JP4951349B2 - 知覚力、集中力、学習力および/または記憶力の改善のために使用される6−アミノ−5−シアノ−ピリミジン−4−オン化合物 - Google Patents
知覚力、集中力、学習力および/または記憶力の改善のために使用される6−アミノ−5−シアノ−ピリミジン−4−オン化合物 Download PDFInfo
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- JP4951349B2 JP4951349B2 JP2006548184A JP2006548184A JP4951349B2 JP 4951349 B2 JP4951349 B2 JP 4951349B2 JP 2006548184 A JP2006548184 A JP 2006548184A JP 2006548184 A JP2006548184 A JP 2006548184A JP 4951349 B2 JP4951349 B2 JP 4951349B2
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- 230000013016 learning Effects 0.000 title description 10
- 230000015654 memory Effects 0.000 title description 8
- 230000008447 perception Effects 0.000 title description 5
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- 238000002360 preparation method Methods 0.000 claims description 39
- -1 methoxy, ethoxy Chemical group 0.000 claims description 24
- 239000002904 solvent Substances 0.000 claims description 23
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 20
- 150000003839 salts Chemical class 0.000 claims description 20
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 19
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 16
- 239000012453 solvate Substances 0.000 claims description 14
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- 125000004076 pyridyl group Chemical group 0.000 claims description 13
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
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- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 9
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- 125000004672 ethylcarbonyl group Chemical group [H]C([H])([H])C([H])([H])C(*)=O 0.000 claims description 3
- 125000004674 methylcarbonyl group Chemical group CC(=O)* 0.000 claims description 3
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- UHBMFGPURFTEIV-UHFFFAOYSA-N o-methyl 2-cyano-3-methylbut-2-enethioate Chemical compound COC(=S)C(C#N)=C(C)C UHBMFGPURFTEIV-UHFFFAOYSA-N 0.000 description 11
- 239000007787 solid Substances 0.000 description 10
- LFNDWFULBRDAEI-UHFFFAOYSA-N 2-[(3-chlorophenyl)methyl]-4-methylsulfanyl-6-oxo-1h-pyrimidine-5-carbonitrile Chemical compound N1C(=O)C(C#N)=C(SC)N=C1CC1=CC=CC(Cl)=C1 LFNDWFULBRDAEI-UHFFFAOYSA-N 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 9
- 238000002953 preparative HPLC Methods 0.000 description 9
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- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 8
- 229910052794 bromium Inorganic materials 0.000 description 8
- 238000001816 cooling Methods 0.000 description 8
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- 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
- 201000000980 schizophrenia Diseases 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 210000002027 skeletal muscle Anatomy 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 125000006253 t-butylcarbonyl group Chemical group [H]C([H])([H])C(C(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 210000001550 testis Anatomy 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 230000000542 thalamic effect Effects 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 208000018726 traumatic encephalopathy Diseases 0.000 description 1
- NHDIQVFFNDKAQU-UHFFFAOYSA-N tripropan-2-yl borate Chemical compound CC(C)OB(OC(C)C)OC(C)C NHDIQVFFNDKAQU-UHFFFAOYSA-N 0.000 description 1
- 241000701447 unidentified baculovirus Species 0.000 description 1
- 229960000744 vinpocetine Drugs 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
-
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- 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
-
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
-
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- 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- 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
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- 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
-
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- 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
- C07D401/04—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 directly linked by a ring-member-to-ring-member bond
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- 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
-
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- 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
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- C07D403/02—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 two hetero rings
- C07D403/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond
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- 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
- C07D405/02—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 two hetero rings
- C07D405/06—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 two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- 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
- C07D405/02—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 two hetero rings
- C07D405/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
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- 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
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- 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
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- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
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- 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
- C07D491/10—Spiro-condensed systems
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Description
WO02/06288は、mGluR拮抗作用を有するシアノピリミジノン類を記載している。
WO95/10506は、鬱病およびアルツハイマー病の処置用のシアノピリミジノン類を開示している。
EP130735は、強心剤としてのシアノピリミジン類を記載している。
US5,256,668およびWO99/41253は、抗ウイルス効果を有するシアノピリミジン類を開示している。
Aは、フェニル、ヘテロアリールまたは式
[ここで、フェニルおよびヘテロアリールは、ヘテロアリール、ハロゲン、C1−C6−アルキル、C1−C6−アルコキシ、トリフルオロメチル、トリフルオロメトキシ、ベンジルオキシおよびベンジルの群から相互に独立して選択される2個までの基により置換されていることもある
{ここで、C1−C6−アルキルは、式−NR3R4(式中、R3はC1−C6−アルキルであり、R4は水素またはC1−C6−アルコキシ(C1−C6)アルキルである)の基により置換されていることもあり、そして、
ヘテロアリールは、C1−C6−アルコキシにより置換されていることもある}]、
R1は、C3−C8−シクロアルキル、C1−C6−アルキル、C1−C6−アルコキシ(C1−C6)アルキル、ベンジルまたは式
(ここで、C3−C8−シクロアルキルは、ヒドロキシ、C1−C6−アルキルまたはトリフルオロメチルにより置換されていることもあり、
C1−C6−アルキルは、ヘテロアリール、C3−C8−シクロアルキルまたはヒドロキシにより置換されていることもあり、そして、
ベンジルは、C1−C6−アルコキシまたはハロゲンにより置換されていることもある)、
R2は水素であるか、
または、
R1およびR2は、それらが結合している窒素原子と一体となって5員ないし6員の複素環を形成し、それは、C1−C6−アルキル、ヒドロキシ、シアノ、オキソ、ヘテロアリール、ベンジル、ホルミル、C1−C6−アルキルカルボニルおよび以下の基
(ここで、C1−C6−アルキルは、ヒドロキシまたはヘテロアリールにより置換されていることもある)、
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 −アルキルは、1個ないし6個、好ましくは1個ないし4個の炭素原子を有する直鎖または分枝鎖のアルキル基である。好ましい例には、メチル、エチル、n−プロピル、イソプロピル、2−ブチル、tert−ブチル、2−ペンチル、3−ペンチルおよびn−ヘキシルが含まれる。
Aが、フェニル、ヘテロアリールまたは式
[ここで、フェニルおよびヘテロアリールは、ヘテロアリール、ハロゲン、C1−C4−アルキル、C1−C4−アルコキシ、トリフルオロメチル、トリフルオロメトキシ、ベンジルオキシおよびベンジルの群から相互に独立して選択される2個までの基により置換されていることもある
{ここで、C1−C4−アルキルは、式−NR3R4(式中、R3はC1−C4−アルキルであり、R4は水素またはC1−C4−アルコキシ(C1−C4)アルキルである)の基により置換されていることもあり、そして、
ヘテロアリールは、C1−C4−アルコキシにより置換されていることもある}]、
R1が、C3−C6−シクロアルキル、C1−C4−アルキル、C1−C4−アルコキシ(C1−C4)アルキル、ベンジルまたは式
(ここで、C3−C6−シクロアルキルは、ヒドロキシ、C1−C4−アルキルまたはトリフルオロメチルにより置換されていることもあり、
C1−C4−アルキルは、ヘテロアリール、C3−C6−シクロアルキルまたはヒドロキシにより置換されていることもあり、そして、
ベンジルは、C1−C4−アルコキシまたはハロゲンにより置換されていることもある)、
R2が水素であるか、または、
R1およびR2が、それらが結合している窒素原子と一体となって5員ないし6員の複素環を形成し、それは、C1−C4−アルキル、ヒドロキシ、シアノ、オキソ、ヘテロアリール、ベンジル、ホルミル、C1−C4−アルキルカルボニルおよび以下の基
(ここで、C1−C4−アルキルは、ヒドロキシまたはヘテロアリールにより置換されていることもある)、
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。
Aが、フェニル、チエニルまたは式
[ここで、フェニルおよびチエニルは、ピリジル、フッ素、塩素、臭素、C1−C4−アルキル、C1−C4−アルコキシ、トリフルオロメチル、トリフルオロメトキシ、ベンジルオキシおよびベンジルの群から相互に独立して選択される2個までの基により置換されていることもある
{ここで、C1−C4−アルキルは、式−NR3R4(式中、R3はC1−C4−アルキルであり、R4は水素またはC1−C4−アルコキシ(C1−C4)アルキルである)の基により置換されていることもあり、そして、
ピリジルは、C1−C4−アルコキシにより置換されていることもある}]、
R1が、C3−C6−シクロアルキル、C1−C4−アルキル、C1−C4−アルコキシ(C1−C4)アルキル、ベンジルまたは式
(ここで、C3−C6−シクロアルキルは、ヒドロキシ、C1−C4−アルキルまたはトリフルオロメチルにより置換されていることもあり、
C1−C4−アルキルは、ピリジル、C3−C6−シクロアルキルまたはヒドロキシにより置換されていることもあり、そして、
ベンジルは、C1−C4−アルコキシ、フッ素、塩素または臭素により置換されていることもある)、
R2が水素であるか、または、
R1およびR2が、それらが結合している窒素原子と一体となって、ピロリジニル、ピペリジニル、ピペラジニルおよびモルホリニルの群から選択される5員ないし6員の複素環を形成し、それは、C1−C4−アルキル、ヒドロキシ、シアノ、オキソ、ヘテロアリール、ベンジル、ホルミル、C1−C4−アルキルカルボニルおよび以下の基
(ここで、C1−C4−アルキルは、ヒドロキシまたはピリジルにより置換されていることもある)、
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。
Aが、フェニル、チエニルまたは式
[ここで、フェニルは、ピリジル、フッ素、塩素、メチル、メトキシ、エトキシ、トリフルオロメチル、トリフルオロメトキシ、ベンジルオキシおよびベンジルの群から相互に独立して選択される2個までの基により置換されていることもある
{ここで、メチルは、式−NR3R4(式中、R3はメチルであり、R4は水素または2−メトキシエチルである)の基により置換されていることもあり、そして、
ピリジルは、メトキシにより置換されていることもある}]、
R1が、C3−C6−シクロアルキル、メチル、エチル、プロピル、2−メトキシエチル、ベンジルまたは式
(ここで、C3−C6−シクロアルキルは、ヒドロキシ、メチルまたはトリフルオロメチルにより置換されていることもあり、
メチル、エチル、プロピルは、ピリジル、シクロプロピルまたはヒドロキシにより置換されていることもあり、そして、
ベンジルは、メトキシ、エトキシ、フッ素または塩素により置換されていることもある)、
R2が水素であるか、または、
R1およびR2が、それらが結合している窒素原子と一体となって、ピロリジニル、ピペリジニル、ピペラジニルおよびモルホリニルの群から選択される5員ないし6員の複素環を形成し、それは、メチル、エチル、プロピル、tert−ブチル、ヒドロキシ、シアノ、オキソ、ピリジル、ベンジル、ホルミル、メチルカルボニル、エチルカルボニル、プロピルカルボニルおよび以下の基
(ここで、メチル、エチルおよびプロピルは、ヒドロキシまたはピリジルにより置換されていることもある)、
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。
[A]式
HNR1R2 (III)
(式中、R1およびR2は、上述の意味を有する)
の化合物を用いて、高い温度で、不活性溶媒中または溶媒の非存在下で、式
の化合物に変換し、
次いで、後者を、不活性溶媒中、塩基の存在下、式
の化合物と反応させるか、
[B]式(II)の化合物を、最初に、式(V)の化合物を用いて、不活性溶媒中、塩基の存在下で、式
の化合物に変換し、
次いで、後者を、高い温度で、不活性溶媒中または溶媒の非存在下で、式(III)の化合物と反応させ、
そして、各場合で得られる式(I)の化合物を、必要に応じて適切な(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。
a)1.トルエン、ボロントリフロリド−エーテレート(boron trifluoride-etherate)、室温、30分;2.アミン成分R1R2NH、150℃、16時間;または:出発化合物の融解状態、150℃、1−16時間;b)DMF、トリエチルアミン、100℃、16時間またはDMF、炭酸カリウム、90℃、16時間。
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(GibcoBRL)を利用して発現させた。
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で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す。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。新たに調製した海馬切片を、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
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と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。
方法1:
器具:HPLC Agilent series 1100 を有する Micromass Platform LCZ;カラム:Grom-Sil 120 ODS-4 HE, 50 mm x 2.0 mm, 3 μm;溶離剤A:水1l+50%蟻酸1ml、溶離剤B:アセトニトリル1l+50%蟻酸1ml;勾配:0.0分100%A→0.2分100%A→2.9分30%A→3.1分10%A→4.5分10%A;オーブン:55℃;流速:0.8ml/分;UV検出:208−400nm。
器具:HPLC Agilent series 1100 を有する Micromass Quattro LCZ;カラム:Grom-Sil 120 ODS-4 HE, 50 mm x 2.0 mm, 3 μm;溶離剤A:水1l+50%蟻酸1ml、溶離剤B:アセトニトリル1l+50%蟻酸1ml;勾配:0.0分100%A→0.2分100%A→2.9分30%A→3.1分10%A→4.5分10%A;オーブン:55℃;流速:0.8ml/分;UV検出:208−400nm。
器具:HPLC Agilent series 1100 を有する Micromass Platform LCZ;カラム:Phenomenex Synergi 2μ Hydro-RP Mercury 20 mm x 4 mm;溶離剤A:水1l+50%蟻酸0.5ml、溶離剤B:アセトニトリル1l+50%蟻酸0.5ml;勾配:0.0分90%A流速1ml/分→2.5分30%A流速2ml/分→3.0分5%A流速2ml/分→4.5分5%A流速2ml/分;オーブン:50℃;UV検出:210nm。
器具:HPLC Agilent series 1100を有する Micromass Quattro LCZ;カラム:Phenomenex Synergi 2μ Hydro-RP Mercury 20 mm x 4 mm;溶離剤A:水1l+50%蟻酸0.5ml、溶離剤B:アセトニトリル1l+50%蟻酸0.5ml;勾配:0.0分90%A流速1ml/分→2.5分30%A流速2ml/分→3.0分5%A流速2ml/分→4.5分5%A流速2ml/分;オーブン:50℃;UV検出:208−400nm。
MS器具タイプ:Micromass ZQ;HPLC器具タイプ:Waters Alliance 2795;カラム:Phenomenex Synergi 2μ Hydro-RP Mercury 20 mm x 4 mm;溶離剤A:水1l+50%蟻酸0.5ml、溶離剤B:アセトニトリル1l+50%蟻酸0.5ml;勾配:0.0分90%A流速1ml/分→2.5分30%A流速2ml/分→3.0分5%A流速2ml/分→4.5分5%A流速2ml/分;オーブン:50℃;UV検出:210nm。
MS器具タイプ:Micromass ZQ;HPLC器具タイプ:HP 1100 シリーズ; UV DAD;カラム:Phenomenex Synergi 2μ Hydro-RP Mercury 20 mm x 4 mm;溶離剤A:水1l+50%蟻酸0.5ml、溶離剤B:アセトニトリル1l+50%蟻酸0.5ml;勾配:0.0分90%A流速1ml/分→2.5分30%A流速2ml/分→3.0分5%A流速2ml/分→4.5分5%A流速2ml/分;オーブン:50℃;UV検出:210nm。
MS器具タイプ:Micromass ZQ;HPLC器具タイプ:HP 1100 シリーズ;UV DAD;カラム:Grom-Sil 120 ODS-4 HE 50 mm x 2 mm, 3.0 μm;溶離剤A:水+50%蟻酸500μl/l、溶離剤B:アセトニトリル+50%蟻酸500μl/l;勾配:0.0分0%B→2.9分70%B→3.1分90%B→4.5分90%B;オーブン:50℃;流速:0.8ml/分;UV検出:210nm。
MS器具タイプ:Micromass ZQ;HPLC器具タイプ:Waters Alliance 2790;カラム:Grom-Sil 120 ODS-4 HE 50 mm x 2 mm, 3.0 μm;溶離剤A:水+50%蟻酸500μl/l、溶離剤B:アセトニトリル+50%蟻酸500μl/l;勾配:0.0分5%B→2.0分40%B→4.5分90%B→5.5分90%B;流速:0.0分0.75ml/分→4.5分0.75ml/分→5.5分1.25ml/分;オーブン:45℃;UV検出:210nm。
MS器具タイプ:Micromass ZQ;HPLC器具タイプ:Waters Alliance 2790;カラム:Grom-Sil 120 ODS-4 HE 50 mm x 2 mm, 3.0 μm;溶離剤A:水+50%蟻酸500μl/l、溶離剤B:アセトニトリル+50%蟻酸500μl/l;勾配:0.0分0%B→0.2分0%B→2.9分70%B→3.1分90%B→4.5分90%B;オーブン:45℃;流速:0.8ml/分;UV検出:210nm。
MS器具タイプ:Micromass ZQ;HPLC器具タイプ:Waters Alliance 2795;カラム:Merck Chromolith SpeedROD RP-18e 50 mm x 4.6 mm;溶離剤A:水+50%強度蟻酸500μl/l、溶離剤B:アセトニトリル+50%蟻酸500μl/l;勾配:0.0分10%B→3.0分95%B→4.0分95%B;オーブン:35℃;流速:0.0分1.0ml/分→3.0分3.0ml/分→4.0分3.0ml/分;UV検出:210nm。
MS器具タイプ:Micromass ZQ;HPLC器具タイプ:Waters Alliance 2790;カラム:Uptisphere C 18 50 mm x 2.0 mm, 3.0 μm;溶離剤B:アセトニトリル+0.05%蟻酸、溶離剤A:水+0.05%蟻酸;勾配:0.0分5%B→2.0分40%B→4.5分90%B→5.5分90%B;オーブン:45℃;流速:0.0分0.75ml/分→4.5分0.75ml/分→5.5分1.25ml/分;UV検出:210nm。
器具:DAD 検出を有する HP 1100;カラム:Kromasil RP-18, 60 mm x 2 mm, 3.5 μm; 溶離剤A:HClO45ml/水1l、溶離剤B:アセトニトリル;勾配:0分2%B→0.5分2%B→4.5分90%B→6.5分90%B;流速:0.75ml/分;温度:30℃;UV検出:210nm。
器具:DAD 検出を有する HP 1100;カラム:Kromasil RP-18, 125 mm x 4 mm, 5 μm;溶離剤A:HClO45ml/水1l、溶離剤B:アセトニトリル;勾配:0分2%B→0.5分2%B→4.5分90%B→6.5分90%B;流速:0.75ml/分;温度:30℃;UV検出:210nm。
以下の反応に必要とされるアミジン類は、対応するニトリル類またはエステル類から、Gielen H., Alonso-Alija C., Hendrix M., Niewoehner U., Schauss D., Tetrahedron Lett. 43, 419-421 (2002) の方法により製造する。
2−(3,4−ジクロロフェニル)エタンアミジン塩酸塩
MS(ESIpos):m/z=203[M+H]+
6−メトキシピリジン−3−イルボロン酸(boronic acid)
MS(ESIpos):m/z=154[M+H]+
1H-NMR (DMSO-d6, 300 MHz): δ = 3.83 (s, 3H), 6.76 (d, 1H), 8.0 (dd, 1H), 8.52 (s, 1H).
メチル[2−(6−メトキシピリジン−3−イル)フェニル]アセテート
LC−MS(方法5):Rt=2.1分、MS(ESIpos):m/z=258[M+H]+
1H-NMR (DMSO-d6, 300 MHz): δ = 3.51 (s, 3H), 3.63 (s, 2H), 3.9 (s, 3H), 6.89 (d, 1H), 7.26 (m, 1H), 7.38 (m, 3H), 7.63 (dd, 1H), 8.08 (m, 1H).
2−[2−(6−メトキシピリジン−3−イル)フェニル]エタンイミドアミド塩酸塩
LC−MS(方法5):Rt=0.94分、MS(ESIpos):m/z=242[M+H]+
1H-NMR (DMSO-d6, 300 MHz): δ = 3.79 (s, 2H), 3.9 (s, 3H), 6.89 (d, 1H), 7.31 (m, 2H), 7.46 (m, 2H), 7.68 (dd, 1H), 8.12 (m, 1H), 8.72 (s, 1H), 8.8 (s, 2H)
2−[2−(6−メトキシピリジン−3−イル)ベンジル]−4−(メチルスルファニル)−6−オキソ−1,6−ジヒドロピリミジン−5−カルボニトリル
LC−MS(方法5):Rt=2.08分、MS(ESIpos):m/z=365[M+H]+
1H-NMR (DMSO-d6, 300 MHz): δ = 2.31 (s, 3H), 3.9 (s, 3H), 3.98 (s, 2H), 6.89 (d, 1H), 7.28 (m, 1H), 7.39 (m, 3H), 7.63 (dd, 1H), 8.08 (m, 1H).
2−ベンジル−4−(メチルスルファニル)−6−オキソ−1,6−ジヒドロ−5−ピリミジンカルボニトリル
HPLC(方法12):Rt=4.2分
MS(ESIpos):m/z=258[M+H]+
2−(3−メチルベンジル)−4−(メチルスルファニル)−6−オキソ−1,6−ジヒドロ−5−ピリミジンカルボニトリル
LC−MS(方法2):Rt=2.83分、MS(ESIpos):m/z=272[M+H]+
1H-NMR (DMSO-d6, 300 MHz): δ = 2.25 (s, 3H), 2.50 (s, 3H), 3.91 (s, 2H), 7.19 (m, 4H).
2−(2−メチルベンジル)−4−(メチルスルファニル)−6−オキソ−1,6−ジヒドロ−5−ピリミジンカルボニトリル
LC−MS(方法10):Rt=2.13分、MS(ESIpos):m/z=272[M+H]+
2−(2−フルオロベンジル)−4−(メチルスルファニル)−6−オキソ−1,6−ジヒドロ−5−ピリミジンカルボニトリル
LC−MS(方法10):Rt=2.03分、MS(ESIpos):m/z=276[M+H]+
1H-NMR (DMSO-d6, 300 MHz): δ = 2.31 (s, 3H), 4.06 (s, 2H), 7.19 (m, 2H), 7.41 (m, 2H).
2−(2−エトキシベンジル)−4−(メチルスルファニル)−6−オキソ−1,6−ジヒドロ−5−ピリミジンカルボニトリル
LC−MS(方法3):Rt=2.32分、MS(ESIpos):m/z=302[M+H]+
1H-NMR (DMSO-d6, 300 MHz): δ = 1.19 (t, 3H), 2.30 (s, 3H), 3.99 (q, 2H + s, 2H), 6.93 (m, 2H), 7.27 (m, 2H).
2−(3−クロロベンジル)−4−(メチルスルファニル)−6−オキソ−1,6−ジヒドロピリミジン−5−カルボニトリル
HPLC(方法12):Rt=4.4分
MS(DCI,NH3):m/z=292[M+H]+、309[M+NH4]+
2−(4−クロロベンジル)−4−(メチルスルファニル)−6−オキソ−1,6−ジヒドロピリミジン−5−カルボニトリル
HPLC(方法12):Rt=4.35分
MS(ESIpos):m/z=292[M+H]+
2−(3,4−ジクロロベンジル)−4−(メチルスルファニル)−6−オキソ−1,6−ジヒドロピリミジン−5−カルボニトリル
HPLC(方法12):Rt=4.7分
MS(DCI,NH3):m/z=343[M+NH4]+
2−(3−フルオロベンジル)−4−(メチルスルファニル)−6−オキソ−1,6−ジヒドロピリミジン−5−カルボニトリル
HPLC(方法12):Rt=4.2分
MS(ESIpos):m/z=276[M+H]+
4−(メチルスルファニル)−6−オキソ−2−[3−(トリフルオロメチル)ベンジル]−1,6−ジヒドロピリミジン−5−カルボニトリル
HPLC(方法12):Rt=4.4分
MS(ESIpos):m/z=326[M+H]+
4−(メチルスルファニル)−6−オキソ−2−(3−チエニルメチル)−1,6−ジヒドロピリミジン−5−カルボニトリル
HPLC(方法12):Rt=4.1分
MS(ESIpos):m/z=263.9[M+H]+
メチル(2E/Z)−2−シアノ−3−(シクロヘキシルアミノ)−3−メチルチオプロプ−2−エノエート
HPLC(方法12):Rt=4.85分
MS(DCI,NH3):m/z=254.9[M+H]+、272[M+NH4]+
メチル(2E/Z)−2−シアノ−3−(シクロペンチルアミノ)−3−メチルチオプロプ−2−エノエート
HPLC(方法12):Rt=4.6分
MS(DCI,NH3):m/z=241[M+H]+、258[M+NH4]+
以下の化合物を、スキームIに記載の一般的合成経路により製造する:
スキームI:
a)エタノール、トリエチルアミン、5−16時間還流;b)アセトニトリル、85−90℃、1−7日間。
2−(3,4−ジクロロベンジル)−6−オキソ−4−(1−ピペリジニル)−1,6−ジヒドロピリミジン−5−カルボニトリル
HPLC(方法12):Rt=4.8分
MS(ESIpos):m/z=363[M+H]+
1H-NMR (DMSO-d6, 200 MHz): δ = 1.45-1.70 (m, 6H), 3.73-3.89 (m, 6H), 7.35 (dd, 1H), 7.57-7.66 (m, 2H), 11.1 (s, 1H).
2−ベンジル−6−オキソ−4−(1−ピペリジニル)−1,6−ジヒドロピリミジン−5−カルボニトリル
HPLC(方法12):Rt=4.3分
MS(ESIpos):m/z=295[M+H]+
1H-NMR (CD3OD, 300 MHz): δ = 1.59-1.77 (m, 6H), 3.83 (s, 2H), 3.93 (t, 4H), 7.24-7.34 (m, 5H).
4−[4−(2−ヒドロキシエチル)−1−ピペリジニル]−2−(3−メチルベンジル)−6−オキソ−1,6−ジヒドロ−5−ピリミジンカルボニトリル
LC−MS(方法7):Rt=3.01分、MS(ESIpos):m/z=353[M+H]+
1H-NMR (DMSO-d6, 300 MHz): δ = 1.05 (m, 2H), 1.36 (m, 2H), 1.69 (m, 3H), 2.25 (s, 3H), 2.89 (t, 2H), 3.42 (t, 2H), 3.68 (s, 2H), 4.51 (d, 2H), 7.18 (m, 4H).
4−(シクロペンチルアミノ)−2−(3−メチルベンジル)−6−オキソ−1,6−ジヒドロ−5−ピリミジンカルボニトリル
LC−MS(方法10):Rt=2.27分、MS(ESIpos):m/z=309[M+H]+
4−[(2S)−2−(ヒドロキシメチル)−1−ピロリジニル]−2−(3−メチルベンジル)−6−オキソ−1,6−ジヒドロ−5−ピリミジンカルボニトリル
LC−MS(方法7):Rt=2.91分、MS(ESIpos):m/z=325[M+H]+
1H-NMR (DMSO-d6, 300 MHz): δ = 1.94 (m, 4H), 2.28 (s, 2H), 3.76 (m, 3H), 3.70 (s, 2H), 3.81 (m, 2H), 4.4 (m, 1H), 7.15 (m, 4H), 12.34 (s, 1H).
4−[4−(2−ヒドロキシエチル)−1−ピペリジニル]−2−(2−メチルベンジル)−6−オキソ−1,6−ジヒドロ−5−ピリミジンカルボニトリル
LC−MS(方法5):Rt=1.74分、MS(ESIpos):m/z=353[M+H]+
1H-NMR (DMSO-d6, 300 MHz): δ = 1.06 (m, 2H), 1.34 (m, 2H), 1.68 (m, 3H), 2.30 (s, 3H), 3.00 (t, 2H), 3.42 (t, 2H), 3.80 (s, 2H), 4.51 (d, 2H), 7.16 (m, 4H), 12.33 (s, 1H).
2−(2−フルオロベンジル)−4−[4−(2−ヒドロキシエチル)−1−ピペリジニル]−6−オキソ−1,6−ジヒドロ−5−ピリミジンカルボニトリル
LC−MS(方法2):Rt=2.94分、MS(ESIpos):m/z=357[M+H]+
1H-NMR (DMSO-d6, 300 MHz): δ = 1.01 (m, 2H), 1.33 (m, 2H), 1.67 (m, 3H), 2.97 (t, 2H), 3.41 (dd, 2H), 3.87 (s, 2H), 4.32 (t, 1H), 4.47 (d, 2H), 7.16 (m, 2H), 7.36 (m, 2H), 12.38 (s, 1H).
2−(2−エトキシベンジル)−4−[4−(2−ヒドロキシエチル)−1−ピペリジニル]−6−オキソ−1,6−ジヒドロ−5−ピリミジンカルボニトリル
LC−MS(方法6):Rt=2.01分、MS(ESIpos):m/z=383[M+H]+
1H-NMR (DMSO-d6, 200 MHz): δ = 1.04 (m, 2H), 1.23 (t, 3H), 1.34 (m, 2H), 1.67 (m, 3H), 2.94 (t, 2H), 3.41 (t, 2H), 3.87 (s, 2H), 3.96 (q, 2H), 4.48 (d, 2H), 6.92 (m, 2H), 7.17 (m, 2H), 12.26 (s, 1H).
2−(3−クロロベンジル)−6−オキソ−4−(プロピルアミノ)−1,6−ジヒドロピリミジン−5−カルボニトリル
HPLC(方法12):Rt=4.4分
MS(ESIpos):m/z=303[M+H]+
1H-NMR (DMSO-d6, 200 MHz): δ = 0.75 (t, 3H), 1.40 (m, 2H), 3.23 (m, 2H), 3.83 (s, 2H), 7.23-7.38 (m, 4H), 7.42 (s, 1H), 12.34 (s, 1H).
2−(3−クロロベンジル)−4−(シクロペンチルアミノ)−6−オキソ−1,6−ジヒドロピリミジン−5−カルボニトリル
MS(ESIpos):m/z=329[M+H]+
1H-NMR (DMSO-d6, 200 MHz): δ = 1.38-1.85 (m, 8H), 3.82 (s, 2H), 4.20-4.37 (m, 1H), 7.23-7.46 (m, 4H), 7.66-7.80 (s, 1H), 12.25-12.44 (s, 1H).
2−(3−クロロベンジル)−6−オキソ−4−(1−ピロリジニル)−1,6−ジヒドロピリミジン−5−カルボニトリル
HPLC(方法12):Rt=4.4分
MS(ESIpos):m/z=315[M+H]+
1H-NMR (DMSO-d6, 200 MHz): δ = 1.80-1.95 (m, 4H), 3.58-3.71 (m, 4H), 3.79 (s, 2H), 7.25-7.45 (m, 4H), 12.28-12.39 (s, 1H).
4−(4,4−ジメチルピペリジン−1−イル)−2−(3−クロロベンジル)−6−オキソ−1,6−ジヒドロピリミジン−5−カルボニトリル
HPLC(方法12):Rt=4.8分
MS(ESIpos):m/z=357[M+H]+
1H-NMR (DMSO-d6, 200 MHz): δ = 0.96 (s, 6H), 1.30-1.41 (m, 4H), 3.75-3.87 (m, 6H, s at 3.81), 7.24-7.45 (m, 4H), 12.39 (s, 1H).
2−(3−クロロベンジル)−4−[(2−メトキシエチル)アミノ]−6−オキソ−1,6−ジヒドロピリミジン−5−カルボニトリル
HPLC(方法12):Rt=4.0分
MS(ESIpos):m/z=319[M+H]+
1H-NMR (CDCl3, 300 MHz): δ = 3.38 (s, 3H), 3.53 (t, 2H), 3.75 (q, 2H), 3.88 (s, 2H), 6.00 (t, 1H), 7.25-7.31 (m, 3H), 7.38 (s, 1H), 12.56 (s, 1H).
2−(3−クロロベンジル)−4−(モルホリン−4−イル)−6−オキソ−1,6−ジヒドロピリミジン−5−カルボニトリル
HPLC(方法12):Rt=4.0分
MS(ESIpos):m/z=331[M+H]+
1H-NMR (DMSO-d6, 200 MHz): δ = 3.59-3.69 (t, 4H), 3.79-3.90 (m, 6H, s at 3.82), 7.25-7.44 (m, 4H), 12.53 (s, 1H).
2−(3−クロロベンジル)−4−(4−メチルピペラジン−1−イル)−6−オキソ−1,6−ジヒドロピリミジン−5−カルボニトリル
HPLC(方法12):Rt=3.5分
MS(ESIpos):m/z=344[M+H]+
1H-NMR (DMSO-d6, 200 MHz): δ = 2.18 (s, 3H), 2.35 (t, 4H), 3.79-3.88 (m, 6H, s at 3.82), 7.25-7.44 (m, 4H), 12.48 (s, 1H).
2−(3−クロロベンジル)−4−[(2−メトキシベンジル)アミノ]−6−オキソ−1,6−ジヒドロピリミジン−5−カルボニトリル
HPLC(方法12):Rt=4.6分
MS(ESIpos):m/z=381[M+H]+
1H-NMR (DMSO-d6, 300 MHz): δ = 3.77 (s, 2H), 3.79 (s, 3H), 4.52 (d, 2H), 6.84 (t, 1H), 6.92-6.99 (m, 2H), 7.12 (d, 1H), 7.19-7.33 (m, 4H), 8.14 (t, 1H), 12.39 (s, 1H).
2−(4−クロロベンジル)−4−(シクロブチルアミノ)−6−オキソ−1,6−ジヒドロピリミジン−5−カルボニトリル
HPLC(方法12):Rt=4.5分
MS(ESIpos):m/z=315[M+H]+
1H-NMR (DMSO-d6, 300 MHz): δ = 1.50-1.67 (m, 2H), 2.03-2.15 (m, 4H), 3.79 (s, 2H), 4.37-4.51 (m, 1H), 7.31-7.43 (m, 4H), 8.00 (s, 1H), 12.33 (s, 1H).
2−(4−クロロベンジル)−6−オキソ−4−(1−ピロリジニル)−1,6−ジヒドロピリミジン−5−カルボニトリル
HPLC(方法12):Rt=4.4分
MS(ESIpos):m/z=315[M+H]+
1H-NMR (CD3OD, 300 MHz): δ = 1.88-2.03 (m, 4H), 3.69-3.86 (m, 6H, s at 3.82), 7.25-7.35 (m, 4H).
4−(シクロペンチルアミノ)−2−(3−フルオロベンジル)−6−オキソ−1,6−ジヒドロピリミジン−5−カルボニトリル
HPLC(方法12):Rt=4.4分
MS(ESIpos):m/z=313[M+H]+
1H-NMR (DMSO-d6, 200 MHz): δ = 1.29-1.71 (m, 8H), 3.89 (s, 2H), 3.98-4.14 (m, 1H), 7.11-7.42 (m, 4H), 7.63-7.75 (s, 1H), 12.34-12.43 (s, 1H).
2−(3−フルオロベンジル)−6−オキソ−4−(1−ピペリジニル)−1,6−ジヒドロピリミジン−5−カルボニトリル
HPLC(方法12):Rt=4.3分
MS(ESIpos):m/z=313[M+H]+
1H-NMR (DMSO-d6, 200 MHz): δ = 1.40-1.66 (m, 6H), 3.66-3.76 (m, 4H), 3.76 (s, 2H), 7.12-7.42 (m, 4H), 12.27-12.41 (s, 1H).
6−オキソ−4−(1−ピペリジニル)−2−[3−(トリフルオロメチル)ベンジル]−1,6−ジヒドロピリミジン−5−カルボニトリル
HPLC(方法12):Rt=4.7分
MS(ESIpos):m/z=363[M+H]+
1H-NMR (DMSO-d6, 200 MHz): δ = 1.43-1.70 (m, 6H), 3.71-3.83 (m, 4H), 3.93 (s, 2H), 7.51-7.78 (m, 4H), 12.42 (s, 1H).
6−オキソ−4−(プロピルアミノ)−2−(3−チエニルメチル)−1,6−ジヒドロピリミジン−5−カルボニトリル
HPLC(方法12):Rt=4.1分
MS(ESIpos):m/z=275.2[M+H]+
1H-NMR (DMSO-d6, 300 MHz): δ = 0.79 (t, 3H), 1.46 (m, 2H), 3.29 (m, 2H), 3.81 (s, 2H), 7.06 (d, 1H), 7.33 (s, 1H), 7.49 (m, 1H), 7.87 (s, 1H), 12.27 (s, 1H).
4−(シクロプロピルアミノ)−6−オキソ−2−(3−チエニルメチル)−1,6−ジヒドロピリミジン−5−カルボニトリル
HPLC(方法12):Rt=3.8分
MS(ESIpos):m/z=273[M+H]+
1H-NMR (DMSO-d6, 300 MHz): δ = 0.60-0.78 (m, 4H), 2.84-2.98 (m, 1H), 3.80 (s, 2H), 7.08 (d, 1H), 7.35 (s, 1H), 7.49 (m, 1H), 7.85-8.05 (s, 1H), 12.32 (s, 1H).
4−(シクロペンチルアミノ)−6−オキソ−2−(3−チエニルメチル)−1,6−ジヒドロピリミジン−5−カルボニトリル
HPLC(方法12):Rt=4.4分
MS(ESIpos):m/z=301.2[M+H]+
1H-NMR (DMSO-d6, 300 MHz): δ = 1.40-1.91 (m, 8H), 3.81 (s, 2H), 4.36 (m, 1H), 7.07 (d, 1H), 7.34 (s, 1H), 7.50 (m, 1H), 7.65 (s, 1H), 12.28 (s, 1H).
6−オキソ−4−(1−ピロリジニル)−2−(3−チエニルメチル)−1,6−ジヒドロピリミジン−5−カルボニトリル
HPLC(方法12):Rt=4.1分
MS(ESIpos):m/z=287[M+H]+
1H-NMR (DMSO-d6, 300 MHz): δ = 1.80-1.96 (m, 4H), 3.60-3.76 (m, 4H), 3.78 (s, 2H), 7.08 (d, 1H), 7.35 (s, 1H), 7.48 (m, 1H), 12.27 (s, 1H).
4−(4−メチルピペリジン−1−イル)−6−オキソ−2−(3−チエニルメチル)−1,6−ジヒドロピリミジン−5−カルボニトリル
HPLC(方法12):Rt=4.5分
MS(ESIpos):m/z=315[M+H]+
1H-NMR (DMSO-d6, 300 MHz): δ = 0.91 (d, 3H), 1.05-1.18 (t, 2H), 1.62-1.77 (m, 3H), 3.06 (t, 2H), 3.80 (s, 2H), 4.61 (d, 2H), 7.07 (d, 1H), 7.34 (s, 1H), 7.49 (m, 1H), 12.32 (s, 1H).
4−(4,4−ジメチルピペリジン−1−イル)−6−オキソ−2−(3−チエニルメチル)−1,6−ジヒドロピリミジン−5−カルボニトリル
HPLC(方法12):Rt=4.6分
MS(ESIpos):m/z=329[M+H]+
1H-NMR (DMSO-d6, 300 MHz): δ = 0.97 (s, 6H), 1.37 (t, 4H), 3.77-3.87 (m, 6H, s at 3.80), 7.06 (d, 1H), 7.34 (s, 1H), 7.49 (m, 1H), 12.31 (s, 1H).
4−[4−(tert−ブチル)ピペリジン−1−イル]−6−オキソ−2−(3−チエニルメチル)−1,6−ジヒドロピリミジン−5−カルボニトリル
HPLC(方法12):Rt=4.9分
MS(ESIpos):m/z=357[M+H]+
1H-NMR (DMSO-d6, 200 MHz): δ = 0.82 (s, 9H), 1.02-1.42 (m, 3H), 1.74 (d, 2H), 2.96 (t, 2H), 3.78 (s, 2H), 4.72 (d, 2H), 7.06 (d, 1H), 7.33 (s, 1H), 7.49 (m, 1H), 12.35 (s, 1H).
4−(4−ヒドロキシピペリジン−1−イル)−6−オキソ−2−(3−チエニルメチル)−1,6−ジヒドロピリミジン−5−カルボニトリル
HPLC(方法12):Rt=3.50分
MS(ESIpos):m/z=317[M+H]+
1H-NMR (DMSO-d6, 200 MHz): δ = 1.29-1.50 (m, 2H), 1.72-1.90 (m, 2H), 3.42-3.60 (m, 2H), 3.68-3.86 (m, 3H, s at 3.79), 4.10-4.26 (m, 2H), 4.83 (d, 1H, OH), 7.07 (d, 1H), 7.35 (s, 1H), 7.50 (m, 1H), 11.79-12.29 (s, 1H, NH).
4−[4−(2−ヒドロキシエチル)ピペリジン−1−イル]−6−オキソ−2−(3−チエニルメチル)−1,6−ジヒドロピリミジン−5−カルボニトリル
HPLC(方法12):Rt=3.70分
MS(ESIpos):m/z=345[M+H]+
1H-NMR (DMSO-d6, 300 MHz): δ = 1.02-1.20 (m, 2H), 1.32-1.42 (q, 2H), 1.68-1.81 (m, 3H), 3.05 (t, 2H), 3.44 (q, 2H), 3.80 (s, 2H), 4.34 (t, 1H, OH), 4.62 (d, 2H), 7.06 (d, 1H), 7.34 (s, 1H), 7.49 (m, 1H), 12.31 (s, 1H, NH).
4−[(2−メトキシエチル)アミノ]−6−オキソ−2−(3−チエニルメチル)−1,6−ジヒドロピリミジン−5−カルボニトリル
HPLC(方法12):Rt=3.7分
MS(ESIpos):m/z=291[M+H]+
1H-NMR (DMSO-d6, 300 MHz): δ = 3.20 (s, 3H), 3.35-3.42 (m, 2H), 3.47-3.56 (m, 2H), 3.82 (s, 2H), 7.07 (d, 1H), 7.34 (s, 1H), 7.49 (m, 1H), 7.79 (s, 1H), 12.33 (s, 1H).
4−(1,4−ジオキサ−8−アザスピロ[4.5]デカ−8−イル)−6−オキソ−2−(3−チエニルメチル)−1,6−ジヒドロピリミジン−5−カルボニトリル
HPLC(方法12):Rt=4.0分
MS(ESIpos):m/z=359[M+H]+
1H-NMR (DMSO-d6, 300 MHz): δ = 1.70 (t, 4H), 3.81 (s, 2H), 3.86-3.95 (m, 8H, 3.92にs), 7.07 (d, 1H), 7.34 (s, 1H), 7.49 (m, 1H), 12.41 (s, 1H).
4−(7,11−ジオキサ−3−アザスピロ[5.5]ウンデカ−3−イル)−6−オキソ−2−(3−チエニルメチル)−1,6−ジヒドロピリミジン−5−カルボニトリル
HPLC(方法12):Rt=4.0分
MS(ESIpos):m/z=373[M+H]+
1H-NMR (DMSO-d6, 200 MHz): δ = 1.56 (m, 2H), 1.82-1.94 (m, 4H), 3.75-3.92 (m, 10H, 3.80にs), 7.07 (d, 1H), 7.35 (s, 1H), 7.50 (m, 1H), 12.43 (br. s, 1H).
4−(4−メチルピペラジン−1−イル)−6−オキソ−2−(3−チエニルメチル)−1,6−ジヒドロピリミジン−5−カルボニトリル
HPLC(方法12):Rt=3.2分
MS(ESIpos):m/z=316[M+H]+
1H-NMR (DMSO-d6, 200 MHz): δ = 2.19 (s, 3H), 2.37 (t, 4H), 3.77-3.91 (m, 6H, s at 3.80), 7.07 (d, 1H), 7.35 (s, 1H), 7.50 (m, 1H), 12.43 (s, 1H).
6−オキソ−4−(ピペラジン−1−イル)−2−(3−チエニルメチル)−1,6−ジヒドロピリミジン−5−カルボニトリル
HPLC(方法12):Rt=3.15分
MS(ESIpos):m/z=302[M+H]+
1H-NMR (DMSO-d6, 200 MHz): δ = 2.75 (t, 4H), 3.76-3.82 (m, 6H, s at 3.80), 7.06 (d, 1H), 7.34 (s, 1H), 7.49 (m, 1H).
4−(ベンジルアミノ)−6−オキソ−2−(3−チエニルメチル)−1,6−ジヒドロピリミジン−5−カルボニトリル
HPLC(方法12):Rt=4.3分
MS(ESIpos):m/z=323[M+H]+
1H-NMR (DMSO-d6, 200 MHz): δ = 3.80 (s, 2H), 4.52 (d, 2H), 6.95 (d, 1H), 7.16-7.32 (m, 6H), 7.45 (m, 1H), 8.49 (t, 1H), 12.40 (s, 1H).
4−[(2−メトキシベンジル)アミノ]−6−オキソ−2−(3−チエニルメチル)−1,6−ジヒドロピリミジン−5−カルボニトリル
HPLC(方法12):Rt=4.4分
MS(ESIpos):m/z=353[M+H]+
1H-NMR (DMSO-d6, 300 MHz): δ = 3.75 (s, 2H), 3.80 (s, 3H), 4.56 (d, 2H), 6.84-6.90 (m, 2H), 6.96-7.04 (m, 2H), 7.16 (s, 1H), 7.23 (t, 1H), 7.39 (m, 1H), 8.15 (t, 1H), 12.34 (s, 1H).
4−[4−(2−ヒドロキシエチル)ピペリジン−1−イル]−2−[2−(6−メトキシピリジン−3−イル)ベンジル]−6−オキソ−1,6−ジヒドロピリミジン−5−カルボニトリル
スキームII:
a)1.トルエン、ボロントリフロリド−エーテレート、室温、30分;2.アミン成分R1R2NH、150℃、16時間;または:出発化合物の融解状態、150℃、1−16時間;b)DMF、トリエチルアミン、100℃、16時間またはDMF、炭酸カリウム、90℃、16時間。
4−(シクロヘキシルアミノ)−6−オキソ−2−(3−チエニルメチル)−1,6−ジヒドロピリミジン−5−カルボニトリル
HPLC(方法12):Rt=4.55分
MS(DCI,NH3):m/z=315[M+H]+
1H-NMR (DMSO-d6, 400 MHz): δ = 0.98-1.43 (m, 5H), 1.53-1.74 (m, 5H), 3.78-3.94 (m, 3H, s at 3.82), 7.06 (d, 1H), 7.33 (s, 1H), 7.50 (m, 1H), 7.54 (m, 1H), 12.28 (s, 1H).
4−(4−ホルミルピペラジン−1−イル)−6−オキソ−2−(3−チエニルメチル)−1,6−ジヒドロピリミジン−5−カルボニトリル
HPLC(方法12):Rt=3.4分
MS(ESIpos):m/z=330[M+H]+
1H-NMR (DMSO-d6, 200 MHz): δ = 3.42-3.54 (m, 4H), 3.79-3.94 (m, 6H, s at 3.82), 7.09 (d, 1H), 7.36 (s, 1H), 7.51 (m, 1H), 8.06 (s, 1H), 12.55 (s, 1H).
4−(4−アセチルピペラジン−1−イル)−6−オキソ−2−(3−チエニルメチル)−1,6−ジヒドロピリミジン−5−カルボニトリル
HPLC(方法12):Rt=3.5分
MS(ESIpos):m/z=344[M+H]+
1H-NMR (DMSO-d6, 300 MHz): δ = 2.02 (s, 3H), 3.50-3.61 (m, 4H), 3.80-3.95 (m, 6H, s at 3.82), 7.08 (d, 1H), 7.36 (s, 1H), 7.50 (m, 1H), 12.47 (s, 1H).
4−(4−エチルピペラジン−1−イル)−6−オキソ−2−(3−チエニルメチル)−1,6−ジヒドロピリミジン−5−カルボニトリル
HPLC(方法12):Rt=3.3分
MS(ESIpos):m/z=330[M+H]+
1H-NMR (DMSO-d6, 300 MHz): δ = 1.00 (t, 3H), 2.34 (q, 2H), 2.42 (t, 4H), 3.80 (s, 2H), 3.86 (t, 4H), 7.06 (d, 1H), 7.34 (s, 1H), 7.49 (m, 1H), 12.39 (s, 1H).
Claims (5)
- 式
Aは、フェニル、チエニルまたは式
[ここで、フェニルは、ピリジル、フッ素、塩素、メチル、メトキシ、エトキシ、トリフルオロメチル、トリフルオロメトキシ、ベンジルオキシおよびベンジルの群から相互に独立して選択される2個までの基により置換されていることもある
{ここで、メチルは、式−NR3R4(式中、R3はメチルであり、R4は水素または2−メトキシエチルである)の基により置換されていることもあり、そして、
ピリジルは、メトキシにより置換されていることもある}]、
R1は、C3−C6−シクロアルキル、メチル、エチル、プロピル、2−メトキシエチル、ベンジルまたは式
(ここで、C3−C6−シクロアルキルは、ヒドロキシ、メチルまたはトリフルオロメチルにより置換されていることもあり、
メチル、エチル、プロピルは、ピリジル、シクロプロピルまたはヒドロキシにより置換されていることもあり、そして、
ベンジルは、メトキシ、エトキシ、フッ素または塩素により置換されていることもある)、
R2は水素であるか、
または、
R1およびR2は、それらが結合している窒素原子と一体となって、ピロリジニル、ピペリジニル、ピペラジニルおよびモルホリニルの群から選択される5員ないし6員の複素環を形成し、それは、メチル、エチル、プロピル、tert−ブチル、ヒドロキシ、シアノ、オキソ、ピリジル、ベンジル、ホルミル、メチルカルボニル、エチルカルボニル、プロピルカルボニルおよび以下の基
(ここで、メチル、エチルおよびプロピルは、ヒドロキシまたはピリジルにより置換されていることもある)、
の化合物またはその塩、
ただし、該化合物は、
- [A]式
HNR1R2 (III)
(式中、R1およびR2は、請求項1に記載の意味を有する)
の化合物を用いて、70℃ないし200℃の温度で、不活性溶媒中または溶媒の非存在下で、式
の化合物に変換し、
次いで、後者を、不活性溶媒中、塩基の存在下、式
の化合物と反応させるか、
または、反応物の順序を変更して、
[B]式(II)の化合物を、最初に、式(V)の化合物を用いて、不活性溶媒中、塩基の存在下で、式
の化合物に変換し、
次いで、後者を、50℃ないし150℃の温度で、不活性溶媒中または溶媒の非存在下で、式(III)の化合物と反応させ、
そして、各場合で得られる式(I)の化合物を、必要に応じて適切な(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、
のいずれかを特徴とする、請求項1に記載の式(I)の化合物の製造方法。 - 疾患の処置および/または予防のための、請求項1または請求項2に記載の化合物。
- 少なくとも1種の請求項1または請求項2に記載の化合物、および、少なくとも1種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。
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JP2012014419A Active JP5457476B2 (ja) | 2004-01-14 | 2012-01-26 | 知覚力、集中力、学習力および/または記憶力の改善のために使用される6−アミノ−5−シアノ−ピリミジン−4−オン化合物 |
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US (2) | US8088769B2 (ja) |
EP (1) | EP1709009B1 (ja) |
JP (2) | JP4951349B2 (ja) |
KR (1) | KR20070015372A (ja) |
CN (2) | CN102382063A (ja) |
AU (1) | AU2004313696B2 (ja) |
BR (1) | BRPI0418407A (ja) |
CA (1) | CA2553200A1 (ja) |
DE (1) | DE102004001873A1 (ja) |
IL (1) | IL176780A0 (ja) |
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RU (1) | RU2006129164A (ja) |
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DE102004001873A1 (de) * | 2004-01-14 | 2005-09-29 | Bayer Healthcare Ag | Cyanopyrimidinone |
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EA201100446A1 (ru) | 2008-09-08 | 2011-10-31 | Бёрингер Ингельхайм Интернациональ Гмбх | Пиразолопиримидины и их применение для лечения нарушений цнс |
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Publication number | Publication date |
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JP2012097115A (ja) | 2012-05-24 |
US20080255118A1 (en) | 2008-10-16 |
DE102004001873A1 (de) | 2005-09-29 |
AU2004313696B2 (en) | 2011-08-18 |
AU2004313696A1 (en) | 2005-07-28 |
JP2007518726A (ja) | 2007-07-12 |
US8431573B2 (en) | 2013-04-30 |
WO2005068436A1 (de) | 2005-07-28 |
US8088769B2 (en) | 2012-01-03 |
CA2553200A1 (en) | 2005-07-28 |
ZA200605781B (en) | 2008-02-27 |
BRPI0418407A (pt) | 2007-05-15 |
RU2006129164A (ru) | 2008-02-20 |
JP5457476B2 (ja) | 2014-04-02 |
IL176780A0 (en) | 2006-10-31 |
KR20070015372A (ko) | 2007-02-02 |
US20110207735A1 (en) | 2011-08-25 |
EP1709009A1 (de) | 2006-10-11 |
CN1926117A (zh) | 2007-03-07 |
CN102382063A (zh) | 2012-03-21 |
NZ548470A (en) | 2010-09-30 |
CN1926117B (zh) | 2011-12-07 |
EP1709009B1 (de) | 2013-11-20 |
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