WO1997013509A1 - Inhibiteur de permeation vasculaire - Google Patents
Inhibiteur de permeation vasculaire Download PDFInfo
- Publication number
- WO1997013509A1 WO1997013509A1 PCT/JP1996/002945 JP9602945W WO9713509A1 WO 1997013509 A1 WO1997013509 A1 WO 1997013509A1 JP 9602945 W JP9602945 W JP 9602945W WO 9713509 A1 WO9713509 A1 WO 9713509A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- group
- alkyl
- rubamoyl
- vascular permeability
- formula
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
- C07D303/18—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by etherified hydroxyl radicals
- C07D303/20—Ethers with hydroxy compounds containing no oxirane rings
- C07D303/22—Ethers with hydroxy compounds containing no oxirane rings with monohydroxy compounds
-
- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/336—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having three-membered rings, e.g. oxirane, fumagillin
Definitions
- the present invention relates to a novel vascular permeability inhibitor, particularly, for example, a vascular permeability inhibitor that exerts an inhibitory action on the retention of cancerous pleural effusion or cancerous ascites based on inhibition of vascular permeability, and a cancerous pleural effusion or cancerous ascites
- the present invention also relates to a method for suppressing the retention of sexual pleural effusion or intimal ascites using the same.
- R 1 is a carbamoyl group; a lower alkyl rubamoyl group; a hydroxy (lower) alkyl rubamoyl group; a lower alkoxy (lower) alkynolecarbamoyl group; a lower alkylthio (lower) alkyl rubamoyl group; (Lower) alkyl rubamoyl group; lower alkyl carbamoyloxy (lower) alkyl rubamoyl group, di (lower) alkyl carbamoyl group; N — [hydroxy (lower) alkyl] (lower) alkyl rubamoy N— [hydroxy (lower) alkyl] (lower) Alkyl rubamoyloxy (lower) Alkyl rubamoyl group; lower alkyl lubamoyloxy (lower) alkenoyl group; N _ [heterocyclic carboxy ( Lower) alkyl] (lower) alkyl group;
- R 6 is a protected carboxy group
- R 7 is a protected carboxy (lower) alkyl group or an ar (lower) alkyl group optionally having halogen), or
- R 8 is an acyl group
- the oxaspirooctane derivative represented by the formula (1) and a method for producing the same are known, for example, as described in JP-A-2-85272.
- the oxaspirooctane derivative (I) is known to have an angiogenesis inhibitory action as described in Japanese Patent Application Laid-Open No. 2-85272.
- drugs that inhibit the permeability of blood vessels themselves, or drugs that prevent lesions that can occur due to increased permeability of blood vessels, such as severe ascites or pleural effusion are no known drugs that inhibit the permeability of blood vessels themselves, or drugs that prevent lesions that can occur due to increased permeability of blood vessels, such as severe ascites or pleural effusion.
- drugs that inhibit the permeability of blood vessels themselves or drugs that prevent lesions that can occur due to increased permeability of blood vessels, such as severe ascites or pleural effusion.
- there are only passive measures such as removal of ascites or pleural effusion with a syringe, etc., and a drug that actively suppresses ascites or pleural effusion itself.
- oxasvirooctane derivative (I) has an excellent inhibitory action on vascular permeability, and further has an inhibitory action on S-based ascites and pleural effusion based on this action.
- this invention was completed. Disclosure of the invention
- the vascular permeability inhibitor provided by the present invention for example, an agent for inhibiting the storage of, for example, cancerous pleural effusion or cancerous ascites based on the action, is an oxaspirooctane derivative (1) represented by the above chemical formula or
- the gist of the invention is to include a pharmaceutically acceptable salt thereof as an active ingredient.
- the pharmaceutically acceptable salts thereof include conventional pharmaceutically acceptable salts such as sodium salts, ammonium salts and the like.
- “Lower” means 1 to 6 carbon atoms unless otherwise specified.
- lower alkoxy (lower) alkyl rubamoyl group Suitable “lower alkoxy (lower) alkyl rubamoyl group”, “lower alkoxycarbonyl (lower) alkyl rubamoyl group”, “lower alkoxy carbonyl group” and “lower alkoxy (lower) alkyl group”
- lower alkoxy group examples include a methoxy group, an ethoxy group, a propoxy group, a butoxy group, a pentyloxy group and a hexyloxy group.
- Examples of the suitable r lower alkylthio group in the “lower alkylthio (lower) alkyl group” include a methylthio group, an ethylthio group, a propylthio group, a butylthio group, a pentylthio group, a hexylthio group and the like.
- r lower alkyl group rubamoyloxy (lower) alkenoyl group, "hydroxy (lower) alkenoyl group", r roxyloxy (lower) alkenoyl group, “diasyloxy (lower) alkenoyl group” and “al (lower) alkenoyl group suitable “lower Arukenoiru group” in "Akuri Royle group, C 3, such as crotonyl Noiru group - include C 6 Arukenoiru group.
- cyclo (lower) alkyl force Rubamoiru group is a cyclopropyl force Rubamoiru group, cyclo butyl Kano lever moil group, cyclopentyl carbamoylthiopheno Honoré group And a cyclohexylcarbamoyl group, and a cycloheptylcarbamoyl group.
- aryl in “(lower) alkyl” and “ar (lower) alkenoyl” include phenyl, tolyl, xylyl and naphthyl.
- Suitable halogens in "haloaryl” and “halogen” include chlorine, bromine, iodine and fluorine.
- Nitrogen-containing heteromonocycles eg, pyridyl group, pyrrolidyl group, piperidyl group, piperazinyl group, 2-oxopyrrolidyl group, etc.
- nitrogen- and oxygen-containing heterocycles eg, morpholinyl group, etc.
- nitrogen- and sulfur-containing Examples include a heterocyclic monocyclic ring (for example, a thiomorpholinyl group) and a benzene-fused nitrogen-containing heterocyclic ring (for example, a quinolyl group).
- Suitable "protected lubamoyl groups J" include those protected with a conventional lubamoyl protecting group such as a halo (lower) phenol group such as trichloroacetyl, diacetyl acetinol, and monochloroacetyl. Carbamoyl group.
- a conventional lubamoyl protecting group such as a halo (lower) phenol group such as trichloroacetyl, diacetyl acetinol, and monochloroacetyl. Carbamoyl group.
- the suitable r-protected carboxy group in the “protected carboxy (lower) alkyl group” and “protected carboxy group” includes a lower alkoxycarbonyl group (for example, a methoxycarbonyl group, an ethoxycarboxy group).
- Esterified carboxy groups such as benzyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycanolebonyl group, pentyloxycarbonyl group, hexinoleoxycanolebonyl group and the like.
- the preferred “asyl group” is a lower alkanoyl group (for example, a formyl group, an acetyl group, a propionyl group, etc.), an aroyl group (for example, benzoyl, etc.) ), Lower alkanesulfonyl groups (eg, methanesulfonyl group, ethanesulfonyl group, etc.).
- oxaspirooctane derivatives (I) having the above-exemplified groups particularly preferred are those having a lower alkyl group or a protected carbamoyl group as R ′ and a lower alkyl group as R 2. Having an alkoxy group, and R 3 having the formula
- the dosage form of the vascular permeability inhibitor provided by the present invention or the agent for inhibiting the retention of, for example, pleural effusion or ascites based on the action is not particularly limited, and may be pharmaceutically acceptable.
- an acceptable carrier By blending with an acceptable carrier, it is provided as various dosage forms such as capsules, tablets, granules, powders, buccal preparations, sublingual preparations, and liquid preparations. These drugs are then orally or parenterally administered to mammals, including humans.
- Pharmaceutically acceptable carriers include various organic or inorganic carrier materials useful for pharmaceutical purposes. That is, excipients (eg, sucrose, starch, mannitol, sorbitol, lactose, darcos, cellose, talc, calcium phosphate, calcium carbonate, etc.), binders (cellulose, methylcellulose) , Hydroxypropylcellulose, polypropylpyrrolidone, gelatin, gum arabic, polyethylene glycol, sucrose, starch, etc.), disintegrant (starch, carboxymethyl senorelose, carboxymethyl cellulose calcium salt, Hydroxypropyl starch, glycol starch sodium salt, sodium bicarbonate, calcium phosphate, calcium citrate, etc.), lubricants (eg magnesium stearate, air-mouthed gill, talc, Flavoring agents (such as sodium lauryl sulfate) , Glycine, orange powder, etc.), preservatives (eg, sodium benzoate, sodium bisulfit
- the dosage of the oxaspirooctane derivative (I) depends on the type of compound, the type of underlying disease that leads to enhanced vascular permeability, such as the type and location of cancer, the weight and / or age of the patient, and It can be increased or decreased depending on various factors such as the route, and the preferred dosage is usually between 0.01 and 10 mg / kg for injection / day and between 0.5 and 50 mg / day for oral and oral administration.
- the dosage can be selected from a range of kg days.
- Sustained-release preparations were stored in the freezer.
- the above-mentioned sustained-release preparation (60.4 mg: in the preparation of the present invention, equivalent to 10 mg as a test compound) was added to the above-mentioned vehicle (20 ml). ) And gently stir with a spatula to obtain a suspension.
- Meth A fibrosarcoma (mouse fibrosarcoma) was used as tumor cells, which were maintained in the abdominal cavity of BALB / c mice every 7 days.
- the Meth A cells obtained here are washed with Hanks 'solution, and the cells suspended in Hanks' solution are washed with Trypan blue dye.
- mice BALB / c mice were divided into two groups (six in each group), and Meth A cells (5 ⁇ 10 5 cells / 0.1 ml / mouse) were implanted into each thoracic cavity.
- Meth A cells 5 ⁇ 10 5 cells / 0.1 ml / mouse
- the preparation of the present invention was administered subcutaneously (10 mg / kg) three times in total, two days and four days after the transplantation.
- the other group also received the placebo on the same schedule.
- Pleural effusion was collected 6 days after transplantation of the tumor.
- BALB / c mice were divided into two groups (six in each group), and Meth A cells (2.5 ⁇ 10 6 cells / 0.2 ml / mouse) were implanted in each abdominal cavity.
- Meth A cells 2.5 ⁇ 10 6 cells / 0.2 ml / mouse
- the preparation of the present invention was administered subcutaneously (10 mg / kg) three times in total, two days and four days after the transplantation.
- the other group also received a placebo formulation on the same schedule. Seven days after the transplantation of the tumor, ascites was collected.
- mice in the placebo group were 2 because four out of six mice died and only two mice were available, as described below.
- the total amount of stored pleural effusion (including cells) was 1.1 ml in the group receiving the placebo preparation, but was 0.4 ml in the group receiving the preparation of the present invention. An effect of suppressing the amount was observed.
- the pleural effusion volume after removal of intrathoracic cells was 0.7 ml in the group administered with the placebo formulation, but 0.2 ml in the group administered with the formulation of the present invention. A significant pleural effusion suppression effect was observed.
- the total amount of ascites stored (including cells) was 3.5 ml in the group administered with the placebo preparation, whereas it was 1.0 ml in the group administered with the preparation of the present invention. An effect of suppressing the amount was observed.
- the ascites volume after removal of the cells in the abdominal cavity was 2.2 ml in the group administered with the placebo preparation, but was 0.5 ml in the group administered with the preparation of the present invention. A significant ascites retention suppression effect was observed.
- the formulation of the present invention was prepared by dissolving 86.0 mg of the test compound in 3.0 ml of propylene glycol and sealing it in a minipump (Note 1). On the other hand, for the placebo preparation, only the propylene glycol was used by sealing it in the minipump.
- AZLET Mini-Osomotic Pump Model 2001 1.0 ⁇ . 1 / hour ⁇ mean pumpingrate, capable of releasing drug solution continuously for 7 days.
- mice BALB / c mice were divided into two groups (5 mice in each group), and Meth A cells (5 ⁇ 10 5 cells / 0.1 ml / mouse) were implanted into each thoracic cavity.
- Meth A cells 5 ⁇ 10 5 cells / 0.1 ml / mouse
- One group was subcutaneously transplanted with the preparation of the present invention encapsulated in the above-mentioned minipump on the day of transplantation, and the other group was also administered a placebo preparation on the same schedule. In the group administered with the preparation of the present invention, this corresponds to administration of the test compound at a dose of 32 mg / kg / day.
- Pleural effusion was collected 5 days after tumor transplantation.
- the total amount of pleural effusion (including cells) stored was 0 in the placebo group.
- a solution prepared by dissolving 105 mg of a test compound in 6.0 ml of a physiological saline solution containing 10% polyxethylenated hydrogenated castor oil (HCO—60) was used.
- HCO—60 polyxethylenated hydrogenated castor oil
- placebo preparation only the physiological saline containing 10% polyoxyethylene hydrogenated castor oil was used.
- Tumor cells were prepared by using Meth A fibrosarcoma (mouse fibrosarcoma) prepared and maintained under the same conditions as in Test Example 1. Was implanted into mice. Ascites was collected from the mice on day 6 after transplantation, tumor cells were removed (2000 rpm, 10 min), and the ascites supernatant was used as a vascular permeability enhancer derived from tumor cells.
- Hartley guinea pigs were divided into two groups (four animals in each group), and one of the groups was subcutaneously administered the present preparation (dose: 32 mg / kg). The other group received the same amount of placebo subcutaneously.
- One hour after administration 1 ml of a solution of Evans blue (10 mg / ml) dissolved in physiological saline was intravenously administered, and immediately thereafter, 0.1 ml of ascites was intradermally administered. Then the leaked guinea pig skin was the Evans blue after 3 0 min was collected, immersed in 0.1 N-KOH solution in 1 m l, and dissolved overnight. After dissolution, acetone - 2.5 N Ri I acid mixed-solution (1 7: 3) was added to 4 ml to extract Evans blue, extract of OD 62. Was measured.
- Table 6 shows the results of measuring the OD 620 of the extract. In each case, the average is shown as ⁇ SE.
- the OD 620 of the group administered with the placebo preparation was 0.117
- the OD 62fl of the group administered with the present invention was 0.082, indicating that the leakage amount of Evans blue from the blood vessels was less than that of the present invention. It is evident that the administration of the formulation resulted in a significant decrease. That is, it became clear that the present invention preparation can significantly suppress the vascular permeability promoting action based on the vascular permeability enhancer derived from tumor cells.
- vascular permeability inhibitor particularly, for example, a drug capable of suppressing the retention of cancerous pleural effusion and cancerous ascites is provided.
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
Claims
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US09/051,086 US6180626B1 (en) | 1995-10-11 | 1996-10-11 | Vascular-permeability suppressants |
EP96933614A EP0867180A4 (en) | 1995-10-11 | 1996-10-11 | VASCULAR PERMEATION INHIBITOR |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP7/263363 | 1995-10-11 | ||
JP26336395 | 1995-10-11 | ||
JP27600495 | 1995-10-24 | ||
JP7/276004 | 1995-10-24 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1997013509A1 true WO1997013509A1 (fr) | 1997-04-17 |
Family
ID=26545989
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP1996/002945 WO1997013509A1 (fr) | 1995-10-11 | 1996-10-11 | Inhibiteur de permeation vasculaire |
Country Status (4)
Country | Link |
---|---|
US (1) | US6180626B1 (ja) |
EP (1) | EP0867180A4 (ja) |
CA (1) | CA2234401A1 (ja) |
WO (1) | WO1997013509A1 (ja) |
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US20120004162A1 (en) | 2008-12-04 | 2012-01-05 | Vath James E | Methods of Treating an Overweight or Obese Subject |
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CN102791699B (zh) | 2010-01-08 | 2016-04-06 | 扎夫根公司 | 烟曲霉醇型化合物和其制造和使用方法 |
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MX342257B (es) | 2011-03-08 | 2016-09-21 | Zafgen Inc | Derivados y análogos de oxaspiro [2.5] octano. |
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WO2013109735A1 (en) | 2012-01-18 | 2013-07-25 | Zafgen, Inc. | Tricyclic sulfone compounds and methods of making and using same |
EP2804866B1 (en) | 2012-01-18 | 2016-11-16 | Zafgen, Inc. | Tricyclic sulfonamide compounds and methods of making and using same |
MX2014013525A (es) | 2012-05-07 | 2015-10-22 | Zafgen Inc | Sal polimorfica de la sal de oxalato de 6-o-(4-dimetilaminoetoxi)c inamoil fumagilol y metodos para elaborarla y utilizarla. |
BR112014028041A2 (pt) | 2012-05-08 | 2017-06-27 | Zafgen Inc | tratamento de obesidade hipotalâmica com inibidores de metap2 |
CN104364251B (zh) | 2012-05-09 | 2017-02-22 | 扎夫根股份有限公司 | 烟曲霉醇型化合物及其制备和使用方法 |
EP2925737B1 (en) | 2012-11-05 | 2017-06-14 | Zafgen, Inc. | Tricyclic compounds for use in the treatment and/or control of obesity |
NZ707773A (en) | 2012-11-05 | 2019-05-31 | Zafgen Inc | Methods of treating liver diseases |
US10174009B2 (en) | 2012-11-05 | 2019-01-08 | Zafgen, Inc. | Tricyclic sulphonamide compounds and methods of making and using same |
EP2968250B1 (en) | 2013-03-14 | 2019-06-19 | Zafgen, Inc. | Methods of treating renal disease and other disorders |
CN106432255A (zh) | 2015-08-11 | 2017-02-22 | 扎夫根公司 | 烟曲霉素醇螺环化合物和制备和使用其的方法 |
AR105671A1 (es) | 2015-08-11 | 2017-10-25 | Zafgen Inc | Compuestos heterocíclicos de fumagillol y sus métodos de elaboración y uso |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH0285272A (ja) * | 1988-08-12 | 1990-03-26 | Fujisawa Pharmaceut Co Ltd | オキサスピロオクタン誘導体 |
JPH037222A (ja) * | 1988-09-01 | 1991-01-14 | Takeda Chem Ind Ltd | 血管新生阻害剤 |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5164410A (en) | 1988-01-09 | 1992-11-17 | Takeda Chemical Industries, Ltd. | Fumagillol derivatives and pharmaceutical compositions thereof |
US5166172A (en) | 1988-09-01 | 1992-11-24 | Takeda Chemical Industries, Ltd. | Fumagillol derivatives and pharmaceutical compositions thereof |
-
1996
- 1996-10-11 US US09/051,086 patent/US6180626B1/en not_active Expired - Fee Related
- 1996-10-11 EP EP96933614A patent/EP0867180A4/en not_active Withdrawn
- 1996-10-11 WO PCT/JP1996/002945 patent/WO1997013509A1/ja not_active Application Discontinuation
- 1996-10-11 CA CA002234401A patent/CA2234401A1/en not_active Abandoned
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH0285272A (ja) * | 1988-08-12 | 1990-03-26 | Fujisawa Pharmaceut Co Ltd | オキサスピロオクタン誘導体 |
JPH037222A (ja) * | 1988-09-01 | 1991-01-14 | Takeda Chem Ind Ltd | 血管新生阻害剤 |
Non-Patent Citations (1)
Title |
---|
See also references of EP0867180A4 * |
Also Published As
Publication number | Publication date |
---|---|
US6180626B1 (en) | 2001-01-30 |
CA2234401A1 (en) | 1997-04-17 |
EP0867180A1 (en) | 1998-09-30 |
EP0867180A4 (en) | 1999-09-15 |
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