WO2001074362A1 - Inhibition of cyclooxygenase-2 activity - Google Patents
Inhibition of cyclooxygenase-2 activity Download PDFInfo
- Publication number
- WO2001074362A1 WO2001074362A1 PCT/US2001/010581 US0110581W WO0174362A1 WO 2001074362 A1 WO2001074362 A1 WO 2001074362A1 US 0110581 W US0110581 W US 0110581W WO 0174362 A1 WO0174362 A1 WO 0174362A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- cyclooxygenase
- dioxopiperidine
- imide
- activity
- phthalimido
- Prior art date
Links
- KYEACNNYFNZCST-UHFFFAOYSA-N CN(C(CC1)=O)C1=O Chemical compound CN(C(CC1)=O)C1=O KYEACNNYFNZCST-UHFFFAOYSA-N 0.000 description 1
- ZXLYYQUMYFHCLQ-UHFFFAOYSA-N CN(C(c1ccccc11)=O)C1=O Chemical compound CN(C(c1ccccc11)=O)C1=O ZXLYYQUMYFHCLQ-UHFFFAOYSA-N 0.000 description 1
- JHMBTUMIVBSJFS-UHFFFAOYSA-N CN(Cc1c2cccc1)C2=O Chemical compound CN(Cc1c2cccc1)C2=O JHMBTUMIVBSJFS-UHFFFAOYSA-N 0.000 description 1
Classifications
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- 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
-
- 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
- A61K31/435—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
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- 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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
Definitions
- the present invention pertains to methods for inhibiting the activity of the enzyme cyclooxygenase-2.
- angiogenesis relating to vascular endothelial cell proliferation, migration and invasion, have been found to be regulated in part by polypeptide growth factors.
- Endothelial cells exposed to a medium containing suitable growth factors can be induced to evoke some or all of the angiogenic responses.
- Polypeptides with in vitro endothelial growth promoting activity include acidic and basic fibroblast growth factors, transforming growth factors ⁇ and ⁇ , platelet-derived endothelial cell growth factor, granulocyte colony-stimulating factor, interleukin-8, hepatocyte growth factor, proliferin, vascular endothelial growth factor and placental growth factor. Folkman et al., 1995, N. Engl. J. Med., 333:1757-1763.
- Various cell types of the body can be transformed into benign or malignant tumor cells.
- the most frequent tumor site is lung, followed by colorectal, breast, prostate, bladder, pancreas, and then ovary.
- Other prevalent types of cancer include leukemia, central nervous system cancers, including brain cancer, melanoma, lymphoma, erythroleukemia, uterine cancer, and head and neck cancer.
- Unregulated angiogenesis sustains progression of many neoplastic and non-neoplastic diseases including solid tumor growth and metastases. See, e.g., Moses et al., 1991 , Biotech. 9:630-634; Folkman et al., 1995, N. Engl. J. Med., 333:1757-1763; Auerbach et al., 1985, J. Microvasc. Res. 29:401-411 ; Folkman, 1985, Advances in Cancer Research, eds. Klein and Weinhouse, Academic Press, New York, pp. 175-203; Patz, 1982, Am. J. Opthalmol. 94:715-743; Folkman et al., 1983, Science 221:719-725; and Folkman and Klagsbrun, 1987, Science 235:442-447.
- Cyclooxygenase-2 the rate-limiting enzyme in prostaglandin biosynthesis, is expressed in tumor associated macrophages. Because prostaglandins, notable PGE 2 , are important mediators of inflammatory response and angiogenesis, inhibition of their biosynthesis can be used to combat these effects. Inhibition of the cyclooxygenase-2 protein by a test compound can be conveniently observed in cells in which induction of the protein has been induced by lipo- polysaccharide (LPS). Thus it is known that LPS enhances cyclooxygenase-2 transcription and this effect thus can be used as convenient model for evaluat- ing cyclooxygenase-2 inhibition.
- LPS lipo- polysaccharide
- amide or imide that can be employed in the present invention include all of those described in US Patents Nos. 2,830,991 , 5,385,901 , 5,635,517, 5,798,368, and 5,874,448, in PCT WO98/54170, and in Serial No. 09/270,411 filed March 16, 1999, the disclosure of each being incorporated herein by reference.
- amides and imides include compounds of the formula:
- R is hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, morpholinomethyl, phenyl, or benzyl, and
- R' is:
- Representative species include 3-phthalimido-2,6-dioxopiperidine, 1 -aliyl-3- phthalimido-2,6-dioxopiperidine, 1 -ethyl-3-phthalimido-2,6-dioxopiperidine, I- phenyl-3-phthal-imido-2,6-dioxopiperidine, 1-benzyl-3-phthalimido-2,6-dioxo- piperidine, 3-succimido-2, 6-dioxopiperidine, and 1-allyl-3-succimido-2,6- dioxopiperidine.
- the preferred compound is 3-phthalimido-2, 6-dioxopiperidine, also known as thalidomide.
- compositions thus comprise the amide or imide associated with at least one pharmaceutically acceptable carrier, diluent or excipient.
- thalidomide is usually mixed with or diluted by an excipient or enclosed within such a carrier which can be in the form of a capsule or sachet.
- the excipient serves as a diluent, it may be a solid, semi-solid, or liquid material which acts as a vehicle, carrier, or medium for the active ingredient.
- the compositions can be in the form of tablets, pills, powders, elixirs, suspensions, emulsions, solutions, syrups, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders.
- excipients examples include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum acacia, calcium silicate, microcrystalline cellulose, poly- vinylpyrrolidinone polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose
- the formulations can additionally include lubricating agents such as talc, magnesium stearate and mineral oil, wetting agents, emulsifying and suspending agents, preserving agents such as methyl- and propylhydroxybenzoates, sweetening agents or flavoring agents.
- the amide or imide compositions preferably are formulated in unit dosage form, meaning physically discrete units suitable as a unitary dosage, or a predetermined fraction of a unitary dose to be administered in a single or multiple dosage regimen to human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with a suitable pharmaceutical excipient.
- the compositions can be formulated so as to provide an immediate, sustained or delayed release of active ingredient after administration to the patient by employing procedures well known in the art.
- the amide or imide may possess a center of chirality and in such cases can exist as optical isomers.
- Both the chirally pure (R)- and (S)-isomers as well as mixtures (including but not limited to racemic mixtures) of these isomers, are within the scope of the present invention.
- Mixtures can be used as such or can be separated into their individual isomers mechanically as by chromatography using a chiral absorbent.
- the individual isomers can be prepared in chiral form or separated chemically.
- the dosage employed must be carefully titrated to the patient considering his or her, weight, severity of the condition, and clinical profile.
- the amount administered will be sufficient to produce a blood level of at least 0.01 ⁇ g/mL, preferably at least about 0.1 ⁇ g/mL.
- the total blood volume in an average human is about 5 liters, so that an effective dose should provide a minimum of about 0.5 mg but can be as high as about 500 mg.
- Even higher doses may be required when the gut is inflamed, as it is in graft versus host disease and HIV infection.
- Clinical experience may suggest doses from as low as 50 mg three times a week to as high as several grams per day but, as noted, the actual decision as to dosage must be made by the attending physician.
- Tablets each containing 50 mg of 3-phthalimido-2, 6-dioxopiperidine, can be prepared in the following manner:
- 3-phthalimido-2, 6-dioxopiperidine 50 Og lactose : 50.7g wheat starch 7.5g polyethylene glycol 6000 5.0g talc 5.0g magnesium stearate 1.8g demineralized water q.s.
- the solid ingredients are first forced through a sieve 25 of 0.6 mm mesh width.
- the active imide ingredient, the lactose, the talc, the magnesium stearate and half of the starch then are mixed.
- the other half of the starch is suspended in 40 ml of water and this suspension is added to a boiling solution of the polyethylene glycol in 100 ml of water.
- the resulting paste is added to the pulverulent substances and the mixture is granulated, if necessary with the addition of water.
- the granulate is dried overnight at 35°C, forced through a sieve of 1.2 mm mesh width and compressed to form tablets of approximately 6 mm diameter which are concave on both sides.
- Tablets each containing 100 mg of 1-allyl-3-phthal-imido-2,6-dioxopiperi- dine, can be prepared in the following manner:
- 6-dioxopiperidine 100 Og lactose 100.0g wheat starch 47.0g magnesium stearate 3.0g
- All the solid ingredients are first forced through a sieve of 0.6 mm mesh width.
- the active imide ingredient, the lactose, the magnesium stearate and half of the starch then are mixed.
- the other half of the starch is suspended in 40 ml of water and this suspension is added to 100 ml of boiling water.
- the resulting paste is added to the pulveru20 lent substances and the mixture is granulated, if necessary with the addition of water.
- the granulate is dried overnight at 35°C, forced through a sieve of 1.2 mm mesh width and compressed to form tablets of approximately 6 mm diameter which are concave on both sides.
- Tablets each containing 10 mg of 3-succimido-2,6-dioxopiperidine, can be prepared in the following manner:
- the solid ingredients are first forced through a sieve of 0.6 mm mesh width. Then the 3-succimido-2, 6-dioxopiperidine, lactose, talc, magnesium stearate and half of the starch are intimately mixed. The other half of the starch is suspended in 65 ml of water and this suspension is added to a boiling solution of the polyethylene glycol in 260 ml of water. The resulting paste is added to the pulverulent substances, and the whole is mixed and granulated, if necessary with the addition of water. The granulate is dried overnight at 35°C, forced through a sieve of 1.2 mm mesh width and compressed to form tablets of approximately 10 mm diameter which are concave on both sides and have a breaking notch on the upper side. EXAMPLE 4
- the sodium lauryl sulphate is sieved into the 3-phthalimido-2,6- dioxopiperidine through a sieve of 0.2 mm mesh through a sieve of 0.9 mm mesh width and the whole is again intimately mixed for 10 minutes. Finally, the magnesium stearate is added through a sieve of 0.8 mm width and, after mixing for a further 3 minutes, the mixture is introduced in portions of 140 mg each into size 0 (elongated) gelatin dry-fill capsules.
- a 0.2% injection or infusion solution can be prepared, for example, in the following manner:
- 3-phthalimido-2,6-dioxopiperidine 5.0 g sodium chloride 22.5 g phosphate buffer pH 7.4 300.0 g demineralized water to 2500.0 mL
- the active imide ingredient is dissolved in 1000 ml of water and filtered through a microfilter.
- the buffer solution is added and the whole is made up to 2500 ml with water.
- portions of 1.0 or 2.5 mL each are introduced into glass ampoules (each containing respectively 2.0 or 5.0 mg of imide).
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- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pain & Pain Management (AREA)
- Heart & Thoracic Surgery (AREA)
- Rheumatology (AREA)
- Cardiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
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Abstract
Description
Claims
Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU2001249755A AU2001249755A1 (en) | 2000-03-31 | 2001-03-30 | Inhibition of cyclooxygenase-2 activity |
NZ521937A NZ521937A (en) | 2000-03-31 | 2001-03-30 | Inhibition of cyclooxygenase-2 activity |
EP01923016A EP1272189A4 (en) | 2000-03-31 | 2001-03-30 | Inhibition of cyclooxygenase-2 activity |
CA002404152A CA2404152C (en) | 2000-03-31 | 2001-03-30 | Inhibition of cyclooxygenase-2 activity |
MXPA02009665A MXPA02009665A (en) | 2000-03-31 | 2001-03-30 | Inhibition of cyclooxygenase 2 activity. |
JP2001572106A JP2003528918A (en) | 2000-03-31 | 2001-03-30 | Inhibition of cyclooxygenase-2 activity |
NO20024627A NO20024627L (en) | 2000-03-31 | 2002-09-27 | Inhibition of cyclooxygenase-2 activity |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US19398100P | 2000-03-31 | 2000-03-31 | |
US09/193,981 | 2000-03-31 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2001074362A1 true WO2001074362A1 (en) | 2001-10-11 |
Family
ID=22715841
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2001/010581 WO2001074362A1 (en) | 2000-03-31 | 2001-03-30 | Inhibition of cyclooxygenase-2 activity |
Country Status (11)
Country | Link |
---|---|
US (4) | US20020022627A1 (en) |
EP (1) | EP1272189A4 (en) |
JP (1) | JP2003528918A (en) |
KR (1) | KR20030003708A (en) |
CN (1) | CN1420776A (en) |
AU (1) | AU2001249755A1 (en) |
CA (1) | CA2404152C (en) |
MX (1) | MXPA02009665A (en) |
NO (1) | NO20024627L (en) |
NZ (1) | NZ521937A (en) |
WO (1) | WO2001074362A1 (en) |
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US7320991B2 (en) | 2001-02-27 | 2008-01-22 | The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services, National Institutes Of Health | Analogs of thalidomide as potential angiogenesis inhibitors |
US9006267B2 (en) | 2002-11-14 | 2015-04-14 | Celgene Corporation | Pharmaceutical compositions and dosage forms of thalidomide |
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- 2001-03-30 KR KR1020027013123A patent/KR20030003708A/en not_active Application Discontinuation
- 2001-03-30 WO PCT/US2001/010581 patent/WO2001074362A1/en active Search and Examination
- 2001-03-30 JP JP2001572106A patent/JP2003528918A/en active Pending
- 2001-03-30 NZ NZ521937A patent/NZ521937A/en not_active IP Right Cessation
- 2001-03-30 AU AU2001249755A patent/AU2001249755A1/en not_active Abandoned
- 2001-03-30 MX MXPA02009665A patent/MXPA02009665A/en active IP Right Grant
- 2001-03-30 EP EP01923016A patent/EP1272189A4/en not_active Withdrawn
- 2001-03-30 US US09/823,057 patent/US20020022627A1/en not_active Abandoned
- 2001-03-30 CN CN01807481A patent/CN1420776A/en active Pending
- 2001-03-30 CA CA002404152A patent/CA2404152C/en not_active Expired - Fee Related
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2002
- 2002-09-27 NO NO20024627A patent/NO20024627L/en not_active Application Discontinuation
-
2003
- 2003-10-07 US US10/680,606 patent/US20040077686A1/en not_active Abandoned
-
2006
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2009
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Cited By (11)
Publication number | Priority date | Publication date | Assignee | Title |
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US7320991B2 (en) | 2001-02-27 | 2008-01-22 | The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services, National Institutes Of Health | Analogs of thalidomide as potential angiogenesis inhibitors |
US8716315B2 (en) | 2001-02-27 | 2014-05-06 | The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | Analogs of thalidomide as potential angiogenesis inhibitors |
WO2003092691A1 (en) * | 2002-04-30 | 2003-11-13 | Pharmacia Coporation | Combination of cyclooxygenase-2 inhibitors and thalidomide for the treatment of neoplasia |
WO2004045579A3 (en) * | 2002-11-14 | 2004-09-10 | Celgene Corp | Pharmaceutical compositions and dosage forms of thalidomide |
JP2006508983A (en) * | 2002-11-14 | 2006-03-16 | セルジーン・コーポレーション | Pharmaceutical composition and dosage form of thalidomide |
AU2003290982B2 (en) * | 2002-11-14 | 2009-07-02 | Celgene Corporation | Pharmaceutical compositions and dosage forms of thalidomide |
JP2009215310A (en) * | 2002-11-14 | 2009-09-24 | Celgene Corp | Pharmaceutical composition of thalidomide and dosage form |
CN101816626A (en) * | 2002-11-14 | 2010-09-01 | 细胞基因公司 | Pharmaceutical compositions and dosage forms of thalidomide |
AU2003290982C1 (en) * | 2002-11-14 | 2010-10-07 | Celgene Corporation | Pharmaceutical compositions and dosage forms of thalidomide |
EP2277512A3 (en) * | 2002-11-14 | 2012-07-04 | Celgene Corporation | Pharmaceutical compositions and dosage forms of thalidomide |
US9006267B2 (en) | 2002-11-14 | 2015-04-14 | Celgene Corporation | Pharmaceutical compositions and dosage forms of thalidomide |
Also Published As
Publication number | Publication date |
---|---|
CN1420776A (en) | 2003-05-28 |
AU2001249755A1 (en) | 2001-10-15 |
US20040077686A1 (en) | 2004-04-22 |
JP2003528918A (en) | 2003-09-30 |
US20090156641A1 (en) | 2009-06-18 |
US20020022627A1 (en) | 2002-02-21 |
EP1272189A1 (en) | 2003-01-08 |
NZ521937A (en) | 2004-08-27 |
EP1272189A4 (en) | 2004-01-14 |
NO20024627D0 (en) | 2002-09-27 |
MXPA02009665A (en) | 2005-09-08 |
KR20030003708A (en) | 2003-01-10 |
NO20024627L (en) | 2002-11-22 |
US20060199819A1 (en) | 2006-09-07 |
CA2404152C (en) | 2008-08-05 |
CA2404152A1 (en) | 2001-10-11 |
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