JP2009539851A - 置換ピラゾロ[1,5−a]ピリジン化合物およびその使用方法 - Google Patents
置換ピラゾロ[1,5−a]ピリジン化合物およびその使用方法 Download PDFInfo
- Publication number
- JP2009539851A JP2009539851A JP2009514381A JP2009514381A JP2009539851A JP 2009539851 A JP2009539851 A JP 2009539851A JP 2009514381 A JP2009514381 A JP 2009514381A JP 2009514381 A JP2009514381 A JP 2009514381A JP 2009539851 A JP2009539851 A JP 2009539851A
- Authority
- JP
- Japan
- Prior art keywords
- substituted
- pyrazolo
- pyridin
- pyridine
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 238000000034 method Methods 0.000 title claims abstract description 83
- DVUBDHRTVYLIPA-UHFFFAOYSA-N pyrazolo[1,5-a]pyridine Chemical class C1=CC=CN2N=CC=C21 DVUBDHRTVYLIPA-UHFFFAOYSA-N 0.000 title claims abstract description 59
- 150000001875 compounds Chemical class 0.000 claims abstract description 231
- -1 pyrazolo [1,5-a] pyridine compound Chemical class 0.000 claims abstract description 166
- 208000004296 neuralgia Diseases 0.000 claims abstract description 39
- 208000021722 neuropathic pain Diseases 0.000 claims abstract description 38
- 208000019695 Migraine disease Diseases 0.000 claims abstract description 4
- 206010027599 migraine Diseases 0.000 claims abstract description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 99
- 208000002193 Pain Diseases 0.000 claims description 48
- 230000036407 pain Effects 0.000 claims description 45
- 125000003118 aryl group Chemical group 0.000 claims description 44
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 41
- 125000001424 substituent group Chemical group 0.000 claims description 38
- 239000003814 drug Substances 0.000 claims description 36
- 125000003545 alkoxy group Chemical group 0.000 claims description 26
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 26
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 24
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 24
- 125000002252 acyl group Chemical group 0.000 claims description 23
- 125000003107 substituted aryl group Chemical group 0.000 claims description 23
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 22
- 125000000962 organic group Chemical group 0.000 claims description 19
- 229920006395 saturated elastomer Polymers 0.000 claims description 19
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 19
- 125000004001 thioalkyl group Chemical group 0.000 claims description 19
- WSNMPAVSZJSIMT-UHFFFAOYSA-N COc1c(C)c2COC(=O)c2c(O)c1CC(O)C1(C)CCC(=O)O1 Chemical group COc1c(C)c2COC(=O)c2c(O)c1CC(O)C1(C)CCC(=O)O1 WSNMPAVSZJSIMT-UHFFFAOYSA-N 0.000 claims description 18
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 17
- 125000003342 alkenyl group Chemical group 0.000 claims description 16
- 125000000304 alkynyl group Chemical group 0.000 claims description 16
- 125000005000 thioaryl group Chemical group 0.000 claims description 15
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 claims description 14
- 125000004104 aryloxy group Chemical group 0.000 claims description 14
- 125000000524 functional group Chemical group 0.000 claims description 14
- 125000005843 halogen group Chemical group 0.000 claims description 13
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 13
- 229910052760 oxygen Inorganic materials 0.000 claims description 13
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 12
- 238000004519 manufacturing process Methods 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 12
- 230000009467 reduction Effects 0.000 claims description 12
- 125000005017 substituted alkenyl group Chemical group 0.000 claims description 12
- 125000004426 substituted alkynyl group Chemical group 0.000 claims description 12
- LENLQGBLVGGAMF-UHFFFAOYSA-N tributyl([1,2,4]triazolo[1,5-a]pyridin-6-yl)stannane Chemical compound C1=C([Sn](CCCC)(CCCC)CCCC)C=CC2=NC=NN21 LENLQGBLVGGAMF-UHFFFAOYSA-N 0.000 claims description 11
- 229910052799 carbon Inorganic materials 0.000 claims description 10
- 239000003795 chemical substances by application Substances 0.000 claims description 10
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 230000004968 inflammatory condition Effects 0.000 claims description 9
- 208000033808 peripheral neuropathy Diseases 0.000 claims description 9
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 8
- 150000002148 esters Chemical class 0.000 claims description 8
- JLKPIOQFGACSJO-UHFFFAOYSA-N 2-amino-1-(2-propan-2-ylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one Chemical compound C1=CC=CC2=C(C(=O)C(C)N)C(C(C)C)=NN21 JLKPIOQFGACSJO-UHFFFAOYSA-N 0.000 claims description 7
- 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 claims description 7
- 229910052736 halogen Inorganic materials 0.000 claims description 7
- 150000002367 halogens Chemical class 0.000 claims description 7
- LVPUMCMRDDQXQP-UHFFFAOYSA-N n-[1-[2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-methylpropylidene]hydroxylamine Chemical compound N=1N2C=CC=CC2=C(C(=NO)C(C)C)C=1C1=CC=C(F)C=C1 LVPUMCMRDDQXQP-UHFFFAOYSA-N 0.000 claims description 7
- 201000001119 neuropathy Diseases 0.000 claims description 7
- 230000007823 neuropathy Effects 0.000 claims description 7
- ANXOZVKTXWJGOY-UHFFFAOYSA-N 2-aminoethanone Chemical compound NC[C]=O ANXOZVKTXWJGOY-UHFFFAOYSA-N 0.000 claims description 6
- UAVFCYBJMKCBAU-UHFFFAOYSA-N 2-aminopropan-1-one Chemical compound CC(N)[C]=O UAVFCYBJMKCBAU-UHFFFAOYSA-N 0.000 claims description 6
- SYJPAKDNFZLSMV-UHFFFAOYSA-N 2-methylpropanal oxime Chemical compound CC(C)C=NO SYJPAKDNFZLSMV-UHFFFAOYSA-N 0.000 claims description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
- 206010061218 Inflammation Diseases 0.000 claims description 6
- 206010028980 Neoplasm Diseases 0.000 claims description 6
- UXZJMNJRHFIRKA-UHFFFAOYSA-N [[2-methyl-1-(2-propan-2-ylpyrazolo[1,5-a]pyridin-3-yl)propylidene]amino] carbamate Chemical compound C1=CC=CC2=C(C(=NOC(N)=O)C(C)C)C(C(C)C)=NN21 UXZJMNJRHFIRKA-UHFFFAOYSA-N 0.000 claims description 6
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 230000004054 inflammatory process Effects 0.000 claims description 6
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
- 125000005415 substituted alkoxy group Chemical group 0.000 claims description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 6
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 6
- ZVIYTHIXIJASHB-UHFFFAOYSA-N (2-methylpropylideneamino) carbamate Chemical compound CC(C)C=NOC(N)=O ZVIYTHIXIJASHB-UHFFFAOYSA-N 0.000 claims description 5
- IFNVZEWSEBGDLY-UHFFFAOYSA-N 2-propan-2-yl-3-pyridin-4-ylpyrazolo[1,5-a]pyridine Chemical compound CC(C)C1=NN2C=CC=CC2=C1C1=CC=NC=C1 IFNVZEWSEBGDLY-UHFFFAOYSA-N 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 5
- 201000011510 cancer Diseases 0.000 claims description 5
- 238000002512 chemotherapy Methods 0.000 claims description 5
- 125000004122 cyclic group Chemical group 0.000 claims description 5
- 230000008569 process Effects 0.000 claims description 5
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
- RYDOQJPDRXMRRP-UHFFFAOYSA-N 2-methylpropan-1-one Chemical compound CC(C)[C]=O RYDOQJPDRXMRRP-UHFFFAOYSA-N 0.000 claims description 4
- 208000001640 Fibromyalgia Diseases 0.000 claims description 4
- 238000005863 Friedel-Crafts acylation reaction Methods 0.000 claims description 4
- 150000001721 carbon Chemical group 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- OXFSTTJBVAAALW-UHFFFAOYSA-N 1,3-dihydroimidazole-2-thione Chemical compound SC1=NC=CN1 OXFSTTJBVAAALW-UHFFFAOYSA-N 0.000 claims description 3
- 206010003694 Atrophy Diseases 0.000 claims description 3
- 208000032131 Diabetic Neuropathies Diseases 0.000 claims description 3
- XQFRJNBWHJMXHO-RRKCRQDMSA-N IDUR Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(I)=C1 XQFRJNBWHJMXHO-RRKCRQDMSA-N 0.000 claims description 3
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 3
- 230000037444 atrophy Effects 0.000 claims description 3
- 125000003917 carbamoyl group Chemical class [H]N([H])C(*)=O 0.000 claims description 3
- 230000008030 elimination Effects 0.000 claims description 3
- 238000003379 elimination reaction Methods 0.000 claims description 3
- 125000001475 halogen functional group Chemical group 0.000 claims description 3
- 125000005059 halophenyl group Chemical group 0.000 claims description 3
- 150000003230 pyrimidines Chemical group 0.000 claims description 3
- 230000011514 reflex Effects 0.000 claims description 3
- 230000002889 sympathetic effect Effects 0.000 claims description 3
- 208000011580 syndromic disease Diseases 0.000 claims description 3
- 206010044652 trigeminal neuralgia Diseases 0.000 claims description 3
- 229910052721 tungsten Inorganic materials 0.000 claims description 3
- 208000026251 Opioid-Related disease Diseases 0.000 claims description 2
- 206010036376 Postherpetic Neuralgia Diseases 0.000 claims description 2
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 2
- 208000028867 ischemia Diseases 0.000 claims description 2
- 201000005040 opiate dependence Diseases 0.000 claims description 2
- 230000001568 sexual effect Effects 0.000 claims description 2
- 230000000472 traumatic effect Effects 0.000 claims description 2
- 125000001589 carboacyl group Chemical group 0.000 claims 6
- 238000010276 construction Methods 0.000 claims 2
- 150000003222 pyridines Chemical class 0.000 claims 2
- UXGVCEOWAWTYJZ-UHFFFAOYSA-N C(C)(C)C1=NN2C(C=CC=C2)=C1C=1N=CSC1 Chemical compound C(C)(C)C1=NN2C(C=CC=C2)=C1C=1N=CSC1 UXGVCEOWAWTYJZ-UHFFFAOYSA-N 0.000 claims 1
- 206010013754 Drug withdrawal syndrome Diseases 0.000 claims 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims 1
- 150000002431 hydrogen Chemical class 0.000 claims 1
- 230000000269 nucleophilic effect Effects 0.000 claims 1
- 150000003254 radicals Chemical class 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 89
- 230000015572 biosynthetic process Effects 0.000 abstract description 87
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 156
- 239000000203 mixture Chemical class 0.000 description 132
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 106
- 239000000243 solution Substances 0.000 description 93
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 60
- 235000019439 ethyl acetate Nutrition 0.000 description 57
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 57
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 42
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 42
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 42
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 42
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 38
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- 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
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Abstract
Description
本願は、2006年6月6日に出願された、米国仮特許出願第60/811,604号に対する優先権の利益を主張し、この出願の内容は、したがってその全体を明確に本明細書中に参考として援用される。
本発明は、一般に、置換ピラゾロ[1,5−a]ピリジン化合物およびそれらの組成物、ならびに特にそのような化合物を製造および使用するための方法に関する。
イブジラスト、(3−イソブチリル−2−イソプロピルピラゾロ[1,5−a]ピリジン)は、日本および韓国において長年にわたり気管支喘息の治療ならびに脳卒中後めまいなどの脳血管障害の治療のために使用されてきた小分子薬である。イブジラストは、これらの国々ではKetas(登録商標)の商標名で販売されている。日本におけるイブジラストについての販売適応には、血管拡張剤としての使用、アレルギーの治療、眼組織再生、眼疾患、およびアレルギー性眼疾患の治療が含まれる(Thompson Current Drug Reports)。慢性脳梗塞(ClinicalTrials.gov)および多発性硬化症(News.Medical.Net;Pharmaceutical News, 2 Aug 2005)の両方の治療におけるその使用は、現在は別個の進行中の臨床試験で調査中である。
本発明は、一般に、置換ピラゾロ[1,5−a]ピリジン化合物に向けられる。本発明の化合物は、特に神経因性疼痛および偏頭痛などの状態の治療において特に有用である。
R2は、独立してH、またはアルキル、置換アルキル、アリール、置換アリール、アルケニル、置換アルケニル、アルキニル、置換アルキニル、ヒドロキシ、スルフヒドリル、アルコキシ、置換アルコキシ、アリールオキシ、置換アリールオキシ、カルバモイルオキシ、チオアルキル、置換チオアルキル、カルバモイルチオ、チオアリール、置換チオアリール、アミノ、およびカルバモイルアミノからなる群から選択される有機基である;
R3は、独立してH、またはアルキル、置換アルキル、アリール、置換アリール、アルケニル、置換アルケニル、アルキニル、および置換アルキニルからなる群から選択される有機基である;および
R6は、独立してH、またはヒドロキシ、スルフヒドリル、アルコキシ、アリールオキシ、チオアルキル、チオアリール、アミノ、ハロゲン、アルキル、アルケニル、アルキニル、アリール、シアノ、カルボキシル、およびカルボキサミドからなる群から選択される有機基である。具体的なカルボキサミド部分には、直鎖状アミド部分、ならびにラクタム、モルホリンアミド、テトラヒドロキノリンアミド、テトラヒドロイソキノリンアミド、クマリンアミドなどの両方が含まれる。
本発明を詳細に記載する前に、本発明は、添付の明細書、実施例および図面から明白であるように、それ自体が変動する可能性があるので、特定の実施形態には限定されないことを理解されたい。
本発明は、一般に、置換ピラゾロ[1,5−a]ピリジン化合物を包含する。標準的なインビトロおよびインビボアッセイの両方における結果に基づいて、本発明の化合物は、神経因性疼痛を治療する際に、ならびに炎症を治療する際に有効であることが見いだされている。さらに、本発明の所定の化合物は、ホスホジエステラーゼの阻害剤である。以下では、これに続くセクションにおいて本発明のこれらやその他の特徴を説明しよう。
R3は、独立してH、またはアルキル、置換アルキル、アリール、置換アリール、アルケニル、置換アルケニル、アルキニル、および置換アルキニルからなる群から選択される有機基である;および
R6は、独立してH、またはヒドロキシ、スルフヒドリル、アルコキシ、アリールオキシ、チオアルキル、チオアリール、アミノ、ハロゲン、アルキル、アルケニル、アルキニル、アリール、シアノ、カルボキシル、およびカルボキサミドからなる群から選択される有機基である。具体的なカルボキサミド部分には、直鎖状アミノ部分、ならびにラクタム、モルホリンアミド、テトラヒドロキノリンアミド、テトラヒドロイソキノリンアミド、クマリンアミドなどが含まれる。好ましくは、R6はHである。
本発明の2,3,6−置換ピラゾロ[1,5−a]ピリジン化合物は、従来型の有機化学合成技術を用いて調製される。具体的な合成は、本明細書の少なくとも実施例1〜71および75〜78に提供されている。
上述したような標準動物モデルを用いた試験結果に基づいて、本発明者らは、所定の置換ピラゾロ[1,5−a]ピリジンの投与は、驚くべきことに神経因性疼痛の重症度の測定可能な減少を提供することに、および詳細には、機械的異痛症などの所定のタイプの神経因性疼痛の重症度の測定可能な減少を提供することに有効であることを見出した。さらに、本明細書に提供される所定の化合物は、リポ多糖誘導性サイトカイン産生を阻害することに、そこで炎症状態を治療する際にそれらの有効性の適応を提供することに特に有効である。さらに、本発明の所定の化合物は、有効なホスホジエステラーゼ阻害剤である。そこで、本明細書に提供される薬理学的データ(表2を参照)に基づいて、本発明の化合物は以下の状態の1つまたは複数を治療する際に特に有効であると考えられる。
本明細書に提供した化合物の潜在的治療使用を評価するためには、標準的インビトロおよびインビボモデルを使用できる。例えば、任意の1つまたは複数の以下の標準的疼痛モデルは、例えば本明細書に記載した神経因性疼痛を治療するための化合物の能力を評価するために使用できる。
本発明の化合物は、全身性もしくは局所性のいずれかで投与できる。そのような投与経路には、経口、動脈内、クモ膜下腔、髄腔内、筋肉内、腹腔内、静脈内、鼻腔内、皮下、および吸入経路が含まれるがそれらに限定されない。
治療量は、経験によって決定することができ、そして治療される特定の状態、被験者、ならびに組成物中に含有される活性物質各々の有効性および毒性に伴って変動するであろう。投与される実際用量は、被験者の年齢、体重、および全身状態、ならびに治療される状態の重症度、医療従事者の判断、および投与される特定の置換ピラゾロ[1,5−a]ピリジンに依存して変動するであろう。
本発明の置換ピラゾロ[1,5−a]ピリジンを含むことに加えて、本発明の治療用調製物は任意で以下に記載する1つまたは複数の追加の成分を含有していてよい。
本明細書に記載した組成物は、すべてのタイプの調製物を、そして詳細には全身性もしくはクモ膜下投与のために適合する調製物を包含している。経口製剤には、錠剤、ロゼンジ剤、カプセル剤、シロップ剤、経口懸濁剤、エマルジョン剤、顆粒剤、およびペレット剤が含まれる。代替調製物には、エアロゾル剤、経皮パッチ、ゲル剤、クリーム剤、軟膏剤、坐剤、復元できる散剤もしくは凍結乾燥剤、ならびに液剤が含まれる。例えば注射前に固体組成物を復元するために適切な希釈剤の例には、注射用静菌水、5%デキストロース水溶液、リン酸緩衝食塩液、リンガー液、食塩液、無菌水、脱イオン水、およびそれらの組み合わせが含まれる。液状医薬組成物に関しては、液剤および懸濁剤が想定されている。好ましくは、本発明の組成物は、経口投与のために適合する組成物である。
添付の実施例において言及したすべての化学試薬、溶媒などは、他に指示しない限り、市販で入手できる。全NMRデータは、Bruker社またはVarian社によって製造された300MHzのNMR分析計によって生成した。
2−アミノ−1−(2−イソプロピルピラゾロ[1,5−a]ピリジン−3−イル)エタノンの合成
2−アミノ−1−(2−イソプロピルピラゾロ[1,5−a]ピリジン−3−イル)プロパン−1−オンの合成
1−(2−イソプロピルピラゾロ[1,5−a]ピリジン−3−イル)−2−メチルプロパン−1−オンオキシムの合成
1−(2−イソプロピルピラゾロ[1,5−a]ピリジン−3−イル)−2−メチルプロパン−1−オン−O−カルバモイルオキシムの合成
2−メチル−1−(2−フェニルピラゾロ[1,5−a]ピリジン−3−イル)プロパン−1−オン
2−メチル−1−(2−フェニルピラゾロ[1,5−a]ピリジン−3−イル)プロパン−1−オンオキシムの合成
2−メチル−1−(2−フェニルピラゾロ[1,5−a]ピリジン−3−イル)プロパン−1−オン−O−カルバモイルオキシムの合成
1−(2−(4−フルオロフェニル)ピラゾロ[1,5−a]ピリジン−3−イル)−2−メチルプロパン−1−オンの合成
1−(2−(4−フルオロフェニル)ピラゾロ[1,5−a]ピリジン−3−イル)−2−メチルプロパン−1−オンオキシムの合成
1−(2−(4−フルオロフェニル)ピラゾロ[1,5−a]ピリジン−3−イル)−2−メチルプロパン−1−オン−O−カルバモイルオキシムの合成
1−(2−(4−メトキシフェニル)ピラゾロ[1,5−a]ピリジン−3−イル)−2−メチルプロパン−1−オンの合成
1−(2−(4−メトキシフェニル)ピラゾロ[1,5−a]ピリジン−3−イル)−2−メチルプロパン−1−オンオキシムの合成
1−(2−(4−メトキシフェニル)ピラゾロ[1,5−a]ピリジン−3−イル)−2−メチルプロパン−1−オン−O−カルバモイルオキシムの合成
1−(2−(4−クロロフェニル)ピラゾロ[1,5−a]ピリジン−3−イル)−2−メチルプロパン−1−オンの合成
1−(2−(4−クロロフェニル)ピラゾロ[1,5−a]ピリジン−3−イル)−2−メチルプロパン−1−オンオキシムの合成
1−(2−(4−クロロフェニル)ピラゾロ[1,5−a]ピリジン−3−イル)−2−メチルプロパン−1−オン−O−カルバモイルオキシムの合成
(4−クロロフェニル)(2−イソプロピルピラゾロ[1,5−a]ピリジン−3−イル)メタノンの合成
(2−イソプロピルピラゾロ[1,5−a]ピリジン−3−イル)(4−メトキシフェニル)メタノンの合成
1−(2−(4−フルオロフェニル)−6−(トリフルオロメチル)ピラゾロ[1,5−a]ピリジン−3−イル)−2−メチルプロパン−1−オンの合成
1−(2−イソプロピルピラゾロ[1,5−a]ピリジン−3−イル)プロパン−1−オンの合成
1−(2−イソプロピルピラゾロ[1,5−a]ピリジン−3−イル)−2−メチルプロパン−1−オールの合成
1−(2−イソプロピル−4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジン−3−イル)−2−メチルプロパン−1−アミンの合成
1−(2−イソプロピルピラゾロ[1,5−a]ピリジン−3−イル)−2−モルホリノプロパン−1−オン塩酸塩の合成
1−(2−イソプロピルピラゾロ[1,5−a]ピリジン−3−イル)−2−(4−メチルピペラジン−1−イル)プロパン−1−オン塩酸塩の合成
1−(2−イソプロピルピラゾロ[1,5−a]ピリジン−3−イル)−2−(ピペリジン−1−イル)プロパン−1−オン塩酸塩の合成
1−(2−イソプロピルピラゾロ[1,5−a]ピリジン−3−イル)−2−(ピペラジン−1−イル)プロパン−1−オン塩酸塩の合成
(3−クロロピリジン−2−イル)(2−イソプロピルピラゾロ[1,5−a]ピリジン−3−イル)メタノンの合成
2−アミノ−1−(2−イソプロピルピラゾロ[1,5−a]ピリジン−3−イル)−2−フェニルエタノンの合成
1−(2−エチルピラゾロ[1,5−a]ピリジン−3−イル)プロパン−1−オンの合成
2−(ベンジル(メチル)アミノ)−1−(2−イソプロピルピラゾロ[1,5−a]ピリジン−3−イル)プロパン−1−オンの合成
1−(2−イソプロピルピラゾロ[1,5−a]ピリジン−3−イル)−2−(メチルアミノ)プロパン−1−オン塩酸塩の合成
N−(1−(2−イソプロピルピラゾロ[1,5−a]ピリジン−3−イル)−2−メチルプロピル)シクロプロパンアミンの合成
N−(シクロプロピルメチル)−1−(2−イソプロピルピラゾロ[1,5−a]ピリジン−3−イル)−2−メチルプロパン−1−アミン塩酸塩の合成
2−(シクロプロピルアミノ)−1−(2−イソプロピルピラゾロ[1,5−a]ピリジン−3−イル)プロパン−1−オン塩酸塩の合成
1−(2−イソプロピルピラゾロ[1,5−a]ピリジン−3−イル)−2−メチルプロパン−1−アミン塩酸塩の合成
2−アミノ−1−(2−(4−フルオロフェニル)ピラゾロ[1,5−a]ピリジン−3−イル)プロパン−1−オン塩酸塩の合成
シクロプロピル(2−イソプロピルピラゾロ[1,5−a]ピリジン−3−イル)メタノンの合成
シクロプロピル(2−シクロプロピルピラゾロ[1,5−a]ピリジン−3−イル)メタノンの合成
1−(2−メトキシピラゾロ[1,5−a]ピリジン−3−イル)−2−メチルプロパン−1−オンの合成
2−アミノ−1−(2−メトキシピラゾロ[1,5−a]ピリジン−3−イル)プロパン−1−オンの合成
2−アミノ−1−(2−イソプロピルピラゾロ[1,5−a]ピリジン−3−イル)ブタン−1−オンの合成
2−アミノ−1−(2−イソプロピルピラゾロ[1,5−a]ピリジン−3−イル)−4−メチルペンタン−1−オンの合成
1−(2−(4−フルオロフェニル)ピラゾロ[1,5−a]ピリジン−3−イル)プロパン−1−オンの合成
1−(2−(ジメチルアミノ)ピラゾロ[1,5−a]ピリジン−3−イル)−2−メチルプロパン−1−オンの合成
2−アミノ−1−(2−(ジメチルアミノ)ピラゾロ[1,5−a]ピリジン−3−イル)プロパン−1−オンの合成
2−アミノ−1−(2−イソプロピルピラゾロ[1,5−a]ピリジン−3−イル)ヘキサン−1−オンの合成
2−アミノ−1−(2−イソプロピルピラゾロ[1,5−a]ピリジン−3−イル)−3−メトキシプロパン−1−オンの合成
(Z)−2−(ヒドロキシイミノ)−1−(2−イソプロピルピラゾロ[1,5−a]ピリジン−3−イル)プロパン−1−オンの合成
4−(2−イソプロピルピラゾロ[1,5−a]ピリジン−3−イル)−1H−イミダゾール−2(3H)−チオンの合成
4−(2−イソプロピルピラゾロ[1,5−a]ピリジン−3−イル)チアゾール−2(5H)−イミンの合成
1−(2−イソプロピルピラゾロ[1,5−a]ピリジン−3−イル)−1−オキソプロパン−2−イルアセテートの合成
2−ヒドロキシ−1−(2−イソプロピルピラゾロ[1,5−a]ピリジン−3−イル)プロパン−1−オンの合成
1−(2−イソプロピルピラゾロ[1,5−a]ピリジン−3−イル)−2−メトキシプロパン−1−オンの合成
2−イソプロピルピラゾロ[1,5−a]ピリジン−3−カルボアルデヒドの合成
(E)−2−((2−イソプロピルピラゾロ[1,5−a]ピリジン−3−イル)メチレン)ヒドラジン−カルボキサミドの合成
S−1−(2−イソプロピルピラゾロ[1,5−a]ピリジン−3−イル)−1−オキソプロパン−2−イルエタンチオエートの合成
2−イソプロピルピラゾロ[1,5−a]ピリジン−3−カルボン酸の合成
1−(2−イソプロピルピラゾロ[1,5−a]ピリジン−3−イル)エタノンの合成
3−(2−イソプロピル−ピラゾロ[1,5−a]ピリジン−3−イル)−フェニルアミンの合成
化合物1100〜1104および1111〜1112を合成するために利用したSuzuki反応のための一般合成方法は、以下に提供されている。下記に示した特定の合成は、化合物1100についてである。
工程2。2−イソプロピル−ピラゾロ[1,5−a]ピリジン(18.42g、115mmol)およびN−ヨードスクシンイミド(28.45g、126mmol)を1,2−ジクロロエタン(300mL)およびテトラヒドロフラン(300mL)の混合液中に溶解させた。この混合液を還流で18時間攪拌した。この混合液を冷却して真空で濃縮した。粗物質をシリカゲルフラッシュクロマトグラフィー(ヘキサン中の0〜20%の酢酸エチル)によって精製すると、30.9g(94%)の3−ヨード−2−イソプロピル−ピラゾロ[1,5−a]ピリジンが得られた。1H−NMR(250MHz,CDCl3)δ8.36(d,J=7.0Hz,1H),7.36(d,J=9.0Hz,1H),7.12(t,J=7.9Hz,1H),6.67(t,J=7.6Hz,1H),3.20(sept,J=7.0Hz,1H),1.37(d,J=6.8Hz,6H).
工程3。20mLのマイクロ波反応バイアルに3−ヨード−2−イソプロピル−ピラゾロ[1,5−a]ピリジン(690mg、2.41mmol)、3−アミノフェニルボロン酸一水和物(411mg、2.65mmol)、ジクロロメタン(197mg、0.24mmol)との[1,1’−ビス(ジフェニルホスフィノ)フェロセン]ジクロロパラジウム(II)複合体、アセトニトリル(8mL)、および1MのNa2CO3水溶液(5mL)を加えた。この混合液を140℃で2時間にわたりマイクロ波反応器内へ配置した。この反応混合液を真空で濃縮し、粗物質をジクロロメタンと水との間に分配させた。有機相を分離し、硫酸ナトリウムの上方に通して乾燥させ、濾過し、そして真空で濃縮した。粗物質をシリカゲルフラッシュクロマトグラフィー(ヘキサン中の0〜30%の酢酸エチル)によって精製すると、205mg(34%)の3−(2−イソプロピル−ピラゾロ[1,5−a]ピリジン−3−イル)−フェニルアミンが得られた。1H−NMR(250MHz,DMSO−d6)δ8.40(d,J=7.0Hz,1H),7.44(d,J=9.0Hz,1H),7.25−7.18(m,1H),7.03−6.97(m,1H),6.81(d,J=7.3Hz,1H),6.71(s,1H),6.67−6.62(m,2H),3.65(broad s,2H),3.35(sept,J=6.9Hz,1H),1.35(d,J=6.8Hz,6H). LC/MS 252.3 m/z(M+H+).化合物1100。
4−(2−イソプロピル−ピラゾロ[1,5−a]ピリジン−3−イル)−フェニルアミンの合成
2−イソプロピル−3−(4−モルホリン−4−イル−フェニル)−ピラゾロ[1,5−a]ピリジンの合成
2−イソプロピル−3−ピリジン−4−イル−ピラゾロ[1,5−a]ピリジンの合成
2−イソプロピル−3−(1H−ピラゾール−4−イル)−ピラゾロ[1,5−a]ピリジンの合成
2−イソプロピル−3−ピリジン−3−イル−ピラゾロ[1,5−a]ピリジンの合成
2−イソプロピル−3−(1−メチル−1H−ピラゾール−4−イル)−ピラゾロ[1,5−a]ピリジンの合成
イソプロピル−[4−(2−イソプロピルピラゾロ[1,5−a]ピリジン−3−イル)−ピリミジン−2−イル]−アミンの合成
化合物1137、1139、および1134〜1136を合成するために利用した一般化方法は、下記に提供されている。下記のスキームは、化合物1137の合成を示している。
工程2。1−(2−イソプロピル−ピラゾロ[1,5−a]ピリジン−3−イル)−エタノン(7.56g、3.74mmol)およびN,N−ジメチルホルムアミドジメチルアセタール(80mL)を結合し、還流させながら24時間攪拌した。この反応混合液を真空で濃縮し、濃縮した反応混合液に新鮮N,N−ジメチルホルムアミドジメチルアセタール(80mL)を加え、攪拌させながら24時間攪拌した。この反応混合液を真空でもう一度濃縮し、濃縮した反応混合液にN,N−ジメチルホルムアミドジメチルアセタールの第3部分(80mL)を加え、攪拌させながら3度目の24時間にわたり攪拌した。反応混合液を真空で濃縮し、粗物質をシリカゲルフラッシュクロマトグラフィー(ジクロロメタン中で0〜40%アセトン)により精製すると、E−3−ジメチルアミノ−1−(2−イソプロピル−ピラゾロ[1,5−a]ピリジン−3−イル)−プロペノンおよびZ−3−ジメチルアミノ−1−(2−イソプロピル−ピラゾロ[1,5−a]ピリジン−3−イル)−プロペノンの4.30g(44%)の2:1混合物が得られた。1H−NMR(250MHz,CDCl3)δ8.37(d,J=6.8Hz,1H),7.99(d,J=9.0Hz,1H),7.69(d,J=12.5Hz,1H),7.17(t,J=7.0Hz,1H),6.72(t,J=6.0Hz,1H),5.49(d,J=12.5Hz,1H),3.70(sept,J=6.8Hz,1H),2.95(s,6H),1.37(d,J=7.0Hz,6H);E−3−ジメチルアミノ−1−(2−イソプロピル−ピラゾロ[1,5−a]ピリジン−3−イル)−プロペノンについてはLC/MS 258.4 m/z(M+H+).1H−NMR(250MHz, CDCl3)δ8.39(d,J=6.8Hz,1H),8.00(d,J=9.0Hz,1H),7.71(d,J=12.3Hz,1H),7.17(t,J=6.8Hz,1H),6.73(t,J=7.0Hz,1H),5.50(d,J=12.3Hz,1H),3.72(sept,J=6.9Hz,1H),2.97(s,6H),1.39(d,J=7.0Hz,6H);Z−3−ジメチルアミノ−1−(2−イソプロピル−ピラゾロ[1,5−a]ピリジン−3−イル)−プロペノンについてはLC/MS 258.4 m/z(M+H+).
工程3。イソプロピルアミン(9.2mL、108.0mmol)、2−メチル−2−チオプソイドウレア硫酸塩(15.00g、107.9mmol)、およびピリジン(30mL)を結合し、30℃で18時間にわたり攪拌した。この混合液をインバキュオで濃縮すると、N−イソプロピル−グアニジンが得られた。LC/MS 102.1 m/z(M+H+).
工程4。3−ジメチルアミノ−1−(2−イソプロピル−ピラゾロ[1,5−a]ピリジン−3−イル)−プロペノン(2.90g、11.3mmol)およびN−イソプロピル−グアニジン(4.00g、39.5mmol)をエタノール(150mL)中の2Mナトリウムエトキシドに溶解させ、この混合液を還流させながら攪拌した。反応混合液は完了についてHPLCによって監視した(24時間)。この混合液を濃縮し、飽和重炭酸ナトリウム溶液でクエンチした。クエンチした混合液を酢酸エチルで抽出した。有機層を硫酸ナトリウムの上方に通して乾燥させ、濾過し、真空で濃縮した。粗物質は、シリカゲルフラッシュクロマトグラフィー(ジクロロメタン中の0〜10%メタノール)によって精製した。メタノールおよびヘキサン中での再結晶化によりイソプロピル−[4−(2−イソプロピルピラゾロ[1,5−a]ピリジン−3−イル)−ピリミジン−2−イル]−アミンが得られた。生成物をジオキサン(4mL)中の4N塩化水素中に溶解させ、次にエーテルを用いて沈殿させると、塩酸塩が得られた。沈降物を水に溶解させ、−78℃へ冷却し、凍結乾燥機上で乾燥させると、塩酸塩としてイソプロピル−[4−(2−イソプロピル−ピラゾロ[1,5−a]ピリジン−3−イル)−ピリミジン−2−イル]−アミンが得られた(798mg、24%)。1H−NMR(250MHz,DMSO−d6)δ8.87(d,J=6.8Hz,1H),8.36−8.22(m,2H),7.66−7.55(m,1H),7.20−7.07(m,2H),4.18(broad s,1H),3.72(sept,J=6.9Hz,1H),1.37(d,J=7.0Hz,6H),1.28(d,J=6.5Hz,6H);LC/MS 296.3 m/z(M+H+).化合物1137。
4−(2−イソプロピル−ピラゾロ[1,5−a]ピリジン−3−イル)−ピリミジン−2−イルアミンの合成
3−[4−(2−イソプロピル−ピラゾロ[1,5−a]ピリジン−3−イル)−ピリミジン−2−イルアミノ]プロパン−1−オールの合成
工程2。3−[4−(2−イソプロピル−ピラゾロ[1,5−a]ピリジン−3−イル)−ピリミジン−2−イルアミノ]−プロパン−1−オールは、再結晶化の代わりに分取的HPLC精製を使用した以外は、イソプロピル−[4−(2−イソプロピルピラゾロ[1,5−a]ピリジン−3−イル)−ピリミジン−2−イル]−アミンの合成の工程4(実施例66)で使用した方法にしたがって3−ジメチルアミノ−1−(2−イソプロピル−ピラゾロ[1,5−a]ピリジン−3−イル)−プロペノンおよびN−(3−ヒドロキシ−プロピル)−グアニジンから調製した(166mg、18%)。1H−NMR(250MHz,DMSO−d6)δ8.85(d,J=7.0Hz,1H),8.44−8.22(m,3H),7.59(t,J=7.0Hz,1H),7.18−7.05(m,2H),4.07(broad s,1H),3.79(sept,J=6.9Hz,1H),3.58−3.33(m,4H),1.77(pent,J=6.6Hz,2H),1.37(d,J=6.5Hz,6H);LC/MS312.3 m/z(M+H+).化合物1134。
[4−(2−イソプロピルピラゾロ[1,5−a]ピリジン−3−イル)−ピリミジン−2−イル]−[3−(4−メチル−ピペラジン−1−イル)−プロピル]−アミン]の合成
工程2。[4−(2−イソプロピル−ピラゾロ[1,5−a]ピリジン−3−イル)−ピリミジン−2−イル]−[3−(4−メチル−ピペラジン−1−イル)−プロピル]−アミンは、再結晶化の代わりに分取的HPLC精製を使用した以外は、イソプロピル−[4−(2−イソプロピルピラゾロ[1,5−a]ピリジン−3−イル)−ピリミジン−2−イル]−アミンの合成の工程4(実施例66)で使用した方法にしたがって3−ジメチルアミノ−1−(2−イソプロピル−ピラゾロ[1,5−a]ピリジン−3−イル)−プロペノンおよびN−[3−(4−メチル−ピペラジン−1−イル)−プロピル]−グアニジンから調製した(162mg、19%)。1H−NMR(250MHz,DMSO−d6)δ8.72(d,J=6.8Hz,1H),8.28−8.20(m,2H),7.37(t,J=7.8Hz,1H),7.16−7.10(m,1H), 6.99(t,J=6.6Hz,1H),6.80(d,J=7.3Hz,1H), 3.78(sept,J=7.3Hz,1H),2.56−2.32(m,10H),2.22(s,3H),2.10−2.06(m,2H),1.73(pent,J=6.9Hz,2H),1.35(d,J=6.8Hz,6H);LC/MS 394.3 m/z(M+H+).化合物1135。
シクロプロピル−[4−(2−イソプロピルピラゾロ[1,5−a]ピリジン−3−イル)−ピリミジン−2−イル]−アミンの合成
工程2。シクロプロピル−[4−(2−イソプロピル−ピラゾロ[1,5−a]ピリジン−3−イル)−ピリミジン−2−イル]−アミンは、再結晶化の代わりに分取的HPLC精製を使用した以外は、イソプロピル−[4−(2−イソプロピルピラゾロ[1,5−a]ピリジン−3−イル)−ピリミジン−2−イル]−アミンの合成の工程4(実施例66)で使用した方法にしたがって3−ジメチルアミノ−1−(2−イソプロピル−ピラゾロ[1,5−a]ピリジン−3−イル)−プロペノンおよびN−シクロプロピル−グアニジンから調製した(34mg、7%)。1H−NMR(250MHz,DMSO−d6)δ8.86(d,J=6.8Hz,1H),8.57(d,J=8.3Hz,1H),8.27(d,J=6.5Hz,1H),7.59(t,J=7.9Hz,1H),7.19−7.10(m,2H),4.62(broad s,1H),3.86−3.78(m,1H),2.80−2.72(m,1H),1.38(d,J=6,5Hz,6H),0.90−0.84(m,2H),0.70−0.64(m,2H);LC/MS 294.2 m/z(M+H+).化合物1136。
2−イソプロピル−3−(1H−ピラゾール−3−イル)−ピラゾロ[1,5−a]ピリジンの合成
本発明の典型的な置換ピラゾロ[1,5−a]ピリジン化合物についてのvon Frey線維に対する反応によって測定した機械的異痛症
異痛症を誘導するために、Sprague−Dawley系雄性ラットにBennett and Xie, Pain 1988;33(1):87−107によって記載された坐骨神経に対する慢性収縮性傷害(CCI)を受けさせた。盲験担当者による引っ込め反応を誘導するために後肢の足底面をvon Freyフィラメント(Stoelting社)を用いて刺激した。50%引っ込め反応を誘導するために必要とされた繊維の屈曲力をCCI手術後に計算した(投与前ベースライン値)。N=5〜6の異痛症性ラットに試験化合物もしくはビヒクルの単回腹腔内投与を受けさせた。投与の2時間後、再びvon Freyフィラメントを使用して盲験担当試験者によって50%足引っ込め閾値が決定された。本発明の様々な置換ピラゾロ[1,5−a]ピリジン化合物についての投与前ベースライン値に比較した50%足引っ込め閾値における変化は、表2に報告されている。
本発明の典型的な置換ピラゾロ[1,5−a]ピリジン化合物についてのPDEの阻害
96ウエルプレート内で、ウシ脳に由来するホスホジエステラーゼ(PDE)酵素(0.5〜1mU/ウエル)を5μM cAMP基質(Sigma社)と結合した。試験化合物(0〜200μM)もしくはビヒクル(0.5% DMSO)を酵素/基質に加え、1時間にわたりインキュベートした。PDELight(登録商標)キット(Cambrex社)を用いて、cAMPの加水分解からの反応において生成されたAMPの量は、AMPをATPへ直接的に変換するPDELight AMP検出試薬を用いて定量した。このアッセイは、新しく形成されたATPおよびルシフェリンからの光線の生成を触媒するルシフェラーゼを使用する。蛍光は、Victor Light 1420照度計上で読み取った。IC50の計算は、非線形回帰曲線当てはめを用いてプロットした。
本発明の典型的な置換ピラゾロ[1,5−a]ピリジン化合物についての末梢血単核球(PBMC)のリポ多糖刺激
IC50値は、それらがヒト末梢血単核球においてLPS誘導性サイトカイン産生を阻害する能力に基づいて本発明の典型的な化合物について決定した。ヒトPBMC(末梢血単核球)は、地元の赤十字から入手したバフィーコートからFicoll勾配の上方で単離した。106個/ウエルのPBMCは、24ウエル組織培養プレート内で10%ヒト血清、ヘペスバッファーおよびピルビン酸ナトリウムを補給したRPMI 1640培地中に播種した。細胞は、0.1% DMSO(ビヒクル)もしくは試験化合物(1、10、および100μM)を用いて10ng/mLでLPS(リポ多糖)(大腸菌(E. Coli))による活性化30分前に処置した。LPS刺激の6〜10時間後に、培養上清を収集し、サイトカインであるTNF−αおよびIL−1βのレベルをELISA(R&D Systems社)および/またはLuminex(Linco Diagnostics社)によって定量した。IC50計算は、本発明の典型的な置換ピラゾロ[1,5−a]ピリジン化合物について非線形回帰曲線当てはめを用いてプロットした;結果は表2に提供されている。
備考(b). 基質としてcAMPを用いる脳抽出物から入手したPDE;
備考(c). PBMCからのLPS刺激性サイトカイン放出の阻害。
1−(2−シクロプロピルピラゾロ[1,5−a]ピリジン−3−イル)−2−メチルプロパン−1−オンの合成
工程1。シクロプロピル(2−シクロプロピルピラゾロ[1,5−a]ピリジン−3−イル)メタノン(1.0g、4.42mmol)は、10分間にわたりTsOH一水和物(0.8g、4.21mmol、0.95当量)の存在下でDean−Stark装置内で還流させるためにベンゼン(80mL)中で加熱した。新しく蒸留したエチレングリコール(2.0g、32.24mmol、7.3当量)を加え、さらに12時間還流させながら2相溶液を維持した。この反応液を室温へ冷却し、飽和NaHCO3溶液(25mL×3)を用いて抽出した。有機相をNa2SO4の上方に通して乾燥させ、濾過し、真空で濃縮した。カラムクロマトグラフィー(4:1、ヘキサン:酢酸エチル)による精製によって、かすかに黄色の油として2−シクロプロピルピラゾロ[1,5−a]ピリジンが得られた(0.61g、3.85mmol、87%)。
3−(ベンジルアミノ)−1−(2−イソプロピルピラゾロ[1,5−a]ピリジン−3−イル)−2−メチルプロパン−1−オン塩酸塩の合成
140℃のn−プロピオン酸無水物(15mL、97%)中の2−イソプロピル−ピラゾロ[1,5−a]ピリジン(6.80g、42.50mmol)を濃H2SO4(0.5mL)に加えた。この混合液を140℃で一晩維持し、室温へ冷却し、pH>11になるまでNaOH(水性50%)を用いて塩基性化した。水層はクロロホルム(3×100mL)を用いて抽出し、乾燥させ(Na2SO4)、濾過し、そして濃縮した。粗生成物をフラッシュカラムクロマトグラフィー(100%ヘキサン、9:1、ヘキサン:酢酸エチル)によって精製すると、黄色油として1−(2−イソプロピルピラゾロ[1,5−a]ピリジン−3−イル)プロパン−1−オン(4.81g、22.27mmol、53%)が得られた。1−(2−イソプロピルピラゾロ[1,5−a]ピリジン−3−イル)プロパン−1−オン(0.500g、2.3mmol)、パラホルムアルデヒド(0.069g、2.3mmol)、および塩酸ベンジルアミン(0.329g、2.3mmol)を5mLの丸底フラスコに加えた。このエタノール性塩酸塩(1mL、エタノール中の1.25%濃HCl)に加え、混合液を還流させるために16時間加熱した。この混合液を次に冷却してEt2O(5mL)および1M NaOH(水性)(10mL)を用いて希釈した。次に水層をEt2O(4×5mL)で抽出した。結合有機相を食塩液で洗浄し、乾燥させ(Na2SO4)、濾過し、濃縮すると暗褐色油が得られた。この油をフラッシュクロマトグラフィー(0〜90%の範囲内のEtOAc/ヘキサンの10%勾配)にかけると淡黄色油として0.073g(収率9.5%)の3−(ベンジルアミノ)−1−(2−イソプロピルピラゾロ[1,5−a]ピリジン−3−イル)−2−メチルプロパン−1−オンが得られた。
3−アミノ−1−(2−イソプロピルピラゾロ[1,5−a]ピリジン−3−イル)−2−メチルプロパン−1−オン塩酸塩の合成
1−(2−イソプロピルピラゾロ[1,5−a]ピリジン−3−イル)−2−メチル−3−(ピペリジン−1−イル)プロパン−1−オン塩酸塩の合成
2−イソプロピル−3−(2−メチルプロプ−1−エニル)ピラゾロ[1,5−a]ピリジンの合成
2−(ベンジルアミノ)−1−(2−イソプロピルピラゾロ[1,5−a]ピリジン−3−イル)プロパン−1−オンの合成
Claims (52)
- 以下の構造:
R2は、独立してH、またはアルキル、置換アルキル、アリール、置換アリール、アルケニル、置換アルケニル、アルキニル、置換アルキニル、ヒドロキシ、スルフヒドリル、アルコキシ、置換アルコキシ、アリールオキシ、置換アリールオキシ、カルバモイルオキシ、チオアルキル、置換チオアルキル、カルバモイルチオ、チオアリール、置換チオアリール、アミノ、およびカルバモイルアミノからなる群から選択される有機基である;
R3は、独立してH、またはアルキル、置換アルキル、アリール、置換アリール、アルケニル、置換アルケニル、アルキニル、および置換アルキニルからなる群から選択される有機基である;および
R6は、独立してH、またはヒドロキシ、スルフヒドリル、アルコキシ、アリールオキシ、チオアルキル、チオアリール、アミノ、ハロゲン、アルキル、アルケニル、アルキニル、アリール、シアノ、カルボキシル、およびカルボキサミドからなる群から選択される有機基である、
このときR2、R3、およびR6の少なくとも1つは水素以外であり、R2がイソプロピルで、R3が2−メチルプロパン−1−オンである場合は、R6は水素以外の有機基である)を有する2,3,6−置換ピラゾロ[1,5−a]ピリジン化合物。 - 第2および第3の環位置で二置換されている、構造Iによる化合物。
- R2は、低級アルキル、置換低級アルキル、アミノ、アリール、もしくは置換アリールからなる群から選択される、請求項1または2に記載の化合物。
- R2は、低級アルキル、置換低級アルキル、フェニル、もしくは置換フェニルである、請求項3に記載の化合物。
- R2は、低級アルキルもしくは一置換低級アルキルである、請求項4に記載の化合物。
- R2は、イソプロピル、2−ヒドロキシプロパン−2−イル、フェニルおよび一置換フェニルから選択される、請求項4に記載の化合物。
- R6はHであり、R2はイソプロピルである、請求項1に記載の化合物。
- R2は、単独のハロゲンもしくはアルコキシ置換基のいずれかを有するフェニル環である、請求項6に記載の化合物。
- R2は、4−ハロフェニルである、請求項8に記載の化合物。
- R3は、構造:
(i)構造II内のCが飽和である場合は、XおよびYは各々独立して−H、またはヒドロキシル、アミノ、アルコキシ、シアノ、ハロ、スルフヒドリル、チオアルキル、低級アルキル、および置換低級アルキルからなる群から選択される有機基からなる群から選択される、
(ii)構造II内のCが不飽和である場合は、XおよびYは、一緒になって、O、S、およびN−R11(式中、R11は、−OH、−O−C(O)−NR12R13、−O−C(O)−R14、およびCR15R16から選択され、R12、R13、R14およびR15は、各々−H、低級アルキル、およびアリールから独立して選択される)から選択される官能基Zに結合した二重結合を形成する、が適用される、そして
R10は、独立してH、またはアルキル、置換アルキル、アリール、置換アリール、アルケニル、置換アルケニル、アルキニル、置換アルキニル、およびエステルから選択される有機基である)を有する、請求項1〜9のいずれか一項に記載の化合物。 - R10は、低級アルキル、置換低級アルキル、およびエステルから選択される、請求項10に記載の化合物。
- R10は、イソプロピルもしくは2−ヒドロキシイソプロピルである、請求項11に記載の化合物。
- Cが不飽和である場合は、XおよびYは、Cと一緒になって、〜C=O、〜C=S、〜C=N−OH、〜C=N−O−C(O)−NR12R13、〜C=N−O−C(O)−R14、および〜C=CR15R16から選択される部分を形成する、請求項10に記載の化合物。
- R12およびR13は、どちらも水素である、請求項13に記載の化合物。
- Cは、X、Y、およびR10と一緒に、それらの各々は任意に一置換もしくは二置換されていてよいピリジン、ピラゾール、ピリミジン、ピリダジン、イミダゾール、1H−イミダゾール−2(3H)−チオン、チアゾール、およびチアゾール−2(5H)−イミンから選択される芳香族複素環の一部を形成する請求項15に記載の化合物。
- Cは不飽和であり、そしてCは、X、Y、およびR10と一緒に、3−ピリジン−4−イル置換基を形成し、R2はイソプロピルである、請求項16に記載の化合物。
- Cは不飽和であり、そしてCは、X、Y、およびR10と一緒に、第2の位置で置換基を有する置換ピリミジン環を形成し、R2はイソプロピルである、請求項16に記載の化合物。
- ピリミジン環の第2位にある置換基はイソプロピルアミノであり、該ピリミジン環はその第4位でコアのピラゾロ[1,5−a]ピリジン環に結合している、請求項18に記載の化合物。
- Wは−CH3もしくは−NH2であり、そしてVはイソプロピルもしくは4−フルオロフェニルである、請求項20に記載の化合物。
- ZはOであり、Wは−NH2であり、そしてVはイソプロピルである、請求項20に記載の化合物。
- ZはN−O−C(O)NH2であり、Wはメチルであり、そしてVはイソプロピルである、請求項20に記載の化合物。
- ZはN−OHであり、Wはメチルであり、そしてVは4−フルオロフェニルである、請求項20に記載の化合物。
- R3は、アルキル、置換アルキル、アルカノイルおよび置換アルカノイルから選択される、請求項1〜9のいずれか一項に記載の化合物。
- R3は、低級アルキル、置換低級アルキル、低級アルカノイル、および置換アルカノイルから選択される、請求項26に記載の化合物。
- R3は、2−アミノエタノン、2−アミノ−プロパン−1−オン、2−メチルプロパン−1−オンオキシム、および2−メチルプロパン−1−オン−O−カルバモイルオキシムから選択される、請求項1〜9のいずれか一項に記載の化合物。
- R2はイソプロピルであり、R3は2−アミノエタノン、2−アミノ−プロパン−1−オン、2−メチルプロパン−1−オンオキシム、および2−メチルプロパン−1−オン−O−カルバモイルオキシムから選択され、R6はHである、請求項1に記載の化合物。
- 化合物1013である(2−アミノ−1−(2−イソプロピルピラゾロ[1,5−a]ピリジン−3−イル)プロパン−1−オン)、1014である(1−(2−イソプロピルピラゾロ[1,5−a]ピリジン−3−イル)−2−メチルプロパン−1−オン−O−カルバモイルオキシム)、1019である(1−(2−(4−フルオロフェニル)ピラゾロ[1,5−a]ピリジン−3−イル)−2−メチルプロパン−1−オンオキシム)、1103である(2−イソプロピル−3−ピリジン−4−イル−ピラゾロ[1,5−a]ピリジン)、1137である(イソプロピル−[4−(2−イソプロピルピラゾロ[1,5−a]ピリジン−3−イル)−ピリミジン−2−イル]−アミン、1085である(4−(2−イソプロピルピラゾロ[1,5−a]ピリジン−3−イル)−1H−イミダゾール−2(3H)−チオン)、および1087である(4−(2−イソプロピルピラゾロ[1,5−a]ピリジン−3−イル)チアゾール−2(5H)−イミン)からなる群から選択される、請求項1に記載の化合物。
- 請求項1〜30のいずれか一項に記載の2,3,6−置換ピラゾロ[1,5−a]ピリジン化合物および医薬上許容される賦形剤を含む医薬組成物。
- 2−置換,3−アルカノイルピラゾロ[1,5−a]ピリジンを調製するための方法であって、第3の環位置でアシル基を含むピラゾロ[1,5−a]ピリジン化合物を提供するために有効な条件下で2−置換ピラゾロ[1,5−a]ピリジンをアシル化する工程を含む方法。
- 前記2−置換ピラゾロ[1,5−a]ピリジンは、第2の環位置でアルキル、置換アルキル、アリール、置換アリール、アルケニル、置換アルケニル、アルキニル、置換アルキニル、ヒドロキシ、スルフヒドリル、アルコキシ、置換アルコキシ、アリールオキシ、置換アリールオキシ、アルカノイル、カルバモイルオキシ、チオアルキル、置換チオアルキル、カルバモイルチオ、チオアリール、置換チオアリール、アミノ、ハロ、およびカルバモイルアミノから選択される部分を有する、請求項32に記載の方法。
- 第2の環位置での前記置換基は、低級アルキル、置換低級アルキル、アリール、置換アリール、アルコキシ、ハロ、およびアルカノイルから選択される、請求項33に記載の方法。
- 第2の環位置での前記置換基は、メチル、エチル、プロピル、イソプロピル、tert−ブチル、sec−ブチル、フェニル、ハロフェニル、およびメトキシフェニルから選択される、請求項34に記載の方法。
- 前記アシル化する工程は、Friedel−Craftsアシル化を含む、請求項32〜35のいずれか一項に記載の方法。
- 前記アシル化する工程は、、塩化アルミニウムの存在下で2−置換ピラゾロ[1,5−a]ピリジンをα−ハロアルカノイル塩化物と反応させ、2−置換,3−(α−ハロアルカノイル)ピラゾロ[1,5−a]ピリジンを提供する工程を含む、請求項32〜35のいずれか一項に記載の方法。
- 前記2−置換,3−(α−ハロアルカノイル)ピラゾロ[1,5−a]ピリジンを求核基と反応させ、それによりα−ハロ基を置換する工程をさらに含む、請求項37に記載の方法。
- 神経因性疼痛を経験している哺乳動物被験者を治療するための方法であって、前記被験者へ請求項1〜30のいずれか一項に記載の治療有効量の置換ピラゾロ[1,5−a]ピリジン化合物を投与する工程を含み、そのような投与する工程の結果として、前記被験者が前記神経因性疼痛の緩和を経験する方法。
- 前記哺乳動物被験者は、ヘルペス後神経痛、三叉神経痛、糖尿病性ニューロパシーから選択される状態に苦しんでいる、請求項39に記載の方法。
- 前記哺乳動物被験者は、偏頭痛、ヘルペス、HIV、外傷性神経障害、脳卒中、虚血後、線維筋痛、反射性交感神経性萎縮症、複合性局所疼痛症候群、および癌化学療法誘導性神経因性疼痛からなる群から選択される状態に関連する神経因性疼痛に苦しんでいる、請求項39に記載の方法。
- 前記投与する工程は、前記神経因性疼痛の軽減もしくは排除を生じさせるために有効な期間にわたる、請求項39〜41のいずれか一項に記載の方法。
- 前記置換ピラゾロ[1,5−a]ピリジン化合物のR6はHであり、R2はイソプロピルである、請求項39〜41のいずれか一項に記載の方法。
- 前記置換ピラゾロ[1,5−a]ピリジン化合物は、化合物1013である(2−アミノ−1−(2−イソプロピルピラゾロ[1,5−a]ピリジン−3−イル)プロパン−1−オン)、1014である(1−(2−イソプロピルピラゾロ[1,5−a]ピリジン−3−イル)−2−メチルプロパン−1−オン−O−カルバモイルオキシム)、1019である(1−(2−(4−フルオロフェニル)ピラゾロ[1,5−a]ピリジン−3−イル)−2−メチルプロパン−1−オンオキシム)、1103である(2−イソプロピル−3−ピリジン−4−イル−ピラゾロ[1,5−a]ピリジン)、および1137である(イソプロピル−[4−(2−イソプロピルピラゾロ[1,5−a]ピリジン−3−イル)−ピリミジン−2−イル]−アミンからなる群から選択される、請求項39〜41のいずれか一項に記載の方法。
- 前記置換ピラゾロ[1,5−a]ピリジン化合物は、疼痛を治療するために有効な少なくとも1つの他の薬剤と組み合わせて投与される、請求項39〜41のいずれか一項に記載の方法。
- 炎症を治療するための方法であって、炎症状態に苦しんでいる被験者へ治療有効量の請求項1〜30のいずれか一項に記載の置換ピラゾロ[1,5−a]ピリジン化合物を投与する工程による方法。
- 神経因性疼痛を治療する際の獣医学的もしくはヒト医学的使用のための請求項1〜30のいずれか一項に記載の化合物。
- 哺乳動物被験者における神経因性疼痛を治療するための医薬品の製造における請求項1〜30のいずれか一項に記載の化合物の使用。
- 哺乳動物被験者における炎症状態を治療するための医薬品の製造における請求項1〜30のいずれか一項に記載の化合物の使用。
- 哺乳動物被験者におけるオピオイド依存性もしくはオピオイド離脱症状症候群を治療するための、請求項1〜30のいずれか一項に記載の化合物の使用。
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2007
- 2007-06-06 AU AU2007258567A patent/AU2007258567B2/en not_active Ceased
- 2007-06-06 US US11/810,885 patent/US7585875B2/en active Active
- 2007-06-06 WO PCT/US2007/013456 patent/WO2007146087A2/en active Application Filing
- 2007-06-06 RU RU2008152776/04A patent/RU2008152776A/ru not_active Application Discontinuation
- 2007-06-06 MX MX2008015616A patent/MX2008015616A/es active IP Right Grant
- 2007-06-06 JP JP2009514381A patent/JP5352452B2/ja active Active
- 2007-06-06 CA CA002654498A patent/CA2654498A1/en not_active Abandoned
- 2007-06-06 BR BRPI0712381-7A patent/BRPI0712381A2/pt not_active IP Right Cessation
- 2007-06-06 EP EP07795865A patent/EP2038279A2/en not_active Withdrawn
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2009
- 2009-06-10 US US12/482,307 patent/US20090318437A1/en not_active Abandoned
- 2009-08-31 US US12/551,245 patent/US20100035920A1/en not_active Abandoned
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- 2013-07-03 JP JP2013139664A patent/JP2013189479A/ja active Pending
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JP2013519696A (ja) * | 2010-02-18 | 2013-05-30 | アルミラル・ソシエダッド・アノニマ | Jak阻害剤としてのピラゾール誘導体 |
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MX2008015616A (es) | 2009-02-11 |
US20080070912A1 (en) | 2008-03-20 |
RU2008152776A (ru) | 2010-07-20 |
US20100035920A1 (en) | 2010-02-11 |
US20090318437A1 (en) | 2009-12-24 |
JP2013189479A (ja) | 2013-09-26 |
AU2007258567B2 (en) | 2012-04-19 |
BRPI0712381A2 (pt) | 2012-07-10 |
CA2654498A1 (en) | 2007-12-21 |
WO2007146087A3 (en) | 2008-03-20 |
EP2038279A2 (en) | 2009-03-25 |
WO2007146087A2 (en) | 2007-12-21 |
US7585875B2 (en) | 2009-09-08 |
JP5352452B2 (ja) | 2013-11-27 |
AU2007258567A1 (en) | 2007-12-21 |
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