JP2006507242A - フェニル置換ピラゾロピリミジン類 - Google Patents
フェニル置換ピラゾロピリミジン類 Download PDFInfo
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- JP2006507242A JP2006507242A JP2004530129A JP2004530129A JP2006507242A JP 2006507242 A JP2006507242 A JP 2006507242A JP 2004530129 A JP2004530129 A JP 2004530129A JP 2004530129 A JP2004530129 A JP 2004530129A JP 2006507242 A JP2006507242 A JP 2006507242A
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 10
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- GMEBDKGPPKAPEM-UHFFFAOYSA-N methyl 2-[3-(trifluoromethyl)phenyl]acetate Chemical compound COC(=O)CC1=CC=CC(C(F)(F)F)=C1 GMEBDKGPPKAPEM-UHFFFAOYSA-N 0.000 description 1
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- 125000001298 n-hexoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- YZMHQCWXYHARLS-UHFFFAOYSA-N naphthalene-1,2-disulfonic acid Chemical compound C1=CC=CC2=C(S(O)(=O)=O)C(S(=O)(=O)O)=CC=C21 YZMHQCWXYHARLS-UHFFFAOYSA-N 0.000 description 1
- 239000007923 nasal drop Substances 0.000 description 1
- 229940100662 nasal drops Drugs 0.000 description 1
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- 229940049964 oleate Drugs 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 210000000956 olfactory bulb Anatomy 0.000 description 1
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- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- RPDAUEIUDPHABB-UHFFFAOYSA-N potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 0.000 description 1
- 229910000105 potassium hydride Inorganic materials 0.000 description 1
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 210000002243 primary neuron Anatomy 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- OGHBATFHNDZKSO-UHFFFAOYSA-N propan-2-olate Chemical compound CC(C)[O-] OGHBATFHNDZKSO-UHFFFAOYSA-N 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- IUYQIJQHYDZUDF-UHFFFAOYSA-N pyrazolo[3,4-d]pyrimidin-4-one Chemical class O=C1N=CN=C2N=NC=C12 IUYQIJQHYDZUDF-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
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000008844 regulatory mechanism Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- HJORMJIFDVBMOB-UHFFFAOYSA-N rolipram Chemical compound COC1=CC=C(C2CC(=O)NC2)C=C1OC1CCCC1 HJORMJIFDVBMOB-UHFFFAOYSA-N 0.000 description 1
- 229950005741 rolipram Drugs 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 210000004761 scalp Anatomy 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
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- 229910002027 silica gel Inorganic materials 0.000 description 1
- 210000002027 skeletal muscle Anatomy 0.000 description 1
- 210000003625 skull Anatomy 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 235000010339 sodium tetraborate Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
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- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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- BSVBQGMMJUBVOD-UHFFFAOYSA-N trisodium borate Chemical compound [Na+].[Na+].[Na+].[O-]B([O-])[O-] BSVBQGMMJUBVOD-UHFFFAOYSA-N 0.000 description 1
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- 229960000744 vinpocetine Drugs 0.000 description 1
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Classifications
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- General Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
Description
DE2408906は、例えば浮腫の処置用の抗菌および抗炎症剤として用いることができるスチレンピラゾロピリミジン類を記載している。
R1は、ハロゲン、C1−C6−アルキル、トリフルオロメチル、トリフルオロメトキシ、シアノ、ヒドロキシ、ニトロおよびC1−C6−アルコキシの群から相互に独立して選択される1個ないし5個の置換基により置換されているフェニルであり、
R2は、ペンタン−3−イル、C4−C6−シクロアルキルであり、
Xは、酸素または硫黄である、
の化合物、並びにそれらの塩、溶媒和物および/または塩の溶媒和物に関する。
化合物(I)の生理的に許容し得る塩には、無機酸、カルボン酸およびスルホン酸の酸付加塩、例えば、塩酸、臭化水素酸、硫酸、リン酸、メタンスルホン酸、エタンスルホン酸、トルエンスルホン酸、ベンゼンスルホン酸、ナフタレンジスルホン酸、酢酸、プロピオン酸、乳酸、酒石酸、リンゴ酸、クエン酸、フマル酸、マレイン酸および安息香酸の塩が含まれる。
C 1 −C 6 −アルコキシは、1個ないし6個、好ましくは1個ないし4個、特に好ましくは1個ないし3個の炭素原子を有する直鎖または分枝のアルコキシ基である。好ましい例は、メトキシ、エトキシ、n−プロポキシ、イソプロポキシ、tert−ブトキシ、n−ペントキシおよびn−ヘキソキシである。
R1が、フッ素、塩素、臭素、C1−C4−アルキル、トリフルオロメチル、トリフルオロメトキシ、シアノ、ヒドロキシ、ニトロおよびC1−C4−アルコキシの群から相互に独立して選択される1個ないし3個の置換基により置換されているフェニルであり、
R2が、ペンタン−3−イル、C5−C6−シクロアルキルであり、
Xが、酸素または硫黄である、
式(I)の化合物、並びにそれらの塩、溶媒和物および/または塩の溶媒和物に関する。
R3は、水素または塩素であり、
R4は、フッ素、塩素、臭素、メチル、トリフルオロメチルであり、
R2は、ペンタン−3−イル、シクロペンチルであり、
Xは、酸素または硫黄である、
の化合物、並びにそれらの塩、溶媒和物および/または塩の溶媒和物に関する。
R3が、水素または塩素であり、
R4が、フッ素、塩素、臭素、メチル、トリフルオロメチルであり、
R2が、ペンタン−3−イル、シクロペンチルであり、
Xが酸素である、
式(I)および(Ia)の化合物、並びにそれらの塩、溶媒和物および/または塩の溶媒和物に関する。
の化合物を、式
R1−CH2−C(O)−Z (IIIa)
式中、R1は上記の意味を有し、
Zは、塩素または臭素である、
の化合物と、不活性溶媒中、塩基の存在下で反応させることにより、最初に式
の化合物に変換し、次いで、不活性溶媒中、塩基の存在下で、式
の化合物に環化する、
または、
[B]式(II)の化合物を、式
R1−CH2−C(O)−OR5 (IIIb)
式中、R1は上記の意味を有し、
R5は、メチルまたはエチルである、
の化合物と、不活性溶媒中、塩基の存在下、(Ib)への直接的環化で反応させる、
または、
[C]式
の化合物を、最初に式(IIIa)の化合物と、不活性溶媒中、塩基の存在下で反応させることにより、式
の化合物に変換し、後者を第2工程で、不活性溶媒中、塩基および酸化剤の存在下で、(Ib)に環化する;
次いで、式(Ib)の化合物を、適するならば例えば五硫化二リンなどの硫化剤との反応により、式
のチオノ誘導体に変換し、
そして、生じる式(I)の化合物を、適するならば適切な(i)溶媒および/または(ii)塩基もしくは酸と反応させ、それらの溶媒和物、塩および/または塩の溶媒和物を得る。
R2−NH−NH2 (VII)
式中、R2は上記の意味を有する、
のヒドラジン誘導体と、不活性溶媒中で縮合させて式(V)のピラゾールニトリルを得、次いで、後者をアンモニアの存在下で、上記の酸化剤の1つ、好ましくは過酸化水素と反応させることにより製造できる[例えば、A. Miyashita et al., Heterocycles 1990, 31, 1309ff 参照]。
従って、それらは、ヒトおよび動物における疾患の処置および/または予防用の医薬としての使用に適する。
本発明のために、用語「処置」は、予防を含む。
PDE阻害
組換えPDE1C(GenBank/EMBL 受託番号: NM_005020, Loughney et al. J. Biol. Chem. 1996 271, 796-806)、PDE2A(GenBank/EMBL 受託番号: NM_002599, Rosman et al. Gene 1997 191, 89-95)、PDE3B(GenBank/EMBL 受託番号: NM_000922, Miki et al. Genomics 1996, 36, 476-485)、PDE4B(GenBank/EMBL 受託番号: NM_002600, Obernolte et al. Gene. 1993, 129, 239-247)、PDE5A(GenBank/EMBL 受託番号: NM_001083, Loughney et al. Gene 1998, 216, 139-147)、PDE7B(GenBank/EMBL 受託番号: NM_018945, Hetman et al. Proc. Natl. Acad. Sci. U.S.A. 2000, 97, 472-476)、PDE8A(GenBank/EMBL 受託番号: AF_056490, Fisher et al. Biochem. Biophys. Res. Commun. 1998 246, 570-577)、PDE9A(Fisher et al., J. Biol. Chem, 1998, 273 (25): 15559-15564)、PDE10A(GenBank/EMBL 受託番号: NM_06661, Fujishige et al. J Biol Chem. 1999, 274, 18438-45)、PDE11A(GenBank/EMBL 受託番号: NM_016953, Fawcett et al. Proc. Natl. Acad. Sci. 2000, 97, 3702-3707)を、Sf9細胞にpFASTBACバキュロウイルス発現系を利用して発現させた(GibcoBRL)。
PDE9A阻害因子は、培養した初代大脳皮質ニューロンの細胞内ニューロン性cGMPを増大させる。
ラットの胚(胚日齢(embryonic day)E17−E19)を断頭し、解剖培地(DMEM、ペニシリン/ストレプトマイシン;両方とも Gibco より)を満たした解剖皿に頭部を移した。頭皮および頭蓋頂部を除去し、露出した脳を解剖培地を有する別のペトリ皿に移した。双眼顕微鏡と2本のピンセットを使用して、大脳(大脳皮質)を単離し、氷を使用して4℃に冷却した。次いで、この大脳皮質ニューロンの解剖と単離を、標準的なプロトコールに従い、パパインキット(Worthington Biochemical Corporation, Lakewood, New Jersey 08701, USA)を使用して実行した(Huettner et al. J. Neurosci. 1986, 6, 3044-3060)。機械的に単離した大脳皮質のニューロンを、150000細胞/ウェルで、200μl Neurobasal 培地/ウェル(Neurobasal; B27 Supplement;2mM L−グルタミン;ペニシリン/ストレプトマイシンの存在下;全試薬は、Gibco より)中、96ウェルプレート(ポリ−D−リジン100μg/mlで30分間予処理した)で、標準条件下(37℃、5%CO2)、7日間培養した。7日後、培地を除去し、細胞をHBSS緩衝液(ハンクス平衡塩溶液、Gibco/BRL)で洗浄した。次いで、HBSS緩衝液に溶解した本発明の化合物(予め100%DMSOに溶解した:10mM)100μlを細胞に載せる。次いで、本発明の化合物の最終濃度が例えば20nMないし10μMの範囲になるように、さらに100μlのHBSS緩衝液を添加し、37℃で20分間インキュベートする。次いで、アッセイ緩衝液を完全に除去する。次いで、細胞を200μlの溶解緩衝液(cGMP Kit コード RPN 226; Amersham Pharmacia Biotech.より)に溶解し、製造業者が定めた通りにcGMP濃度を測定する。全測定は、3重に実行する。統計学的分析は、Prism Software バージョン 2.0 (GraphPad Software Inc., San Diego, CA USA)を使用して実行する。
長期増強は、学習および記憶の過程に対する細胞の相関現象と見なされる。以下の方法を使用して、PDE9阻害が長期増強に影響を与えるか否かを判定できる:
ラットの海馬を切断刃(包丁)に対して約70度の角度に置く。厚さ400μmの海馬切片を調製する。非常に柔らかい、入念に湿らせた刷毛(テンの毛)を使用して切片を刃から取り、95%O2/5%CO2ガス供給した冷たい栄養溶液(124mM NaCl、4.9mM KCl、1.3mM MgSO4x7H2O、2.5mM無水CaCl2、1.2mM KH2PO4、25.6mM NaHCO3、10mMグルコース、pH7.4)の入ったガラス容器に移した。測定の間、温度制御チャンバー中、高さ1−3mmの液体レベルで切片を維持する。流速は2.5ml/分である。予備的なガス供給は、わずかな加圧下(約1atm)で、微小針(microneedle)を通して、前チャンバー(prechamber)中で行う。切片用チャンバーは、小循環(minicirculation)を維持できるようなやり方で前チャンバーに連結する。小循環は、微小針を通って流れ出す95%O2/5%CO2により押し進める。新たに製造した海馬切片を、切片用チャンバー中、33℃で、少なくとも1時間順応させる。
社会的認識試験は、学習力および記憶力の試験である。それは、ラットが同種の既知メンバーと未知メンバーを区別する能力を測定する。従って、この試験は、本発明の化合物の学習力または記憶力の改善効果を調べるのに適している。
本発明の化合物は、これらの投与経路に適する投与形で投与できる。
実施例1A
5−アミノ−1−シクロヘキシル−1H−ピラゾール−4−カルボニトリル
収量:1.95g(理論値の51%)
MS(DCI):m/z=191(M+H)+
1H NMR (200 MHz, DMSO-d6): δ = 7.5 (s, 1H), 6.5 (s, 2H), 4.0 (m, 1H), 1.95-1.05 (m, 10H) ppm.
5−アミノ−1−シクロペンチル−1H−ピラゾール−4−カルボニトリル
MS(ESI):m/z=177(M+H)+
1H NMR (200 MHz, CDCl3): δ = 7.5 (s, 1H), 4.45 (br. s, 2H), 4.35 (m, 1H), 2.2-1.55 (m, 6H) ppm.
5−アミノ−1−(1−エチルプロピル)−1H−ピラゾール−4−カルボニトリル
MS(ESI):m/z=179(M+H)+
1H NMR (300 MHz, DMSO-d6): δ = 7.55 (s, 1H), 6.45 (s, 2H), 4.0 (m, 1H), 1.8-1.55 (m, 4H), 0.65 (t, 6H) ppm.
5−アミノ−1−シクロヘキシル−1H−ピラゾール−4−カルボキサミド
収量:1.77g(理論値の86%)
MS(DCI):m/z=209(M+H)+
1H NMR (300 MHz, DMSO-d6): δ = 7.6 (s, 1H), 7.3-6.4 (broad, 2H), 6.1 (s, 2H), 3.95 (m, 1H), 1.95-1.05 (m, 10H) ppm.
5−アミノ−1−シクロペンチル−1H−ピラゾール−4−カルボキサミド
MS(ESI):m/z=195(M+H)+
1H NMR (200 MHz, CDCl3): δ = 7.5 (s, 1H), 5.6-4.8 (broad, 4H), 4.35 (m, 1H), 2.2 1.55 (m, 8H) ppm.
5−アミノ−1−(1−エチルプロピル)−1H−ピラゾール−4−カルボキサミド
MS(ESI):m/z=197(M+H)+
1H NMR (300 MHz, DMSO-d6): δ = 7.65 (s, 1H), 6.9 (br. s, 2H), 6.1 (s, 2H), 3.9 (m, 1H), 1.85-1.6 (m, 4H), 0.7 (t, 6H) ppm.
実施例1
6−(3−クロロベンジル)−1−シクロペンチル−1,5−ジヒドロ−4H−ピラゾロ[3,4−d]ピリミジン−4−オン
収量:244mg(理論値の81%)
MS(ESI):m/z=329(M+H)+
m.p.:159℃
1H NMR (200 MHz, DMSO-d6): δ = 12.3 (s, 1H), 8.0 (s, 1H), 7.5-7.2 (m, 4H), 5.05 (m, 1H), 3.95 (s, 2H), 2.2-1.5 (m, 8H) ppm.
6−(2−フルオロベンジル)−1−シクロペンチル−1,5−ジヒドロ−4H−ピラゾロ[3,4−d]ピリミジン−4−オン
収量:100mg(理論値の63%)
MS(DCI):m/z=313(M+H)+
m.p.:180℃
1H NMR (400 MHz, DMSO-d6): δ = 12.25 (s, 1H), 8.0 (s, 1H), 7.4-7.3 (m, 2H), 7.2-7.1 (m, 2H), 4.95 (m, 1H), 4.05 (s, 2H), 2.05-1.55 (m, 8H) ppm.
6−(3−ブロモベンジル)−1−シクロペンチル−1,5−ジヒドロ−4H−ピラゾロ[3,4−d]ピリミジン−4−オン
収量:93mg(理論値の62%)
MS(ESI):m/z=373(M+H)+
m.p.:159℃
1H NMR (400 MHz, DMSO-d6): δ = 12.2 (s, 1H), 8.0 (s, 1H), 7.6 (s, 1H), 7.5-7.35 (m, 3H), 5.05 (m, 1H), 4.0 (s, 2H), 2.1-1.6 (m, 8H) ppm.
6−(3,4−ジクロロベンジル)−1−シクロペンチル−1,5−ジヒドロ−4H−ピラゾロ[3,4−d]ピリミジン−4−オン
収量:94mg(理論値の68%)
MS(ESI):m/z=363(M+H)+
m.p.:198℃
1H NMR (400 MHz, DMSO-d6): δ = 12.2 (s, 1H), 8.0 (s, 1H), 7.65 (d, 1H, J = 1 Hz), 7.55 (d, 1H, J = 7.5 Hz), 7.3 (dd, 1H, J = 7.5 Hz, 1 Hz), 5.05 (m, 1H), 4.0 (s, 2H), 2.1-1.6 (m, 8H) ppm.
6−(3,5−ジクロロベンジル)−1−シクロペンチル−1,5−ジヒドロ−4H−ピラゾロ[3,4−d]ピリミジン−4−オン
収量:159mg(理論値の58%)
MS(ESI):m/z=363(M+H)+
m.p.:177℃
1H NMR (200 MHz, DMSO-d6): δ = 12.25 (s, 1H), 8.0 (s, 1H), 7.55 (t, 1H, J = 1 Hz), 7.45 (d, 2H, J = 1 Hz), 5.05 (m, 1H), 4.0 (s, 2H), 2.2-1.5 (m, 8H) ppm.
6−(2,3−ジクロロベンジル)−1−シクロペンチル−1,5−ジヒドロ−4H−ピラゾロ[3,4−d]ピリミジン−4−オン
収量:114mg(理論値の41%)
MS(ESI):m/z=363(M+H)+
m.p.:181℃
1H NMR (200 MHz, DMSO-d6): δ = 12.35 (s, 1H), 8.0 (s, 1H), 7.6 (m, 1H), 7.4-7.3 (m, 2H), 4.9 (m, 1H), 4.2 (s, 2H), 2.1-1.5 (m, 8H) ppm.
6−(3−クロロベンジル)−1−(1−エチルプロピル)−1,5−ジヒドロ−4H−ピラゾロ[3,4−d]ピリミジン−4−オン
収量:210mg(理論値の83%)
MS(ESI):m/z=331(M+H)+
m.p.:138℃
1H NMR (200 MHz, DMSO-d6): δ = 12.3 (s, 1H), 8.0 (s, 1H), 7.45-7.25 (m, 4H), 4.45 (m, 1H), 4.0 (s, 2H), 2.0-1.7 (m, 4H), 0.6 (t, 6H, J = 7.5 Hz) ppm.
6−(3−メチルベンジル)−1−シクロペンチル−1,5−ジヒドロ−4H−ピラゾロ[3,4−d]ピリミジン−4−オン
収量:222mg(理論値の71%)
MS(ESI):m/z=309(M+H)+
m.p.:152℃
1H NMR (200 MHz, DMSO-d6): δ = 12.2 (s, 1H), 8.0 (s, 1H), 7.3-7.0 (m, 4H), 5.1 (m, 1H), 3.95 (s, 2H), 2.3 (s, 3H), 2.2-1.55 (m, 8H) ppm.
6−(2,5−ジクロロベンジル)−1−(1−エチルプロピル)−1,5−ジヒドロ−4H−ピラゾロ[3,4−d]ピリミジン−4−オン
収量:51mg(理論値の14%)
MS(ESI):m/z=365(M+H)+
m.p.:134℃
1H NMR (300 MHz, DMSO-d6): δ = 12.3 (s, 1H), 8.0 (s, 1H), 7.55-7.35 (m, 3H), 4.2 (m, 1H), 4.15 (s, 2H), 1.9-1.65 (m, 4H), 0.55 (t, 6H, J = 7.5 Hz) ppm.
6−(3−メチルベンジル)−1−(1−エチルプロピル)−1,5−ジヒドロ−4H−ピラゾロ[3,4−d]ピリミジン−4−オン
収量:187mg(理論値の60%)
MS(ESI):m/z=311(M+H)+
m.p.:128℃
1H NMR (200 MHz, DMSO-d6): δ = 12.25 (s, 1H), 8.0 (s, 1H), 7.25-7.0 (m, 4H), 4.5 (m, 1H), 3.95 (s, 2H), 2.25 (s, 3H), 2.0-1.7 (m, 4H), 0.6 (t, 6H, J = 7.5 Hz) ppm.
1−(1−エチルプロピル)−6−[3−(トリフルオロメチル)ベンジル]−1,5−ジヒドロ−4H−ピラゾロ[3,4−d]ピリミジン−4−オン
収量:159mg(理論値の58%)
MS(ESI):m/z=365(M+H)+
m.p.:120℃
1H NMR (400 MHz, DMSO-d6): δ = 12.3 (s, 1H), 8.0 (s, 1H), 7.7 (s, 1H), 7.7-7.5 (m, 3H), 4.4 (m, 1H), 4.1 (s, 2H), 1.95-1.75 (m, 4H), 0.6 (t, 6H, J = 7.5 Hz) ppm.
1−シクロペンチル−6−(3−ニトロベンジル)−1,5−ジヒドロ−4H−ピラゾロ[3,4−d]ピリミジン−4−オン
収量:10mg(理論値の1%)
MS(ESI):m/z=340(M+H)+
1H NMR (300 MHz, DMSO-d6): δ = 12.3 (s, 1H), 8.3 (s, 1H), 8.15 (m, 1H), 8.0 (s, 1H), 7.8 (d, 1H, J = 8 Hz), 7.6 (t, 1H, J = 8 Hz), 5.0 (m, 1H), 4.15 (s, 2H), 2.1-1.6 (m, 8H).
6−(3−クロロベンジル)−1−シクロペンチル−1,5−ジヒドロ−4H−ピラゾロ[3,4−d]ピリミジン−4−チオン
収量:36mg(理論値の68%)
MS(ESI):m/z=345(M+H)+
m.p.:154℃
1H NMR (300 MHz, DMSO-d6): δ = 13.6 (s, 1H), 8.15 (s, 1H), 7.5 (s, 1H), 7.4-7.25 (m, 3H), 5.05 (m, 1H), 4.1 (s, 2H), 2.1-1.6 (m, 8H).
1−シクロペンチル−6−[2−(トリフルオロメトキシ)ベンジル]−1,5−ジヒドロ−4H−ピラゾロ[3,4−d]ピリミジン−4−オン
収量:64mg(理論値の63%)
MS(DCI):m/z=379(M+H)+
m.p.:161℃
1H NMR (400 MHz, DMSO-d6): δ = 12.25 (s, 1H), 8.0 (s, 1H), 7.5-7.3 (m, 4H), 4.9 (m, 1H), 4.1 (s, 2H), 2.05-1.5 (m, 8H) ppm.
Claims (12)
- 式中、
R1が、フッ素、塩素、臭素、C1−C4−アルキル、トリフルオロメチル、トリフルオロメトキシ、シアノ、ヒドロキシ、ニトロおよびC1−C4−アルコキシの群から相互に独立して選択される1個ないし3個の置換基により置換されているフェニルであり、
R2が、ペンタン−3−イル、C5−C6−シクロアルキルであり、
Xが、酸素または硫黄である、
請求項1に記載の化合物、並びにそれらの塩、溶媒和物および/または塩の溶媒和物。 - 式中、
R3が、水素または塩素であり、
R4が、フッ素、塩素、臭素、メチル、トリフルオロメチルであり、
R2が、ペンタン−3−イル、シクロペンチルであり、
Xが酸素である、
請求項1ないし請求項3のいずれかに記載の式(Ia)の化合物、並びにそれらの塩、溶媒和物および/または塩の溶媒和物。 - 以下を特徴とする、請求項1に記載の化合物の製造方法;
[A]式
の化合物を、式
R1−CH2−C(O)−Z (IIIa)
式中、R1は請求項1に記載の意味を有し、そして、
Zは、塩素または臭素である、
の化合物と、最初に塩基の存在下で反応させることにより、式
の化合物に変換し、次いで、塩基の存在下で、式
の化合物に環化する、
または、
[B]式(II)の化合物を、式
R1−CH2−C(O)−OR5 (IIIb)
式中、R1は請求項1に記載の意味を有し、そして、
R5は、メチルまたはエチルである、
の化合物と、塩基の存在下、(Ib)への直接的環化で反応させる、
または、
[C]式
の化合物を、最初に式(IIIa)の化合物と、塩基の存在下で反応させることにより、式
の化合物に変換し、後者を第2工程で、塩基および酸化剤の存在下で、(Ib)に環化する;
次いで、式(Ib)の化合物を、適するならば例えば五硫化二リンなどの硫化剤との反応により、式
のチオノ誘導体に変換し、
そして、生じる式(I)の化合物を、適するならば適切な(i)溶媒および/または(ii)塩基もしくは酸と反応させ、それらの溶媒和物、塩および/または塩の溶媒和物を得る。 - 疾患の処置および/または予防用の、請求項1ないし請求項4のいずれかに記載の化合物。
- 少なくとも1の請求項1ないし請求項4のいずれかに記載の化合物、および少なくとも1の医薬的に許容し得る本質的に非毒性の担体または賦形剤を含む、医薬。
- 知覚力、集中力、学習力および/または記憶力の障害の処置および/または予防用の医薬を製造するための、請求項1ないし請求項4のいずれかに記載の化合物の使用。
- 障害がアルツハイマー病の結果である、請求項8に記載の使用。
- 知覚力、集中力、学習力および/または記憶力の改善用の医薬を製造するための、請求項1ないし請求項4のいずれかに記載の化合物の使用。
- 請求項1ないし請求項4のいずれかに記載の化合物の有効量を投与することによる、ヒトまたは動物における知覚力、集中力、学習力および/または記憶力の障害の制御方法。
- 障害がアルツハイマー病の結果である、請求項11に記載の方法。
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WO2008072778A1 (ja) * | 2006-12-13 | 2008-06-19 | Aska Pharmaceutical Co., Ltd. | 尿路系疾患の処置剤 |
JP2011504913A (ja) * | 2007-11-30 | 2011-02-17 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | 1,5−ジヒドロ−ピラゾロ[3,4−d]ピリミジン−4−オン誘導体及びcns障害の治療のためのpde9aモジュレーターとしてのそれらの使用 |
JP2012502008A (ja) * | 2008-09-08 | 2012-01-26 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | ピラゾロピリミジン及びcns障害の治療のためのそれらの使用 |
JP2015524447A (ja) * | 2012-08-08 | 2015-08-24 | ジョンシャン ユニバーシティSun Yat−Sen University | N−置換ピラゾロ[3,4−d]ピリミジノン類化合物、その製造方法及びその使用 |
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- 2003-08-12 EP EP03792301A patent/EP1534711B1/de not_active Expired - Lifetime
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WO2008018306A1 (fr) * | 2006-08-08 | 2008-02-14 | Aska Pharmaceutical Co., Ltd. | Dérivé quinazoline |
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JP5193866B2 (ja) * | 2006-08-08 | 2013-05-08 | あすか製薬株式会社 | キナゾリン誘導体 |
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JP2011504913A (ja) * | 2007-11-30 | 2011-02-17 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | 1,5−ジヒドロ−ピラゾロ[3,4−d]ピリミジン−4−オン誘導体及びcns障害の治療のためのpde9aモジュレーターとしてのそれらの使用 |
JP2012502008A (ja) * | 2008-09-08 | 2012-01-26 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | ピラゾロピリミジン及びcns障害の治療のためのそれらの使用 |
JP2015524447A (ja) * | 2012-08-08 | 2015-08-24 | ジョンシャン ユニバーシティSun Yat−Sen University | N−置換ピラゾロ[3,4−d]ピリミジノン類化合物、その製造方法及びその使用 |
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Publication number | Publication date |
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CA2496194C (en) | 2011-07-05 |
JP4757491B2 (ja) | 2011-08-24 |
WO2004018474A1 (de) | 2004-03-04 |
US8158633B2 (en) | 2012-04-17 |
EP1534711A1 (de) | 2005-06-01 |
US20060106035A1 (en) | 2006-05-18 |
EP1534711B1 (de) | 2006-04-19 |
CA2496194A1 (en) | 2004-03-04 |
DE10238723A1 (de) | 2004-03-11 |
ES2263057T3 (es) | 2006-12-01 |
AU2003258601A1 (en) | 2004-03-11 |
US20120165349A1 (en) | 2012-06-28 |
DE50303054D1 (de) | 2006-05-24 |
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