JP6510498B2 - 腫瘍疾患の治療に有用な化合物 - Google Patents
腫瘍疾患の治療に有用な化合物 Download PDFInfo
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- JP6510498B2 JP6510498B2 JP2016516618A JP2016516618A JP6510498B2 JP 6510498 B2 JP6510498 B2 JP 6510498B2 JP 2016516618 A JP2016516618 A JP 2016516618A JP 2016516618 A JP2016516618 A JP 2016516618A JP 6510498 B2 JP6510498 B2 JP 6510498B2
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- ORRDHOMWDPJSNL-UHFFFAOYSA-N melanin concentrating hormone Chemical compound N1C(=O)C(C(C)C)NC(=O)C(CCCNC(N)=N)NC(=O)CNC(=O)C(C(C)C)NC(=O)C(CCSC)NC(=O)C(NC(=O)C(CCCNC(N)=N)NC(=O)C(NC(=O)C(NC(=O)C(N)CC(O)=O)C(C)O)CCSC)CSSCC(C(=O)NC(CC=2C3=CC=CC=C3NC=2)C(=O)NC(CCC(O)=O)C(=O)NC(C(C)C)C(O)=O)NC(=O)C2CCCN2C(=O)C(CCCNC(N)=N)NC(=O)C1CC1=CC=C(O)C=C1 ORRDHOMWDPJSNL-UHFFFAOYSA-N 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- PXNOLLHARLSLHY-UHFFFAOYSA-N methyl 4-hydroxy-3-iodobenzoate Chemical compound COC(=O)C1=CC=C(O)C(I)=C1 PXNOLLHARLSLHY-UHFFFAOYSA-N 0.000 description 1
- 229940095102 methyl benzoate Drugs 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 238000006396 nitration reaction Methods 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 239000001272 nitrous oxide Substances 0.000 description 1
- ODUCDPQEXGNKDN-UHFFFAOYSA-N nitroxyl Chemical compound O=N ODUCDPQEXGNKDN-UHFFFAOYSA-N 0.000 description 1
- 150000007523 nucleic acids Chemical group 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 208000013371 ovarian adenocarcinoma Diseases 0.000 description 1
- 201000006588 ovary adenocarcinoma Diseases 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 239000006179 pH buffering agent Substances 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- AZQWKYJCGOJGHM-UHFFFAOYSA-N para-benzoquinone Natural products O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 description 1
- 125000004115 pentoxy group Chemical group [*]OC([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- YWDZXOMXNXGRJS-UHFFFAOYSA-N phenyl 5-(dimethylamino)naphthalene-1-sulfonate Chemical compound C1=CC=C2C(N(C)C)=CC=CC2=C1S(=O)(=O)OC1=CC=CC=C1 YWDZXOMXNXGRJS-UHFFFAOYSA-N 0.000 description 1
- FCJSHPDYVMKCHI-UHFFFAOYSA-N phenyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OC1=CC=CC=C1 FCJSHPDYVMKCHI-UHFFFAOYSA-N 0.000 description 1
- OPYYWWIJPHKUDZ-UHFFFAOYSA-N phenyl cyclohexanecarboxylate Chemical compound C1CCCCC1C(=O)OC1=CC=CC=C1 OPYYWWIJPHKUDZ-UHFFFAOYSA-N 0.000 description 1
- IGJYWORNVRWOKZ-UHFFFAOYSA-N phenyl naphthalene-1-carboxylate Chemical compound C=1C=CC2=CC=CC=C2C=1C(=O)OC1=CC=CC=C1 IGJYWORNVRWOKZ-UHFFFAOYSA-N 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- 229940067631 phospholipid Drugs 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 229920001515 polyalkylene glycol Polymers 0.000 description 1
- 238000010837 poor prognosis Methods 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 230000009757 proliferative dysfunction Effects 0.000 description 1
- XJMOSONTPMZWPB-UHFFFAOYSA-M propidium iodide Chemical compound [I-].[I-].C12=CC(N)=CC=C2C2=CC=C(N)C=C2[N+](CCC[N+](C)(CC)CC)=C1C1=CC=CC=C1 XJMOSONTPMZWPB-UHFFFAOYSA-M 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 229940058287 salicylic acid derivative anticestodals Drugs 0.000 description 1
- 150000003872 salicylic acid derivatives Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 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
- 229910000077 silane Inorganic materials 0.000 description 1
- 208000000587 small cell lung carcinoma Diseases 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 150000003459 sulfonic acid esters Chemical class 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 1
- CWMFRHBXRUITQE-UHFFFAOYSA-N trimethylsilylacetylene Chemical group C[Si](C)(C)C#C CWMFRHBXRUITQE-UHFFFAOYSA-N 0.000 description 1
- 230000005760 tumorsuppression Effects 0.000 description 1
- 230000004222 uncontrolled growth Effects 0.000 description 1
- 210000003932 urinary bladder Anatomy 0.000 description 1
- ZENOXNGFMSCLLL-UHFFFAOYSA-N vanillyl alcohol Chemical compound COC1=CC(CO)=CC=C1O ZENOXNGFMSCLLL-UHFFFAOYSA-N 0.000 description 1
- 230000001018 virulence Effects 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- 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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
-
- 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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
-
- 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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
- A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
-
- 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
- A61K31/60—Salicylic acid; Derivatives thereof
- A61K31/618—Salicylic acid; Derivatives thereof having the carboxyl group in position 1 esterified, e.g. salsalate
- A61K31/621—Salicylic acid; Derivatives thereof having the carboxyl group in position 1 esterified, e.g. salsalate having the hydroxy group in position 2 esterified, e.g. benorylate
-
- 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
- A61K31/695—Silicon compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C203/00—Esters of nitric or nitrous acid
- C07C203/02—Esters of nitric acid
- C07C203/04—Esters of nitric acid having nitrate groups bound to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C247/00—Compounds containing azido groups
- C07C247/02—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton
- C07C247/08—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton being unsaturated
- C07C247/10—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton being unsaturated and containing rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/63—Esters of sulfonic acids
- C07C309/72—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C309/76—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/74—Esters of carboxylic acids having an esterified carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring
- C07C69/75—Esters of carboxylic acids having an esterified carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring of acids with a six-membered ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
- C07C69/78—Benzoic acid esters
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
- C07C69/84—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of monocyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of a six-membered aromatic ring
- C07C69/86—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of monocyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of a six-membered aromatic ring with esterified hydroxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
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- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Emergency Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Oncology (AREA)
- Hematology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
R3が、(C1乃至C5)アルキル、1乃至3のハロゲン置換基を有する(C1乃至C3)アルキル、ハロゲン又は水素を示し;
R4が、(C1乃至C5)アルキル、(C1乃至C5)アルコキシ又は水素を示し;
R5が、(C1乃至C5)アルキル、(C1乃至C5)アルコキシ、アセトキシ、ハロゲン又は水素を示し;
Xが、OTBS、ヒドロキシ、ホルミルオキシ、アセトキシ、ニトロオキシ、ニトロオキシメチル又はハロゲンを示す;
但し、R1が [一般式B]で、R2、R3及びR5が水素であり、及びXがヒドロキシルであるとき、R4は、メトキシではない;
又は、その薬学上許容される塩。
一般式Aにおいて、OR1残基及び−CH2X残基が、ベンゼン環のパラ位に結合した化合物が特に有用である。
本発明は、また、腫瘍疾患又は増殖障害の治療のために使用される化合物を志向する。ここで、そのような、病気又は障害は、好ましくは、癌である。より好ましくは、癌は、前立腺、膵臓、肺、皮膚、乳がん、腎臓(bladder)、大腸(colon)及び血液(blood cancer)からなる群から選択される。ここで、より好ましい癌は、慢性リンパ性白血病(CLL)である。
本発明の化合物において、R1残基との結合によって、一般式Aのベンゼン環に、エステル基が得られたものが好ましい。
好ましい塩基又は塩は、例えば、アルミニウム、カルシウム、リチウム、マグネシウム、カリウム、ナトリウム、亜鉛、及びジエタノールアミン塩を含み、これらに限定されない。
薬学上許容される塩の総説は、Berge et al.、66 J. PHARM. SCI. 1-19(1977)を参照する。
(i) 病気に罹っているかもしれないが、罹っていると、まだ、診断されていない、患者に起こる病気を予防すること;
(ii) 疾患を阻害すること、即ち、その進行を阻止すること;
(iii)疾患を回復すること、即ち、病気の退縮を引き起こすこと。
腫瘍の前に、細胞は、しばしば、成長の異常なパターンを起こす。腫瘍細胞の増殖は、その周りの正常組織の増殖を超え、一体とならない。成長は、刺激中止後でさえも、同様の過剰な態様に保持され、通常、しこりや腫瘍が発生する。腫瘍は、良性、悪性前又は悪性(腫瘍)でありえる。増殖疾患又は増殖障害は、細胞の機能不全を意味し、ここで、協調した増殖(生物的細胞の新しい進行及び成長) は、制御できず、そして、細胞の生産と成長は、増加し、通常の細胞の速度を超える。
医薬としての、一般式の化合物:
R3は、メチル、トリフルオロメチル、フッ素又は水素を示し;
R4は、メチル、メトキシ又は水素を示し;
R5は、アセトキシ、メトキシ、塩素又は水素を示し;
Xは、OTBS、ヒドロキシ、ホルミルオキシ、ニトロオキシ、ニトロオキシメチル又は塩素を示す;
但し、R1が [一般式B]で、R2、R3及びR5が水素であり、及びXがヒドロキシルであるとき、R4は、メトキシではない;
又は、その薬学上許容される塩。
本一般式で表される、いくつかの化合物は、先行技術に知られている。しかし、それらは、医薬として記載されていない。しかし、本出願において、提供された大抵の化合物は、先行技術に知られた化合物と比較して、新しい。特に、一般式の化合物:
R3は、(C1乃至C5)アルキル、1乃至3個のハロゲンで置換された(C1乃至C3)アルキル、ハロゲン又は水素を示し;
R4は、(C1乃至C5)アルキル、(C1乃至C5)アルコキシ又は水素を示し;
R5は、(C1乃至C5)アルキル、(C1乃至C5)アルコキシ、アセトキシ、ハロゲン又は水素を示し;
Xは、OTBS、ヒドロキシ、ホルミルオキシ、アセトキシ、ニトロオキシ、ニトロオキシメチル又はハロゲンを示す;
但し、R1が[一般式B]で、Xがニトロオキシで、そして、R5がアセトキシのとき、少なくともR2乃至R4の1つは水素でない;また、R1が[一般式B]で、R3乃至R5が水素で、Xがヒドロキシルのとき、R2は、水素でも、メトキシでもない;更に、R1が[一般式B]で、R2、R3及びR5が水素で、そして、Xがヒドロキシルのとき、R4はメトキシでなく;R1が[一般式B]で、R3乃至R5が水素で、そして、XがOTBSであるとき、R2はメトキシでなく;及び、R1がメトキシで、及びXがニトロオキシのとき、R2は 水素でない。
R2は、メトキシ、エチニル、アジドメチル又は水素を示し;
R3は、メチル、トリフルオロメチル、フッ素又は水素を示し;
R4は、メチル、メトキシ又は水素を示し;
R5は、アセトキシ、メトキシ、塩素又は水素を示し;
Xは、OTBS、ヒドロキシ、ホルミルオキシ、ニトロオキシ、ニトロオキシメチル又は塩素を示す;
但し、R1が[一般式B]で、Xがニトロオキシで、R5がアセトキシのとき、R2乃至R4の少なくとも1つは水素ではなく;R1が[一般式B]で、R3乃至R5が水素で、及びXがヒドロキシルのとき、R2は水素でも、メトキシでもなく;R1が[一般式B]で、R2、R3及びR5が水素で、及びXがヒドロキシルのとき、R4はメトキシでなく;R1が[一般式B]で、R3乃至R5が水素で、及びXがOTBSのとき、R2はメトキシでなく;及び、R1がメトキシで、Xがニトロオキシのとき、R2は水素ではない。
4−((ニトロオキシ)メチル)フェニル 2−アセトキシ−5−メチルベンゾエート、
4−((ニトロオキシ)メチル)フェニル 2−アセトキシ−5−フルオロベンゾエート、
4−((ニトロオキシ)メチル)フェニル 2−アセトキシ−4−メチルベンゾエート、
4−(((tert−ブチルジメチル-シリル)オキシ)メチル)フェニル 2−クロロ−5−(トリフルオロメチル)ベンゾエート、
4−(ヒドロキシメチル)フェニル 2−クロロ−5−(トリフルオロメチル)ベンゾエート、
4−((ニトロオキシ)メチル)フェニル 2−クロロ−5−(トリフルオロメチル)ベンゾエート、
4−(((tert−ブチルジメチルシリル)オキシ)メチル)フェニル ベンゾエート、
4−((ニトロオキシ)メチル)フェニル ベンゾエート、
4−((ホルミルオキシ)メチル)フェニル ベンゾエート、
2−メトキシ−4−((ニトロオキシ)メチル)フェニル ベンゾエート、
4−(クロロメチル)フェニル ベンゾエート、
4−((ニトロオキシ)メチル)フェニル 1−ナフトエート、
4−((ニトロオキシ)メチル)フェニル シクロヘキサンカルボキシレート、
4−((ニトロオキシ)メチル)フェニル 5−アミノナフタレン−1−スルホネート、
4−(2−(ニトロオキシ)エチル)フェニル ベンゾエート、
4−((ニトロオキシ)メチル)フェニル 2−メトキシベンゾエート、
4−((ニトロオキシ)メチル)フェニル 4−メトキシベンゾエート、
2−エチニル−4−((ニトロオキシ)メチル)フェニル ベンゾエート、
2−(アジドメチル)−4−((ニトロオキシ)メチル)フェニル ベンゾエート、
4−((ニトロオキシ)メチル)フェニル 2−オキソ−2−フェニルアセテート、及び
4−((ニトロオキシ)メチル)フェニル 2−オキソプロピオネート又はその薬学上許容される塩。
4−((ニトロオキシ)メチル)フェニル−2−アセトキシ−5−メチル ベンゾエート、
4−((ニトロオキシ)メチル)フェニル−2−アセトキシ−4−メチル ベンゾエート、
4−((ニトロオキシ)メチル)フェニル ベンゾエート、
4−((クロロ)メチル)フェニル ベンゾエート、
4−((ニトロオキシ)メチル)フェニル ナフトエート
この中で、4−((ニトロオキシ)メチル)フェニル ベンゾエートと4−((クロロ)メチル)フェニル ベンゾエートが特に好ましい。特に、そのような化合物は、好ましい高い有効性(低濃度が効果のために必須である。表1参照)と、良好な化学的安定性を有する。
更に、本タイプの化合物の一般的製造方法は、WO2002/30866及びWO2001/04082に開示されている。
このような非経口の組成物に含まれる活性化合物の割合は、本化合物の活性及び患者の必要性と同様に、その特定の性質に大きく依存する。しかし、溶液において、0.1から10重量%の本発明化合物の1つの割合を採用でき、もし、組成物が、後に希釈されてえ上記の割合になる、固体である場合、より高くできる。好ましくは、本組成物は、溶液中に、本化合物の1つを0.2から2重量%含む。
初代(Primary)CLL又は健康なドナー(5*106/ml)の末梢血単核球細胞(peripheral blood mononuclear cells)を、24時間、本発明に従い、異なった化合物及び、対照としてのNO−ASAで培養した。化合物は、異なる濃度、特に、0.01−100μmの濃度範囲、で添加された。細胞の生存は、AnnexinV/PIアッセイ(キットは市販、例えば、Biotium株式会社、米国;又はフェニックス フロー システム社、米国)によって評価された。結果は、DMSO対照[プラセボ]に対して正規化され、非線型回帰モデルを用いた用量反応曲線を求めた。
その有利な特性のために、B9が、CLL異種移植片マウスモデルで(CLL xenograft mouse model)のin vivo試験のために選択された。JVM3細胞(ヒトの慢性的なB細胞性白血病細胞系)は、免疫応答性のない(immunincompetent) マウスの側面(flank)に、皮下で注入された。進行している固形腫瘍は、化合物B9又はゴマ油(プラセボ)の8mg/kgを、一日おきに、腹腔内注射(intraperitoneal injections)によって処理された(図4を参照)。
1*107のJVM3細胞を、SCID beigeマウスに皮下注射した(CB17.Cg−PrkdcscidLystbg−J/Crl)。カリバス(caliper)によって、一日おきに、腫瘍を測定し、腫瘍体積を求めた V=(長さ*(0.5*幅2))。50 mm3以上の腫瘍を持つマウスを、ごま油(プラセボ対照)又は8mg/kgのB9を溶かした、ごま油を用いて、腹腔内注射で、一日おきに注射した。担癌マウスのために、GV−SOLAS条約によって与えられる中絶の基準が適用された。p値は、対応のない両側スチューデント検定(unpaired two-tailed students test)を用いて、算出した。
図4は、B9による治療による、腫瘍の成長の大幅な削減を示す。腫瘍の成長阻害は11日後、非常に顕著であった。成長阻害の比率(IR)は、17日目で、65.33%と最高であった。対照群の2つの動物は、彼らの腫瘍が、直径(中絶基準)15mmを超えたので、犠牲にならなければならなかった。プラセボ又はB9による治療中に、重篤な副作用は認められなかった。マウスは、治療により、飲食は正常であったが、15〜30分の間、少し不自由な移動性を示した。体重の減少は観察されなかった。B9は、異種移植腫瘍モデルマウスにおいて、腫瘍の成長を大幅に削減した(9日目;B9 治療=82.97mm3)。
CLLにおける、治療の成功は、例えば、del13q又はTP53遺伝子破壊(gene disruption)に対する、細胞遺伝学的及び分子のパラメーターに依存する。それ故、NO−ASA誘導体は、異なる遺伝子型及び表現型(JVM3、EHEB、U2932、MEC−1、GRANTA−519)を有する、(慢性)B細胞リンパ腫細胞株において試験された。細胞は、0.01から1000μMの濃度で、24時間、処理され、次いで、luminogenic CellTiter Glo(R)試薬が加えられた。
p−NO−ASAは、B9(MEC−1:EC50=6.62mM;GRANTA−519:EC50=2.28mM)、B12(MEC−1:EC50=3.24mM;GRANTA−519:EC50=0.68mM)及びB13(MEC−1:EC50=24.13mM;GRANTA−519:EC50=19.72mM)と比較して、MEC−1(EC50=53.44mM、p<0、001)及びGRANTA−519(EC50=22.21mM、p<0、001)に対して、有意に効果が劣った。図5参照。
更に、B9、B12、及びB13の誘導体は、パラ−NO−ASAと比較して、TP53 突然変異を有する、CLL細胞において、試験された。TP53中断を有する、患者のサブグループは、重篤な予後不良が特徴である。TP53の突然変異の有無にかかわらず、患者のCLL細胞は、パラ−NO−ASA、B9、B12、及びB13について、5つの異なる濃度で、24時間、処理された(0.01、0.1、1、10、100μM)。
図6は、上記の様に処理された細胞のFACS解析した結果を示す。全ての化合物、特に、B9及びB12は、TP53の突然変異のない、CLL細胞に大きな効果を有すること示す。更に、B9、B12、及びB13の、3つの化合物は、パラ−NO−ASA(B1)と比較すると、TP53変異CLL細胞に、より効果があった。B9は、TP53の突然変異の有無にかかわらず、CLL細胞に対して、最も顕著な効果を示すグループの化合物であった。
次の実験で、NO−ASA誘導体の、可能な治療可能時間域(therapeutic window)を調べた。従って、細胞生存率と、いくつかの癌細胞株におけるアポトーシスの誘導に、最も効果的な誘導体の影響は、アネキシン染色(Annexin staining)によって分析した。悪性黒色腫細胞株MelJuso、大腸癌細胞株SW480、小細胞肺癌細胞株HCC44、卵巣腺癌細胞株COLO704及び急性骨髄性白血病細胞株SH2は、0.01μMから100μMの範囲の、p−NO−ASA並びに、B9、B12、及びB13の濃度範囲で、24時間、処理され、次いで、luminogenic CellTiter Glo(R)試薬が加えられた。3つの誘導体(B9、B12及びB13)は、全ての癌細胞株に対して、明確な細胞毒素の効果を示した。図7は、当該細胞株における結果を示す。p−NO−ASA、B9、B12、及びB13は、SW480、MelJuso、HCC44、SH2及びCOLO704細胞株で、同様に、大幅に ATP量を減少した。一方、p−NO−ASAは、SW480において、大幅により非効果的であった。
ATPアッセイにより、測定された、生存の結果は、B9、B12、及びB13の3つの誘導体が、異なる腫瘍と固形腫瘍に対する、治療能力を示すことを、更に、強調する。特に、B12は、癌細胞への毒性を示す(SH2 EC50:0.005μM、SW480 EC50:129.5μM、MelJuso EC50:0.54μM、HCC44 EC50:1.05μM、COLO704 EC50:2.77)。また、アポトーシス・アレイの結果は、1−9μMのB9、1−5μMのB12及び7−57μMのB13の濃度において、様々な病気における、アポトーシスの誘導を示す(下表参照)。
CLL細胞に対する毒性が、カスパーゼが介在する、アポトーシスのためかどうかを確認するために、PARP(ポリ(ADP−リボース)ポリメラーゼ1)とXIAP (X−リンクされたアポトーシス阻害剤)の開裂が、イムノブロット(immunoblot)によって解析された。CLL細胞は、単独、DMSO1%、又は、p−NO−ASA、メタ−NO−ASA、B9、B12及びB13のEC50で、24時間、培養し、タンパク溶解(protein lysation)をし、次いで、予後アポトーシスタンパク(prognostic apoptotic proteins)(XIAP、PARP)を検出するために、抗体を用いたウエスタン・ブロットで解析した。EC50の濃度での、薬物治療は、PARPの開裂に影響し、そして、抗アポトーシス タンパクである、XIAPのレベルを、明らかに減少させた。試験された、全ての化合物は、PARPとXIAPの開裂を誘起した(図8A)。更に、カスパーゼ−3/7アッセイを行った。CLL細胞を、パラ−NO−ASAとB9を用いて、0.01μMから20μMの範囲の異なった濃度で、6時間、培養し、luminogenic カスパーゼ−3/7−基質を加えた。これは、p−NO−ASAとB9を用いた治療に基づき、カスパーゼ が介在するアポトーシスの誘発による、CLL細胞の生存の減少を示す。パラ−NO−ASAとB9は、また、特有のカスパーゼ−3/7アッセイにおいて、カスパーゼ3と7の濃度依存性の活性化を示す(図8B)(EC50 B9=0.23mM、95%CI=0.11から0.49mM;EC50 p−NO−ASA=1.84mM、95%CI=0.81から4.21mM)。
BCRシグナル伝達経路は、CLLと、構造的に活性なNFκBへと、しばしば導びかれるリンパ腫において、重要な病原性の役割を果たす(この状態では、NFκBは、リン酸化されている)。従って、NFκBのリン酸化の状態に対する、本誘導体の影響を、ウエスタン ブロットにより、解析した。CLL細胞は、それぞれ、各誘導体について、0.1μM、1μM又は10μMで、3時間、処理した。CLL細胞は、B1、B9、B12及びB13(0.1μM、1μM、10μM)で、3時間、処理した。非処理とDMSO(1%)で処理した細胞を、対照として用いた。GAPDH=ローディング量を考慮した対照。
本NO−ASA誘導体は、リン酸化NFκBp65タンパクの濃度依存性の減少と、それによる、NFκBのシグナル伝達経路の抑制を誘導した。B9、B12及びB13は、丁度10μMの濃度で、減少が誘導されたが、p−NO−ASAは、NFκBp65タンパクの減少の誘導のために、2倍の濃度が、必要であった(図9を参照)。
Claims (8)
- 腫瘍疾患又は増殖障害の治療用医薬を製造するための、以下の一般式を有する化合物の使用:
R1は、以下から選択される;
R3は、(C1乃至C5)アルキル、1乃至3個のハロゲンが置換された(C1乃至C3)アルキル、ハロゲン若しくは水素を示し;
R4は、(C1乃至C5)アルキル、(C1乃至C5)アルコキシ若しくは水素を示し;
R5は、(C1乃至C5)アルキル、(C1乃至C5)アルコキシ、ハロゲン若しくは水素を示し;
Xは、OTBS、ヒドロキシ、ホルミルオキシ、アセトキシ、ニトロオキシ、ニトロオキシメチル若しくはハロゲンを示す、
或いは、
4−((ヒドロキシ)メチル)フェニル ベンゾエート
又は、その薬学上許容される塩。 - 腫瘍疾患又は増殖障害の治療用医薬を製造するための、請求項1に記載された化合物の使用:
ここで、
化合物は、以下の群から選択される化合物を示す;
- 癌の治療用医薬を製造するための、請求項1または2のいずれか1項に記載された使用。
- 癌が、前立腺がん、腎がん、肺がん、皮膚がん、乳がん、膀胱がん、大腸がん、及び血液癌からなる群から選択される、請求項3に記載の使用。
- 癌が、卵巣がんである、請求項3に記載された使用。
- 癌が、慢性リンパ性白血病である、請求項3または4に記載された使用。
- 請求項1または2に規定された、一般式を有する化合物、又はその薬学上許容される塩を含有する、腫瘍疾患又は増殖障害の医薬組成物。
- 請求項1または2に規定された化合物の製剤、又は請求項7に記載された組成物を含む、腫瘍疾患又は増殖障害の治療用キット。
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