JP5596139B2 - 二置換フタラジンヘッジホッグ経路アンタゴニスト - Google Patents
二置換フタラジンヘッジホッグ経路アンタゴニスト Download PDFInfo
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- JP5596139B2 JP5596139B2 JP2012516178A JP2012516178A JP5596139B2 JP 5596139 B2 JP5596139 B2 JP 5596139B2 JP 2012516178 A JP2012516178 A JP 2012516178A JP 2012516178 A JP2012516178 A JP 2012516178A JP 5596139 B2 JP5596139 B2 JP 5596139B2
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- methyl
- cancer
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- trifluoromethyl
- fluoro
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- OGFAWKRXZLGJSK-UHFFFAOYSA-N 1-(2,4-dihydroxyphenyl)-2-(4-nitrophenyl)ethanone Chemical compound OC1=CC(O)=CC=C1C(=O)CC1=CC=C([N+]([O-])=O)C=C1 OGFAWKRXZLGJSK-UHFFFAOYSA-N 0.000 description 1
- PFTYSHQEEHFCJJ-UHFFFAOYSA-N 1-(2-tert-butylpiperidin-1-yl)-4-chlorophthalazine Chemical compound CC(C)(C)C1CCCCN1C2=NN=C(C3=CC=CC=C32)Cl PFTYSHQEEHFCJJ-UHFFFAOYSA-N 0.000 description 1
- KGLPWQKSKUVKMJ-UHFFFAOYSA-N 2,3-dihydrophthalazine-1,4-dione Chemical compound C1=CC=C2C(=O)NNC(=O)C2=C1 KGLPWQKSKUVKMJ-UHFFFAOYSA-N 0.000 description 1
- QCKGMJDOJRNSMS-UHFFFAOYSA-N 4-chloro-2h-phthalazin-1-one Chemical compound C1=CC=C2C(Cl)=NNC(=O)C2=C1 QCKGMJDOJRNSMS-UHFFFAOYSA-N 0.000 description 1
- GPROYWJIIVDBHZ-UHFFFAOYSA-N 4-chloro-n-methyl-n-[1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]piperidin-4-yl]-2-methylsulfonylbenzamide;hydrochloride Chemical class Cl.C=1C=C(Cl)C=C(S(C)(=O)=O)C=1C(=O)N(C)C(CC1)CCN1C(C1=CC=CC=C11)=NN=C1C1=CC=NN1C GPROYWJIIVDBHZ-UHFFFAOYSA-N 0.000 description 1
- OEYHURRIOWWRMD-UHFFFAOYSA-N 4-fluoro-2-(trifluoromethyl)benzoyl chloride Chemical compound FC1=CC=C(C(Cl)=O)C(C(F)(F)F)=C1 OEYHURRIOWWRMD-UHFFFAOYSA-N 0.000 description 1
- ZULPZIIPOBSSNQ-UHFFFAOYSA-N 4-fluoro-n-methyl-n-[1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]piperidin-4-yl]-2-(trifluoromethyl)benzamide;hydrochloride Chemical compound Cl.C=1C=C(F)C=C(C(F)(F)F)C=1C(=O)N(C)C(CC1)CCN1C(C1=CC=CC=C11)=NN=C1C1=CC=NN1C ZULPZIIPOBSSNQ-UHFFFAOYSA-N 0.000 description 1
- KWLOIDOKWUESNM-UHFFFAOYSA-N 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1h-pyrazole Chemical compound O1C(C)(C)C(C)(C)OB1C1=CC=NN1 KWLOIDOKWUESNM-UHFFFAOYSA-N 0.000 description 1
- FDNAEFGYDIKFBW-UHFFFAOYSA-N C(C1)CNCC1C1=NN=CC2=CC=CC=C12 Chemical compound C(C1)CNCC1C1=NN=CC2=CC=CC=C12 FDNAEFGYDIKFBW-UHFFFAOYSA-N 0.000 description 1
- CSLLCOIAXVXFNF-UHFFFAOYSA-N CC(C)(C)OC(NC(CC1)CCN1c(nn1)c(cccc2)c2c1Cl)=O Chemical compound CC(C)(C)OC(NC(CC1)CCN1c(nn1)c(cccc2)c2c1Cl)=O CSLLCOIAXVXFNF-UHFFFAOYSA-N 0.000 description 1
- 0 Cc1c(C(N(*)C(CC2)CCN2c2nnc(-c3ccn[n]3*)c3c2cccc3)=O)c(C)c(*)c(*)c1* Chemical compound Cc1c(C(N(*)C(CC2)CCN2c2nnc(-c3ccn[n]3*)c3c2cccc3)=O)c(C)c(*)c(*)c1* 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 1
- 102000053602 DNA Human genes 0.000 description 1
- 108010067770 Endopeptidase K Proteins 0.000 description 1
- 108700042658 GAP-43 Proteins 0.000 description 1
- 206010017993 Gastrointestinal neoplasms Diseases 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 241000596871 Ixia Species 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- 241001460678 Napo <wasp> Species 0.000 description 1
- JQGPBDSMTHZOMO-UHFFFAOYSA-N OBO.C=1C=NNC=1 Chemical compound OBO.C=1C=NNC=1 JQGPBDSMTHZOMO-UHFFFAOYSA-N 0.000 description 1
- 241000051107 Paraechinus aethiopicus Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 238000006069 Suzuki reaction reaction Methods 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 241000489524 Veratrum californicum Species 0.000 description 1
- 108010088665 Zinc Finger Protein Gli2 Proteins 0.000 description 1
- 101710185494 Zinc finger protein Proteins 0.000 description 1
- 102100023597 Zinc finger protein 816 Human genes 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- XSCHRSMBECNVNS-UHFFFAOYSA-N benzopyrazine Natural products N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 description 1
- 210000000013 bile duct Anatomy 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 239000013592 cell lysate Substances 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 230000009918 complex formation Effects 0.000 description 1
- 230000021615 conjugation Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 239000003596 drug target Substances 0.000 description 1
- 230000008406 drug-drug interaction Effects 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 210000003238 esophagus Anatomy 0.000 description 1
- 239000003797 essential amino acid Substances 0.000 description 1
- 235000020776 essential amino acid Nutrition 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 208000005017 glioblastoma Diseases 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 230000009459 hedgehog signaling Effects 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000009396 hybridization Methods 0.000 description 1
- 238000005805 hydroxylation reaction Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000000099 in vitro assay Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 239000006166 lysate Substances 0.000 description 1
- 239000012139 lysis buffer Substances 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- GTCAXTIRRLKXRU-UHFFFAOYSA-N methyl carbamate Chemical compound COC(N)=O GTCAXTIRRLKXRU-UHFFFAOYSA-N 0.000 description 1
- 210000001589 microsome Anatomy 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000000116 mitigating effect Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- LAHSIPAAIPQMCT-UHFFFAOYSA-N n-[3-(1h-benzimidazol-2-yl)-4-chlorophenyl]-3,5-dimethoxybenzamide Chemical compound COC1=CC(OC)=CC(C(=O)NC=2C=C(C(Cl)=CC=2)C=2NC3=CC=CC=C3N=2)=C1 LAHSIPAAIPQMCT-UHFFFAOYSA-N 0.000 description 1
- OFJKIQVFEHNTQI-UHFFFAOYSA-N n-methyl-1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]piperidin-4-amine Chemical compound C1CC(NC)CCN1C(C1=CC=CC=C11)=NN=C1C1=CC=NN1C OFJKIQVFEHNTQI-UHFFFAOYSA-N 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- VIKNJXKGJWUCNN-XGXHKTLJSA-N norethisterone Chemical compound O=C1CC[C@@H]2[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 VIKNJXKGJWUCNN-XGXHKTLJSA-N 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 238000000059 patterning Methods 0.000 description 1
- LWMPFIOTEAXAGV-UHFFFAOYSA-N piperidin-1-amine Chemical compound NN1CCCCC1 LWMPFIOTEAXAGV-UHFFFAOYSA-N 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 230000007781 signaling event Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000012064 sodium phosphate buffer Substances 0.000 description 1
- 229940054269 sodium pyruvate Drugs 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- CKXZPVPIDOJLLM-UHFFFAOYSA-N tert-butyl n-piperidin-4-ylcarbamate Chemical compound CC(C)(C)OC(=O)NC1CCNCC1 CKXZPVPIDOJLLM-UHFFFAOYSA-N 0.000 description 1
- 231100000583 toxicological profile Toxicity 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
-
- 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
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Oncology (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Hematology (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Peptides Or Proteins (AREA)
Description
(a)R1が、メチルである;
(b)R2が、メチルである;
(c)R3、R4、R5、R6又はR7が、独立して、水素、フルオロ、クロロ、トリフルオロメチル、又はメチルスルホニルである;
(d)R3、R4、R5、R6又はR7が、独立して、水素、フルオロ、又はトリフルオロメチルである;
(e)R3、R4、R5、R6及びR7のうちの少なくとも2つが、独立して、フルオロ、クロロ、トリフルオロメチル、又はメチルスルホニルであるが、但し、R3及びR7が同時に水素であることはない;
(f)R3、R4、R5、R6及びR7のうちの少なくとも2つが、独立して、フルオロ又はトリフルオロメチルであるが、但し、R3及びR7が同時に水素であることはない;
(g)R4、R6及びR7が、水素である;
(h)R3及びR5が、独立して、フルオロ、クロロ、トリフルオロメチル、又はメチルスルホニルであり;且つR4、R6及びR7が、水素である;
(i)R3及びR5が、独立して、フルオロ又はトリフルオロメチルであり;且つR4、R6及びR7が、水素である;
(j)R1が、メチルであり;且つR2が、メチルである;
(k)R1が、メチルであり;R2が、メチルであり;且つR3、R4、R5、R6又はR7が、独立して、水素、フルオロ、クロロ、トリフルオロメチル、又はメチルスルホニルである;
(l)R1が、メチルであり;R2が、メチルであり;且つR3、R4、R5、R6又はR7が、独立して、水素、フルオロ、又はトリフルオロメチルである;
(m)R1が、メチルであり;R2が、メチルであり;且つR3、R4、R5、R6及びR7のうちの少なくとも2つが、独立して、フルオロ、クロロ、トリフルオロメチル、又はメチルスルホニルであるが、但し、R3及びR7が同時に水素であることはない;
(n)R1が、メチルであり;R2が、メチルであり;R3、R4、R5、R6及びR7のうちの少なくとも2つが、独立して、フルオロ又はトリフルオロメチルであるが、但し、R3及びR7が同時に水素であることはない;
(o)R1が、メチルであり;R2が、メチルであり;且つR4、R6及びR7が、水素である;
(p)R1が、メチルであり;R2が、メチルであり;R3及びR5が、独立して、フルオロ、クロロ、トリフルオロメチル、又はメチルスルホニルであり;且つR4、R6及びR7が、水素である;並びに
(q)R1が、メチルであり;R2が、メチルであり;R3及びR5が、独立して、フルオロ又はトリフルオロメチルであり;且つR4、R6及びR7が、水素である。
tert−ブチル1−(4−クロロフタラジン−1−イル)ピペリジン−4−イル(メチル)カルバメート
tert−ブチル1−(4−クロロフタラジン−1−イル)ピペリジン−4−イルカルバメート
tert−ブチルメチル(1−(4−(1−メチル−1H−ピラゾール−5−イル)フタラジン−1−イル)ピペリジン−4−イル)カルバメート
1,4−ジブロモフタラジン
tert−ブチル1−(4−ブロモフタラジン−1−イル)ピペリジン−4−イル(メチル)カルバメート
tert−ブチルメチル(1−(4−(1−メチル−1H−ピラゾール−5−イル)フタラジン−1−イル)ピペリジン−4−イル)カルバメート
tert−ブチル1−(4−(1H−ピラゾール−5−イル)フタラジン−1−イル)ピペリジン−4−イル(メチル)カルバメート
tert−ブチル1−(4−(1−メチル−1H−ピラゾール−5−イル)フタラジン−1−イル)ピペリジン−4−イルカルバメート
N−メチル−1−(4−(1−メチル−1H−ピラゾール−5−イル)フタラジン−1−イル)ピペリジン−4−アミン
4−フルオロ−N−メチル−N−(1−(4−(1−メチル−1H−ピラゾール−5−イル)フタラジン−1−イル)ピペリジン−4−イル)−2−(トリフルオロメチル)ベンズアミド
4−フルオロ−N−メチル−N−(1−(4−(1−メチル−1H−ピラゾール−5−イル)フタラジン−1−イル)ピペリジン−4−イル)−2−(トリフルオロメチル)ベンズアミド塩酸塩
4−フルオロ−N−メチル−N−(1−(4−(1−メチル−1H−ピラゾール−5−イル)フタラジン−1−イル)ピペリジン−4−イル)−2−(トリフルオロメチル)ベンズアミド(7.13g、13.91mmol)をジクロロメタン(100mL)に溶解させ、過剰量のジエチルエーテル(30mL、30mmol)中1N HClを添加する。減圧下で溶媒を除去して、表題化合物(7.05g、92%)を得る。ES/MS m/z 513.0(M+1)。NMRは、アミド回転異性体の2:1混合物であることを示した。多数の回転異性体;1H NMR(400MHz,DMSO−d6):δ 8.34(m,1H),8.26(m,2H),7.95(m,1H),7.75(m,1H),7.64(m,2H),7.55(m,1H),6.72(d,1H,J=2Hz),5.15(br,1H),4.71(m,1H),4.22(m,2H),3.84(s,3H),3.48(m,2H),2.65(s,3H),2.19(m,2H),1.89(m,2H)。少数の回転異性体;1H NMR(400MHz,DMSO−d6):δ 8.27(m,1H),8.24(m,2H),7.94(m,1H),7.73(m,1H),7.63(m,3H),6.70(d,1H,J=2Hz),5.15(br,1H),4.71(m,1H),4.07(m,2H),3.81(s,3H),3.16(m,2H),2.92(s,3H),1.90(m,2H),1.62(m 2H)。
4−クロロ−N−メチル−N−(1−(4−(1−メチル−1H−ピラゾール−5−イル)フタラジン−1−イル)ピペリジン−4−イル)−2−(メチルスルホニル)ベンズアミド塩酸塩
以下のアッセイプロトコル及びその結果は、本発明の化合物及び方法の有用性並びに有効性を更に示す。機能アッセイは、本発明の化合物がShhシグナル伝達阻害能を示すことを支持する。以下のアッセイで用いられるリガンド、溶媒、及び試薬は全て、商業的供給元から容易に入手可能であるか、又は当業者により容易に調製され得る。
ヒト肝臓ミクロソーム調製物を試験阻害剤(最終濃度0.05mg/mLのタンパク質、100mM NaPO4中10μM阻害剤、pH7.4緩衝液)に添加し、混合することによって、インキュベーションサンプルを調製する。37℃で約5分間、サンプルをプレインキュベートする。プレインキュベート期間後、酵素基質としてNADPH及びミダゾラムを含有する溶液(最終濃度1mM NADPH、5μMミダゾラム)を添加して反応を開始させる。NADPH溶液を添加した後、約37℃で3分間サンプルをインキュベートする。インキュベート期間後、50μLのメタノール(及びクロマトグラフィー用の内部標準)を添加することにより前記反応をクエンチし、前記サンプルを十分混合する。反応をクエンチした後、約5℃で15分間、約4000rpmにて混合物を遠心分離し、LC/MS分析によって分析する。
この相互作用の速度定数kinact及びKIを得るために、CYP3Aの機序に基づく阻害剤として実施例1aの化合物を評価する。(Kinactは不活性酵素複合体形成の最高速度定数である。KIは最大不活性化濃度の半分の濃度である)。2段階のインビトロインキュベーション(阻害剤に酵素を不活化させる不活化反応、及びプローブとしてミダゾラムの1’−ヒドロキシル化を使用して、ミクロゾームタンパク質の残存活性を評価する活性アッセイ)において、前記化合物をヒト肝ミクロソーム(CYP3A4活性が高発現するヒト肝ミクロソームのプール)と共にインキュベートする。
等式1:阻害率(t)=100(t=0)×e(−λt)
(式中、λは、以下の通り定義される
等式2:λ=(kinact×I)/(KI+I))。
Claims (12)
- R1がメチルである請求項1に記載の化合物又はその薬学的に許容できる塩。
- R2がメチルである請求項1又は2に記載の化合物又はその薬学的に許容できる塩。
- R3、R4、R5、R6及びR7が、独立して、水素、フルオロ、クロロ、トリフルオロメチル、又はメチルスルホニルである請求項1〜3のいずれか一項に記載の化合物又はその薬学的に許容できる塩。
- R3、R4、R5、R6及びR7が、独立して、水素、フルオロ、又はトリフルオロメチルである請求項1〜4のいずれか一項に記載の化合物又はその薬学的に許容できる塩。
- R4、R6及びR7が水素である請求項1〜5のいずれか一項に記載の化合物又はその薬学的に許容できる塩。
- 4−フルオロ−N−メチル−N−(1−(4−(1−メチル−1H−ピラゾール−5−イル)フタラジン−1−イル)ピペリジン−4−イル)−2−(トリフルオロメチル)ベンズアミドである請求項1記載の化合物又はその薬学的に許容できる塩。
- 4−フルオロ−N−メチル−N−(1−(4−(1−メチル−1H−ピラゾール−5−イル)フタラジン−1−イル)ピペリジン−4−イル)−2−(トリフルオロメチル)ベンズアミド塩酸塩である請求項1記載の化合物。
- 4−フルオロ−N−(1−(4−(1−メチル−1H−ピラゾール−5−イル)フタラジン−1−イル)ピペリジン−4−イル)−2−(トリフルオロメチル)ベンズアミドである請求項1記載の化合物又はその薬学的に許容できる塩。
- 4−フルオロ−N−(1−(4−(1−メチル−1H−ピラゾール−5−イル)フタラジン−1−イル)ピペリジン−4−イル)−2−(トリフルオロメチル)ベンズアミド塩酸塩である請求項1記載の化合物。
- 薬学的に許容できる担体、希釈剤、又は賦形剤と共に、請求項1〜10のいずれか一項に記載の化合物又はその薬学的に許容できる塩を含む医薬組成物。
- 癌の治療において使用するための請求項11に記載の医薬組成物。
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