CH2CH2OH、CH2CH2OCH3、CH2CH2CN、CH2CN、オキセタン、エチル-ピペリジン-カルボキシレートから選択され、またはR4およびR3が結合して縮合5員脂肪族環を形成する、請求項8に記載の化合物。
- R4またはR5が、メチル、エチル、シクロプロピル、シクロブチル、プロピル、イソプロピル、CF3、CF2H、フルオロ、クロロ、ブロモ、シアノ、メトキシから選択されるか、またはR4およびR5が結合して縮合5もしくは6員環を形成するか、またはR4およびR3が結合して縮合5員脂肪族環を形成する、請求項8または請求項9に記載の化合物。
- H4受容体活性を有する、請求項1から18のいずれか一項に記載の化合物。
- 低hERG活性を示す、請求項19に記載の化合物。
- 請求項1から20のいずれか一項に記載の化合物、および薬学的に許容される賦形剤を含む医薬組成物。
- 医薬における使用のための、請求項1から21のいずれか一項に記載の化合物または組成物。
- 喘息、慢性掻痒、皮膚炎、関節リウマチ、胃潰瘍発生および大腸炎を含む炎症性障害の処置における使用のための、請求項1から21のいずれか一項に記載の化合物または組成物。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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GBGB1817047.2A GB201817047D0 (en) | 2018-10-19 | 2018-10-19 | H4 antagonist compounds |
GB1817047.2 | 2018-10-19 | ||
PCT/GB2019/052997 WO2020079457A1 (en) | 2018-10-19 | 2019-10-21 | Pyrazole derivatives as h4 antagonist compounds |
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JP2022507013A true JP2022507013A (ja) | 2022-01-18 |
JPWO2020079457A5 JPWO2020079457A5 (ja) | 2022-10-31 |
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JP2021521390A Pending JP2022507013A (ja) | 2018-10-19 | 2019-10-21 | H4アンタゴニスト化合物としてのピラゾール誘導体 |
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US (1) | US20210300906A1 (ja) |
EP (1) | EP3867248A1 (ja) |
JP (1) | JP2022507013A (ja) |
KR (1) | KR20210079318A (ja) |
CN (1) | CN113272297B (ja) |
AU (1) | AU2019360428B2 (ja) |
BR (1) | BR112021007372A2 (ja) |
CA (1) | CA3116628A1 (ja) |
GB (1) | GB201817047D0 (ja) |
MX (1) | MX2021004280A (ja) |
SG (1) | SG11202103133QA (ja) |
WO (1) | WO2020079457A1 (ja) |
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GB202005858D0 (en) * | 2020-04-22 | 2020-06-03 | Heptares Therapeutics Ltd | H4 Antagonist compounds |
KR102655210B1 (ko) * | 2021-03-26 | 2024-04-08 | 주식회사 스탠다임 | 아데노신 a2a 수용체 길항제 및 이의 용도 |
WO2023068200A1 (ja) * | 2021-10-19 | 2023-04-27 | ユニマテック株式会社 | 含フッ素ピラゾール化合物およびその製造方法 |
KR102621694B1 (ko) * | 2022-09-15 | 2024-01-08 | 주식회사 스탠다임 | 아데노신 a2a 수용체 길항제 및 이의 용도 |
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AU4800299A (en) * | 1998-07-24 | 2000-02-14 | Daiichi Pharmaceutical Co., Ltd. | Pyrazole derivatives and salts thereof |
WO2005054239A1 (en) * | 2003-12-05 | 2005-06-16 | Bayer Healthcare Ag | 2-aminopyrimidine derivatives |
NL2000323C2 (nl) * | 2005-12-20 | 2007-11-20 | Pfizer Ltd | Pyrimidine-derivaten. |
ES2548141T3 (es) * | 2008-11-20 | 2015-10-14 | Glaxosmithkline Llc | Compuestos químicos |
-
2018
- 2018-10-19 GB GBGB1817047.2A patent/GB201817047D0/en not_active Ceased
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2019
- 2019-10-21 CN CN201980084053.7A patent/CN113272297B/zh active Active
- 2019-10-21 EP EP19794235.2A patent/EP3867248A1/en active Pending
- 2019-10-21 WO PCT/GB2019/052997 patent/WO2020079457A1/en active Application Filing
- 2019-10-21 SG SG11202103133QA patent/SG11202103133QA/en unknown
- 2019-10-21 MX MX2021004280A patent/MX2021004280A/es unknown
- 2019-10-21 CA CA3116628A patent/CA3116628A1/en active Pending
- 2019-10-21 US US17/285,776 patent/US20210300906A1/en active Pending
- 2019-10-21 BR BR112021007372-8A patent/BR112021007372A2/pt unknown
- 2019-10-21 AU AU2019360428A patent/AU2019360428B2/en active Active
- 2019-10-21 KR KR1020217014805A patent/KR20210079318A/ko unknown
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CA3116628A1 (en) | 2020-04-23 |
BR112021007372A2 (pt) | 2021-07-20 |
EP3867248A1 (en) | 2021-08-25 |
AU2019360428B2 (en) | 2024-05-09 |
GB201817047D0 (en) | 2018-12-05 |
AU2019360428A1 (en) | 2021-04-29 |
WO2020079457A1 (en) | 2020-04-23 |
MX2021004280A (es) | 2021-05-31 |
CN113272297B (zh) | 2024-03-19 |
KR20210079318A (ko) | 2021-06-29 |
US20210300906A1 (en) | 2021-09-30 |
CN113272297A (zh) | 2021-08-17 |
SG11202103133QA (en) | 2021-05-28 |
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