JP6254730B2 - ベンズアミド類 - Google Patents
ベンズアミド類 Download PDFInfo
- Publication number
- JP6254730B2 JP6254730B2 JP2017043934A JP2017043934A JP6254730B2 JP 6254730 B2 JP6254730 B2 JP 6254730B2 JP 2017043934 A JP2017043934 A JP 2017043934A JP 2017043934 A JP2017043934 A JP 2017043934A JP 6254730 B2 JP6254730 B2 JP 6254730B2
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- JP
- Japan
- Prior art keywords
- het
- atoms
- cyc
- piperazin
- tolyl
- Prior art date
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- 125000004434 sulfur atom Chemical group 0.000 claims description 28
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 25
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 25
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—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
- C07D417/02—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
- 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
-
- 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
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
-
- 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
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
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- A—HUMAN NECESSITIES
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Description
本出願は、2011年7月18日に提出された米国特許仮出願第61/508,861号及び2011年8月23日に提出された米国特許仮出願第61/526,342号の利益を主張し、その個々は参照により本明細書に組込まれる。
R1は、−(CY2)n−E−(CY2)n−Het3、−(CY2)n−Cyc−Het3、 −(CY2) n−NY−Het3、 −(CY2) n−CONH−Het3、 −(CY2) n−NHCO−Het3、 −(CY2) n−C(Y)(OH)−(CY2) n−Het3、 −(CY2) n−Het1、 −(CY2) n−CONH−Het1、 −(CY2) n−NHCO−Het1 、−(CY2) n−Ar、 −Cyc−Ar、 −(CY2) n−NY−Ar、 −(CY2) n−CONH−Ar、 −(CY2) n−NHCO−Ar、 −(CY2) n−C(Y)(OH)−(CY2) n−Ar、 −(CY2) n−Cyc、 −(CY2) n−NY−Cyc、 −(CY2) n−CONH−Cyc、 −(CY2) n−NHCO−Cyc、 −(CY2) n−NHCO−NH−Cyc、 Y、 −(CYR8)−OY、 −(CY2) n−COOY、 −(CY2)n−SO2Y、 −(CYR8) n−CO−(CY2) n−N(R8)2、 −(CY2)n−[C(Y)(OH)]m−(CYR8) n−NY2、 [−(CY2)n−0]m−(CYR8) n−NYCOY、 −(CY2) n−NYCOOY、 −(CY2)n−NYSO2Y、 −(CY2) n−NYCON(R8)2、 −(CY2)n−NHCO−CH=CH2、 −(CY2)n−NHCO−NH−(CY2) n=CH2 又は −(CY2) n−CNを示し;
R2は、Yを示し;
R1、R2は、また一緒に、−(CY2)P−NH−(CY2)P−、 −(CY2)p−NHCO−(CY2)p−、−(CY2)p−CONH−(CY2)p−、 −(CY2)p−N(COA)−(CY2)p−、 −(CY2)p−N(COOA)−(CY2)p−、 −(CY2)p−C(Y)(Het3)−(CY2)p−、
R3は、−(CY2)n−Het1、−(CY2)n−Het3、−(CY2)n−Ar、−C(Y)(OY)−Ar、Y 又は −(CY2)n−Cycを示し;
R4は、Y、COY又はSO2Yを示し;
R5は、E−Ar、 NY−Ar、 Cyc、 Y、 OY、 NYY、 NYCOOY、 NYCOY、 COY、 COOY、 SO2Y、 Het1又はHet3を示し;
R6、R7は、互いに独立して、Hを示し;
R6、R7は、また一緒に、−(CY2)p−を示し;
R8は、Y又はArを示し;
X、Eは、互いに独立して、−(CY2)m−、 O、 CO、 −COO− 又はSO2を示し;
Yは、H又はAを示し;
Aは、1〜10個のC原子を有する、枝なし又は分枝アルキルを示し、ここで1〜7個のH原子は互いに独立して、Hal、=O及び/又はOHにより置換され得;
Cycは、3〜7個のC原子を有するシクロアルキルを示し、ここで1〜4個のH原子は互いに独立して、Hal及び/又はOHにより置換され得;
Arは、3〜10個のC原子を有する、不飽和又は芳香族単環又はニ環式炭素環を示し、前記炭素環はA、Hal、−(CY2)n−OY、COOY、CONH2、NHCOY、−(CY2)n−NYCOOY、−(CY2)n−NY2、NO2、SO2Y、SO2NY2、NYSO2Y、−(CY2)n−CN、−(CY2)n−Het2及びCycの群から選択される少なくとも1つの置換基により置換され得るか、又はCycに対して融合され得;
Het1は、1〜10個のC原子及び1〜4個のN、O及び/又はS原子を有する、不飽和又は芳香族単環又はニ環式複素環を示し、前記複素環はHal、 A、 Cyc、 OY、 =O、 COOY、 CONH2、 NHCOY、−(CY2)n −NY2、 SO2Y、 SO2NY2、 NHSO2Y、 CN、 Ar 及び−(CY2)n −Het3の群から選択される少なくとも1つの置換基により置換され得;
Het2は、1〜4個のC原子及び1〜4個のN、O及び/又はSを有する、飽和又は不飽和単環式5−又は6−員の複素環を示し、前記複素環は、A及び/又は=Oにより置換され得:
Het3は、3〜7個のC原子及び1〜4個のN、O及び/又はS原子を有する、飽和単環又はニ環式複素環を示し、前記複素環は=O、 A、 Hal、 −(CY2)n−Cyc、 −(CY2)n−OY、 COY、 COOY、 CONY2、 NHCOY、 −(CY2)n−NY2、 CN、 SO2Y及び−(CY2)n−Arの群から選択された少なくとも1つの置換基により置換され得;
Halは、F、Cl、Br又はIを示し;
m、nは、互いに独立して、0、1、2、3、4、5又は6を示し;そして
pは、1、2又は3を示す]で表される化合物、及び/又は生理学的に許容できるその塩(但し、3−(3−クロロ−ベンゾイルアミノ)−N−[2−(2,4−ジクロロ−フェニル)−エチル]−4−(4−エチル −ピペラジン−1 −イル)−ベンズアミド;
3− (3−クロロ−ベンゾイルアミノ)−N−[2−(2,4−ジクロロ−フェニル)−エチル]−4−[4−(1−メチル−ピペリジン−4−イル)−ピペラジン−1−イル]−ベンズアミド;及び
4− [1 ,4’]ビピペリジニル−1’−イル−3−(3−クロロ−ベンゾイルアミノ)−N−[2−(4−クロロ−フェニル)−エチル]− ベンズアミドを除く)に関する。
R1は、−(CY2)n−E−Het3、−(CY2)n−Cyc−Het3、−(CY2)n−Het1、 −(CY2)n−CONH−Het1、 −(CY2)n−NHCO−Het1、 −(CY2)n−Ar、 −(CY2)n−Cyc、−(CY2)n−CONH−Cyc、 −(CY2)n−NHCO−Cyc、A、 −(CYR8)n−OY、 −(CY2)n−COOY、 −(CY2)n−SO2Y、 −(CYR8)n−CONY2、 −(CYR8)n−NY2、 −(CYR8)n−NYCOY、 −(CY2)n−NYCOOY、−(CY2)n−NYCONY2又は−(CY2)n−NHCO−CH=CH2を示し;
R1、R2は、また一緒に、−(CY2)P−NH−(CY2)P−、 −(CY2)p−NHCO−(CY2)p−、−(CY2)p−CONH−(CY2)p−、 −(CY2)p−N(COA)−(CY2)p−、 −(CY2)p−N(COOA)−(CY2)p−、
R3は、−(CY2)n−Het1、−(CY2)n−Het3、−(CY2)n−Ar、H、A又は −(CY2)n−Cycを示し;
R4は、Yを示し;
R5は、E−Ar、H、 A、COOY、 SO2Y、 Het1又はHet3を示し;
R2、R6、R7は、互いに独立して、Hを示し;
R6、R7は、また一緒に、−(CY2)p−を示し;
R8は、H、A又はArを示し;
X、Eは、互いに独立して、−(CY2)m−、 O、 CO、 −COO− 又はSO2を示し;
Yは、H又はAを示し;
Aは、1〜10個のC原子を有する、枝なし又は分枝アルキルを示し、ここで1〜7個のH原子は互いに独立して、Hal、及び/又は=Oにより置換され得;
Cycは、3〜7個のC原子を有するシクロアルキルを示し、ここで1〜4個のH原子は互いに独立して、Halにより置換され得;
Arは、3〜10個のC原子を有する、不飽和又は芳香族単環又はニ環式炭素環を示し、前記炭素環はA、Hal、OY、COOY、CONH2、NHCOY、NY2、NO2、SO2Y、CN、及びHet2の群から選択される少なくとも1つの置換基により置換され得るか、又はCycに対して融合され得;
Het1は、1〜10個のC原子及び1〜4個のN、O及び/又はS原子を有する、不飽和又は芳香族単環又はニ環式複素環を示し、前記複素環はHal、 A、 Cyc、 OY、COOY、 CONH2、 NHCOY、NY2、 SO2Y、 SO2NY2、 NHSO2Y、 CN、 及びArの群から選択される少なくとも1つの置換基により置換され得;
Het2は、1〜3個のC原子及び2−4個のN、及び/又はSを有する、不飽和単環式5−員の複素環を示し、前記複素環は、Aにより置換され得:
Het3は、3〜7個のC原子及び1〜4個のN、O及び/又はS原子を有する、飽和単環又はニ環式複素環を示し、前記複素環は=O、 A、 Hal、 −(CY2)n−Cyc、 −(CY2)n−OY、 COY、 COOY、 CONY2、 NHCOY、NY2、 CN、 SO2Y及び−(CY2)n−Arの群から選択された少なくとも1つの置換基により置換され得;
Halは、F、Cl、Br又はIを示し;
m、nは、互いに独立して、0、1、2、3、4、5又は6を示し;そして
pは、1、2又は3を示す]で表される化合物、及び/又は生理学的に許容できるその塩(但し、3−(3−クロロ−ベンゾイルアミノ)−N−[2−(2,4−ジクロロ−フェニル)−エチル]−4−(4−エチル −ピペラジン−1 −イル)−ベンズアミド;
3− (3−クロロ−ベンゾイルアミノ)−N−[2−(2,4−ジクロロ−フェニル)−エチル]−4−[4−(1−メチル−ピペリジン−4−イル)−ピペラジン−1−イル]−ベンズアミド;及び
4− [1 ,4’]ビピペリジニル−1 ’−イル−3−(3−クロロ−ベンゾイルアミノ)−N−[2−(4−クロロ−フェニル)−エチル]− ベンズアミドを除く)に関する。
本発明の意味においては、化合物は、医薬的に使用可能なその誘導体、溶媒和物、プロドラッグ、互変異体、鏡像異性体、ラセミ体及び立体異性体、並びにそれらの全比率での混合物を含むよう定義される。
本発明の別の好ましい実施形態によれば、式(I)のスキャフォールドにおけるフェニル環は、−NXR3R4部分に関してメタ位置で−CONR1R2により置換される。
R3は、Het1、Het3、Ar、H、A又はCycを示し;
R5は、E−Ar、H、A、COOA又はHet1を示し;
R8、Yは、互いに独立して、H又はAを示し;
Xは、CO又は−(CY2)mを示し;
Eは、−(CY2)m−、CO、−COO−又はSO2を示し;
Aは、1〜10個のC原子を有する枝なし又は分枝アルキルを示し、ここで1〜7個のH原子は互いに独立して、Hal及び/又はOHにより置換され得;
Cycは、3〜7個のC原子を有するシクロアルキルを示し、ここで1〜4個のH原子は互いに独立して、Hal及び/又はOHにより置換され得;
Arは、A、Hal、OY、COOY、CONH2、NHCOY、−(CH2)n−NY2、SO2NH2、NO2、CN及びHet2の群から選択される少なくとも1つの置換基により置換され得る、5〜10個のC原子を有する、不飽和又は芳香族単環又はニ環式炭素環を示し;
Het1は、Hal、A、 Cyc、OY、CONH2、NHCOY、−(CH2)n−NY2、SO2NY2、 NHSO2Y、CN及びArの群から選択される少なくとも1つの置換基により一又は二置換され得る、1〜9個のC原子及び1〜3個のN、O及び/又はS原子を有する、不飽和又は芳香族単環又はニ環式複素環を示し;
Het2は、メチルにより一置換され得る、イミダゾリル、ピラジル、チアジル又はテトラジルを示し;
Het3は、=O、A、Hal、−(CY2)n−Cyc、−(CY2)n−OY、COY、COOY、CONY2、NHCOY、NY2、CN、SO2Y及び−(CY2)n−Arの群から選択される少なくとも1つの置換基により一、二又は三置換され得る、3〜6個のC原子及び1〜3個のN、O及び/又はS原子を有する、飽和単環式複素環を示し;
Halは、F、Cl、Br又はIを示し;そして
m、nは、互いに独立して、0、1、2又は3を示す]で表されるベンズアミド誘導体、及び/又は生理学的に許容できるその塩(但し、3−(3−クロロ−ベンゾイルアミノ)−N−[2−(2,4−ジクロロ−フェニル)−エチル]−4−(4−エチル −ピペラジン−1 −イル)−ベンズアミドを除く)が提供される。
Yは、H又はAを示し;
Aは、1〜6個のC原子を有する枝なし又は分枝アルキルを示し、ここで1〜4個のH原子は互いに独立して、Hal及び/又はOHにより置換され得;
Cycは、3〜6個のC原子を示し、ここで1〜4個のH原子はOHにより置換され得;
Arは、A、Hal、OY、CONH2、−(CH2)n−NA2,SO2NH2及びHet2の群から選択される少なくとも1つの置換基により一又は二置換され得る、6〜8個のC原子を有する芳香族単環式炭素環を示し;
Het1は、Hal、A、 Cyc及び−(CH2)n−NA2の群から選択される少なくとも1つの置換基により一又は二置換され得る、1〜6個のC原子及び1〜3個のN、O及び/又はS原子を有する、不飽和又は芳香族単環式複素環を示し;
Het2は、テトラジルを示し;
Het3は、=O、A及びOYの群から選択される少なくとも1つの置換基により一、二又は三置換され得る、3〜6個のC原子及び1〜3個のN、O及び/又はS原子を有する、飽和単環式複素環を示し;
Halは、F、Cl又はBrを示し;そして
nは、0、1、2、又は3を示す]で表されるベンズアミド誘導体、及び/又は生理学的に許容できるその塩が提供される。
R3は、Het1、Het3、Ar、H、A又はCycを示し;
R5は、E−Ar、H、A、COOA又はHet1を示し;
R8、Yは、互いに独立して、H又はAを示し;
Eは、−(CY2)m−、CO、−COO−又はSO2を示し;
Aは、1〜10個のC原子を有する枝なし又は分枝アルキルを示し、ここで1〜7個のH原子は互いに独立して、Hal及び/又はOHにより置換され得;
Cycは、3〜7個のC原子を有するシクロアルキルを示し、ここで1〜4個のH原子は互いに独立して、Halにより置換され得;
Arは、A、Hal、OY、COOY、CONH2、NHCOY、NY2、NO2、CN及びHet2の群から選択される少なくとも1つの置換基により置換され得る、5〜10個のC原子を有する、不飽和又は芳香族単環又はニ環式炭素環を示し;
Het1は、Hal、A、 Cyc、OY、CONH2、NHCOY、NY2、SO2NY2、 NHSO2Y、CN及びArの群から選択される少なくとも1つの置換基により一又は二置換され得る、1〜9個のC原子及び1〜3個のN、O及び/又はS原子を有する、不飽和又は芳香族単環又はニ環式複素環を示し;
Het2は、メチルにより一置換され得る、イミダゾリル、ピラジル、チアジル又はテトラジルを示し;
Het3は、=O、A、Hal、−(CY2)n−Cyc、−(CY2)n−OY、COY、COOY、CONY2、NHCOY、 NY2、CN、SO2Y及び−(CY2)n−Arの群から選択される少なくとも1つの置換基により一、二又は三置換され得る、3〜6個のC原子及び1〜3個のN、O及び/又はS原子を有する、飽和単環式複素環を示し;
Halは、F、Cl、Br又はIを示し;そして
m、nは、互いに独立して、0、1、2又は3を示す]で表されるベンズアミド誘導体、及び/又は生理学的に許容できるその塩(但し、3−(3−クロロ−ベンゾイルアミノ)−N−[2−(2,4−ジクロロ−フェニル)−エチル]−4−(4−エチル−ピペラジン−1−イル)−ベンズアミドは除かれる)が提供される。
Aは、1〜10個のC原子を有する枝なし又は分枝アルキルを示し、ここで1〜4個のH原子は互いに独立して、Hal及び/又はOHにより置換され得;
Cycは、3〜6個のC原子を有するシクロアルキルを示し;
Arは、A、Hal、OA、CONH2、NY2、NO2、及びCNの群から選択される少なくとも1つの置換基により置換され得る、6〜8個のC原子を有する、飽和単環式炭素環を示し;
Het1は、Hal、A、Cyc、OA、CONH2、NHCOA、NHA、SO2NH2及びCNの群から選択される少なくとも1つの置換基により一又は二置換され得る、1〜6個のC原子及び1〜3個のN、O及び/又はS原子を有する不飽和又は芳香族単環式複素環、又はAにより一置換され得る、6〜9個のC原子及び1〜3個のN及び/又はS原子を有する芳香族二環式複素環を示し;
Het3は、=O、A、Cyc、OY、COA、COOA、CONHA、及びSO2Aの群から選択される少なくとも1つの置換基により一、二又は三置換され得る、3〜6個のC原子及び1〜3個のN、O及び/又はS原子を有する、飽和単環式複素環を示し;
Halは、F、Cl又はBrを示し;そして
nは、0、1、2又は3である]で表されるベンズアミド誘導体、及び/又は生理学的に許容できるその塩が提供される。
(a)下記式(II);
(b)式(I)の化合物の塩基又は酸を、その塩に転換する段階から成る、式(I)の化合物の製造方法にも関する。
本発明は、本明細書に記載される、特定の化合物、医薬組成物、使用及び方法に、そのような物質はもちろん変化するので、制限されないことは理解されるべきである。本明細書に使用される用語は、特定の実施形態を単に記載するためであり、本発明の範囲を制限するものではなく、付随する請求項により単に定義されることもまた、理解されるべきである。付随する請求項を含む、本明細書に使用される場合、単数形の用語、例えば「a」、「an」、及び「the」は、特にことわらない限り、それらの対応する複数の支持対象も包含する。従って、例えば「化合物」(a compound)への言及は、単一又は複数の異なった化合物を包含し、そして「方法」(a method)への言及は、当業者に知られている等価な段階及び方法、及び等の言及も包含する。特にことわらない限り、本明細書に使用されるすべての技術及び科学用語は、本発明が属する当業者により通常理解されるものと同じ意味を有する。
NMRスペクトルは、自動トリプルブロードバンド(ATB)プローブを備えたVarian Unllylnova 400 MHz NMR分光計により得られた。ATBプローブは同時に、1H、19F及び13Cに同調された。典型的な1H NMRスペクトルに関しては、パルス角度は45°であり、合計8スキャンし、そしてスペクトル幅は16ppm(−2ppm〜14ppm)であった。合計32768の複合体点(complex points)が5.1秒の取得時間の間収集され、そして再循環遅延は1秒に設定された。スペクトルを25℃で収集した。1H NMRスペクトルは典型的には、フーリエ変換の前、0.2Hzの線拡大及び131072点までのゼロ−充填(zero−filling to 131072 points)により処理される。
DMF(20ml)中、4−フルオロ−3−ニトロ−安息香酸(6.0g、32.4mモル)の溶液に、K2CO3(8.94g、65.8mモル)を添加し、続いて1−o−トリル−ピペラジン(6.85g、38.9mモル)を添加し、そしてその反応混合物を室温で16時間、撹拌した。DMF(5.0ml)を添加し、そして濾過した。固形物をメタノール(300ml)により洗浄し、そしてメタノール層を蒸発し、酸性3−ニトロ−4−(4−o−トリル−ピペラジン−1−イル)−安息香酸を、第1収穫物(4.0g、36%)として得た。
エタノール(100ml)及びメタノール(100ml)の混合液に、化合物酸性3−ニトロ−4−(4−o−トリル−ピペラジン−1−イル)−安息香酸(2.0g、5.86mモル)を溶解し、そして5分間、排気した。これを、Pd/C(5wt%の0.2g)を含む三ツ首フラスコに、窒素下で添加した。反応混合物を排気し、そして2度、窒素パージし、そして水素バルーン下で4時間、撹拌した。LC−MSは、反応の完結を示し、そして内容物を排気し、そして窒素パージし、そしてセライトを通して濾過し、そして濃縮し、アニリン3−アミノ−4−(4−o−トリル−ピペラジン−1−イル)−安息香酸(1.7g、95%)を得た。
CH2Cl2(50ml)に、アニリン3−アミノ−4−(4−o−トリル−ピペラジン−1−イル)−安息香酸(1.5g、4.8mモル)及びTEA(3.3ml、24mモル)を取り、そして0℃に冷却した。CH2Cl2(5ml)中、塩化フロイル(1.38g、10.6mモル)を滴下し、そしてその反応を0−25℃で6時間、撹拌した。反応混合物を濃縮し、そしてメタノール(20ml)及びTHF(20ml)の混合液に溶解し、そして2NのNaOH(20ml)の溶液と共に2時間、撹拌した。溶媒を除き、そして内容物を水に溶解し、そしてその溶液を、2NのHClを用いて、pH5.0にした。固形生成物3−[(フラン−2−カルボニル)−アミノ]−4−(4−o−トリル−ピペラジン−1−イル)−安息香酸を濾過し、そして乾燥した(1.1g、56%)。
CH2Cl2(3.0ml)中、3−[(フラン−2−カルボニル)−アミノ]−4−(4−o−トリル−ピペラジン−1−イル)−安息香酸(0.1g、0.247mモル)及びHOBt(0.05g、0.37mモル)の溶液に、a−メチルベンジルアミン(0.035g、0.296mモル)、続いてEDC・HCl(0.05g、0.321mモル)を添加し、そして反応混合物を室温で3時間、撹拌した。粗生成物をCH2Cl2(10.0ml)により希釈し、そして水により洗浄し、濃縮し、そして溶離剤としてCH2Cl2/メタノール(10%)を用いて、シリカゲルカラム上で精製し、オフホワイト色の固形物を得、これを、ジオキサン中、2MのHCl(5ml)、続いてエーテルにより処理した。沈殿した生成物を濾過し、そして乾燥した(0.02g、16%の収率)。
実施例2:(R)−3−[3−[(フラン−2−カルボニル)−アミノ]−4−(4−o−トリル− ピペラジン−1−イル)−ベンゾイルアミノ]−ピペリジン−1−カルボン酸 エチルアミド(化合物番号48)への合成路
(R)−3−[3−[(フラン−2−カルボニル)−アミノ]−4−(4−o−トリル−ピペラジン−1−イル)−ベンゾイルアミノ]−ピペリジン−1− カルボン酸 tert−ブチルエステル(0.12g、0.204mモル)を、DCM(1.0ml)及びTFA(1.0ml)の混合物と共に4時間、撹拌した。LC−MSが、保護解除の完結を示した。混合物を濃縮し、そしてピリジン(5.0ml)に溶解した。EtNCO(29mg、0.41mモル)を添加し、そして反応混合物を45℃で6時間、撹拌した。ピリジンを回転蒸発し、そして粗生成物をメタノールに溶解し、そして溶離剤として水/メタノールを用いて、分取HPLC上で精製し、所望する生成物(0.02g、18%)を得た。
3−ニトロ−4−(4−o−ピペラジン−1−イル)−安息香酸(1.0g、2.9mモル)を、硫酸(1.0ml)と共にメタノール(100ml)に取り、そして16時間、還流した。濃縮し、そして酢酸エチル(300ml)に溶解し、そして有機層を飽和炭酸水素ナトリウム溶液により洗浄し、乾燥し、そして濃縮し、0.37gの3−ニトロ−4−(4−o−トリル−ピペラジン−1−イル)−安息香酸メチルエステルを得た。
同じ方法を、3−アミノ−4−(4−o−トリル−ピペラジン−1−イル)−安息香酸の調製に適用した。
CH2Cl2(50ml)中、3−アミノ−4−(4−o−トリル−ピペラジン−1−イル)−安息香酸メチルエステル(2.0g、6.15mモル)に、トリエチルアミン(1.7ml、12.3mモル)を添加し、そして0℃に冷却した。CH2Cl2(5.0ml)中、5−メチルフロイルクロライド(1.06g、7.38mモル)を滴下し、そして反応を0−25℃で6時間、撹拌した。反応を、CH2Cl2(100ml)により希釈し、そして飽和炭酸水素ナトリウム溶液により洗浄し、乾燥し、そして濃縮し、粗生成物を得、これを、メタノール(60ml)及びTHF(60ml)の混合液に溶解し、そして水(20ml)中、LiOH・H2O(2.17g、53mモル)の溶液と共に6時間、撹拌した。溶媒を除き、そして内容物を水に溶解し、そして2NのHClを用いて、pH5.0に酸性化した。3−[(5−メチル−フラン−2−カルボニル)−アミノ]−4−(4−o−トリル−ピペラジン−1−イル)−安息香酸を濾過し、そして乾燥した(1.37g、64%)。
これは、酸性中間体3−[(5−メチル−フラン−2−カルボニル)−アミノ]−4−(4−o−トリル−ピペラジン−1−イル)−安息香酸及び4−アミノ−ピペリジン−1−カルボン酸tert−ブチルエステルから、化合物番号11の調製に記載されるEDCアミド化方法に従って調製された。
CH2Cl2(150ml)中、4−フルオロ−3−ニトロ−安息香酸(5.0g、27.02mモル)の溶液に、HOBt(6.5g、48.63mモル)及びEDC・HCl(6.2g、40.53mモル)、続いてDIPEA(6.12ml、35.12mモル)を添加した。反応を室温で6時間、撹拌した。水(50.0ml)を添加し、そして層を分離した。有機層をブラインにより洗浄し、そして濃縮し、粗生成物4−フルオロ−3−ニトロ−N−[3−(2−オキソ−ピロリジン−1−イル)−プロピル]−ベンズアミド(7.5g、90%)を得た。これを、さらに精製しないで、次の段階に用いた。
DMF(10ml)中、4−フルオロ−3−ニトロ−N−[3−(2−オキソ−ピロリジン−1−イル)−プロピル]−ベンズアミド(2.0g、6.47mモル)の溶液に、K2CO3(1.7g、12.94mモル)を、続いて、1−o−トリル−ピペラジン(1.7g、9.7mモル)を添加し、そして反応混合物を室温で16時間、撹拌した。DMF(2.0ml)を添加し、そして濾過した。固形物をメタノール(300ml)により洗浄し、そしてメタノール層を蒸発し、酸性3−ニトロ−N−[3−(2−オキソ−ピロリジン−1−イル)−プロピル]−4−(4−o−トリル− ピペラジン−1−イル)−ベンズアミドを、第1収穫物(1.8g、62%)として得た
3−ニトロ−N−[3−(2−オキソ−ピロリジン−1−イル)−プロピル]−4−(4−o−トリル− ピペラジン−1−イル)−ベンズアミド(1.5g、3.2mモル)を、エタノール/メタノール(50.0ml/20.0ml)の混合液に取った。これを、Pd/C(5重量%)(0.15g)を含むフラスコに添加した。この溶液を排気し、そして窒素パージし、そして窒素バルーン下で8時間、撹拌した。LC−MSは反応の完結を示した。反応を停止し、排気し、そして窒素パージし、そしてセライト上で濾過した。溶媒を回転蒸発し、3−アミノ−N−[3−(2−オキソ−ピロリジン−1 −イル)−プロピル]−4−(4−o−トリル−ピペラジン−1 −イル)−ベンズアミド(0.7g、47%)を得た。
20mlのシンチレーションバイアルにおいて、窒素下で、3−アミノ−N−[3−(2−オキソ−ピロリジン−1 −イル)−プロピル]−4−(4−o−トリル−ピペラジン−1 −イル)−ベンズアミド(0.06g、0.137mモル)を、CH2Cl2(2.0ml)に溶解し、次にDIPEA(0.12ml、0.685mモル)及びDMAP(0.0016g、0.0137mモル)を添加し、そしてその混合物を0℃に冷却した。次に、CH2Cl2(1.0ml)中、2−チオフェンクロライド(0.206mモル、0.03g)を滴下した。40分後、反応は完結した。10.0mlのCH2Cl2を添加し、そして次に、それを40mlの水、続いて3.0mlの飽和炭酸水素ナトリウム溶液及び3.0mlのブラインにより洗浄した。有機物を無水硫酸ナトリウム上で乾燥し、濾過し、そして濃縮した。粗生成物をメタノール溶解し、そしてメタノール/水(0.1%TFA)を用いて、分取HPLC上で精製し、所望する生成物(0.06g、81%)を得た。
反応は、化合物番号11と同様の方法で行った。
段階5及び6(段階5及び6)
アセトニトリル(3.0ml)及びDMF(0.5ml)中、フラン−2−カルボン酸 {5−[3−(2−オキソ−ピロリジン−1−イル)−プロピルカルバモイル]−2− ピペラジン−1−イル−フェニル}−アミド(0.1g、0.23mモル)の溶液に、K2CO3(0.094g、0.68mモル)及び1−ブロモメチル−2−メチル−ベンゼン(0.05g、0.3mモル)を添加し、そして反応を室温で4時間、撹拌した。水を添加し、そしてDCMにより抽出し、濃縮し、そして粗生成物を、DCM/メタノール(10%)を用いてシリカゲル上で精製し、生成物(0.027g、22%の収率)を得た。
DMF(20ml)中、NaH(0.505g、12.6mモル)の氷冷却された溶液に、DMF(10.0ml)中、5−メチル−ピロリジン−2−オン(1.0g、10.1mモル)をゆっくり添加した。これを、0−25℃で30分間、撹拌した。2−(3−ブロモ−プロピル)−イソインドール−1,3−ジオン(2.47g、9.0mモル)を添加し、そして反応を室温で16時間、撹拌した。飽和NH4Clの溶液(10.0ml)を添加し、そして酢酸エチルにより抽出した。有機層を、LiCl溶液により洗浄し、そして濃縮した。粗生成物を、溶離剤としてCH2Cl2/メタノール(10%)を用いて、シリカゲル上で精製し、2−[3−(3−メチル−2−オキソ−ピロリジン−1−イル)−プロピル]−イソインドール−1,3−ジオン(1.2g、41%)を得た。
2−[3−(3−メチル−2−オキソ−ピロリジン−1−イル)−プロピル]−イソインドール−1,3−ジオン(0.5g、1.74mモル)を、THF/メタノール(3.0ml/3.0ml)の混合物に取った。ヒドラジン水和物(0.44g、8.7mモル)をこれに添加し、そして反応を50℃で16時間、撹拌した。沈殿物を濾過し、そして濾液を濃縮し、生成物1−(3−アミノ−プロピル)−5−メチル−ピロリジン−5−オン(0.12g、45%)を得た。
1−(3−アミノ−プロピル)−5−メチル−ピロリジン−2−オンを、HATUカップリング方法に従って、3−[(2−シクロプロピル−オキサゾール−4−カルボニル)−アミノ]−4−(4−o−トリル−ピペラジン−1−イル)−安息香酸によりカップリングした。
方法:A−水中、0.1%TFA、B−ACN中、0.1%TFA:流速−2ml/分。
色及び外観:白色固形物。
LCMS:実測質量(M+625.0)。
Rt(分):4.26面積%:−95.75(最大)、95.35(254nm)。
色及び外観:白色固形物。
LCMS:実測質量(M+520.3)。
Rt(分):4.26面積%:−97.85(最大)、98.03(254nm)。
色及び外観:白色固形物。
LCMS:実測質量(M+540.3)。
Rt(分):4.35面積%:−95.75(最大)、98.12(254nm)。
色及び外観:白色固形物。
LCMS:実測質量(M+574.3)。
Rt(分):4.72面積%:−96.54(最大)、97.81(254nm)。
色及び外観:白色固形物。
LCMS:実測質量(M+574.3)。
Rt(分):4.75面積%:−98.33(最大)、98.98(254nm)。
色及び外観:褐色固形物。
LCMS:実測質量(M+558.3)。
Rt(分):4.46面積%:−95.23(最大)、97.78(254nm)。
色及び外観:白色固形物。
LCMS:実測質量(M+558.3)。
Rt(分):4.45面積%:−94.80(最大)、96.67(254nm)。
色及び外観:褐色固形物。
LCMS:実測質量(M+565.3)。
Rt(分):4.16面積%:−97.43(最大)、98.93(254nm)。
色及び外観:白色固形物。
LCMS:実測質量(M+554.3)。
Rt(分):4.66面積%:−95.87最大)、97.22(254nm)。
色及び外観:褐色固形物。
LCMS:実測質量(M+554.3)。
Rt(分):4.67面積%:−97.74最大)、98.64(254nm)。
色及び外観:褐色固形物。
LCMS:実測質量(M+541.3)。
Rt(分):4.23面積%:−96.20最大)、96.53(254nm)。
色及び外観:白色固形物。
LCMS:実測質量(M+541.3)。
Rt(分):3.12面積%:−96.61最大)、96.94(254nm)。
色及び外観:白色固形物。
LCMS:実測質量(M+541.3)。
Rt(分):3.02面積%:−97.96最大)、98.48(254nm)。
色及び外観:白色固形物。
LCMS:実測質量(M+608.3)。
Rt(分):4.98面積%:−98.14最大)、99.10(254nm)。
色及び外観:白色固形物。
LCMS:実測質量(M+608.3)。
Rt(分):5.00面積%:−99.07最大)、98.92(254nm)。
色及び外観:白色固形物。
LCMS:実測質量(M+570.3)。
Rt(分):4.54面積%:−97.66最大)、98.26(254nm)。
色及び外観:白色固形物。
LCMS:実測質量(M+570.3)。
Rt(分):4.36面積%:−94.07最大)、94.05(254nm)。
色及び外観:白色固形物。
LCMS:実測質量(M+590.3)。
Rt(分):4.86面積%:−98.40最大)、97.81(254nm)。
色及び外観:褐色固形物。
LCMS:実測質量(M+591.3)。
Rt(分):4.33面積%:−95.24最大)、97.34(254nm)。
色及び外観:褐色固形物。
LCMS:実測質量(M+561.3)。
Rt(分):3.80面積%:−92.03最大)、95.82(254nm)。
色及び外観:白色固形物。
LCMS:実測質量(M+629.3)。
Rt(分):4.30面積%:−95.39最大)、98.27(254nm)。
色及び外観:白色固形物。
LCMS:実測質量(M+639.0)。
Rt(分):4.54面積%:−94.07最大)、94.89(254nm)。
色及び外観:褐色固形物。
LCMS:実測質量(M+547.2)。
Rt(分):3.98面積%:−96.25最大)、96.95(254nm)。
色及び外観:褐色固形物。
LCMS:実測質量(M+561.3)。
Rt(分):4.32面積%:−96.08最大)、98.00(254nm)。
色及び外観:褐色固形物。
LCMS:実測質量(M+545.3)。
Rt(分):4.02面積%:−96.73最大)、97.79(254nm)。
色及び外観:白色固形物。
LCMS:実測質量(M+613.3)。
Rt(分):4.81面積%:−98.99最大)、99.59(254nm)。
色及び外観:オフホワイト色固形物。
LCMS:実測質量(M+559.3)。
Rt(分):4.38面積%:−93.67最大)、97.04(254nm)。
色及び外観:白色固形物。
LCMS:実測質量(M+545.3)。
Rt(分):4.04面積%:−91.51最大)、97.19(254nm)。
色及び外観:白色固形物。
LCMS:実測質量(M+559.3)。
Rt(分):4.42面積%:−93.72最大)、96.42(254nm)。
色及び外観:白色固形物。
LCMS:実測質量(M+545.3)。
Rt(分):3.78面積%:−96.87最大)、98.58(254nm)。
色及び外観:白色固形物。
LCMS:実測質量(M+573.3)。
Rt(分):4.41面積%:−95.41最大)、97.34(254nm)。
色及び外観:褐色固形物。
LCMS:実測質量(M+546.3)。
Rt(分):4.56面積%:−95.44最大)、95.51(254nm)。
色及び外観:白色固形物。
LCMS:実測質量(M+534.3)。
Rt(分):3.98面積%:−98.49最大)、98.11(254nm)。
色及び外観:褐色固形物。
LCMS:実測質量(M+561.3)。
Rt(分):2.85面積%:−95.09最大)、97.27(254nm)。
色及び外観:白色固形物。
LCMS:実測質量(M+504.3)。
Rt(分):3.56面積%:−95.97最大)、97.03(254nm)。
色及び外観:褐色固形物。
LCMS:実測質量(M+574.3)。
Rt(分):4.28面積%:−93.60最大)、96.10(254nm)。
色及び外観:褐色固形物。
LCMS:実測質量(M+558.3)。
Rt(分):4.39面積%:−96.46最大)、96.94(254nm)。
色及び外観:褐色固形物。
LCMS:実測質量(M+583.3)。
Rt(分):3.73面積%:−92.47最大)、94.61(254nm)。
色及び外観:褐色固形物。
LCMS:実測質量(M+608.3)。
Rt(分):4.49面積%:−95.91最大)、97.61(254nm)。
色及び外観:褐色固形物。
LCMS:実測質量(M+590.3)。
Rt(分):4.70面積%:−90.60最大)、91.80(254nm)。
Rt(分):5.42面積%:−90.74最大)、92.59(254nm)。
色及び外観:黄色固形物。
LCMS:実測質量(M+513.3)。
Rt(分):4.49面積%:−99.33最大)、99.86(254nm)。
色及び外観:褐色固形物。
LCMS:実測質量(M+544.3)。
Rt(分):4.72面積%:−90.79最大)、90.20(254nm)。
アッセイは、参照により本発明の開示に組込まれる、Yanofsky et al. (2006) Allosteric activation of the follicle-stimulating hormone (FSH) receptor by selective, nonpeptide agonists. JBC 281 (19): 13226-13233の教示に従って行われた。結果は、表1及び2に与えられている。
(A)注射バイアル:3Lの2回蒸留された水中、100gの本発明の活性成分及び5gのリン酸水素二ナトリウムの溶液を、2Nの塩酸を用いてpH6.5に調節し、濾過減菌し、注射用バイアルに移し、無菌条件下で凍結乾燥し、そして無菌条件下で密封した。各注射バイアルは、5mgの活性成分を含んだ。
Claims (8)
- 下記部分式(I−A):
R3は、Het1、Het3、Ar、A又はCycを示し;
R5は、E−Ar又はHet1を示し;
R8、Yは、互いに独立して、H又はAを示し;
Xは、CO又は−(CY2)m −を示し;
Eは、−(CY2)m−、CO、−COO−又はSO2を示し;
Aは、1〜10個のC原子を有する枝なし又は分枝アルキルを示し、ここで1〜7個のH原子は互いに独立して、Hal及び/又はOHにより置換され得;
Cycは、3〜7個のC原子を有するシクロアルキルを示し、ここで1〜4個のH原子は互いに独立して、Hal及び/又はOHにより置換され得;
Arは、A、Hal、OY、COOY、CONH2、NHCOY、−(CH2)n−NY2、SO2NH2、NO2、CN及びHet2の群から選択される少なくとも1つの置換基により置換され得る、5〜10個のC原子を有する、不飽和又は芳香族単環又はニ環式炭素環を示し;
Het1は、Hal、A、 Cyc、OY、CONH2、NHCOY、−(CH2)n−NY2、SO2NY2、 NHSO2Y、CN及びArの群から選択される少なくとも1つの置換基により一又は二置換され得る、1〜9個のC原子及び1〜3個のN、O及び/又はS原子を有する、不飽和又は芳香族単環又はニ環式複素環を示し;
Het2は、メチルにより一置換され得る、イミダゾリル、ピラジル、チアジル又はテトラジルを示し;
Het3は、=O、A、Hal、−(CY2)n−Cyc、−(CY2)n−OY、COY、COOY、CONY2、NHCOY、NY2、CN、SO2Y及び−(CY2)n−Arの群から選択される少なくとも1つの置換基により一、二又は三置換され得る、3〜6個のC原子及び1〜3個のN、O及び/又はS原子を有する、飽和単環式複素環を示し;
Halは、F、Cl、Br又はIを示し;そして
m、nは、互いに独立して、0、1、2又は3を示す]を有する化合物、及び/又は生理学的に許容できるその塩(但し、3−(3−クロロ−ベンゾイルアミノ)−N−[2−(2,4−ジクロロ−フェニル)−エチル]−4−(4−エチル −ピペラジン−1 −イル)−ベンズアミドを除く)。 - 下記式(I):
R1は、−(CY2)n−E−(CY2)n−Het3、−(CY2)n−Cyc−Het3、 −(CY2) n−NY−Het3、 −(CY2) n−CONH−Het3、 −(CY2) n−NHCO−Het3、 −(CY2) n−C(Y)(OH)−(CY2) n−Het3、 −(CY2) n−Het1、 −(CY2) n−CONH−Het1、 −(CY2) n−NHCO−Het1 、−(CY2) n−Ar、 −Cyc−Ar、 −(CY2) n−NY−Ar、 −(CY2) n−CONH−Ar、 −(CY2) n−NHCO−Ar、 −(CY2) n−C(Y)(OH)−(CY2) n−Ar、 −(CY2) n−Cyc、 −(CY2) n−NY−Cyc、 −(CY2) n−CONH−Cyc、 −(CY2) n−NHCO−Cyc、 −(CY2) n−NHCO−NH−Cyc、 Y、 −(CYR8)−OY、 −(CY2) n−COOY、 −(CY2)n−SO2Y、 −(CYR8) n−CO−(CY2) n−N(R8)2、 −(CY2)n−[C(Y)(OH)]m−(CYR8) n−NY2、[−(CY2)n−O]m−(CYR8) n−NYCOY、 −(CY2) n−NYCOOY、 −(CY2)n−NYSO2Y、 −(CY2) n−NYCON(R8)2、 −(CY2)n−NHCO−CH=CH2、 −(CY2)n−NHCO−NH−(CY2) n=CH2 又は −(CY2) n−CNを示し;
R2は、Yを示し;
R1,R2は、また一緒に、−(CY2)P−NH−(CY2)P−、 −(CY2)p−NHCO−(CY2)p−、−(CY2)p−CONH−(CY2)p−、 −(CY2)p−N(COA)−(CY2)p−、 −(CY2)p−N(COOA)−(CY2)p−、 −(CY2)p−C(Y)(Het3)−(CY2)p−、
R3は、−(CY2)n−Het1、−(CY2)n−Het3、−(CY2)n−Ar、−C(Y)(OY)−Ar、Y 又は −(CY2)n−Cycを示し;
R4は、Y、COY又はSO2Yを示し;
R5は、E−Ar、 NY−Ar、 Cyc、 Y、 OY、 NYY、 NYCOOY、 NYCOY、 COY、 COOY、 SO2Y、 Het1又はHet3を示し;
R6、R7は、互いに独立して、Hを示し;
R6、R7は、また一緒に、−(CY2)p−を示し;
R8は、Y又はArを示し;
X、Eは、互いに独立して、−(CY2)m−、 O、 CO、 −COO− 又はSO2を示し;
Yは、H又はAを示し;
Aは、1〜10個のC原子を有する、枝なし又は分枝アルキルを示し、ここで1〜7個のH原子は互いに独立して、Hal、=O及び/又はOHにより置換され得;
Cycは、3〜7個のC原子を有するシクロアルキルを示し、ここで1〜4個のH原子は互いに独立して、Hal及び/又はOHにより置換され得;
Arは、A、Hal、−(CY2)n−OY、COOY、CONH2、NHCOY、−(CY2)n−NYCOOY、−(CY2)n−NY2、NO2、SO2Y、SO2NY2、NYSO2Y、−(CY2)n−CN、−(CY2)n−Het2及びCycの群から選択される少なくとも1つの置換基により置換され得るか、又はCycに対して融合され得る、3〜10個のC原子を有する、不飽和又は芳香族単環又はニ環式炭素環を示し;
Het1は、Hal、 A、 Cyc、 OY、 =O、 COOY、 CONH2、 NHCOY、−(CY2)n −NY2、 SO2Y、 SO2NY2、 NHSO2Y、 CN、 Ar 及び−(CY2)n −Het3の群から選択される少なくとも1つの置換基により置換され得る、1〜10個のC原子及び1〜4個のN、O及び/又はS原子を有する、不飽和又は芳香族単環又はニ環式複素環を示し;
Het2は、A及び/又は=Oにより置換され得る、1〜4個のC原子及び1〜4個のN、O及び/又はSを有する、飽和又は不飽和単環式5−又は6−員の複素環を示し:
Het3は、=O、 A、 Hal、 −(CY2)n−Cyc、 −(CY2)n−OY、 COY、 COOY、 CONY2、 NHCOY、 −(CY2)n−NY2、 CN、 SO2Y及び−(CY2)n−Arの群から選択された少なくとも1つの置換基により置換され得る、3〜7個のC原子及び1〜4個のN、O及び/又はS原子を有する、飽和単環又はニ環式複素環を示し;
Halは、F、Cl、Br又はIを示し;
m、nは、互いに独立して、0、1、2、3、4、5又は6を示し;そして
pは、1、2又は3を示す]の化合物の製造方法であって、前記方法が、
下記段階:
(a)下記式(II):
下記式(I):
(b)前記式(I)の化合物の塩基又は酸を、その塩に転換する段階、
を含んでなる方法。 - 少なくとも1つの請求項1に記載の化合物及び/又は生理学的に許容できるその塩を含んで成る薬剤。
- 活性成分として、少なくとも1つの請求項1に記載の化合物及び/又は生理学的に許容できるその塩、及び経口投与のための医薬的耐容性のアジュバント、並びに任意には、少なくとも別の活性医薬剤を含んでなる医薬組成物。
- 不妊障害の予防又は治療処置及び/又はモニターリングにおける使用のための請求項4に記載の薬剤。
- 不妊障害の治療方法であって、少なくとも1つの請求項1に記載の化合物及び/又は生理学的に許容できるその塩を、そのような治療の必要なヒト以外の哺乳類に投与する方法。
- 下記段階:
(a)請求項6に記載の方法に従ってヒト以外の哺乳類を処理する段階、
(b)前記哺乳類から卵子を採取する段階、
(c)前記卵子を受精する段階、及び
(d)前記受精された卵子を、ヒト以外の宿主哺乳類中に移植する段階、
を含んで成るインビトロ受精方法。 - FSH受容体の調節方法であって、FSH受容体を発現する系と、少なくとも1つの請求項1に記載の化合物及び/又は生理学的に許容できるその塩とを、FSHの存在下で、前記FSH受容体が調節されるような条件下で接触せしめるインビトロ方法。
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