JP6093341B2 - 神経学的および精神的障害の治療のための複素環式化合物 - Google Patents
神経学的および精神的障害の治療のための複素環式化合物 Download PDFInfo
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- JP6093341B2 JP6093341B2 JP2014264706A JP2014264706A JP6093341B2 JP 6093341 B2 JP6093341 B2 JP 6093341B2 JP 2014264706 A JP2014264706 A JP 2014264706A JP 2014264706 A JP2014264706 A JP 2014264706A JP 6093341 B2 JP6093341 B2 JP 6093341B2
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- 239000003223 protective agent Substances 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000001422 pyrrolinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 239000003340 retarding agent Substances 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 229960001534 risperidone Drugs 0.000 description 1
- RAPZEAPATHNIPO-UHFFFAOYSA-N risperidone Chemical compound FC1=CC=C2C(C3CCN(CC3)CCC=3C(=O)N4CCCCC4=NC=3C)=NOC2=C1 RAPZEAPATHNIPO-UHFFFAOYSA-N 0.000 description 1
- 235000005713 safflower oil Nutrition 0.000 description 1
- 239000003813 safflower oil Substances 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 208000022610 schizoaffective disease Diseases 0.000 description 1
- 230000007017 scission Effects 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
- 150000003334 secondary amides Chemical class 0.000 description 1
- 229940125723 sedative agent Drugs 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- 208000019116 sleep disease Diseases 0.000 description 1
- 230000037321 sleepiness Effects 0.000 description 1
- AWUCVROLDVIAJX-GSVOUGTGSA-N sn-glycerol 3-phosphate Chemical compound OC[C@@H](O)COP(O)(O)=O AWUCVROLDVIAJX-GSVOUGTGSA-N 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 208000020431 spinal cord injury Diseases 0.000 description 1
- 238000013222 sprague-dawley male rat Methods 0.000 description 1
- 238000012453 sprague-dawley rat model Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 239000003206 sterilizing agent Substances 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 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
- 150000003511 tertiary amides Chemical class 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- BSYVTEYKTMYBMK-UHFFFAOYSA-N tetrahydrofurfuryl alcohol Chemical compound OCC1CCCO1 BSYVTEYKTMYBMK-UHFFFAOYSA-N 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000001757 thermogravimetry curve Methods 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 231100000886 tinnitus Toxicity 0.000 description 1
- 235000019505 tobacco product Nutrition 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- NVLRFXKSQQPKAD-UHFFFAOYSA-N tricarbon Chemical compound [C]=C=[C] NVLRFXKSQQPKAD-UHFFFAOYSA-N 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 206010044652 trigeminal neuralgia Diseases 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 1
- 229940070710 valerate Drugs 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000019871 vegetable fat Nutrition 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
Images
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- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
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- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
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- 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
- A61K31/4965—Non-condensed pyrazines
- A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
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- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D401/12—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 chain containing hetero atoms as chain links
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- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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Description
本願は、2009年6月25日に出願された米国特許仮出願第61/220,480号および2010年1月7日に出願された同第61/293,087号の利益を主張する。上記出願の全教示は参照により本明細書に援用される。
現在、統合失調症、双極性障害、不眠および不安障害などの神経学的および精神的障害の治療のための臨床使用には、いくつかの薬物がある。これらの化合物の例としては、アリピプラゾール ジプラシドンおよびビフェプルノックス(bifeprunox)が挙げられる。これらの化合物の化学構造を以下に示す。
本願は、式Iの化合物、ならびに統合失調症、躁病、不安および双極性疾患を含む神経学的および精神的障害の治療のための該化合物の使用に関する。特に、本願は、式I:
式I
(式中、
は、単結合または二重結合を表し;
半円は、1、2または3個の環を含む、任意に置換されたシクロアルキル、シクロアルケニル、ヘテロシクリル(heterocyclyl)、アリールまたはヘテロアリールを表し;
Aは、非存在、任意に置換されたアルキル、任意に置換されたアルケニル、任意に置換されたアルキニル、-S-、-O-、-S(O)-、-S(O)2-、-S[C(R10)(R11)]u-、-S(O)[C(R10)(R11)]u-、-S(O)2[C(R10)(R11)]u-、-O[C(R10)(R11)]u-、-N(R10)-、-N(R10)-[C(R10)(R11)]u-、-[C(R10)(R11)]u-から選択され;
各uは、独立して1、2、3、4、5、6または7であり;
各R10およびR11は、独立して非存在、水素、ハロゲン、脂肪族、置換脂肪族、アリールまたは置換アリールであり;
Cy1は、任意に置換されたシクロアルキル、任意に置換されたシクロアルケニル、任意に置換されたヘテロシクリルまたは任意に置換されたアリールであり;
Bは、リンカーまたは直接結合であり;
Dは、非存在、-O-、-NR10、-C(R10)(R11)-および-S-、-S(O)-、-S(O)2-、-C(O)-から選択され;
各G1およびG2は、独立して、非存在、-S-、-O-、-S(O)-、-S(O)2-、-SC(R10)(R11)-、-S(O)C(R10)(R11)-、-S(O)2C(R10)(R11)-、OC(R10)(R11)-、-N(R10)-、-C(R10)=C(R11)-、-N(R10)-C(R10)(R11)-、-[C(R10)(R11)]t-から選択され;
tは、1、2または3であり;
各R1、R3およびR4は、独立して、非存在、水素、ハロゲン、-OR10、-SR10、-N(R10)(R11)、-S(O)R10、-S(O)2R10、任意に置換された脂肪族、任意に置換されたアリールまたは任意に置換されたヘテロシクリルから選択され;
代替的に、2つのR3およびR4は、一緒になって、任意に置換された環を形成し;
R5は、-CH(R10)-OR20、-CH(R10)-OC(O)OR20、-CH(R10)-OC(O)R20、-CH(R10)-OC(O)NR20R21、-(CH(R10))-OPO3MY、-(CH(R10))-OP(O)(OR20)(OR21)、-[CH(R10)O]z-R20、-[CH(R10)O]z-C(O)OR20、-[CH(R10)O]z-C(O)R20、-[CH(R10)O]z-C(O)NR20R21、-[CH(R10)O]z-OPO3MY、-[CH(R10)O]z-P(O)2(OR20)Mおよび-[CH(R10)O]z-P(O)(OR20)(OR21)から選択され;
zは、1、2、3、4、5、6または7であり;
各R20およびR21は、独立して、水素、脂肪族、置換脂肪族、アリールまたは置換アリールから選択され;YおよびMは同じであるかまたは異なり、それぞれは一価のカチオンであるか;あるいはMおよびYは一緒になって二価のカチオンであり;
n、mおよびqは、独立して0、1および2から選択される)
の化合物ならびにその幾何異性体、エナンチオマー、ジアステレオマー、ラセミ化合物、薬学的に許容され得る塩および溶媒和物に関する。
〔1〕式I:
(式中、
は、単結合または二重結合を表し;
半円は、1、2または3個の環を含む、任意に置換されたシクロアルキル、シクロアルケニル、ヘテロシクリル、アリールまたはヘテロアリールを表し;
Aは、非存在、任意に置換されたアルキル、任意に置換されたアルケニル、任意に置換されたアルキニル、-S-、-O-、-S(O)-、-S(O)2-、-S[C(R10)(R11)]u-、-S(O)[C(R10)(R11)]u-、-S(O)2[C(R10)(R11)]u-、-O[C(R10)(R11)]u-、-N(R10)-、-N(R10)-[C(R10)(R11)]u-、-[C(R10)(R11)]u-から選択され;
各uは、独立して1、2、3、4、5、6または7であり;
各R10およびR11は、独立して非存在、水素、ハロゲン、脂肪族、置換脂肪族、アリールまたは置換アリールであり;
Cy1は、任意に置換されたシクロアルキル、任意に置換されたシクロアルケニル、任意に置換されたヘテロシクリルまたは任意に置換されたアリールであり;
Bは、リンカーまたは直接結合であり;
Dは、非存在、-O-、-NR10、-C(R10)(R11)-および-S-、-S(O)-、-S(O)2-、-C(O)-から選択され;
各G1およびG2は、独立して非存在、-S-、-O-、-S(O)-、-S(O)2-、-SC(R10)(R11)-、-S(O)C(R10)(R11)-、-S(O)2C(R10)(R11)-、-OC(R10)(R11)-、-N(R10)-、-C(R10)=C(R11)-、-N(R10)-C(R10)(R11)-、-[C(R10)(R11)]t-から選択され;
tは、1、2または3であり;
各R1、R3およびR4は、独立して非存在、水素、ハロゲン、-OR10、-SR10、-N(R10)(R11)、-S(O)R10、-S(O)2R10、任意に置換された脂肪族、任意に置換されたアリールまたは任意に置換されたヘテロシクリルから選択されるか;
あるいは、2つのR3およびR4は、一緒になって任意に置換された環を形成し;
R5は、-CH(R10)-OR20、-CH(R10)-OC(O)OR20、-CH(R10)-OC(O)R20、-CH(R10)-OC(O)NR20R21、-(CH(R10))-OPO3MY、-(CH(R10))-OP(O)(OR20)(OR21)、-[CH(R10)O]z-R20、-[CH(R10)O]z-C(O)OR20、-[CH(R10)O]z-C(O)R20、-[CH(R10)O]z-C(O)NR20R21、-[CH(R10)O]z-OPO3MY、-[CH(R10)O]z-P(O)2(OR20)Mおよび-[CH(R10)O]z-P(O)(OR20)(OR21)から選択され;
zは、1、2、3、4、5、6または7であり;
各R20およびR21は、独立して水素、脂肪族、置換脂肪族、アリールまたは置換アリールから選択され;YおよびMは、同じであるか異なり、それぞれが一価のカチオンであるか;あるいはMおよびYは、一緒になって二価のカチオンであり;
n、mおよびqは、独立して0、1および2から選択される)
で表される化合物、またはその幾何異性体、エナンチオマー、ジアステレオマー、ラセミ化合物、それらの薬学的に許容され得る塩および溶媒和物、
〔2〕R1が:
(式中、R100およびR101は、独立して水素、ハロゲン、任意に置換されたC1-C8アルキル、任意に置換されたC2-C8アルケニル、任意に置換されたC2-C8アルキニル、任意に置換されたC3-C8シクロアルキル、任意に置換されたC1-C8アルコキシ、任意に置換されたC1-C8アルキルアミノおよび任意に置換されたC1-C8アリールから選択される)
から選択される、〔1〕記載の化合物、
〔3〕Cy1が:
から選択される、〔1〕記載の化合物、
〔4〕R5が:
(式中、R105、R106およびR107は、独立して水素、ハロゲン、任意に置換されたC1-C24アルキル、任意に置換されたC2-C24アルケニル、任意に置換されたC2-C24アルキニル、任意に置換されたC3-C24シクロアルキル、任意に置換されたC1-C24アルコキシ、任意に置換されたC1-C24アルキルアミノおよび任意に置換されたC1-C24アリールから選択される)
から選択される、〔1〕記載の化合物、
〔5〕R5が:
(式中、各xおよびyは、独立して0〜30の整数であり、R105、R106およびR107は上述で定義されるとおりである)
から選択される、〔1〕記載の化合物、
〔6〕式:
(式中A、R1、R3、R4、R5、R10、R11、D、mおよびqは、上述で定義されるとおりであり;
X3は-CH-または-N-であり;
R2は、非存在、水素、ハロゲン、-OR10、-SR10、-N(R10)(R11)、-S(O)R10、-S(O)2R10、任意に置換された脂肪族、任意に置換されたアリールまたは任意に置換されたヘテロシクリルから選択され;
各G3およびG4は、独立して-N-、-C(R10)-[C(R10)(R11)]a-から選択され、aは0、1または2であり;
rは、0、1、2、3、4、5、6、7、8、9、10または11であり;
pは、0、1、2、3または4である)
を有する〔1〕記載の化合物、またはその幾何異性体、エナンチオマー、ジアステレオマー、ラセミ化合物、それらの薬学的に許容され得る塩および溶媒和物、
〔7〕式:
(式中、
は、単結合または二重結合を表し;
R1、R2、R3、R4、R5、A、B、D、G3、G4、n、m、pおよびqは、上述で定義されるとおりである)
を有する〔6〕記載の化合物、またはその幾何異性体、エナンチオマー、ジアステレオマー、ラセミ化合物、それらの薬学的に許容され得る塩および溶媒和物、
〔8〕式:
(式中、R2、R3、R4、R5、R10、R11、D、m、p、qおよびrは、上述で定義されるとおりであり;
各R6は、独立して水素、ハロゲン、OR10、SR10、NR10R11、脂肪族、置換脂肪族、芳香族、置換芳香族から選択され、各R10およびR11は、独立して水素、ハロゲン、脂肪族、置換脂肪族アリールまたは置換アリールであるか;あるいは2つの隣接するR6基は、第2の環を形成し;
tおよびsは、独立して0、1および2から選択される)
を有する〔7〕記載の化合物、またはその幾何異性体、エナンチオマー、ジアステレオマー、ラセミ化合物、それらの薬学的に許容され得る塩および溶媒和物、
〔9〕式:
(式中、
は、単結合または二重結合を表し;
R5は上述で定義されるとおりであり;
wは、0、1、2、3、4、5、6、7、8、9、10または11である)
を有する〔8〕記載の化合物、またはその幾何異性体、エナンチオマー、ジアステレオマー、ラセミ化合物、それらの薬学的に許容され得る塩および溶媒和物、
〔10〕式:
(式中、A、R1、R2、R3、R4、R5、R10、R11、G3、G4、m、p、qおよびrは、上述で定義されるとおりであり;
X2は、-S-または-O-である)
を有する〔6〕記載の化合物、またはその幾何異性体、エナンチオマー、ジアステレオマー、ラセミ化合物、それらの薬学的に許容され得る塩および溶媒和物、
〔11〕式:
(式中、R2、R5、R10、R11、X2、pおよびrは上述で定義されるとおりである)
を有する〔10〕記載の化合物、またはその幾何異性体、エナンチオマー、ジアステレオマー、ラセミ化合物、それらの薬学的に許容され得る塩および溶媒和物、
〔12〕式:
(式中、R1、R2、R3、R5、A、B、D、G3、G4、p、q、R10およびR11は、上述で定義されるとおりであり;
X1は-S-、-O-、-NR10-または-C(R10)(R11)-である)
を有する〔1〕記載の化合物、またはその幾何異性体、エナンチオマー、ジアステレオマー、ラセミ化合物、それらの薬学的に許容され得る塩および溶媒和物、
〔13〕式:
(式中、R2、R3、R4、R5、A、D、G3、G4、m、q、r、X2、R10およびR11は、上述で定義されるとおりである)
を有する〔12〕記載の化合物、またはその幾何異性体、エナンチオマー、ジアステレオマー、ラセミ化合物、それらの薬学的に許容され得る塩および溶媒和物、
〔14〕式:
(式中、X2、D、R2、R5、r、R10およびR11は、上述で定義されるとおりである)
を有する〔13〕記載の化合物、またはその幾何異性体、エナンチオマー、ジアステレオマー、ラセミ化合物、それらの薬学的に許容され得る塩および溶媒和物、
〔15〕式:
(式中、R5は上述で定義されるとおりである)
を有する〔14〕記載の化合物、またはその幾何異性体、エナンチオマー、ジアステレオマー、ラセミ化合物、それらの薬学的に許容され得る塩および溶媒和物、
〔16〕式:
(式中、A、B、D、G3、G4、R1、R2、R5およびpは、上述で定義されるとおりである)
を有する〔12〕記載の化合物、またはその幾何異性体、エナンチオマー、ジアステレオマー、ラセミ化合物、それらの薬学的に許容され得る塩および溶媒和物、
〔17〕式:
(式中、R5は上述で定義されるとおりである)
を有する〔16〕記載の化合物、またはその幾何異性体、エナンチオマー、ジアステレオマー、ラセミ化合物、それらの薬学的に許容され得る塩および溶媒和物、
〔18〕R5が、表1、2、3または4から選択される、〔1〕記載の化合物、
〔19〕式:
(式中、R5は表1から選択される)
を有する〔12〕記載の化合物、またはその幾何異性体、エナンチオマー、ジアステレオマー、ラセミ化合物、それらの薬学的に許容され得る塩および溶媒和物、
〔20〕式:
(式中、R5は表1から選択される)
を有する〔12〕記載の化合物、またはその幾何異性体、エナンチオマー、ジアステレオマー、ラセミ化合物、それらの薬学的に許容され得る塩および溶媒和物、
〔21〕式:
(式中、R5は表1から選択される)
を有する〔12〕記載の化合物、またはその幾何異性体、エナンチオマー、ジアステレオマー、ラセミ化合物、それらの薬学的に許容され得る塩および溶媒和物、
〔22〕式:
(式中、R5は表1から選択される)
を有する〔12〕記載の化合物、またはその幾何異性体、エナンチオマー、ジアステレオマー、ラセミ化合物、それらの薬学的に許容され得る塩および溶媒和物、
〔23〕式:
(式中、R5は表1から選択される)
を有する〔12〕記載の化合物、またはその幾何異性体、エナンチオマー、ジアステレオマー、ラセミ化合物、それらの薬学的に許容され得る塩および溶媒和物、
〔24〕表A、B、C、DまたはEから選択される〔1〕記載の化合物、ならびにその幾何異性体、エナンチオマー、ジアステレオマー、ラセミ化合物、薬学的に許容され得る塩および溶媒和物、
〔25〕〔1〕〜〔24〕いずれか記載の化合物を、神経学的障害または精神的障害の治療を必要とする患者に投与することによる、神経学的障害または精神的障害の治療方法、
〔26〕前記障害が統合失調症である、〔25〕記載の方法、
〔27〕式XXIII:
(式中、A、B、D、R1、R2、R3、R4、Cy1、G1、G2、qおよびmは、上述で定義されるとおりである)
の化合物の持続送達のための方法であって、
該化合物の持続送達を必要とする患者に〔1〕〜〔31〕いずれか記載の化合物を投与する工程を含み、
患者への投与時の式XXIIIの化合物の放出が持続放出である、方法、
〔28〕持続放出が、患者の血流中において、プロドラッグの投与後、少なくとも約36時間の間、前記式XXIIIの化合物の治療有効量を含む、〔27〕記載の方法、
〔29〕前記式XXIIIの化合物が、患者の血流中に、少なくとも7、15、30、60、75または90日から選択される期間存在する、〔28〕記載の方法、
〔30〕投与工程が注射によるものである、〔29〕記載の方法、
〔31〕式XXIII:
の化合物を、式;C(O)-C(R101)(R103)のアルデヒドまたはケトンと反応させる工程を含む、式XXIV:
の化合物の合成方法、
〔32〕前記アルデヒドがパラホルムアルデヒドである、〔31〕記載の方法、
〔33〕前記式XXIIIの化合物を酸無水物と反応させる工程をさらに含む、〔31〕記載の方法、
〔34〕前記酸無水物が、無水酢酸、無水酪酸、無水ヘキサン酸、無水オクタン酸、無水デカン酸、無水ドデカン酸、無水ラウリル酸および無水パルミチン酸から選択される、〔33〕記載の方法
に関する。
式I
(式中、
は、単結合または二重結合を表し;
半円は、1、2または3個の環を含む任意に置換されたシクロアルキル、シクロアルケニル、ヘテロシクリル、アリールまたはヘテロアリールを表し;
Aは、非存在、任意に置換されたアルキル、任意に置換されたアルケニル、任意に置換されたアルキニル、-S-、-O-、-S(O)-、-S(O)2-、-S[C(R10)(R11)]u-、-S(O)[C(R10)(R11)]u-、-S(O)2[C(R10)(R11)]u-、-O[C(R10)(R11)]u-、-N(R10)-、-N(R10)-[C(R10)(R11)]u-、[C(R10)(R11)]uから選択され;
各uは、独立して1、2、3、4、5、6または7であり;
各R10およびR11は、独立して非存在、水素、ハロゲン、脂肪族、置換脂肪族、アリールまたは置換アリールであり;
Cy1は、任意に置換されたシクロアルキル、任意に置換されたシクロアルケニル、任意に置換されたヘテロシクリルまたは任意に置換されたアリールであり;
Bは、リンカーまたは直接結合であり;
Dは、非存在、-O-、-NR10、-C(R10)(R11)-および-S-、-S(O)-、-S(O)2-、-C(O)-から選択され;
各G1およびG2は、独立して非存在、-S-、-O-、-S(O)-、-S(O)2-、-SC(R10)(R11)-、-S(O)C(R10)(R11)-、-S(O)2C(R10)(R11)-、OC(R10)(R11)-、-N(R10)-、-C(R10)=C(R11)-、-N(R10)-C(R10)(R11)-、-[C(R10)(R11)]t-から選択され;
tは1、2または3であり;
各R1、R3およびR4は、独立して非存在、水素、ハロゲン、-OR10、-SR10、-N(R10)(R11)、-S(O)R10、-S(O)2R10、任意に置換された脂肪族、任意に置換されたアリールまたは任意に置換されたヘテロシクリルから選択され;
代替的に、2つのR3およびR4は一緒になって、任意に置換された環を形成し;
R5は、-CH(R10)-OR20、-CH(R10)-OC(O)OR20、-CH(R10)-OC(O)R20、-CH(R10)-OC(O)NR20R21、-(CH(R10))-OPO3MY、-(CH(R10))-OP(O)(OR20)(OR21)、-[CH(R10)O]z-R20、-[CH(R10)O]z-C(O)OR20、-[CH(R10)O]z-C(O)R20、-[CH(R10)O]z-C(O)NR20R21、-[CH(R10)O]z-OPO3MY、-[CH(R10)O]z-P(O)2(OR20)Mおよび-[CH(R10)O]z-P(O)(OR20)(OR21)から選択され;
zは、1、2、3、4、5、6または7であり;
各R2OおよびR21は、独立して水素、脂肪族、置換脂肪族、アリールまたは置換アリールから選択され;YおよびMは同じであるかまたは異なり、それぞれは一価のカチオンであるか;あるいはMおよびYは一緒になって二価のカチオンであり;
n、mおよびqは、独立して0、1および2から選択される)
を有する化合物、またはその幾何異性体、エナンチオマー、ジアステレオマー、ラセミ化合物、それらの薬学的に許容され得る塩および溶媒和物を提供する。
式II
(式中、
は単結合または二重結合を表し、
R1、R3、R4、R5、A、B、D、n、m、p、およびqは、上述に規定されるとおりであり;
R2は、非存在、水素、ハロゲン、-OR10、-SR10、-N(R10)(R11)、-S(O)R10、-S(O)2R10、任意に置換された脂肪族、任意に置換されたアリールまたは任意に置換されたヘテロシクリルから選択され;
各G3およびG4は、独立して-N-、-C(R10)-[C(R10)(R11)]a-から選択され、aは0、1または2であり;
pは0、1、2、3または4である)
により表されるか、またはその幾何異性体、エナンチオマー、ジアステレオマー、ラセミ化合物、それらの薬学的に許容され得る塩および溶媒和物である。
式III
(式中、R1、R2、R3、R4、R5、R10、R11、A、D、m、pおよびqは、上述に規定されるとおりであり;
rは0、1、2、3、4、5、6、7、8、9、10または11である)
により表されるか、またはその幾何異性体、エナンチオマー、ジアステレオマー、ラセミ化合物、それらの薬学的に許容され得る塩および溶媒和物である。
式IV
(式中、R2、R3、R4、R5、R10、R11、D、m、p、qおよびrは上述に規定されるとおりであり;
各R6は、独立して水素、ハロゲン、OR10、SR10、NR10R11、脂肪族、置換脂肪族、芳香族、置換芳香族から選択され、各R10およびR11は、独立して水素、ハロゲン、脂肪族、置換脂肪族、アリールまたは置換アリールであるか;あるいは2つの隣接するR6基は第二の環を形成し;
tおよびsは、独立して0、1および2から選択される)
により表されるか、またはその幾何異性体、エナンチオマー、ジアステレオマー、ラセミ化合物、それらの薬学的に許容され得る塩および溶媒和物である。
式V
(式中、
は、単結合または二重結合を表し;
R5は上述に規定されるとおりであり;
wは、0、1、2、3、4、5、6、7、8、9、10または11である)
により表されるか、またはその幾何異性体、エナンチオマー、ジアステレオマー、ラセミ化合物、それらの薬学的に許容され得る塩および溶媒和物である。
式VI
(式中、R1、R2、R3、R5、A、B、D、G3、G4、p、q、R10およびR11は、上述に規定されるとおりであり;
X1は、-S-、-O-、-NR10-または-C(R10)(R11)-である)
に示されるか、またはその幾何異性体、エナンチオマー、ジアステレオマー、ラセミ化合物、それらの薬学的に許容され得る塩および溶媒和物である。
式VII
(式中、R1、R2、R3、R4、R5、A、D、G3、G4、m、p、q、r、R10およびR11は上述に規定されるとおりである)
に示されるか、またはその幾何異性体、エナンチオマー、ジアステレオマー、ラセミ化合物、それらの薬学的に許容され得る塩および溶媒和物である。
式VIII
(式中、R2、R3、R4、R5、A、D、G3、G4、m、q、r、R10およびR11は、上述に規定されるとおりであり;
X2は、-S-または-O-である)
に示されるか、またはその幾何異性体、エナンチオマー、ジアステレオマー、ラセミ化合物、それらの薬学的に許容され得る塩および溶媒和物である。
(式中、X2、D、R2、R5、r、R10およびR11は、上述に規定されるとおりである)
に示されるか、またはその幾何異性体、エナンチオマー、ジアステレオマー、ラセミ化合物、それらの薬学的に許容され得る塩および溶媒和物である。
(式中、R5は上述に規定されるとおりである)
に示されるか、またはその幾何異性体、エナンチオマー、ジアステレオマー、ラセミ化合物、それらの薬学的に許容され得る塩および溶媒和物である。
(式中、R1、R2、R5、G3、G4、X1、A、B、Dおよびpは、上述に規定されるとおりである)
に示されるか、またはその幾何異性体、エナンチオマー、ジアステレオマー、ラセミ化合物、それらの薬学的に許容され得る塩および溶媒和物である。
(式中、R5は上述に規定されるとおりである)
の化合物、またはその幾何異性体、エナンチオマー、ジアステレオマー、ラセミ化合物、それらの薬学的に許容され得る塩および溶媒和物である。
(式中、A、R1、R2、R3、R4、R5、R1O、R11、G3、G4、D、m、p、q、およびrは上述に規定されるとおりであり;
X3は-CH-または-N-である)
の化合物、またはその幾何異性体、エナンチオマー、ジアステレオマー、ラセミ化合物、それらの薬学的に許容され得る塩および溶媒和物である。
(式中、A、R1、R2、R3、R4、R5、R10、R11、G3、G4、X2、m、p、qおよびrは上述に規定されるとおりである)
の化合物またはその幾何異性体、エナンチオマー、ジアステレオマー、ラセミ化合物、それらの薬学的に許容され得る塩および溶媒和物である。
(式中、A、R1、R2、R3、R4、R5、R10、R11、X2、m、p、qおよびrは上述に規定されるとおりである)
の化合物またはその幾何異性体、エナンチオマー、ジアステレオマー、ラセミ化合物、それらの薬学的に許容され得る塩および溶媒和物である。
(式中、R2、R5、R10、R11、X2、pおよびrは上述に規定されるとおりである)
の化合物またはその幾何異性体、エナンチオマー、ジアステレオマー、ラセミ化合物、それらの薬学的に許容され得る塩および溶媒和物である。
から選択されるアリールまたはヘテロアリール基である。
から選択される。
本発明を説明するために使用される種々の用語の定義を以下に列挙する。これらの定義は、用語が、具体例において限定されていない限り、個々に、または大きな群の一部としてのいずれかで本明細書および特許請求の範囲を通じて使用されるように、該用語に適用される。
本発明の医薬組成物は、調製された本発明の化合物の治療有効量と共に、1つ以上の薬学的に許容され得る担体または賦形剤を含む。
本発明の化合物および方法は、例示のみを意図し、本発明の範囲の限定を意図しない以下の実施例と関連して良好に理解されよう。開示される態様に対する種々の変更および改変は、当業者に明らかであり、限定されないが、本発明の化学構造、置換、誘導体、製剤および/または方法に関するかかる変更および改変は、本発明の精神および添付の特許請求の範囲を逸脱することなくなされ得る。ラクタム化合物の調製のための一般的な方法論は、以下の刊行物:米国特許第7,160,888号;米国特許第5,462,934号;米国特許第4,914,094号;米国特許第4,234,584号;米国特許第4,514,401号;米国特許第5,462,934号;米国特許第4,468,402号;WO 2006/090273 A2;WO 2008/150848 A1;WO 2006/112464 A1;WO 2008/132600 A1に見られ得る。
アリピプラゾール(20g、45mmol)、トリエチルアミン(1mL、7.1mmol)、ホルムアルデヒド(37%水溶液、70mL)およびジメチルホルムアミド(200mL)の混合物を80℃に20時間加熱した。該反応混合物を冷却し、酢酸エチル(400mL)で希釈し、水/ブライン(1:1、3x500mL)で洗浄した。有機相をMgSO4で乾燥させ、ろ過して真空下で乾燥まで蒸発させて、ヘミアミナール(hemi-aminal)A1を白色固体として得た(18.6g、25%アリピプラゾールを含む、A1に対して65%収率)。1H NMR (CDCl3, 300MHz)アリピプラゾールの夾雑によるシグナルの複合混合物、メインシグナルδ5.34 (s, 2H, OHCH2N); m/z (M+H) 478および480。
実施例1由来のヘミアミナールA1(4g、8.4mmol)、4-ジメチルアミノピリジン(0.15g、1.3mmol)およびトリエチルアミン(1.1mL、7.5mmol)のジクロロメタン(30mL)中の溶液に、ベンジルイソシアネート(1.03mL、8.3mmol)を添加し、反応混合物を24時間攪拌した。次いで、反応混合物を35℃で20時間加熱し、冷却して水/ブライン(1:1、50mL)で洗浄した。有機相をMgSO4で乾燥させ、ろ過して真空下で蒸発させた。残渣をさらに、酢酸エチル/ジクロロメタン/メタノール(1:1:0.1)で溶出するシリカ上のクロマトグラフィーで精製し、所望の生成物をオフホワイトの泡状物として得た(530mg、14%収率)。1H NMR (CDCl3, 300MHz) δ1.58-1.88 (m, 4H), 2.48 (t, 2H), 2.60-2.72 (m, 6H), 2.85 (m, 2H), 300-3.12 (m, 4H), 3.96 (t, 2H), 4.40 (d, 2H), 5.13 (NH), 5.96 (s, 2H), 6.58 (dd, 1H), 6.79 (d, 1H), 6.92-6.98 (m, 1H), 7.04 (d, 1H), 7.12-7.16 (m, 1H), 7.23-7.35 (m, 6H); m/z (M+H) 611.12および613.10。
1H NMR (CDCl3, 300MHz) δ 1.18 (d, 6H), 1.68-1.88 (m, 4H), 2.45-2.73 (m, 9H), 2.87 (dd, 2H), 3.03-3.12 (m, 2H), 3.95 (t, 2H), 5.91 (s, 2H), 6.55-6.60 (m, 2H), 6.93-6.97 (m, 1H), 7.04-7.09 (m, 1H), 7.12-7.19 (m, 2H). m/z (M+H) 548.15。
1H NMR (CDCl3, 300MHz) δ 1.47-1.93 (m, 13H), 2.50-2.60 (m, 2H), 2.60-2.90 (m, 8H), 3.02-3.15 (m, 4H), 3.95 (t, 2H), 5.89 (s, 2H), 6.50-6.60 (m, 2H), 6.90-6.95 (m, 1H), 7.02-7.07 (m, 1H), 7.10-7.19 (m, 2H). m/z (M+H) 574.15。
1H NMR (CDCl3, 300MHz) δ 1.82-1.91 (m, 3H), 1.22-1.30 (m, 2H), 1.75-2.05 (m, 6H), 2.05-2.40 (m, 6H), 2.68-2.73 (m, 2H), 2.84-2.90 (m, 2H), 3.06-3.22 (m, 4H), 3.96 (t, 2H), 5.91 (s, 2H), 6.55-6.59 (m, 2H), 6.97 (dd, 1H), 7.07 (d, 1H), 7.12-7.18 (m, 2H). m/z (M+H) 560.19。
1H NMR (CDCl3, 300MHz) δ 1.15-1.35 (m, 3H), 1.35-1.55 (m, 2H), 1.55-1.95 (m, 10H), 2.21-2.40 (m, 1H), 2.52-2.60 (m, 1H), 2.62-3.00 (m, 8H), 3.02-3.12 (m, 4H), 3.95 (t, 2H), 5.89 (s, 2H), 6.50-6.60 (m, 2H), 6.93-6.97 (m, 1H), 7.02-7.06 (m, 1H), 7.10-7.15 (m, 2H). m/z (M+H) 588.24。
1H NMR (CDCl3, 300MHz) δ 1.56-1.90 (m, 6H), 2.43-2.55 (m, 2H), 2.55-2.80 (m, 4H), 2.81-2.90 (m, 2H), 3.37 (s, 3H), 3.55-3.61 (m, 2H), 3.72-3.79 (m, 2H), 4.20 (s, 2H), 5.97 (s, 2H), 6.55-6.59 (m, 2H), 6.91-6.98 (m, 1H), 7.09 (d, 1H), 7.11-7.15 (m, 2H). m/z (M+H) 594.17。
1H NMR (CDCl3, 300MHz) δ 1.65-1.93 (m, 6H), 2.49-2.60 (m, 2H), 2.61-2.77 (m, 4H), 2.81-2.90 (m, 2H), 3.02-3.20 (m, 4H), 3.36 (s, 3H), 3.51-3.57 (m, 2H), 3.60-3.70 (m, 4H), 3.72-3.78 (m, 2H), 3.92-3.99 (m, 2H), 4.20 (s, 2H), 5.97 (s, 2H), 6.55-6.59 (m, 2H), 6.95-6.99 (m, 1H), 7.05-7.09 (m, 1H), 7.11-7.18 (m, 2H). m/z (M+H) 638.30。
1H NMR (CDCl3, 300MHz) δ 1.21 (s, 9H), 1.65-1.88 (m, 4H), 2.45-2.55 (m, 2H), 2.60-2.73 (m, 6H), 2.82-2.91 (m, 2H), 3.02-3.13 (m, 4H), 3.95 (t, 2H), 5.89 (s, 2H), 6.54-6.60 (m, 2H), 6.92-6.99 (m, 1H), 7.06 (d, 1H), 7.13-7.17 (m, 2H); m/z (M+H) 562.39。
2-(((7-(4-(4-(2,3-ジクロロフェニル)ピペラジン-1-イル)ブトキシ)-2-オキソ-3,4-ジヒドロキノリン-1(2H)-イル)メトキシ)カルボニルアミノ)エチルメタクリレート(2.0g)を実施例2と同様の方法で合成した。これを16% NH3/MeOHと室温で18時間反応させ、次いで40℃で濃縮した。残渣を1:1:0.1〜1:1:0.2 DCM/EtOAc/MeOHで溶出するシリカクロマトグラフィーで精製した。得られた黄色油を、EtOAc/ヘプタンから再結晶化し、表題の化合物を白色固体として得た(1.2g、67%)。1H NMR (CDCl3, 300MHz) δ 1.60-1.88 (m, 4H), 2.40-2.50 (m, 2H), 2.50-2.75 (m, 6H), 2.75-2.89 (m, 2H), 2.95-3.15 (m, 4H), 3.20-3.40 (m, 2H), 2.58-3.78 (m, 2H), 3.89-4.05 (m, 2H), 5.30-5.45 (m, NH), 5.91 (s, 2H), 6.55 (dd, 1H), 6.73 (d, 1H), 6.91-6.96 (m, 1H), 6.98-7.03 (m, 1H), 7.04-7.18 (m, 2H). m/z (M+H) 565.16。
ヘミアミナールA1(2g、0.0042mol)のジクロロメタン(30mL)中の溶液に、室温でピリジン(0.68mL)、次いでp-ニトロフェニルクロロホルメート(1.27g、0.0063mol)を添加した。90分後、ジエタノールアミン(3.5g、0.0334mol)およびトリエチルアミン(1.2mL、0.084mol)を添加した。3時間後、反応をジクロロメタンで希釈し、飽和NaHCO3で洗浄して、MgSO4で乾燥させて蒸発させた。残渣を1:1:0.1〜1:1:0.2 DCM/EtOAc/MeOHで溶出するシリカ上で精製し、表題の化合物を無色のゴム状物質として得た(0.83g、33%)。1H NMR (CDCl3, 300MHz) δ 1.70-1.82 (m, 4H), 2.42-2.52 (m, 2H), 2.59-2.79 (m, 6H), 2.80-2.90 (m, 2H), 3.00-3.12 (m, 4H), 3.40-3.48 (m, 2H), 3.50-3.58 (m, 2H), 3.61-3.70 (m, 2H), 3.85-3.90 (m, 2H), 3.99-4.06 (m, 2H), 5.90 (m, 2H), 6.57 (d, 1H), 6.70 (dd, 1H), 6.92-6.98 (m, 1H), 7.07 (d, 1H), 7.10-7.20 (m, 2H). m/z (M+H) 609.21。
化合物141を実施例28と同様の方法で合成した。1H NMR (CDCl3, 300MHz) δ1.68-1.88 (m, 4H), 2.25-2.42 (m, 7H), 2.45-2.55 (m, 2H), 2.61-2.76 (m, 6H), 2.85 (dd, 2H), 3.02-3.16 (m, 4H), 3.40-3.60 (m, 4H), 3.97 (t, 2H), 5,92 (s, 2H), 6.59 (d, 1H), 6.74 (d, 1H), 6.92-6.98 (m, 1H), 7.02-7.07 (m, 1H), 7.10-7.16 (m, 2H). m/z (M+H) 604.24。
化合物142を実施例28と同様の方法で合成した。1H NMR (CDCl3, 300MHz) δ1.26-2.06 (m, 14H), 2.31-2.91 (m, 17H), 2.95-3.18 (m, 4H), 3.97 (t, 2H), 4.0-4.37 (m, 2H), 5.91 (s, 2H), 6.58 (dd, 1H), 6.74 (d, 1H), 6.90-6.99 (m, 1H), 7.05 (d, 1H), 7.11-7.18 (m, 2H); m/z (M+H) 672.25。
ヘミアミナールA1(2.0g、4.2mmol)のジクロロメタン(20mL)中の混合物に塩化チオニル(1.5mL、12.6mmol)を添加し、室温で2時間攪拌した。反応混合物にメタノール(10mL)を添加し、さらに2時間攪拌した。反応物をNaHCO3(水性)に注いで、ジクロロメタンで抽出した。有機相をMgSO4で乾燥させ、蒸発させて、残渣を1:1:0.1ジクロロメタン/酢酸エチル/メタノールで溶出するシリカ上で精製し、表題の化合物を乳色固体として得た(1.3g、63%)。1H NMR (CDCl3, 300MHz) δ 1.65-1.83 (m, 4H), 2.47 (t, 2H), 2.58-2.70 (m, 6H), 2.82 (dd, 2H), 2.99-3.01 (m, 4H), 3.38 (s, 3H), 3.96 (t, 2H), 5.27 (s, 2H), 6.55 (dd, 1H), 6.88 (dd, 1H), 6.91-6.96 (m, 1H), 7.03 (d, 1H), 7.08-7.15 (m, 2H). m/z (M+H) 492.05。
アリピプラゾール(2.0g、4.5mmol)、エチルグリコキシレート(glyoxylate)(トルエン中50%溶液、2.7mL)、K2CO3(0.49g、3.6mmol)、テトラブチル臭化アンモニウム(0.57g、1.8mmol)およびジクロロメタン(20mL)の混合物を還流で4時間加熱した。反応混合物を冷却して、水で迅速に洗浄して、MgSO4で乾燥させ、ろ過した。得られた溶液をピリジン(1.8mL、22.2mmol)、次いでデカノイルクロライド(4.6mL、22.2mmol)で処理した。3時間攪拌した後、メタノール(1mL)を添加して、さらに10分攪拌した。反応混合物を飽和NaHCO3(水性)で洗浄して、MgSO4で乾燥させ、蒸発させた。残渣を1:1:0.1ジクロロメタン/酢酸エチル/メタノールで溶出するシリカ上で精製して、表題の化合物を黄色油として得た(1.2g、38%)。1H NMR (CDCl3, 300MHz) δ 0.86 (t, 3H), 1.11 (t, 3H), 1.05-1.40 (m, 12H), 1.59-1.75 (m, 2H), 1.75-1.98 (m, 4H), 2.40-2.54 (m, 2H), 2.60-3.07 (m, 10H), 3.15-3.32 (m, 4H), 3.89-3.99 (m, 2H), 4.09-4.21 (m, 2H), 6.57 (dd, 1H), 6.67 (d, 1H), 6.95-7.00 (m, 1H), 7.08 (dd, 1H), 7.12-7.20 (m, 2H), 7.27-7.32 (m, 1H). m/z (M+H) 704.38。
ヘミアミナールA1(2.6g、5.5mmol)のジクロロメタン(30mL)中の懸濁液にトリエチルアミン(2.3mL、16.4mmol)を添加し、次いで塩化メタンスルホニル(0.47g、6.0mmol)を3分間かけて添加した。反応混合物を25分間攪拌して、次いでN-アセチル-4-アミノ酪酸(1.6g、10.1mmol)を添加した。次いで、反応混合物を還流で18時間攪拌して、冷却して飽和NaHCO3(水性)で洗浄した。有機相をMgSO4で乾燥させ、ろ過して蒸発させた。残渣をさらに1:1:0.1〜1:1:0.2ジクロロメタン/酢酸エチル/メタノールで溶出するシリカ上で精製し、表題の化合物をオフホワイトの固体として得た(1.1g、34%)。1H NMR (CDCl3, 300MHz) δ 1.70-1.80 (m, 2H), 1.80-1.90 (m, 4H), 1.97 (s, 3H), 2.41 (t, 2H), 2.50-2.57 (m, 2H), 2.60-2.75 (m, 6H), 2.83-2.88 (m, 2H), 3.03-3.12 (m, 4H), 3.24-3.32 (m, 2H), 3.95-4.00 (m, 2H), 5.85-5.92 (m, 3H), 6.58 (d, 2H), 6.92-6.96 (m, 1H), 7.05 (d, 1H), 7.12-7.16 (m, 2H). ). m/z (M+H) 605.08。
化合物149(1.4g)を化合物148と同様の方法で合成した。1H NMR (d6-DMSO, 300MHz) δ 0.79 (t, 3H), 1.10-1.28 (m, 8H), 1.38-1.48 (m, 2H), 1.50-1.77 (m, 6H), 1.93-2.00 (m, 2H), 2.25-2.40 (m, 4H), 2.40-2.60 (m, 6H), 2.72-2.81 (m, 2H), 2.87-3.02 (m, 6H), 3.90-4.00 (m, 2H), 5.82 (s, 2H), 6.58-6.63 (m, 2H), 7.04-7.02 (m, 2H), 7.20-7.30 (m, 2H). m/z (M+H) 689.47。
質量(m/z) = 541 [M+ + 1].
化合物324を化合物322、実施例38と同様の方法で合成した。1H-NMR(CDCl3, 500 MHz): δ 7.92-7.90 (d, J=7.5, 1H) , 7.82-7.80 (d, J=7.5,1H) ,7.48-7.45 (t, J=7.5, 1H), 7.37-7.34 (t, J=7.5, 1H) , 7.17 (s, 1H),7.05 (s, 1H), 5.72 (s, 2H), 3.60-3.55 (m, 6H) , 2.98-2.95 (t, J=8, 2H) , 2.79-2.77 (m, 4H),2.68-2.65 (t, J=8, 2H),2.34-2.31 (t, J=7,2H), 1.63-1.60 (m, ,2H), 1.24(s, 16H), 0.89-0.86 (t, J=7, 3H)。
質量(m/z) = 625.5 [M+ + 1].
1H-NMR (CDCl3, 500 MHz): δ 7.92-7.90 (d, J=7.5, 1H), 7.82-7.80 (d, J=7.5, 1H), 7.48-7.45 (t, J=7.5, 1H), 7.37-7.34 (t, J=7.5, 1H), 7.17 (s, 1H), 7.05 (s, 1H), 5.72 (s, 2H), 3.60-3.55 (m, 6H), 2.98-2.95 (t, J=8, 2H) , 2.79-2.77 (m, 4H), 2.68-2.65 (t, J=8, 2H), 2.34-2.31 (t, J=8, 2H) , 1.63-1.56 (m, 2H), 1.25-1.23 (m, 24H), 0.88-0.86 (t, J=7, 2H)。
質量(m/z) = 681.5 [M+ + 1].
塩化ブタノイルを使用して、化合物417を実施例41と同様の方法で調製した。フラッシュクロマトグラフィーによる精製で、所望の生成物を得た(1.25g、45%収率)。1H NMR (DMSO, 400MHz) δ 1.065 (t, 3H), 1.448-1.54 (m, 2H), 2.284-2.320 (t , 2H) ,2.564 (s, 4H), 3.184 (s, 4H), 3.597 (s, 2H), 5.787(s, 2H), 6.694-6.713 (d, 1H), 6.878-6.896 (d, 1H), 7.092-7.133 (t, 1H), 7.315-7.370 (q, 2H), 7.422-7.533 (m, 3H), 7.535-7.555 (d, 1H), 7.639 (d, 1H), 7.657-7.660 (d, 2H). m/z (M+H)485。
塩化ヘキサノイルを使用して、化合物413を、実施例41と同様の方法で調製した。フラッシュクロマトグラフィーによる精製で、所望の生成物を得た(0.6g、60%収率)。1H NMR (DMSO, 400MHz) δ 0.774 (t, 3H), 1.114-1.187 (m, 4H), 1.433-1.506 (m , 2H) , 2.291-2.328(t, 2H), 2.564 (s, 4H), 3.182 (s, 4H), 3.597 (s, 2H), 5.783(s, 2H), 6.693-6.713 (d, 1H), 6.870-6.890 (d, 1H), 7.090-7.130 (t, 1H), 7.314-7.351 (q, 2H), 7.422-7.472 (m, 3H), 7.535-7.554 (d, 1H), 7.589 (d, 1H), 7.638-7.656 (d, 2H). m/z (M+H)513。
塩化パルミトイルを使用して、化合物422を、実施例41と同様の方法で調製した。フラッシュクロマトグラフィーによる精製で、所望の生成物を得た(0.5g、47%収率)。1H NMR (DMSO, 400MHz) δ 0.819 (t, 3H),1.127-1.302 (m, 22H), 1.437-1.454 (t , 2H) , 2.287-2.305(t, 2H), 2.564 (s, 4H), 3.182 (s, 4H), 3.596 (s, 2H), 5.784(s, 2H), 6.688-6.708 (d, 1H), 6.863-6.882 (d, 1H), 7.083-7.124 (t, 1H), 7.331-7.368 (q, 2H), 7.400-7.470 (m, 3H), 7.534-7.553 (d, 1H), 7.587 (d, 1H), 7.635-7.653 (d, 2H). m/z (M+H)653。
塩化デカノイルを使用して、化合物419を実施例41と同様の方法で調製した。フラッシュクロマトグラフィーによる精製で、所望の生成物を得た(0.8g、77%収率)。1H NMR (DMSO, 400MHz) δ 0.795-0.829 (t, 3H),1.140-1.211 (m, 12H), 1.438-1.471 (t , 2H) , 2.288-2.324(t, 2H), 2.562 (s, 4H), 3.181 (s, 4H), 3.595 (s, 2H), 5.783(s, 2H), 6.689-6.709 (d, 1H), 6.856-6.884 (d, 1H), 7.083-7.124 (t, 1H), 7.311-7.367 (q, 2H), 7.400-7.470 (m, 3H), 7.533-7.552 (d, 1H), 7.587 (d, 1H), 7.635-7.653 (d, 2H). m/z (M+H)569。
塩化イソブチリルを使用して、化合物414を、実施例41と同様の方法で調製した。フラッシュクロマトグラフィーによる精製で、所望の生成物を得た(0.3g、15%収率)。1H NMR (DMSO, 400MHz) δ 1.027-1.044 (d, 6H),2.478-2.553 (m, 1H), 2.562 (s, 4H), 3.185 (s, 4H), 3.597 (s, 2H), 5.785(s, 2H), 6.692-6.713 (d, 1H), 6.873-6.892 (d, 1H), 7.093-7.134 (t, 1H), 7.315-7.369 (q, 2H), 7.403-7.472 (m, 3H), 7.533-7.555 (d, 1H), 7.590 (d, 1H), 7.657-7.660 (d, 2H). m/z (M+H)485。
(7-(4-(4-(2,3-ジクロロフェニル)ピペラジン-1-イル)ブトキシ)-2-オキソ-3,4-ジヒドロキノリン-1(2H)-イル)メチルブチレート(化合物2)を、上述の実施例16に記載されるように調製した。
化合物159は、化合物10から、実施例47と同様の方法で合成した。2.04g。1H-NMR (400MHz, CDCl3) δ 7.62 (1H, d), 7.44 (1H, d), 7.18-7.10 (2H, m), 6.98-6.91 (1H, m), 6.87-6.80 (2H, m), 6.52 (1H, d), 6.32 (2H, s), 4.05 (2H, t), 3.15-2.99 (4H, bs), 2.74-2.44 (6H, m), 2.35 (2H, t), 1.92-1.83 (2H, m), 1.80-1.68 (2H, m) 1.66-1.55 (2H, m), 1.32-1.14 (24H, m), 0.87 (3H, t)。
化合物156は、化合物7から、実施例47と同様の方法で合成した。1.37g。1H-NMR (400MHz, CDCl3) δ 7.62 (1H, d), 7.43 (1H, d), 7.17-7.10 (2H, m), 6.96-6.92 (1H, m), 6.87-6.80 (2H, m), 6.51 (1H, d), 6.33 (2H, s), 4.06 (2H, t), 3.12-3.01 (4H, bs), 2.71-2.59 (4H, bs), 2.50 (2H, t), 2.35 (2H, t), 1.92-1.83 (2H, m), 1.78-1.69 (2H, m) 1.66-1.55 (2H, m), 1.32-1.16 (16H, m), 0.86 (3H, t)。
化合物160は、化合物11から、実施例47と同様の方法で合成した。1.38g。1H-NMR (400MHz, CDCl3) δ 7.62 (1H, d), 7.44 (1H, d), 7.17-7.11 (2H, m), 6.97-6.92 (1H, m), 6.87-6.79 (2H, m), 6.51 (1H, d), 6.32 (2H, s), 4.05 (2H, t), 3.13-3.00 (4H, bs), 2.73-2.58 (4H, bs), 2.50 (2H, t), 2.35 (2H, t), 1.92-1.83 (2H, m), 1.79-1.69 (2H, m) 1.66-1.55 (2H, m), 1.32-1.14 (28H, m), 0.87 (3H, t)。
化合物150は、化合物1から、実施例47と同様の方法で合成した。1.61g。1H-NMR (300MHz, CDCl3) δ 7.63 (1H, d), 7.45 (1H, d), 7.18-7.11 (2H, m), 6.98-6.92 (1H, m), 6.90-6.80 (2H, m), 6.52 (1H, d), 6.32 (2H, s), 4.07 (2H, t), 3.14-3.01 (4H, bs), 2.73-2.59 (4H, bs), 2.51 (2H, t), 2.12 (3H, s), 1.95-1.82 (2H, m), 1.82-1.68 (2H, m)。
化合物165は、化合物16から、実施例47と同様の方法で合成した。1.02g。1H-NMR (400MHz, CDCl3) δ 7.61 (1H, d), 7.43 (1H, d), 7.17-7.10 (2H, m), 6.97-6.92 (1H, m), 6.83-6.79 (2H, m), 6.51 (1H, d), 6.31 (2H, s), 4.05 (2H, t), 3.12-3.02 (4H, bs), 2.71-2.60 (4H, bs), 2.50 (2H, t), 1.92-1.83 (2H, m), 1.78-1.68 (2H, m) 1.55 (2H, q), 1.15 (6H, s), 0.81 (3H, t)。
筋内注射後のラットにおけるプロドラッグの薬物動態学的評価
動物: 雄Sprague-Dawleyラット(Charles River Laboratories, Wilmington, MA)を入手した。およそ24匹のラットを各試験に使用した。到着時、ラットはおよそ350〜375gであった。ケージあたり2匹のラットを収容し、餌および水に自由にありつけるようにした。飼育部屋の環境条件:64〜67°F、30%〜70%相対湿度、および12:12時間の明暗周期。全ての実験は、施設の動物管理使用委員会に承認された。
導入: 統合失調症および双極性障害の治療に有用な本発明のプロドラッグは、過剰移動のげっ歯類モデルにおいて予測的な妥当性を示す。D-アンフェタミン誘導性移動は、統合失調症の「ドーパミン仮説」について基礎を形成するドーパミン作動性機能亢進を模倣すると仮定する。AMPH誘導性機能亢進モデルにより、抗精神病化合物の有効性の簡単な初期スクリーニングが提供される。Fell et al., Journal of Pharmacology and Experimental Therapeutics, (2008) 326:209-217を参照。アンフェタミン誘導性機能亢進を使用して、アリピプラゾールの経口投与(PO)プロドラッグ製剤の種々の用量をスクリーニングして、急性過剰移動パラダイムにおける薬力学的有効性を測定した。該試験の仮説は、約100〜200ng/mlの血漿濃度を生じるアリピプラゾールプロドラッグ製剤のPO投与は、AMPH誘導性移動の有意な減衰を生じるということである。
Claims (12)
- 式:
(式中、
は、単結合または二重結合を表し;
Aは、非存在、任意に置換されるアルキル、任意に置換されるアルケニル、任意に置換されるアルキニル、-S-、-O-、-S(O)-、-S(O)2-、-S[C(R10)(R11)]u-、-S(O)[C(R10)(R11)]u-、-S(O)2[C(R10)(R11)]u-、-O[C(R10)(R11)]u-、-N(R10)-、-N(R10)-[C(R10)(R11)]u-、および-[C(R10)(R11)]u-から選択され;
各uは、独立して1、2、3、4、5、6または7であり;
各R10およびR11は、独立して非存在、水素、ハロゲン、脂肪族、置換脂肪族、アリールまたは置換アリールであり;
Bは、直接結合、あるいは酸素、硫黄、NR8、C(O)、C(O)NH、SO、SO2、SO2NH、置換もしくは非置換アルキル、置換もしくは非置換アルケニル、置換もしくは非置換アルキニル、アリールアルキル、アリールアルケニル、アリールアルキニル、ヘテロアリールアルキル、ヘテロアリールアルケニル、ヘテロアリールアルキニル、ヘテロシクリルアルキル、ヘテロシクリルアルケニル、ヘテロシクリルアルキニル、アリール、ヘテロアリール、ヘテロシクリル、シクロアルキル、シクロアルケニル、アルキルアリールアルキル、アルキルアリールアルケニル、アルキルアリールアルキニル、アルケニルアリールアルキル、アルケニルアリールアルケニル、アルケニルアリールアルキニル、アルキニルアリールアルキル、アルキニルアリールアルケニル、アルキニルアリールアルキニル、アルキルヘテロアリールアルキル、アルキルヘテロアリールアルケニル、アルキルヘテロアリールアルキニル、アルケニルヘテロアリールアルキル、アルケニルヘテロアリールアルケニル、アルケニルヘテロアリールアルキニル、アルキニルヘテロアリールアルキル、アルキニルヘテロアリールアルケニル、アルキニルヘテロアリールアルキニル、アルキルヘテロシクリルアルキル、アルキルヘテロシクリルアルケニル、アルキルヘテロシクリルアルキニル、アルケニルヘテロシクリルアルキル、アルケニルヘテロシクリルアルケニル、アルケニルヘテロシクリルアルキニル、アルキニルヘテロシクリルアルキル、アルキニルヘテロシクリルアルケニル、アルキニルヘテロシクリルアルキニル、アルキルアリール、アルケニルアリール、アルキニルアリール、アルキルヘテロアリール、アルケニルヘテロアリール、またはアルキニルヘテロアリールであり、ここでこれらの基における1つ以上のメチレンが、O、S、S(O)、SO2、N(R8)、C(O)、置換もしくは非置換アリール、置換もしくは非置換ヘテロアリール、または置換もしくは非置換複素環で中断または終結され得、ここでR8は、水素、アシル、脂肪族または置換脂肪族であり;
Dは、非存在、-O-、-NR10-、-C(R10)(R11)-および-S-、-S(O)-、-S(O)2-、および-C(O)-から選択され;
各R3およびR4は、独立して非存在、水素、ハロゲン、-OR10、-SR10、-N(R10)(R11)、-S(O)R10、-S(O)2R10、任意に置換される脂肪族、任意に置換されるアリールまたは任意に置換されるヘテロシクリルから選択されるか;
あるいは、2つのR3およびR4は、一緒になって任意に置換される環を形成し;
mおよびqは、独立して0、1および2から選択され;
nは、1または2から選択され;
X3は-CH-または-N-であり;
R2は、非存在、水素、ハロゲン、-OR10、-SR10、-N(R10)(R11)、-S(O)R10、-S(O)2R10、任意に置換される脂肪族、任意に置換されるアリールまたは任意に置換されるヘテロシクリルから選択され;
各G3およびG4は、独立して-N-および-C(R10)-[C(R10)(R11)]a-から選択され、aは0、1または2であり;
rは、0、1、2、3、4、5、6、7、8、9、10または11であり;
pは、0、1、2、3または4であり;
R1は、
(式中、R100、R101およびR103は、独立して水素、ハロゲン、任意に置換されるC1-C8アルキル、任意に置換されるC2-C8アルケニル、任意に置換されるC2-C8アルキニル、任意に置換されるC3-C8シクロアルキル、任意に置換されるC1-C8アルコキシ、任意に置換されるC1-C8アルキルアミノおよび任意に置換されるC 6 -C8アリールから選択される)
から選択され;
R5は、
から選択され;
脂肪族は、飽和され得るかまたは不飽和の1つ以上の単位を含み得る非芳香族部分である)
で表される化合物、またはその薬学的に許容され得る塩もしくは溶媒和物(但し、該化合物は、
ではない)。
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Publication number | Priority date | Publication date | Assignee | Title |
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WO2011084849A1 (en) * | 2010-01-07 | 2011-07-14 | Alkermes, Inc. | Diaryldiazepine prodrugs for the treatment of neurological and psychological disorders |
WO2011084850A1 (en) * | 2010-01-07 | 2011-07-14 | Alkermes, Inc. | Prodrugs for the treatment of schizophrenia and bipolar disease |
AU2010339691B2 (en) | 2010-01-07 | 2015-04-02 | Alkermes Pharma Ireland Limited | Prodrugs of heteraromatic compounds |
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US8969337B2 (en) | 2011-12-15 | 2015-03-03 | Alkermes Pharma Ireland Limited | Prodrugs of secondary amine compounds |
NZ630643A (en) * | 2012-03-19 | 2017-08-25 | Alkermes Pharma Ireland Ltd | Pharmaceutical compositions comprising fatty acid esters |
AU2013235526B2 (en) | 2012-03-19 | 2017-11-30 | Alkermes Pharma Ireland Limited | Pharmaceutical compositions comprising benzyl alcohol |
AU2013235523B9 (en) | 2012-03-19 | 2018-01-04 | Alkermes Pharma Ireland Limited | Pharmaceutical compositions comprising glycerol esters |
EP3822273B1 (en) | 2012-06-13 | 2024-04-10 | Incyte Holdings Corporation | Substituted tricyclic compounds as fgfr inhibitors |
PL2861608T3 (pl) | 2012-06-19 | 2019-09-30 | Debiopharm International Sa | Pochodne prolekowe (e)-n-metylo-n-((3-metylobenzofuran-2-ylo)metylo)-3-(7-okso-5,6,7,8-tetrahydro-1,8-naftyrydyn-3-ylo)akryloamidu |
WO2014026125A1 (en) | 2012-08-10 | 2014-02-13 | Incyte Corporation | Pyrazine derivatives as fgfr inhibitors |
NZ631345A (en) | 2012-09-19 | 2017-06-30 | Alkermes Pharma Ireland Ltd | Pharmaceutical compositions having improved storage stability |
US9266892B2 (en) | 2012-12-19 | 2016-02-23 | Incyte Holdings Corporation | Fused pyrazoles as FGFR inhibitors |
JP2014196292A (ja) * | 2013-03-07 | 2014-10-16 | 大塚製薬株式会社 | 医薬 |
SG10201708520YA (en) | 2013-04-19 | 2017-12-28 | Incyte Corp | Bicyclic heterocycles as fgfr inhibitors |
US10525057B2 (en) | 2013-09-24 | 2020-01-07 | Otsuka Pharmaceutical Co., Ltd. | Method of providing aripiprazole to patients having impaired CYP2D6 or CYP3A4 enzyme function |
WO2015143145A1 (en) | 2014-03-20 | 2015-09-24 | Alkermes Pharma Ireland Limited | Aripiprazole formulations having increased injection speeds |
ES2884849T3 (es) | 2014-08-18 | 2021-12-13 | Alkermes Pharma Ireland Ltd | Composiciones de profármaco de aripiprazol |
US10016415B2 (en) | 2014-08-18 | 2018-07-10 | Alkermes Pharma Ireland Limited | Aripiprazole prodrug compositions |
SI3185867T1 (sl) * | 2014-08-25 | 2021-08-31 | Alkermes Pharma Ireland Limited | Postopek kristalizacije aripiprazolnih derivatov v formulacijah s podaljšanim sproščanjem za zdravljenje shizofrenije |
US10851105B2 (en) | 2014-10-22 | 2020-12-01 | Incyte Corporation | Bicyclic heterocycles as FGFR4 inhibitors |
MA41551A (fr) | 2015-02-20 | 2017-12-26 | Incyte Corp | Hétérocycles bicycliques utilisés en tant qu'inhibiteurs de fgfr4 |
MX2017010673A (es) | 2015-02-20 | 2018-03-21 | Incyte Corp | Heterociclos biciclicos como inhibidores de receptores del factor de crecimiento fibroblastico (fgfr). |
WO2016134294A1 (en) | 2015-02-20 | 2016-08-25 | Incyte Corporation | Bicyclic heterocycles as fgfr4 inhibitors |
BR112017022340A2 (pt) | 2015-05-05 | 2018-07-10 | Pfizer | 2-tiopirimidinonas |
US10159671B2 (en) | 2016-02-17 | 2018-12-25 | Alkermes Pharma Ireland Limited | Compositions of multiple aripiprazole prodrugs |
US10751351B2 (en) | 2016-02-26 | 2020-08-25 | Debiopharm International S.A. | Medicament for treatment of diabetic foot infections |
WO2018104953A1 (en) * | 2016-12-07 | 2018-06-14 | Msn Laboratories Private Limited, R&D Center | Improved process for the preparation of 7-{4-[4-(2,3-dichlorophenyl)-piperazin-1-yl]butoxy}-2oxo-3,4-dihydro-2h-quinolin-1-yl)methyl dodecanoate |
US10815216B2 (en) * | 2016-12-14 | 2020-10-27 | Neuland Pharma Research Private Limited | Process for the preparation of aripiprazole lauroxil |
US20180265472A1 (en) * | 2017-03-17 | 2018-09-20 | Scinopharm Taiwan, Ltd. | Process for preparing aripiprazole lauroxil and intermediates thereof |
AR111960A1 (es) | 2017-05-26 | 2019-09-04 | Incyte Corp | Formas cristalinas de un inhibidor de fgfr y procesos para su preparación |
EP3658540B1 (en) | 2017-07-28 | 2021-12-01 | Interquim, S.A. | Process for the preparation of aripiprazole lauroxil |
CN107628999B (zh) * | 2017-10-25 | 2019-07-02 | 苏州华健瑞达医药技术有限公司 | 阿立哌唑十二烷酸酯的制备方法 |
CN110218209B (zh) * | 2018-03-02 | 2022-09-30 | 上海现代药物制剂工程研究中心有限公司 | 一种依匹哌唑月桂酸酯的晶型a、其制备方法及应用 |
AU2019230014A1 (en) | 2018-03-05 | 2020-09-17 | Alkermes Pharma Ireland Limited | Aripiprazole dosing strategy |
CN112867716A (zh) | 2018-05-04 | 2021-05-28 | 因赛特公司 | Fgfr抑制剂的固体形式和其制备方法 |
CN112566912A (zh) | 2018-05-04 | 2021-03-26 | 因赛特公司 | Fgfr抑制剂的盐 |
WO2020185532A1 (en) | 2019-03-08 | 2020-09-17 | Incyte Corporation | Methods of treating cancer with an fgfr inhibitor |
WO2021007269A1 (en) | 2019-07-09 | 2021-01-14 | Incyte Corporation | Bicyclic heterocycles as fgfr inhibitors |
JP2022543990A (ja) | 2019-07-12 | 2022-10-17 | インタークイム,エス.エー. | アリピプラゾールラウロキシルの調製のためのプロセス |
AU2020366006A1 (en) | 2019-10-14 | 2022-04-21 | Incyte Corporation | Bicyclic heterocycles as FGFR inhibitors |
US11566028B2 (en) | 2019-10-16 | 2023-01-31 | Incyte Corporation | Bicyclic heterocycles as FGFR inhibitors |
EP4069696A1 (en) | 2019-12-04 | 2022-10-12 | Incyte Corporation | Tricyclic heterocycles as fgfr inhibitors |
KR20220131900A (ko) | 2019-12-04 | 2022-09-29 | 인사이트 코포레이션 | Fgfr 억제제의 유도체 |
WO2022101444A1 (en) | 2020-11-12 | 2022-05-19 | Alkermes Pharma Ireland Limited | Immediate release multilayer tablet |
CN112656761B (zh) * | 2020-12-30 | 2023-09-08 | 河南合智医药科技有限公司 | 一种低刺激性阿立哌唑前药的油溶缓释注射制剂及其制备方法 |
US11939331B2 (en) | 2021-06-09 | 2024-03-26 | Incyte Corporation | Tricyclic heterocycles as FGFR inhibitors |
Family Cites Families (135)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US528A (en) | 1837-12-20 | Improvement in cooking-stoves | ||
US5006A (en) | 1847-03-06 | Improvement in the process of manufacturing wire grating | ||
US2418499A (en) | 1944-06-20 | 1947-04-08 | Du Pont | 2-alkoxymethylmercapto-thiazoles and thiazolines and a process for preparing the same |
DE1070760B (de) * | 1955-11-19 | 1959-12-10 | Badische Anilin- S- Soda-Fabrik Aktiengesellschaft, Ludwigshafen / Rhein | Verfahren zur Herstellung von Azofarbstoffen |
GB849541A (en) | 1956-02-23 | 1960-09-28 | Rohm & Haas | Preparation of unsaturated cyclic urea derivatives |
DE1273533B (de) | 1962-09-08 | 1968-07-25 | Hoechst Ag | Verfahren zur Herstellung von N-(ª‡-Alkoxy-alkyl)-carbonsaeureamiden |
US3452034A (en) | 1967-03-09 | 1969-06-24 | American Cyanamid Co | Substituted 2-(1,3,4-thiadiazol-2-yl)-4(5)-nitroimidazoles |
US3573308A (en) * | 1969-04-03 | 1971-03-30 | Hoffmann La Roche | 3-lower alkoxy methyl-3,4-dihydro-4-hydroxy-4-aryl quinazolin-2(1h) ones and related compounds |
US3957808A (en) | 1969-09-03 | 1976-05-18 | Rohm And Haas Company | 3-alkoxyisothiazoles |
US3998815A (en) * | 1974-06-24 | 1976-12-21 | Interx Research Corporation | 1-hydrocarbonoyloxymethyl-3-carbamoyl or 3-carboethoxy-pyridinium salts |
US4204065A (en) * | 1975-09-22 | 1980-05-20 | Interx Research Corporation | Soft quaternary surface active agents and method of using same |
JPS5331676A (en) | 1976-09-06 | 1978-03-25 | Mitsui Toatsu Chem Inc | Uracil derivatives and their preparation |
US4260769A (en) * | 1977-04-22 | 1981-04-07 | Interx Research Corporation | 5,5-Diphenylhydantoins |
JPS54130587A (en) | 1978-03-30 | 1979-10-09 | Otsuka Pharmaceut Co Ltd | Carbostyryl derivative |
EP0005828B1 (de) | 1978-06-06 | 1981-03-11 | Hoechst Aktiengesellschaft | Neue substituierte Phenylpiperazinderivate, diese enthaltende Arzneimittel und Verfahren zu deren Herstellung |
FI77852C (fi) | 1981-02-17 | 1989-05-10 | Otsuka Pharma Co Ltd | Foerfarande foer framstaellning av nya, saosom hjaertmediciner anvaendbara substituerade amid- och (maettad heterocykel)karbonylkarbostyrilderivat. |
AU532361B2 (en) | 1981-09-01 | 1983-09-29 | Otsuka Pharmaceutical Co., Ltd. | Carbostyril derivatives |
DE3149010A1 (de) | 1981-12-10 | 1983-07-07 | A. Nattermann & Cie GmbH, 5000 Köln | (+)-2-(1-(2,6-dichlorphenoxy)-ethyl)-1,3- diazacyclopent-2-en, dessen herstellung und seine verwendung in pharamazeutischen praeparaten |
US4428935A (en) * | 1982-05-24 | 1984-01-31 | Pfizer Inc. | Penicillanic acid dioxide prodrug |
IT1212743B (it) * | 1983-05-17 | 1989-11-30 | Dompe Farmaceutici Spa | Sali quaternari di derivati di benzo[ 1,4 ]diazepinonici,pirido [1,4]benzodiazepinonici,prido [1,5]benzodiazepinonici e loro atti vita' farmacologica |
US4760057A (en) * | 1983-06-23 | 1988-07-26 | Merck & Co., Inc. | (Acyloxyalkoxy)carbonyl derivatives as bioreversible prodrug moieties for primary and secondary amine functions in drugs |
DE3544134A1 (de) | 1984-12-15 | 1986-06-19 | Mitsubishi Chemical Industries Ltd., Tokio/Tokyo | Verfahren zur herstellung von n-((alpha)-alkoxyethyl) pyrrolidon |
JPS61171467A (ja) | 1985-01-23 | 1986-08-02 | Mitsubishi Chem Ind Ltd | N−(α−アルコキシエチル)ピロリドンの製造方法 |
AR240698A1 (es) | 1985-01-19 | 1990-09-28 | Takeda Chemical Industries Ltd | Procedimiento para preparar compuestos de 5-(4-(2-(5-etil-2-piridil)-etoxi)benzil)-2,4-tiazolidindiona y sus sales |
GB8513754D0 (en) * | 1985-05-31 | 1985-07-03 | Jones T R | Anti-cancer quinazoline derivatives |
FR2587029B1 (fr) | 1985-09-11 | 1987-10-30 | Synthelabo | Derives de benzimidazole, leur preparation et leur application en therapeutique |
DK588486A (da) | 1985-12-09 | 1987-06-10 | Otsuka Pharma Co Ltd | Anvendelse af en forbindelse til behandling af hypoxi |
GB8607683D0 (en) * | 1986-03-27 | 1986-04-30 | Ici Plc | Anti-tumor agents |
MX173362B (es) * | 1987-03-02 | 1994-02-23 | Pfizer | Compuestos de piperazinil heterociclicos y procedimiento para su preparacion |
US4925860A (en) | 1987-08-05 | 1990-05-15 | E. I. Du Pont De Nemours And Company | Stable pharmaceutical composition of 3-(hydroxymethyl)-5,5-diphenylhydantoin disodium phosphate ester |
US4831031A (en) * | 1988-01-22 | 1989-05-16 | Pfizer Inc. | Aryl piperazinyl-(C2 or C4) alkylene heterocyclic compounds having neuroleptic activity |
GB8809978D0 (en) * | 1988-04-27 | 1988-06-02 | Ici Plc | Anti-tumour agents |
JP2608788B2 (ja) * | 1988-10-31 | 1997-05-14 | 大塚製薬 株式会社 | 精神分裂病治療剤 |
US5006528A (en) * | 1988-10-31 | 1991-04-09 | Otsuka Pharmaceutical Co., Ltd. | Carbostyril derivatives |
DK24089D0 (da) * | 1989-01-20 | 1989-01-20 | Hans Bundgaard | Novel prodrug derivatives of biologically active agents containing hydroxyl groups or nh-acidic groups |
ATE126512T1 (de) | 1989-05-19 | 1995-09-15 | Hoechst Roussel Pharma | N-(aryloxyalkyl)heteroarylpiperidine und - heteroarylpiperazine, verfahren zu ihrer herstellung und ihre verwendung als medikamente. |
US5350747A (en) | 1989-07-07 | 1994-09-27 | Pfizer Inc | Heteroaryl piperazine antipsychotic agents |
WO1991000863A1 (en) * | 1989-07-07 | 1991-01-24 | Pfizer Inc. | Heteroaryl piperazine antipsychotic agents |
US5041659A (en) | 1990-04-26 | 1991-08-20 | The Standard Oil Company | Synthesis of n-disubstituted amides by reaction of amides with certain organic hydroxyl compounds |
DK238190D0 (da) | 1990-10-03 | 1990-10-03 | Lundbeck & Co As H | Depotderivater |
US5206386A (en) | 1991-03-20 | 1993-04-27 | Isp Investments Inc. | Controlled release N-substituted pyrrolidone esters and process for the use thereof |
AU645681B2 (en) | 1991-05-02 | 1994-01-20 | John Wyeth & Brother Limited | Piperazine derivatives |
IE914218A1 (en) | 1991-09-11 | 1993-03-24 | Mcneilab Inc | Novel 4-arylpiperazines and 4-arylpiperidines |
TW226016B (ja) * | 1991-12-30 | 1994-07-01 | Sterling Winthrop Inc | |
US5462934A (en) | 1992-03-09 | 1995-10-31 | Takeda Chemical Industries | Condensed heterocyclic ketone derivatives and their use |
EP0647133A4 (en) | 1992-06-12 | 1997-10-29 | Affymax Tech Nv | COMPOSITIONS AND METHODS FOR IMPROVED DRUG DELIVERY. |
US5719303A (en) * | 1993-03-08 | 1998-02-17 | Eisai Co., Ltd. | Phosphonic acid derivatives |
US5497763A (en) | 1993-05-21 | 1996-03-12 | Aradigm Corporation | Disposable package for intrapulmonary delivery of aerosolized formulations |
US5508269A (en) | 1994-10-19 | 1996-04-16 | Pathogenesis Corporation | Aminoglycoside formulation for aerosolization |
DE4439493A1 (de) | 1994-10-25 | 1996-05-02 | Schering Ag | Neue Chinoxalindionderivate, deren Herstellung und Verwendung in Arzneimitteln |
JP3571795B2 (ja) | 1995-04-18 | 2004-09-29 | 株式会社日本触媒 | N−(1−アルキルオキシアルキル)カルバメート類の気相分子内脱アルコール反応用触媒およびn−ビニルカルバメート類の製造方法 |
JP3989554B2 (ja) * | 1996-03-29 | 2007-10-10 | デユフアー・インターナシヨナル・リサーチ・ベー・ブイ | ピペラジンおよびピペリジン化合物 |
US6083922A (en) | 1996-04-02 | 2000-07-04 | Pathogenesis, Corp. | Method and a tobramycin aerosol formulation for treatment prevention and containment of tuberculosis |
ES2169375T3 (es) | 1996-04-30 | 2002-07-01 | Warner Lambert Co | Proceso mejorado para la sintesis de diesteres del ester 2,5-dioxo-4,4-difenil-imidazolidin-1-ilmetilico de acido fosforico. |
DE19619819A1 (de) | 1996-05-16 | 1997-11-20 | Boehringer Mannheim Gmbh | Neue Thiazolidindione, Verfahren zu ihrer Herstellung und diese enthaltenden Arzneimittel |
US5767068A (en) | 1997-02-13 | 1998-06-16 | Pathogenesis Corporation | Pure biologically active colistin, its components and a colistin formulation for treatment of pulmonary infections |
HUP0001122A3 (en) * | 1997-04-25 | 2002-03-28 | Janssen Pharmaceutica Nv | Farnesyltransferase inhibiting quinazolinones |
WO1998056422A1 (en) * | 1997-06-13 | 1998-12-17 | The University Of Kansas | Polar drug or prodrug compositions with extended shelf-life storage and a method of making thereof |
AR016384A1 (es) * | 1997-07-30 | 2001-07-04 | Smithkline Beecham Corp | Inhibidores de caspasas, composiciones farmaceuticas que comprenden dichos inhibidores de caspasas y uso de los inhibidores de caspasas para prepararun medicamento util para el tratamiento de apoptosis y desordenes asociados con excesiva actividad de la convertosa il-1 beta. |
US6180095B1 (en) * | 1997-12-17 | 2001-01-30 | Enzon, Inc. | Polymeric prodrugs of amino- and hydroxyl-containing bioactive agents |
EP1051181B1 (en) | 1997-12-31 | 2004-03-17 | The University Of Kansas | Water soluble prodrugs of tertiary amine containing drugs and methods of making thereof |
ATE346841T1 (de) * | 1998-08-26 | 2006-12-15 | Aventis Pharma Ltd | Azabicyclo-verbindungen welche die inhibition der zell adhesion modulieren |
FR2783519B1 (fr) * | 1998-09-23 | 2003-01-24 | Sod Conseils Rech Applic | Nouveaux derives d'amidines, leur preparation, leur application a titre de medicaments et les compositions pharmaceutiques les contenant |
US6509334B1 (en) * | 1999-05-04 | 2003-01-21 | American Home Products Corporation | Cyclocarbamate derivatives as progesterone receptor modulators |
US6444668B1 (en) * | 1999-05-04 | 2002-09-03 | Wyeth | Combination regimens using progesterone receptor modulators |
TWI270545B (en) | 2000-05-24 | 2007-01-11 | Sugen Inc | Mannich base prodrugs of 3-(pyrrol-2-ylmethylidene)-2-indolinone derivatives |
MXPA03005870A (es) * | 2001-02-14 | 2005-02-14 | Warner Lambert Co | Inhibirores de benzotiadiazina de metaloproteinasas de la matriz. |
EP1414798A2 (en) | 2001-04-03 | 2004-05-06 | Aryx Therapeutics | Ultrashort-acting opioids for transdermal application |
AU2003245773A1 (en) * | 2002-02-15 | 2003-09-04 | Glaxo Group Limited | Vanilloid receptor modulators |
WO2003080047A1 (en) | 2002-03-20 | 2003-10-02 | Bristol-Myers Squibb Company | Phosphate prodrugs of fluorooxindoles |
NZ537995A (en) | 2002-08-20 | 2007-11-30 | Bristol Myers Squibb Co | Inclusion complex of aripiprazole in a substituted b-cyclodextrin |
EA200500342A1 (ru) * | 2002-09-17 | 2005-08-25 | УОРНЕР-ЛАМБЕРТ КОМПАНИ Эл-Эл-Си | Гетероциклические замещённые пиперазины для лечения шизофрении |
CA2500485C (en) * | 2002-10-24 | 2010-03-23 | Pfizer Products Inc. | Acyl derivatives of 5-(2-(4-(1,2 benzisothiazole-3-yl)-1-piperazinyl)ethyl)-6-chloro-1,3-dihydro-2h-indol-2-one having neuroleptic activity |
DE10303669A1 (de) | 2003-01-28 | 2004-07-29 | Hans-Knöll-Institut für Naturstoff-Forschung e.V. | Tetraalkylammoniumsalze vom Kohlensäureestertyp, Verfahren zu ihrer Herstellung und diese Verbindungen enthaltende pharmazeutische Zusammensetzungen |
JP2006523237A (ja) | 2003-04-03 | 2006-10-12 | セマフォア ファーマシューティカルズ, インコーポレイテッド | Pi−3キナーゼインヒビタープロドラッグ |
CN102000336A (zh) * | 2003-05-23 | 2011-04-06 | 大塚制药株式会社 | 用于治疗情感障碍的喹诺酮衍生物和情绪稳定剂 |
US20050032811A1 (en) | 2003-08-06 | 2005-02-10 | Josiah Brown | Methods for administering aripiprazole |
US7160888B2 (en) | 2003-08-22 | 2007-01-09 | Warner Lambert Company Llc | [1,8]naphthyridin-2-ones and related compounds for the treatment of schizophrenia |
EP1701954A1 (en) | 2003-12-31 | 2006-09-20 | Warner-Lambert Company LLC | N-substituted piperidine and piperazine derivatives |
AR047530A1 (es) * | 2004-02-04 | 2006-01-25 | Novartis Ag | Formas de sal de 4-(4-metilpiperazin-1-ilmetil)-n-(4-metil-3-(4-piridin-3-il)pirimidin-2-ilamino)fenil)-benzamida |
CN1917882A (zh) | 2004-02-13 | 2007-02-21 | 辉瑞产品公司 | 非典型抗精神病药物与促肾上腺皮质激素释放因子拮抗剂的治疗剂组合 |
US7169803B2 (en) * | 2004-03-15 | 2007-01-30 | Bristol-Myers Squibb Company | N-substituted prodrugs of fluorooxindoles |
CA2558139C (en) * | 2004-03-23 | 2012-01-17 | Nissan Chemical Industries, Ltd. | Tricyclic benzopyran compound as anti-arrhythmic agents |
US7119214B2 (en) * | 2004-04-13 | 2006-10-10 | Cephalon France | Thio-substituted tricyclic and bicyclic aromatic methanesulfinyl derivatives |
WO2006037090A2 (en) | 2004-09-28 | 2006-04-06 | Purdue Research Foundation | Drug-phosphate conjugates as prodrugs |
WO2006090273A2 (en) | 2005-02-22 | 2006-08-31 | Warner-Lambert Company Llc | [1,8]naphthyridin-2-ones and related compounds with keto or hydroxyl linkers for the treatment of schizophrenia |
TWI320783B (en) | 2005-04-14 | 2010-02-21 | Otsuka Pharma Co Ltd | Heterocyclic compound |
EP1777222A1 (en) * | 2005-09-22 | 2007-04-25 | Galantos Pharma GmbH | Cholinergic enhancers with improved blood-brain barrier permeability for the treatment of diseases accompanied by cognitive impairment |
CN101300256A (zh) | 2005-10-31 | 2008-11-05 | 辉瑞产品公司 | 7-[4-(4-萘-1-基-哌嗪-1-基)-丁氧基]-3,4-二氢-1h-[1,8]萘啶-2-酮的结晶盐 |
WO2007059111A2 (en) | 2005-11-14 | 2007-05-24 | Entremed, Inc. | Anti-angiogenic activity of 2-methoxyestradiol in combination with anti-cancer agents |
ES2389062T3 (es) * | 2006-01-18 | 2012-10-22 | Amgen, Inc | Compuestos de tiazol como inhibidores de proteína cinasa B (PKB) |
TW200804359A (en) * | 2006-01-19 | 2008-01-16 | Speedel Experimenta Ag | Substituted 4-phenylpiperidines |
US20090068290A1 (en) * | 2006-08-31 | 2009-03-12 | Michel Bourin | Bifeprunox doses for treating schizophrenia |
AU2007291235A1 (en) | 2006-08-31 | 2008-03-06 | H. Lundbeck A/S | Bifeprunox doses for treating schizophrenia |
WO2008034041A2 (en) * | 2006-09-15 | 2008-03-20 | Astrazeneca Ab | Therapeutic combinations |
RU2009125597A (ru) * | 2006-12-05 | 2011-01-20 | Ньюроджесэкс, Инк. (Us) | Пролекарства и способы их получения и применения |
TWI325694B (en) * | 2006-12-15 | 2010-06-01 | Ind Tech Res Inst | All digital delay locked loop |
CA2672270A1 (en) * | 2006-12-15 | 2008-06-26 | Gennadi V. Glinksy | Treatments of therapy resistant diseases and drug combinations for treating the same |
US20080186971A1 (en) * | 2007-02-02 | 2008-08-07 | Tarari, Inc. | Systems and methods for processing access control lists (acls) in network switches using regular expression matching logic |
JP2010522198A (ja) * | 2007-03-19 | 2010-07-01 | アカドイア プハルマセウチカルス インコーポレーテッド | 5−ht2aインバースアゴニスト及びアンタゴニストの抗精神病薬との併用 |
ES2571533T3 (es) | 2007-04-27 | 2016-05-25 | Purdue Pharma Lp | Antagonistas de TRPV1 y usos de los mismos |
NZ582124A (en) | 2007-05-21 | 2012-07-27 | Reviva Pharmaceuticals Inc | Compositions, synthesis, and methods of using quinolinone based atypical antipsychotic agents |
WO2008150848A1 (en) | 2007-05-30 | 2008-12-11 | Wyeth | Antidepressant heteroaryl derivatives of heterocycle-fused benzodioxans |
WO2009003136A1 (en) * | 2007-06-26 | 2008-12-31 | Rigel Pharmaceuticals, Inc. | Substituted pyrimidine-2, 4 -diamines for treating cell proliferative disorders |
US20100292316A1 (en) * | 2007-07-18 | 2010-11-18 | Research Development Foundation | Improved therapeutic methods and compositions comprising chroman ring compounds |
US8076334B2 (en) * | 2007-09-20 | 2011-12-13 | Hoffmann-La Roche Inc. | Prodrugs of thyroid hormone analogs |
WO2009052467A1 (en) | 2007-10-19 | 2009-04-23 | Board Of Regents Of The University Of Texas System | Methods of identifying pi-3-kinase inhibitor resistance |
NZ594323A (en) | 2009-01-23 | 2013-05-31 | Rigel Pharmaceuticals Inc | Compositions and methods for inhibition of the jak pathway |
US9307454B2 (en) * | 2009-02-09 | 2016-04-05 | Qualcomm Incorporated | Method and apparatus for maintaining location continuity for a UE following handover |
JP5732453B2 (ja) * | 2009-06-25 | 2015-06-10 | アルカーメス ファーマ アイルランド リミテッド | Nh酸性化合物のプロドラッグ |
FI2445502T4 (fi) * | 2009-06-25 | 2023-01-13 | Heterosyklisiä yhdisteitä neurologisten ja psykologisten häiriöiden hoitamiseksi | |
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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JP2019172699A (ja) * | 2009-06-25 | 2019-10-10 | アルカーメス ファーマ アイルランド リミテッド | 神経学的および精神的障害の治療のための複素環式化合物 |
JP7042239B2 (ja) | 2009-06-25 | 2022-03-25 | アルカーメス ファーマ アイルランド リミテッド | 神経学的および精神的障害の治療のための複素環式化合物 |
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