JP5707131B2 - 抗炎症性化合物とその用途 - Google Patents
抗炎症性化合物とその用途 Download PDFInfo
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- JP5707131B2 JP5707131B2 JP2010520344A JP2010520344A JP5707131B2 JP 5707131 B2 JP5707131 B2 JP 5707131B2 JP 2010520344 A JP2010520344 A JP 2010520344A JP 2010520344 A JP2010520344 A JP 2010520344A JP 5707131 B2 JP5707131 B2 JP 5707131B2
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- 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
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 208000005809 status epilepticus Diseases 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 210000000434 stratum corneum Anatomy 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 230000035882 stress Effects 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- MVGSNCBCUWPVDA-MFOYZWKCSA-N sulindac sulfone Chemical compound CC1=C(CC(O)=O)C2=CC(F)=CC=C2\C1=C/C1=CC=C(S(C)(=O)=O)C=C1 MVGSNCBCUWPVDA-MFOYZWKCSA-N 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 238000002636 symptomatic treatment Methods 0.000 description 1
- 210000000225 synapse Anatomy 0.000 description 1
- 230000003956 synaptic plasticity Effects 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000010189 synthetic 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
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 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
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 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
- 238000011285 therapeutic regimen Methods 0.000 description 1
- 125000005307 thiatriazolyl group Chemical group S1N=NN=C1* 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000004001 thioalkyl group Chemical group 0.000 description 1
- 125000005032 thiofuranyl group Chemical group S1C(=CC=C1)* 0.000 description 1
- 230000036962 time dependent Effects 0.000 description 1
- 239000011732 tocopherol Substances 0.000 description 1
- 235000010384 tocopherol Nutrition 0.000 description 1
- 229930003799 tocopherol Natural products 0.000 description 1
- 229960001295 tocopherol Drugs 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000041 toxicology testing Toxicity 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 230000002103 transcriptional effect Effects 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000006168 tricyclic group Chemical group 0.000 description 1
- 150000005691 triesters Chemical class 0.000 description 1
- 230000005748 tumor development Effects 0.000 description 1
- 230000005740 tumor formation Effects 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 239000000717 tumor promoter Substances 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 1
- 150000004670 unsaturated fatty acids Chemical class 0.000 description 1
- 235000021122 unsaturated fatty acids Nutrition 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
- 238000010200 validation analysis Methods 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 208000016261 weight loss Diseases 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
- 229960001296 zinc oxide Drugs 0.000 description 1
- 235000014692 zinc oxide Nutrition 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
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- A61K31/6615—Compounds having two or more esterified phosphorus acid groups, e.g. inositol triphosphate, phytic acid
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Description
Bは任意に置換された脂肪族、脂環族、ヘテロ脂肪族、ヘテロサイクリック、芳香族、またはヘテロ芳香族の基であり、
Bは、水素、ハロゲン、ヒドロキシル、アルコキシルもしくは-CN;任意に置換された脂肪族、脂環族、ヘテロ脂肪族、ヘテロサイクリック、芳香族、ヘテロ芳香族の部分;-ORR、-S(=O)nRd、-NRbRc、-C(=O)Raおよび-C(=O)ORaからなる群より独立して選択される1以上のX2で任意に置換され;nは0〜2であり、RRは任意に置換された脂肪族、脂環族、ヘテロ脂肪族、ヘテロサイクリック、アリールまたはアラルキル、ヘテロ芳香族の基またはアシル部分であり;
Raは、それぞれ存在する場合、水素および任意に置換された脂肪族、脂環族、ヘテロ脂肪族、ヘテロサイクリック、芳香族、またはヘテロ芳香族部分からなる群より、独立して選択され;
RbおよびRcは、それぞれ存在する場合、水素;ヒドロキシ;SO2Rd;および脂肪族、脂環族、ヘテロ脂肪族、ヘテロサイクリック、芳香族、ヘテロ芳香族またはアシル部分からなる群より、独立して選択され;
Rdは、それぞれ存在する場合、水素;-N(Re)2;脂肪族、アリールおよびヘテロアリールからなる群より、独立して選択され;および
Reは、それぞれ存在する場合、独立して水素または脂肪族基であり;
Aは、任意に置換された脂肪族、脂環族、ヘテロ脂肪族、ヘテロサイクリック、芳香族、またはヘテロ芳香族の基、例えば、限定されるものでないが、本明細書で以下にさらに詳しく記載した部分であり;
Dはヒドロキシル;ハライド;トシレート;リン酸エステル(-O-P(ORf)3)または亜リン酸エステル(-O-P(ORg)2)、-OSO2NRxRyであり;RxおよびRyは独立して水素、または置換されたもしくは無置換の脂肪族、脂環族、ヘテロ脂肪族、ヘテロサイクリック、アリールまたはアラルキル、ヘテロ芳香族またはアシル部分;-O-C6H4OC(=O)CH3;アルコキシ部分;またはアシル部分であり、但し、少なくとも1つのRfはHでなくかつ少なくとも1つのRgはHでないことを条件とし、かつもしBが
または
で表される化合物、またはそのエナンチオマー、ラセミ体、ジアステレオマー、または互変異性体、またはそのプロドラッグ、塩、水和物またはエステルを提供する。
例えば、本願発明は以下の項目を提供する。
(項目1)
式I:
[式中、Aは、任意に置換された脂肪族、脂環族、アリール、アラルキル、ヘテロ脂肪族、ヘテロサイクリック、またはヘテロ芳香族の基であり;
X 1 は-O-、-NH-および-S-からなる群より選択され;
Bは任意に置換された脂肪族、脂環族、ヘテロ脂肪族、ヘテロサイクリック、アリール、アラルキル、またはヘテロ芳香族の基であり、
Bは、独立して水素、ハロゲン、ヒドロキシル、アルコキシルまたは-CN;任意に置換された脂肪族、脂環族、ヘテロ脂肪族、ヘテロサイクリック、アリール、アラルキル、ヘテロ芳香族の部分;-OR R 、-S(=O) n R d 、-NR b R c 、-C(=O)R a および-C(=O)OR a からなる群より選択される1以上のX 2 で任意に置換され;
nは0〜2であり、
R a は、それぞれ存在する場合、独立して、水素および任意に置換された脂肪族、脂環族、ヘテロ脂肪族、ヘテロサイクリック、アリール、アラルキル、またはヘテロ芳香族部分からなる群より選択され;
R b およびR c は、それぞれ存在する場合、独立して、水素;ヒドロキシ;SO 2 R d ;および脂肪族、脂環族、ヘテロ脂肪族、ヘテロサイクリック、アリール、アラルキル、ヘテロ芳香族またはアシル部分からなる群より選択され;
R d は、それぞれ存在する場合、独立して、水素;-N(R e ) 2 ;脂肪族、アリールおよびヘテロアリールからなる群より選択され;
R e は、それぞれ存在する場合、独立して水素または脂肪族であり;および
R R は、任意に置換された脂肪族、脂環族、ヘテロ脂肪族、ヘテロサイクリック、アリールまたはアラルキル、ヘテロ芳香族またはアシル部分であり;
そして
Dはヒドロキシル;ハライド;トシレート;リン酸エステル、-OSO 2 NR x R y であり;
R x およびR y は独立して水素、または脂肪族、脂環族、ヘテロ脂肪族、ヘテロサイクリック、アリールまたはアラルキル、ヘテロ芳香族またはアシル部分;-O-C 6 H 4 OC(=O)CH 3 ;アルコキシ部分;またはアシル部分であり、但し、もしBが
または
(式中、R h はアリール、アラルキル、アルキル、アルケニルまたはアルキニルである)であれば、Dはリン酸エステル(-O-P(O)(OR f ) 2 )または亜リン酸エステル(-O-P(OR g ) 2 )(式中、R f およびR g は独立してそれぞれH、順に、置換されているかまたは無置換であってもよいアルキル、アルケニル、アルキニル、アリールまたはアラルキル基である)であることを条件とする]で表される化合物、またはそのエナンチオマー、ジアステレオマー、ラセミ体、互変異性体、またはそのプロドラッグ、塩、水和物またはエステル。
(項目2)
Aは式(II):
[式中、Yは(-C-) n であり、nが0〜4であり、nが2以上である場合、任意に(-C-) n 部分に1以上の不飽和結合を含有する]である、項目1に記載の化合物。
(項目3)
Aが式(III):
[式中、R 2 少なくとも1つのハロゲンであり、およびR 3 およびR 4 は独立して水素または脂肪族基である]である、項目1に記載の化合物。
(項目4)
Aが式(IV):
である、項目1に記載の化合物。
(項目5)
Aが式(V):
または式(VI):
である、項目1に記載の化合物。
(項目6)
Aが式(VII):
[式中、R 5 とR 6 は独立して水素、-OH、アルコキシ、ハライド、トリフルオロアルキル、α-ハロアルキル、トリフルオロアルコキシ、またはR a (ここでR a は独立して水素または任意に置換された脂肪族、脂環族、ヘテロ脂肪族、ヘテロサイクリック、アリールまたはアラルキル、またはヘテロ芳香族部分である)である]である、項目1に記載の化合物。
(項目7)
Aが式(VIII):
[式中、R 5 とR 6 は独立して水素、-OH、アルコキシ、ハライド、トリフルオロアルキル、α-ハロアルキル、トリフルオロアルコキシ、またはR a (ここでR a は水素または任意に置換された脂肪族、脂環族、ヘテロ脂肪族、ヘテロサイクリック、芳香族、またはヘテロ芳香族部分である)である]である、項目1に記載の化合物。
(項目8)
Aが直鎖または分枝鎖の脂肪族部分である、項目1に記載の化合物。
(項目9)
X 2 が式:
[式中、R 5 とR 6 は独立して水素、-OH、アルコキシ、ハライド、トリフルオロアルキル、α-ハロアルキル、トリフルオロアルコキシ、またはR a (ここでR a は、存在する場合、独立して水素または任意に置換された脂肪族、脂環族、ヘテロ脂肪族、ヘテロサイクリック、アリールまたはアラルキル、またはヘテロ芳香族部分である)である]である、項目1に記載の化合物。
(項目10)
Aが非ステロイド抗炎症薬である、項目1に記載の化合物。
(項目11)
Aがアセチルサリチル酸の誘導体、またはアリールアルカン酸の誘導体である、項目10に記載の化合物。
(項目12)
2-アセトキシ-安息香酸4-(ジエトキシ-ホスホリルオキシメチル)-フェニルエステル、2-アセトキシ-安息香酸3-(ジエトキシ-ホスホリルオキシメチル)-フェニルエステル、およびホスホ-スリンダクI、ホスホ-スリンダクII、ホスホフルルビプロフェン、ホスホイブプロフェン、ホスホアスピリンIおよびホスホルアスピリンIIからなる群より選択される、項目11に記載の化合物。
(項目13)
ホスホ-バルプロ酸である、項目1に記載の化合物。
(項目14)
項目1に記載の化合物と製薬上許容される賦形剤を含む医薬組成物。
(項目15)
項目14に記載の医薬組成物を、それを必要とする被験体に投与するステップを含んでなる炎症に関係する疾患を治療する方法。
(項目16)
被験体がヒトである、項目15に記載の方法。
(項目17)
被験体が非ヒト動物である、項目15に記載の方法。
(項目18)
炎症に関係する疾患がリウマチ疾患、心血管疾患、神経変性疾患、脳血管疾患、自己免疫性疾患、器官の慢性炎症、新生物および前新生物疾患からなる群より選択される、請求項15に記載の方法。
(項目19)
疾患が慢性関節リウマチ、シェーグレン症候、冠動脈疾患、末梢血管の疾患、高血圧、アルツハイマー病およびその変種、エリテマトーデス、慢性気管支炎、慢性静脈洞炎、良性前立腺肥大、前立腺癌、結腸腺腫、結腸癌、肺癌、リンパ腫および白血病からなる群より選択される、項目18に記載の方法。
本明細書で使用する用語「脂肪族」は、飽和および不飽和両方の、直鎖(すなわち、非分枝鎖)または分枝鎖の、任意に1以上の官能基により置換された脂肪族炭化水素を含む。当業者は理解しうるように、本明細書において「脂肪族」は、限定されるものでないが、アルキル、アルケニル、およびアルキニル部分を含むことを意図する。従って、本明細書で使用する用語「アルキル」は直鎖および分枝鎖アルキル基を含む。類似の約束事は「アルケニル」、「アルキニル」などの他のジェネリックな用語にも適用される。さらに、本明細書で使用する用語「アルキル」、「アルケニル」、「アルキニル」などは置換された基と無置換の基の両方を包含する。ある特定の実施形態において、本明細書で使用する「低級アルキル」は1〜6個の炭素原子を有するアルキル基(置換された、無置換の、分枝鎖または非分枝鎖の)を示すのに用いられる。
Bは任意に置換された脂肪族、脂環族、ヘテロ脂肪族、ヘテロサイクリック、アリール、アラルキルまたはヘテロ芳香族の基であり、そしてBは1以上の置換基X2により任意に置換され;前記X2は水素、ハロゲン、ヒドロキシル、-NO2、-ONO2、-CN;任意に置換された脂肪族、脂環族、ヘテロ脂肪族、ヘテロサイクリック、芳香族、ヘテロ芳香族の部分;-ORR、-S(=O)nRd、-NRbRc、-C(=O)Raおよび-C(=O)ORaからなる群より独立して選択され;nは0〜2であり、RRは任意に置換された脂肪族、脂環族、ヘテロ脂肪族、ヘテロサイクリック、芳香族、ヘテロ芳香族またはアシル部分であり;
Raが存在する場合、それは独立して水素および任意に置換された脂肪族、脂環族、ヘテロ脂肪族、ヘテロサイクリック、芳香族、またはヘテロ芳香族部分からなる群より選択され;
RbおよびRcがそれぞれ存在する場合、それらは独立して水素;ヒドロキシ;SO2Rd;および脂肪族、脂環族、ヘテロ脂肪族、ヘテロサイクリック、芳香族、ヘテロ芳香族またはアシル部分からなる群より選択され;
Rdが存在する場合、それは独立して水素;-N(Re)2;脂肪族、アリールおよびヘテロアリールからなる群より選択され;そして
Reが存在する場合、それは独立して水素または脂肪族であり;
Aは任意に置換された、脂肪族、脂環族、ヘテロ脂肪族、ヘテロサイクリック、芳香族、または ヘテロ芳香族基、例えば、限定されるものでないが、以下にさらに詳しく記載したそれらの部分であり;
Dはヒドロキシル;ハライド;トシレート;リン酸エステル(-O-P(O)(ORf)2)または亜リン酸エステルエステル(-O-P(ORg)2)、-OSO2NRxRyであり、RxおよびRyは独立して水素、または置換されたまたは無置換の脂肪族、脂環族、ヘテロ脂肪族、ヘテロサイクリック、芳香族、ヘテロ芳香族またはアシル部分;-O-C6H4OC(=O)CH3;アルコキシ部分;またはアシル部分であり、ただし、少なくとも1つのRfはHでなく、かつ少なくとも1つRgのはHでないことを条件とし、かつ
もしBが
または
式(VIIb):
式(VIIc):
および式(VIId):
であってもよい。
式(VIIIb):
および式(VIIIc):
を含む。
で表される。
および式(IXb):
で表される。
式IのD置換基は、ヒドロキシル;ハライド;トシレート;リン酸エステル(-O-P(O)(ORf)2)または亜リン酸エステル(-O-P(ORg)2)、-OSO2NRxRy[式中、RxとRyは独立して水素、または置換されたもしくは無置換の脂肪族、脂環族、ヘテロ脂肪族、ヘテロサイクリック、芳香族、ヘテロ芳香族またはアシル部分;-O-C6H4OC(=O)CH3;アルコキシ部分;またはアシル部分である]であり、但し、少なくとも1つのRfはHでなく、かつ少なくとも1つのRgはHでないことを条件とする。
または
以上考察したように、本発明は、一般に異常な炎症より特徴付けられるいくつもの症状もしくは疾患のいずれかの治療、またはかかる症状もしくは疾患の出現のリスクが存在する場合の予防に有用である生物学的特性を有する新規化合物を提供する。さらに、当技術分野において公知の特定の化合物は異常な炎症の予防または治療に活性を有するかまた有用であることが新しく確認されており、本発明はまた、かかる化合物を含む抗炎症組成物に関する。
以上考察したように、本明細書に記載した本化合物のいくつかは、一般「発明の背景」のもとで記載の通り理解される炎症の抑制剤としての活性を表す。従って、ある特定の実施形態において、本発明の化合物は、炎症、特に慢性炎症が病因であるかまたは発症に関係するかまたは連続して出現する、いくつもの症状または疾患のいずれか、例えば、限定されるものでないが、慢性関節リウマチおよびシェーグレン症候などのリウマチ病;心血管疾患、例えば冠動脈疾患、末梢血管疾患および高血圧;神経変性疾患、例えば、アルツハイマー病およびその変種または脳血管疾患;ならびに自己免疫性疾患、例えばエリテマトーデス;肺などの気管の慢性炎症、慢性気管支炎、静脈洞などの慢性静脈洞炎により特徴付けられる他の症状を治療するのに有用である。
他の実施形態において、本発明は、本発明による方法を好都合かつ効果的に実施するキットに関する。一般に、本医薬品パックまたはキットは、本発明の医薬組成物の1以上の成分で満たした1以上の容器を含む。かかるキットは、とりわけ、錠剤またはカプセルなどの固体経口剤形を配達するのに好適である。かかるキットは好ましくは、いくつもの単位用量を含み、かつまた、その意図する使用の順に並べた用量を有するカードを含んでもよい。所望であれば、例えば、数字、文字、または他のマーキングの形式で、または用量を投与しうる治療スケジュールの日を記載したカレンダーを挿入して記憶の助けとしてもよい。あるいは、プラセボ用量、またはカルシウム食事サプルメントを医薬組成物の投与量に類似したまたは別な形態で含ませて、ある用量を毎日摂取するキットを提供してもよい。任意に、かかる容器には医薬製品の製造、使用または販売を規制する政府機関の定めた形式で、ヒト投与用の製造、使用または販売の前記機関による認定を反映する注意書きが付されていてもよい。
次の反応スキームを経て、下記の本発明の化合物5(パラ-ホスホアスピリン)を得た。化合物5は、o-アセチルサリチロイルクロリド(1)と4-ヒドロキシベンズアルデヒド(2)から出発して下記の3ステップで合成した。
4-ヒドロキシベンズアルデヒド(2、1.04g、8.49mmole)のジクロロメタン(10mL)およびピリジン(4.16mL、50mmole)中の予冷した(O℃)溶液へ、塩化メチレン(10mL)中のo-アセチルサリチロイルクロリド(1、1.98g、10mmole)を滴状で0〜5℃にて加えた。反応混合物の温度を徐々に上昇させて室温とし、一晩放置した。この時点で、反応混合物のTLCは反応の完了を示した。反応混合物を水(25mL)で、次いで1N HCl(25mL)により、そして最後はNaHCO3水溶液で洗浄した。有機層を無水硫酸ナトリウム上で乾燥し、濾過し、濃縮した。油の粗重量は2.35g(97%)であった。
化合物3(2.3g、8.1mmole)の塩化メチレン(10mL)および酢酸(2.5mL)中の予冷した(O℃)溶液へ、シアノ水素化ホウ素ナトリウム(253mg、4mmole)を2つの部分に分けて加えた。反応温度は、30分間に徐々に室温へ上昇した。この時点で、反応混合物のTLCは反応の完了を示した。反応混合物を水(2 x 25mL)で、次いで飽和炭酸水素ナトリウム水溶液(25mL)により、そして最後はブラインで洗浄した。それを無水硫酸ナトリウム塩上で乾燥し、濾過し、濃縮した。固体の粗重量は1.95g(83%)であった。
アルコール(4、1.9g、6.64mmole)の塩化メチレン(10mL)およびジイソプロピルエチルアミン(2.2mL、13.28mmole)中の溶液へ、ジエチルクロロホスフェート(2.5mL、17.26mmole)を滴状で、次いでDMAP(25mg)を固体として加えた。反応混合物を還流下で一晩加熱した。この時点で、反応混合物のTLCは反応の完了を示した。反応混合物を水(2 x 25 mL)で洗浄し、無水硫酸ナトリウムで乾燥し、濾過しそして濃縮した。粗残留物をカラムクロマトグラフィにより、ヘキサン:酢酸エチル(60:40)を用いて精製した。純粋な画分を合わせ、蒸発させて固体を得て、これを熱ヘキサンと数回摺り潰し、純粋な表題化合物を固体690mg(25%)として得た。
非ステロイド抗炎症薬(NSAID)は、構造的にかつ、広範囲にわたり、機能的に多様なグループの化合物を含み、50近くの個々の化合物が様々な炎症性疾患の患者治療用に認可されている。これらは全て鎮痛、解熱および抗炎症効果を有する。アセチルサリチル酸(アスピリン)などのこれらのいくつかは、リウマチ、心血管、神経変性および癌などの炎症に関係する疾患に対して効果を有することが実証されていて、その効果は、例えば慢性関節リウマチのような治療効果であり、または、例えば癌、冠動脈疾患またはアルツハイマー病のような予防効果である。
ホスホ-スリンダクI:
ホスホ-スリンダクII:
であり、それらの1H-NMRプロファイルをそれぞれ図1に示す。
ホスホ-イブプロフェン
であり、その1H-NMR プロファイルを図1に示す。
ホスホ-フルビプロフェン
であり、その1H-NMRプロファイルを図1に示す。
グリセロ-ホスホ-アスピリンI:
グリセロ-ホスホ-アスピリンII:
に示し、その1H-NMRプロファイルを図1に示す。
に示す。
4つの代表的NSAIDに基づく6種の化合物、すなわち、アスピリン(リンカーの異なる2つの誘導体)、イブプロフェン、フルビプロフェンおよびスリンダク(スリンダク部分の構造が異なる2つの誘導体)を、Penningら(Penning TD, Talley JJ, Bertenshaw SR, Carter JS, Collins PW, Docter S,ら, 「シクロオキシゲナーゼ-2インヒビターの1,5-ジアリールピラゾールクラスの合成と生物学的評価:4-[5-(4-メチルフェニル)-3-(トリフルオロメチル)-1H-ピラゾール-1-イル]ベンゼンスルホンアミド(SC-58635、セレコキシブ)の同定(Synthesis and biological evaluation of the 1,5-diarylpyrazole class of cyclooxygenase-2 inhibitors: identification of 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benze nesulfonamide (SC-58635, celecoxib))」. J Med Chem 1997;40:1347-65.)の手法および本明細書に記載の方法に従って合成した。これらの構造およびNMRプロファイルは先に示した通りである。
ヒト***(MCF-7およびMDA-MB231)、結腸(HT-29、およびSW-480)および膵臓(MIA PaCa-2およびBxPC-3)の細胞株(American Type Culture Collection、Manassas、VA)を、American Type Culture Collectionが提案した特定の培地中で単層として、かつ10%ウシ胎児血清(Mediatech、Herndon、VA)、ペニシリン(50 U/ml)およびストレプトマイシン(50 μg/ml; Life Technologies、Grand Island、NY)を補充して増殖した。細胞を37℃にて5%CO2中でインキュベートした。細胞を5.5 x 104 細胞/cm2でまいて、一晩付着させ、翌朝、細胞をそれぞれの試験化合物で処理した。MCF-7細胞はエストロゲン受容体陽性であり、MDA-MB231細胞はエストロゲン受容体陰性であった。
本発明者らは、3-(4,5-ジメチルチアゾール-2-イル)-2,5-ジフェニルテトラゾリウムブロミド色素(MTT)の還元に基づくアッセイを使用し、製造業者(Promega、Madison、WI、USA)のプロトコルに従って測定した。
細胞増殖を測定するために、本発明者らは5-ブロモ-2'-デオキシウリジン(BrdU)の新しく合成された細胞DNA中への組込みを、製造業者(BD Biosciences、San Jose、CA)の取扱説明書に従って測定した。
細胞を1×105細胞/ウエルの密度でまいて、24時間、各化合物の様々な濃度またはDMSOの等価体積で処理した。簡単に説明すると、試験化合物とのインキュベーション後に、細胞をトリプシン処理し、アネキシンV-FITC(Invitrogen)とPI(0.5μg/ml)で染色した。室温にて暗所で15分間インキュベーションの後、アネキシンV-FITCとPIの蛍光強度をFACScaliber(BD Bioscience)により分析した。アネキシンV(+)/PI(-)細胞は初期アポトーシスにあり、アネキシンV(+)/PI(+)細胞は後期アポトーシス(二次壊死)にあり、そしてアネキシンV(-)/PI(+)細胞は壊死細胞である。
細胞を培養プレートにまいて、24時間、各化合物の様々な濃度またはDMSOの等価体積で処理した。処理後、細胞をトリプシン処理し、70%エタノールで1時間氷上にて固定し、PI(50μg/ml)とRNase A(4U/ml)を用いて30分間染色し、そしてフローサイトメトリーにかけてそれらの細胞周期の分布を決定した。
ホスホ-スリンダクIが腫瘍のin vivo増殖に与える効果を、2つの大腸がんの動物モデル、APCMin/+マウスおよびヌードマウス中の大腸癌異種移植片で評価した。
Minマウスは、小腸と結腸において胃腸腫瘍発生を素因化するApc遺伝子の末端切断突然変異を有する(Lipkin M, Yang K, Edelmann Wら, 「癌化学予防研究のための前臨床マウスモデル(Preclinical mouse models for cancer chemoprevention studies)」, Ann N Y Acad Sci 1999;889:14-9)。このモデル系は、多数の重要な方法において大腸発癌に関連するステップを再現する有用な(かつ広く利用される)実験系を代表するものである。
雌性のヌードマウスCByJ.Cg-Foxn1(5〜6週齢)の下右横腹に、体積100μl(PBS中に50%マトリゲルを含有する)の1.5x106 SW480大腸癌細胞を皮下接種した。
ジフルオロメチルオルニチン(DFMO)とホスホ-スリンダクIの間の相乗作用の可能性を試験した。併用化学予防の意義深い発展は、大腸癌を予防するためのスリンダク+DFMOの使用である(Gernerら, 「腺腫様ポリポーシス結腸腫瘍抑制遺伝子を標的化する包括的戦略(A comprehensive strategy to combat colon cancer targeting the adenomatous polyposis coli tumor suppressor gene)」, Ann N Y Acad Sci 2005;1059:97-105; Gerner EW, Meyskens FL, Jr., 「ポリアミンと癌:古い分子、新しい理解(Polyamines and cancer: old molecules, new understanding.)」, Nat Rev Cancer 2004;4(10):781-92;Gerner EW, Meyskens FL, Jr., Goldschmid S, Lance P, Pelot D., 「大腸癌化学予防のためにポリアミン代謝を標的化する臨床試験の理論的根拠と設計(Rationale for, and design of, a clinical trial targeting polyamine metabolism for colon cancer chemoprevention)」, Amino Acids 2007;33(2):189-95)。この併用についての理論的根拠は単純であるがなかなか強力である:DFMOは、ポリアミン合成の律速段階を触媒する酵素オルニチンデカルボキシラーゼを抑制する一方、スリンダクは酵素スペルミジン/スペルミンN1-アセチルトランスフェラーゼ(SSAT)に作用することによりポリアミンアセチル化を刺激し、細胞から搬出する。その結果は、ポリアミンレベルの低下であり、癌細胞増殖の抑制をもたらす。最近公開された大規模な臨床試験は、DFMO+スリンダクが全ての線種の再発を69%だけかつ進行した線種を92%だけ低下させることを実証した(Meyskens FL, McLaren CE, Pelot D,ら, 「散発性結腸直腸腺腫を予防するためのジフルオロメチルオルニチン+スリンダク:無作為化プラセボ-制御した、二重盲検(Difluoromethylornithine Plus Sulindac for the Prevention of Sporadic Colorectal Adenomas: A Randomized Placebo-Controlled, Double-Blind Trial.)」 Cancer Prevention Research、2008年4月14日に10.1158/1940-6207.CAPR-08-0042として初めてオンライン出版された)。
ホスホ-スリンダクIの抗炎症効果を、核因子κB(NF-κB)(転写因子であるタンパク質複合体)の活性化に与える効果を評価することにより試験した。NF-κBは、ほとんど全ての動物細胞型に見出され、ストレス、サイトカイン、フリーラジカル、紫外照射、酸化LDL、および細菌またはウイルス抗原などの刺激に対する細胞応答に関わる(Gilmore TD (1999), 「Rel/NF-κBシグナル伝達経路:序論(The Rel/NF-κB signal transduction pathway: introduction)」, Oncogene 18 (49): 6842-4)。NF-κBは感染に対する免疫応答を制御する上で重要な役割を果たす。この役割の通り、NF-κBの不正な調節は癌、炎症性および自己免疫性疾患、敗血症性ショック、ウイルスの感染、および不適当な免疫発生に関わる。NF-κBはまた、シナプスの柔軟性および記憶のプロセスにも関係付けられている(Albensi BC, Mattson MP (2000), 「TNFおよびNF-κBが海馬シナプスの柔軟性に関わることの確証(Evidence for the involvement of in hippocampal synaptic plasticity)」, Synapse 35 (2): 151-9)。一般に、NF-κBは炎症の主な分子制御を表す。さらに重要なのは、とりわけ癌環境における、細胞増殖および炎症に対するNF-κBの調節効果である(Zhang Z, Rigas B. NF-kappaB, 「炎症と膵臓の発癌:化学予防標的としてのNF-κB、総括(inflammation and pancreatic carcinogenesis: NF-kappaB as a chemoprevention target (review).)」, Int J Oncol 2006;29(1):185-92;Karin M, Greten FR. 「NF-κB:炎症と免疫を癌発生と進行に結びつける(NF-kappaB: linking inflammation and immunity to cancer development and progression)」, Nat Rev Immunol 2005;5(10):749-59)。
本発明者らは、ホスホ-スリンダクIの安全性を、エームス(Ames)試験により遺伝毒性を試験することにより、そして胃腸および他の毒性をマウスにおける毒性研究を実施することにより評価した。
バルプロ酸(VPA)は、主に抗痙攣薬および気分安定化薬としての臨床用途があり、今ではとりわけ、ヒストン脱アセチル化を抑制することが見出されたので、強力な抗癌薬として広く研究されている(Abend NS, Dlugos DJ. 「不応状態の癲癇の治療:文献総括とプロトコルの提案(Treatment of refractory status epilepticus: literature review and a proposed protocol.)」 Pediatr Neurol. 2008 Jun; 38(6):377-90;Oki Y, Issa JP. 「総括:後世学的治療法の臨床試験(Review: recent clinical trials in epigenetic therapy.)」 Rev Recent Clin Trials. 2006 May;1 (2):169-82;Barzman DH, Findling RL. 「小児における病的侵襲の薬理学的治療(Pharmacological treatment of pathologic aggression in children.)」 Int Rev Psychiatry. 2008 Apr;20 (2):151-7)。VPAは、いくつかのin vitro および in vivo 系において強力な抗腫瘍効果を示し、有望な結果が初期臨床試験から報じられている(Duenas-Gonzalez A, Candelaria M, Perez-Plascencia C, Perez-Cardenas E, de la Cruz-Hernandez E, Herrera LA. 「後世的な癌薬としてのバルプロ酸:固体腫瘍に対する前臨床、臨床および転写効果(Valproic acid as epigenetic cancer drug: preclinical, clinical and transcriptional effects on solid tumors)」, Cancer Treat Rev. 2008 May;34(3):206-22)。
Claims (8)
- 式I:
[式中、Aは、アルキル、F、Cl、Br、Iまたは−OC(O)Rxで置換されたアリールまたはアラルキルであり、ここでRxはアルキルであり;
X1は-O-または-NH-であり;
Bは無置換のアルキレンであり;
そして
Dはリン酸エステル(-O-P(O)(ORf)2)であり、ここで、Rf は無置換のアルキルである]で表される化合物、またはそのエナンチオマー、ジアステレオマー、ラセミ体、互変異性体、または塩、水和物またはエステルを含む、ヒトまたは動物の治療に使用するための組成物。 - 式I:
[式中、Aが以下:
式(II):
[式中、Yは1〜4個の炭素原子を含有するアルキレンである]、
式(V):
式(VI):
より選択され、ここで、
X1は-O-または-NH-であり;
X2はアルキルまたはハロゲンであり;
Bは無置換のアルキレンであり;
そして
Dはリン酸エステル(-O-P(O)(ORf)2)であり、ここで、Rf は無置換のアルキルである]で表される化合物、またはそのエナンチオマー、ジアステレオマー、ラセミ体、互変異性体、または塩、水和物またはエステルを含む、ヒトまたは動物の治療に使用するための組成物。 - 以下:
- 前記化合物が以下:
- 炎症に関係する疾患の治療に使用するための、請求項1〜4のいずれか1項に記載の組成物。
- リウマチ疾患、心血管疾患、神経変性疾患、脳血管疾患、自己免疫性疾患、器官の慢性炎症および新生物疾患からなる群より選択される疾患の治療に使用するための、請求項1〜4のいずれか1項に記載の組成物。
- 関節リウマチ、シェーグレン症候群、冠動脈疾患、末梢血管の疾患、高血圧、アルツハイマー病およびその変種、エリテマトーデス、慢性気管支炎、慢性静脈洞炎、良性前立腺肥大、前立腺癌、結腸腺腫、結腸癌、肺癌、リンパ腫および白血病からなる群より選択される疾患の治療に使用するための、請求項1〜4のいずれか1項に記載の組成物。
- 以下:
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US20200237787A1 (en) | 2020-07-30 |
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US20120316139A1 (en) | 2012-12-13 |
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