EP1091726A2 - Analogues de l'acide 2-phthalimidinoglutarique - Google Patents

Analogues de l'acide 2-phthalimidinoglutarique

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Publication number
EP1091726A2
EP1091726A2 EP99925585A EP99925585A EP1091726A2 EP 1091726 A2 EP1091726 A2 EP 1091726A2 EP 99925585 A EP99925585 A EP 99925585A EP 99925585 A EP99925585 A EP 99925585A EP 1091726 A2 EP1091726 A2 EP 1091726A2
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EP
European Patent Office
Prior art keywords
methyl
acid
phthalimidinoglutaric
disease
phthalimidinoglutaric acid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP99925585A
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German (de)
English (en)
Inventor
Jamshed H. Shah
Glenn M. Swartz
Adonia E. Papathanassiu
William E. Fogler
John W. Madsen
Shawn J. Green
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Childrens Medical Center Corp
Original Assignee
Childrens Medical Center Corp
Entremed Inc
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Publication of EP1091726A2 publication Critical patent/EP1091726A2/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/46—Iso-indoles; Hydrogenated iso-indoles with an oxygen atom in position 1
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • 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

  • This invention is related to derivatives of 2-methyl glutamic acid, namely 2-methyl-2-phthalimidinoglutaric acid and hydroxylated derivatives of 2-phthalimidinoglutaric. More particularly, the invention relates to the preparation of analogs of 2-phthalimidinoglutaric acid and the separation of the enantiomers of 2-methyl-2-phthalimidinoglutaric acid. Further, the invention relates to the use of such compounds for the treatment of cancer and for the treatment of angiogenesis-associated diseases. BACKGROUND OF THE INVENTION
  • Angiogenesis is the generation of new blood vessels into a tissue or organ. Under normal physiological conditions, humans and animals undergo angiogenesis only in very specific, restricted situations. For example, angiogenesis is normally observed in wound healing, fetal and embryonal development, and formation of the corpus luteum, endometrium and placenta.
  • Angiogenesis is controlled through a highly regulated system of angiogenic stimulators and inhibitors.
  • the control of angiogenesis has been found to be altered in certain disease states and, in many cases, pathological damage associated with the diseases is related to uncontrolled angiogenesis. Both controlled and uncontrolled angiogenesis are thought to proceed in a similar manner.
  • Endothelial cells and pericytes surrounded by a basement membrane, form capillary blood vessels.
  • Angiogenesis begins with the erosion of the basement membrane by enzymes released by endothelial cells and leukocytes. Endothelial cells, lining the lumen of blood vessels, then protrude through the basement membrane.
  • Angiogenic stimulants induce the endothelial cells to migrate through the eroded basement membrane.
  • the migrating cells form a "sprout" off the parent blood vessel where the endothelial cells undergo mitosis and proliferate.
  • the endothelial sprouts merge with each other to form capillary loops, creating a new blood vessel.
  • Persistent, unregulated angiogenesis occurs in many disease states, tumor metastases, and abnormal growth by endothelial cells.
  • the diverse pathological disease states in which unregulated angiogenesis is present have been grouped together as angiogenic-dependent or angiogenic-associated diseases.
  • ocular neo vascular disease This disease is characterized by invasion of new blood vessels into the structures of the eye, such as the retina or cornea. It is the most common cause of blindness and is involved in approximately twenty eye diseases. In age- related macular degeneration, the associated visual problems are caused by an ingrowth of choroidal capillaries through defects in Bruch's membrane with proliferation of fibrovascular tissue beneath the retinal pigment epithelium. Angiogenic damage is also associated with diabetic retinopathy, retinopathy of prematurity, corneal graft rejection, neovascular glaucoma, and retrolental fibroplasia.
  • corneal neovascularization include, but are not limited to, epidemic keratoconjunctivitis, Vitamin A deficiency, contact lens overwear, atopic keratitis, superior limbic keratitis, pterygium keratitis sicca, sjogrens disease, acne rosacea, phylectenulosis, syphilis, Mycobacteria infections, lipid degeneration, chemical burns, bacterial ulcers, fungal ulcers, Herpes simplex infection, Herpes zoster infections, protozoan infections, Kaposi's sarcoma, Mooren's ulcer, Terrien's marginal degeneration, marginal keratolysis, rheumatoid arthritis, systemic lupus, polyarteritis, trauma, Wegener's sarcoidosis, scleritis, Stevens- Johnson's disease, pemphigoid, and radial keratotomy.
  • Diseases associated with retinal/choroidal neovascularization include, but are not limited to, diabetic retinopathy, macular degeneration, sickle cell anemia, sarcoidosis, syphilis, pseudoxanthoma elasticum, Paget's disease, vein occlusion, artery occlusion, carotid obstructive disease, chronic uveitis/vitritis, Mycobacteria infections, lyme's disease, systemic lupus erythematosis, retinopathy of prematurity, Eales' disease, Behcet's disease, infections causing retinitis or choroiditis, presumed ocular histoplasmosis, Best's disease, myopia, optic pits, Stargardt's disease, pars planitis, chronic retinal detachment, hyperviscosity syndromes, toxoplasmosis, trauma and post-laser complications.
  • Other eye-related diseases include, but are not limited to, diseases
  • angiogenesis associated disease is rheumatoid arthritis.
  • the blood vessels in the synovial lining of the joints undergo angiogenesis.
  • the endothelial cells release factors and reactive oxygen species that lead to pannus growth and cartilage destruction.
  • Angiogenesis may also play a role in osteoarthritis.
  • the activation of the chondrocytes by angiogenic-related factors contributes to the destruction of the joint.
  • the angiogenic factors promote new bone growth.
  • Therapeutic intervention that prevents the bone destruction could halt the progress of the disease and provide relief for persons suffering with arthritis.
  • Chronic inflammation may also involve pathological angiogenesis.
  • ulcerative colitis and Crohn's disease show histological changes with the ingrowth of new blood vessels and the inflamed tissues.
  • Bartonelosis a bacterial infection found in South America, can result in a chronic stage that is characterized by proliferation of vascular endothelial cells.
  • Another pathological role associated with angiogenesis is found in atherosclerosis. The plaques formed within the lumen of blood vessels have been shown to have angiogenic stimulatory activity.
  • Tumor 'take' has occurred, every increase in tumor cell population must be preceded by an increase in new capillaries converging on the tumor.
  • Tumor 'take' is currently understood to indicate a prevascular phase of tumor growth in which a population of tumor cells occupying a few cubic millimeters volume, and not exceeding a few million cells, can survive on existing host microvessels. Expansion of tumor volume beyond this phase requires the induction of new capillary blood vessels. For example, pulmonary micrometastases in the early prevascular phase in mice would be undetectable except by high power microscopy on histological sections.
  • Tumors grown in isolated perfused organs where blood vessels do not proliferate are limited to 1 -2 mm 3 but expand rapidly to >1000 times this volume when they are transplanted to mice and become neovascularized. (Folkman, et ah, Annals of Surgery, 164:491-502 (1966)).
  • Tumor growth in the avascular cornea proceeds slowly and at a linear rate, but switches to exponential growth after neovascularization. (Gimbrone, Jr., et al, J. Nat. Cancer Inst., 52:421-27 (1974)).
  • Tumors suspended in the aqueous fluid of the anterior chamber of the rabbit eye remain viable, avascular, and limited in size to ⁇ 1 mm 3 . Once they are implanted on the iris vascular bed, they become neovascularized and grow rapidly, reaching 16,000 times their original volume within 2 weeks. (Gimbrone, Jr., et al., J. Exp. Med., 136:261-76).
  • Vascular casts of metastases in the rabbit liver reveal heterogeneity in size of the metastases, but show a relatively uniform cut-off point for the size at which vascularization is present.
  • Tumors are generally avascular up to 1 mm in diameter, but are neovascularized beyond that diameter. (Lien, et al, Surgery, 68:334-40 (1970)).
  • pre-vascular hyperplastic islets are limited in size to ⁇ 1 mm. At 6-7 weeks of age, 4-10% of the islets become neovascularized, and from these islets arise large vascularized tumors of more than 1000 times the volume of the pre-vascular islets. (Folkman, et ah, Nature, 339:58-61 (1989)).
  • VEGF vascular endothelial growth factor
  • Anti-bFGF monoclonal antibody causes 70% inhibition of growth of a mouse tumor which is dependent upon secretion of bFGF as its only mediator of angiogenesis. The antibody does not inhibit growth of the tumor cells in vitro. (Hori, et al, Cancer Res., 51:6180-84 (1991)).
  • bFGF Intraperitoneal injection of bFGF enhances growth of a primary tumor and its metastases by stimulating growth of capillary endothelial cells in the tumor.
  • the tumor cells themselves lack receptors for bFGF, and bFGF is not a mitogen for the tumors cells in vitro.
  • a specific angiogenesis inhibitor (AGM-1470) inhibits tumor growth and metastases in vivo, but is much less active in inhibiting tumor cell proliferation in vitro. It inhibits vascular endothelial cell proliferation half-maximally at 4 logs lower concentration than it inhibits tumor cell proliferation. (Ingber, et al., Nature, 48:555-57 (1990)). There is also indirect clinical evidence that tumor growth is angiogenesis dependent.
  • Carcinoma of the ovary metastasizes to the peritoneal membrane as tiny avascular white seeds (1-3 mm 3 ). These implants rarely grow larger until one or more of them becomes neovascularized.
  • Metastasis from human cutaneous melanoma is rare prior to neovascularization. The onset of neovascularization leads to increased thickness of the lesion and an increased risk of metastasis. (Srivastava, et al, Am. J. Pathol, 133:419-23 (1988)).
  • bladder cancer the urinary level of an angiogenic protein, bFGF, is a more sensitive indicator of status and extent of disease than is cytology. (Nguyen, et al, f. Nat. Cancer Inst., 85:241-42 (1993)).
  • angiogenesis plays a major role in the metastasis of cancer. If this angiogenic activity could be repressed or eliminated, then the tumor, although present, would not grow. In the disease state, prevention of angiogenesis could avert the damage caused by the invasion of the new microvascular system. Therapies directed at control of the angiogenic processes could lead to the abrogation or mitigation of these diseases.
  • Angiogenesis has been associated with a number of different types of cancer, including solid tumors and blood-borne tumors.
  • Solid tumors with which angiogenesis has been associated include, but are not limited to, rhabdomyosarcomas, retinoblastoma, Ewing's sarcoma, neuroblastoma, and osteosarcoma.
  • Angiogenesis is also associated with blood-borne tumors, such as leukemias, any of various acute or chronic neoplastic diseases of the bone marrow in which unrestrained proliferation of white blood cells occurs, usually accompanied by anemia, impaired blood clotting, and enlargement of the lymph nodes, liver and spleen.
  • angiogenesis plays a role in the abnormalities in the bone marrow that give rise to leukemia-like tumors.
  • a hemangioma is a tumor composed of newly-formed blood vessels. In most cases the tumors are benign and regress without intervention. In more severe cases, the tumors progress to large cavernous and infiltrative forms and create clinical complications. Systemic forms of hemangiomas, hemangiomatoses, have a high mortality rate. Therapy -resistant hemangiomas exist that cannot be treated with therapeutics currently in use.
  • Angiogenesis is also responsible for damage found in heredity diseases such as Osier- Weber-Rendu disease, or heredity hemorrhagic telangiectasia. This is an inherited disease characterized by multiple small angiomas, tumors of blood or lymph vessels. The angiomas are found in the skin and mucous membranes, often accompanied by epitaxis (nose bleeds) or gastrointestinal bleeding and sometimes with pulmonary or hepatitic arteriovenous fistula.
  • composition and method which can inhibit angiogenesis.
  • composition and method which can inhibit the unwanted growth of blood vessels, especially in tumors.
  • Angiogenesis is also involved in normal physiological processes, such as reproduction and wound healing. Angiogenesis is an important step in ovulation and also in implantation of the blastula after fertilization. Prevention of angiogenesis could be used to induce amenorrhea, to block ovulation, or to prevent implantation by the blastula. In wound healing, excessive repair or fibroplasia can be a detrimental side effect of surgical procedures and may be caused or exacerbated by angiogenesis. Adhesions are a frequent complication of surgery and lead to problems such as small bowel obstruction.
  • Interferon a 4 kDa glycoprotein from bovine vitreous humor and a cartilage derived factor
  • a 4 kDa glycoprotein from bovine vitreous humor and a cartilage derived factor have been used to inhibit angiogenesis.
  • Cellular factors such as interferon, inhibit angiogenesis.
  • interferon alpha or human interferon beta have been shown to inhibit tumor-induced angiogenesis in mouse dermis stimulated by human neoplastic cells.
  • Interferon beta is also a potent inhibitor of angiogenesis induced by allogeneic spleen cells. (Sidky, et al, Cancer Res., 47:5155-61(1987)).
  • Thalidomide is a hypnosedative that has been successfully used to treat a number of angiogenesis- associated diseases, such as rheumatoid arthritis (Gutierrez- Rodriguez, Arthritis Rheum., 27 (10): 1118-21 (1984); Gutierrez- Rodriguez, et al, J. Rheumatol, 16(2): 158-63 (1989)), Behcet's disease (Handley, et al, Br. J.
  • thalidomide Although thalidomide has minimal side effects in adults, it is a potent teratogen. Thus, there are concerns regarding its use in women of child-bearing age. Although minimal, there are a number of side effects which limit the desirability of thalidomide as a treatment. One such side effect is drowsiness. In a number of therapeutic studies, the initial dosage of thalidomide had to be reduced because patients became lethargic and had difficulty functioning normally. Another side effect limiting the use of thalidomide is peripheral neuropathy, in which individuals suffer from numbness and disfunction in their extremities.
  • the present invention provides new derivatives to 2- methyl glutamic acid, which are analogs of 2- phthalimidinoglutaric acid. Specifically, the present invention provides a new compound, 2-methyl-2-phthalimidinoglutaric acid and a process for its production. The present invention also provides for the individual (R) and (S) enantiomers of DL-2- methyl-2-phthalimidinoglutaric acid and processes for separating the (R) and (S) enantiomers.
  • 2-methyl-2-phthalimidinoglutaric acid (2-Me-EM- 138) is a derivative of 2-phthalimidinoglutaric acid (EM-138) which has been shown by the present inventors to inhibit angiogenesis.
  • the invention also provides methods for inhibiting angiogenesis and for treating angiogenesis-associated diseases with DL-2-methyl-2-phthalimidinoglutaric acid and with each of the individual enantiomers, R-(+)-2-methyl-2-phthalimidinoglutaric acid and S-(-)-2-methyl-2-phthalimidinoglutaric acid.
  • the invention provides for hydroxylated derivatives of 2-phthalimidinoglutaric and processes for the preparation of such derivatives.
  • the invention also provides for pharmaceutical compositions containing these derivatives and for their use in inhibiting angiogenesis and treating angiogenesis associated diseases.
  • Yet another object of the present invention is to provide hydroxylated derivatives of 2-phthalimidinoglutaric acid. It is another object of the present invention to provide a process for the preparation of hydroxylated analogs of 2-phthalimidinoglutaric acid.
  • the present invention provides for a method of controlling wound healing.
  • the present invention also provides for a method of controlling wound healing by administering analogs of 2- phthalimidinoglutaric acid. Further, the present invention provides for a method of controlling wound healing by administering DL-2-methyl-2- phthalimidinoglutaric acid, (R)-(+)-2-methyl-2-phthalimidino- glutaric acid, or (S)-(-)-2-methyl-2-phthalimidinoglutaric acid.
  • the present invention also provides for a method of controlling wound healing by administering hydroxylated analogs of 2-phthalimidinoglutaric acid.
  • Another object of the present invention is to induce abortion by administering DL-2-methyl-2-phthalimidinoglutaric acid, (R)-(+)-2-methyl-2-phthalimidinoglutaric acid, or (S)-(-)-2- methyl-2-phthalimidinoglutaric acid.
  • Figure 1 depicts the synthesis of DL-2-methyl-2- phthalimidinoglutaric acid and separation of the (R) and (S) enantiomers by chiral HPLC.
  • Figures 2a and 2b depict the synthesis of DL-2- methyl-2-phthalimidinoglutaric acid dimethyl ester, its separation of the (R) and (S) enantiomers using ChiroCLECTM-BL and hydrolysis to form (R)-(+)-2-methyl-2-phthalimidinoglutaric acid and (S)-(-)-2-methyl-2-phthalimidinoglutaric acid.
  • Figure 3 depicts the synthesis of hydroxylated derivatives of 2-phthalimidinoglutaric.
  • Figure 4 shows the effect of EM-138 as compared to thalidomide administered intraperitoneally on the inhibition of metastasis in B16-BL6 melanoma cells.
  • Figure 5 shows the effect of EM-138 as compared to thalidomide administered orally on the inhibition of metastasis in B 16-BL6 melanoma cells.
  • Figure 6 shows the effect of the number of treatments on the activity of 2-phthalimidinoglutaric acid in the B16-BL6 model.
  • Figure 7 shows the effect of initial treatment time on EM-138 activity in B 16/BL6 melanoma cells.
  • FIG 8 shows the lung macropathology of mice treated with 2-phthalimidinoglutaric acid (EM-138).
  • FIG 9 shows the lung histopathology of mice treated with 2-phthalimidinoglutaric acid (EM-138).
  • Figure 10 depicts the crystalline structure of 2- methyl-2-phthalimidinoglutaric acid.
  • Figure 11 shows the chiral resolution of the (R) and (S) enantiomers of DL-2-methyl-2-phthalimidinoglutaric acid by HPLC using CH 3 CN/MeOH/H 2 0/HOAc (1: 1:5:0.1) as the eluant at a flow rate of 2 ml/min at 230 nm.
  • Figure 12 shows the effect of optically-pure enantiomers of 2-methyl-2-phthalimidinoglutaric acid on B16- BL6 melanoma metastases.
  • FIG. 13 shows the relative anti-tumor activity of thalidomide, EM-138, and analogs of EM-138.
  • T/C is the ratio of tumors to control. Thus, the lower the T/C ratio the greater the tumor inhibitory activity of the compound.
  • the present invention provides that the compound 2- phthalimidinoglutaric acid (EM-138) has angiogenesis inhibitory activity and is useful for the treatment of a number of diseases, including various cancers and macular degeneration.
  • This compound has the following structure:
  • 2-phthalimidinoglutaric acid (EM-138) is a stable, orally-active analog of thalidomide. Unlike thalidomide, it is relatively resistant to hydrolysis. It is a potent inhibitor of metastases. Even a single dose is capable of inhibiting metastasis by 50%, and a dose of 0.8 mmol/kg/day has been shown to inhibit metastasis by greater than 90%.
  • one enantiomer of a compound often contains a significantly higher level of beneficial activity when compared to the other enantiomer. It has also been found that in some situations, one of the enantiomers provides beneficial effects while the other contributes to the toxicity or side effects of the drug.
  • the compound may be synthesized in a number of ways.
  • the preferred method of synthesis is from 2- methylglutamic acid.
  • the 2-methylglutamic acid, phthalic anhydride, and an amine, such as triethyl amine, diethyl amine, or pyridine, are mixed in an anhydrous solvent, such as anhydrous toluene.
  • the mixture is then heated under reflux followed by evaporation of the solvents.
  • the intermediate, 2-methyl-N- phthaloylglutamic acid is then crystallized and recovered.
  • the intermediate is then dissolved in acid, such as glacial acetic acid, followed by the addition of zinc dust.
  • acid such as glacial acetic acid
  • the mixture is then heated under reflux in an inert atmosphere, such as nitrogen or argon.
  • the 2-methyl-2-phthalimidinoglutaric acid is then recovered and purified, for example, by recrystallization or elution on a silica gel column.
  • angiogenesis-associated diseases One angiogenesis-associated group of diseases is cancer. Numerous tumors, including solid tumors and blood-borne tumors, require angiogenesis to grow beyond a very small size. Inhibition of angiogenesis will result in inhibition of growth of the tumor.
  • Examples of specific types of cancer which can be treated with 2- methyl-2-phthalimidinoglutaric acid and other derivatives encompassed by the present invention include, but are not limited to, prostate cancer, breast cancer, cervical cancer, uterine cancer, ovarian cancer, gliomas, hemangiomas, Kaposi's sarcoma, pancreatic cancer, retinoblastomas, melanomas, bladder cancer, rhabdomyosarcomas, retinoblastomas, Ewing's sarcoma, neuroblastomas, osteosarcoma, leukemia, and various acute and chronic neoplastic diseases of the bone marrow.
  • the compound, 2-methyl-2-phthalimidinoglutaric acid also inhibits metastases of existing tumors.
  • metastases which can be inhibited include, but are not limited to, lung metastases, liver metastases, and peritoneal metastases.
  • angiogenesis-associated diseases occur in and around the eye.
  • a further group of angiogenesis-associated diseases are those characterized by tissue ulceration or breakdown. A number of these diseases also affect the eyes.
  • Such diseases which can be treated with 2-methyl-2-phthalimidinoglutaric acid and other derivatives encompassed by the present invention include, but are not limited to, sjogrens disease, ulcerative colitis, Crohn's disease, Bartonelosis, acne rosacea, syphilis, sarcoidosis, chemical burns, bacterial ulcers, fungal ulcers, Behcet's syndrome, Stevens- Johnson's disease, Mycobacteria infections, Herpes simplex infections, Herpes zoster infections, protozoan infections, Mooren's ulcer, leprosy, Wegener's sarcoidosis, and pemphigoid.
  • angiogenesis-associated diseases or disorders which can be treated with 2-methyl-2-phthalimidinoglutaric acid and other derivatives encompassed by the present invention include, but are not limited to, rheumatoid arthritis, osteoarthritis, lupus, systemic lupus erythematosis, polyarteritis, artery occlusion, vein occlusion, carotid obstructive disease, sickle cell anemia, pseudoxanthoma elasticum, Paget's disease, lyme's disease, Best's disease, Eale's disease, Stargardt's disease, toxoplasmosis, phylectenulosis, lipid degeneration, chronic inflammation, atherosclerosis, hereditary diseases, such as Osier- Weber-Rendu disease.
  • the present compound can also be used to control wound healing by inhibiting the formation of adhesions and scars, to induce amenorrhea, and to induce abortion by blocking ovulation or preventing implantation of the blastula.
  • the enantiomers of DL-2-methyl-2-phthalimidinoglutaric acid must first be separated. Separation may be accomplished by a number of different methods.
  • the enantiomers of DL-2-methyl-2- phthalimidinoglutaric acid are resolved by chiral high pressure liquid chromatography (HPLC) column. The sample is dissolved in an appropriate solvent and placed on the column. The sample is eluted then with a solvent mixture, such as a mixture of CH 3 CN/MeOH/H 2 0/HOAc (1: 1:5:0.1).
  • HPLC high pressure liquid chromatography
  • the enantiomers are separated by first forming an ester of DL-2-methyl-2- phthalimidinoglutaric acid.
  • the ester may be produced by any known method.
  • the particular ester formed is not critical.
  • Nonlimiting examples of esters which can be formed include methyl esters, ethyl esters, propyl esters, and butyl esters.
  • the dimethyl ester is preferred.
  • the esters are then separated using a hydrolysis agent which is enantiomerically specific, for example, ChiroCLECTM- BL.
  • ChiroCLECTM-BL hydrolyzes one or both of the esters of only one of the enanatiomers, without affecting the other enantiomer.
  • This enantiomerically-specific ester hydrolysis allows for the subsequent separation of the enantiomers using silica gel chromatography.
  • the esters are completely hydrolyzed to form the corresponding (R) and (S) acids. Hydrolysis may be performed in any manner.
  • One preferred method of hydrolyzing the glutaric acid esters is by treatment with a 1: 1 mixture of glacial acetic acid and concentrated hydrochloric acid.
  • the present inventors have also synthesized analogs of EM-138 containing hydroxyl groups on the benzene ring of the phthalimidino group. These compounds have the following structure:
  • each of R 3 and R 4 are independently H or OH.
  • the preferred method of synthesis is from glutamic acid.
  • Glutamic acid is reacted with phthalic anhydride or a derivative of phthalic anhydride under reflux in a solvent, such as pyridine, followed by the addition of diacetate to the reaction mixture.
  • the intermediate produced is then hydrolyzed in an acid medium which opens the cyclic anhydride to form the glutaric acid derivative.
  • the glutaric acid intermediate is then dissolved in acid, such as glacial acetic acid, followed by the addition of zinc dust.
  • the compounds of the present invention may be administered orally, parenterally, rectally, vaginally, topically, transdermally, intravenously, intramuscularly, intraperatoneally, subcutaneously and the like.
  • the dosage of the active compound will, of course, vary depending upon the subject to be treated, the particular disease or condition to be treated, the seriousness of the disease or condition, the route of administration, and the judgment of the prescribing practitioner. Determination of the dosage on the basis of such factors is within the level of ordinary skill in the art. In general, the dosage will range from approximately 100 mg/kg/day to approximately 2000 mg/kg/day.
  • the compounds of the present invention can be conveniently formulated into pharmaceutical compositions in association with a pharmaceutically acceptable carrier.
  • Remington's Pharmaceutical Sciences, latest edition, by E.W. Martin discloses typical carriers and conventional methods of preparing pharmaceutical compositions which may be employed to prepare the compositions of the present invention.
  • the compounds of the present invention can also be administered in conjunction with other active compounds, such as other anti-angiogenic agents.
  • the pharmaceutical compositions may be in the form of solid, semi-solid, or liquid dosage forms.
  • dosage forms include, but are not limited to, tablets, pills, capsules, suppositories, sachets, granules, powders, creams, lotions, ointments, patches, liquid solutions, suspensions, and dispersions, emulsions, syrups, and the like.
  • the active ingredient may also be encapsulated in liposomes, microparticles, or microcapsules, and the like.
  • nontoxic carriers include, but are not limited to, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, talc, cellulose, glucose, sucrose, dextrose, glycerol, magnesium carbonate, triglycerides, oils, solvents, sterile water, and isotonic saline.
  • Solid compositions such as tablets, pills, granules, etc. may conveniently be coated.
  • compositions for intravenous administration are solutions in sterile isotonic aqueous buffer and may include a local anesthetic to ameliorate pain at the injection site.
  • the pharmaceutical may also contain minor amounts of nontoxic auxiliary substances, such as wetting agents, emulsifying agents, pH buffering agents, and the like.
  • auxiliary substances include, but are not limited to, sodium acetate, sorbitan monolaurate, triethanolamine, and triethanolamine oleate.
  • the compositions of the present invention may also include such excipients as stabilizers, antioxidants, binders, coloring agents, flavoring agents, preservatives, and thickeners.
  • B16-BL6 melanoma cells (5 x 10 4 ) were injected intravenously into the tail veins of C57B1/6 mice. Three days later, the mice were treated intraperitoneally with increasing doses of thalidomide or 2-phthalimidinoglutaric acid (EM-138) on alternate days. Fourteen days after tumor cell inoculation, the lungs were removed from the mice and the surface pulmonary metastases were counted. The results of this experiment are shown in Figure 4. The values shown are the mean of 5 mice per group. The bars on the graph represent the standard deviation.
  • B16-BL6 melanoma cells (5 x 10 4 ) were injected intravenously into the tail veins of C57B1/6 mice. Three days later, the mice were treated orally with increasing doses of thalidomide or 2-phthalimidinoglutaric acid (EM-138) on alternate days. Fourteen days after tumor cell inoculation, the lungs were removed from the mice and the surface pulmonary metastases were counted. The results of this experiment are shown in Figure 5. The values shown are the mean of 5 mice per group. The bars on the graph represent the standard deviation.
  • B16-BL6 melanoma cells (5 x 10 4 ) were injected intravenously into the tail veins of C57B1/6 mice. Three days later, the mice received a gavage treatment with 0.8 mmol/kg of 2-phthalimidinoglutaric acid (EM-138). The mice received either a single treatment, five treatments on alternate days, or one treatment every day for eleven days. Fourteen days after tumor cell inoculation, the lungs were removed from the mice and the surface pulmonary metastases were counted. The results of this experiment are shown in Figure 6. The values shown are the mean of 5 mice per group. The bars on the graph represent the standard deviation.
  • B16-BL6 melanoma cells (5 x 10 4 ) were injected intravenously into the tail veins of C57B1/6 mice.
  • the mice were given a single oral treatment of 2-phthalimidinoglutaric acid (EM-138) of 0.8 mmol/kg. The treatment was initiated one day prior to tumor cells or on day 1, 2, 3, 5, or 7 after tumor cells.
  • EM-138 2-phthalimidinoglutaric acid
  • the results of this experiment are shown in Figure 7.
  • the values shown are the mean of 5 mice per group.
  • the bars on the graph represent the standard deviation.
  • mice with pulmonary B 16-BL6 metastases were orally administered either 0.5% carboxymethylcellulose or 0.8 mmol kg of 2-phthalimidinoglutaric acid (EM-138).
  • the results of this experiment are show in Figure 8 (0.5% carboxymethylcellulose (left panel) and 0.8 mmol kg EM-138 (right panel).
  • EXAMPLE 10 Treatment of pulmonary metastasis by 2-methyl-2- phthalimidino glutaric acid.
  • B16-BL6 melanoma cells (5 x 10 4 ) were injected intravenously into the tail veins of C57B1/6 mice.
  • the mice were given intraperitoneal (i.p.) treatments of either 1.0 ml 2.8% DMSO alone (control), 1.0 ml (5.0 mg/ml 2.8% DMSO) 2- phthalimidinoglutaric acid (EM-138) in DMSO, or 1.0 ml (5.0 mg/ml 2.8%) 2-methyl-2-phthalimidinoglutaric acid (2-Me-EM- 138) in DMSO four times a day beginning 72 hours after injection of the tumor cells. Fourteen days after tumor cell inoculation, the lungs were removed from the mice and the surface pulmonary metastases were counted. The results of this experiment are shown in the following table.
  • n number of mice per sample group p ⁇ 0.01, as compared to DMSO-treated control group
  • EXAMPLE 14 Treatment of pulmonary metastasis by R-(+)-2-methyl-2- phthalimidino glutaric acid and S(-)-2-methyl-2- phthalimidino glutaric acid.
  • B16-BL6 melanoma cells (5 x 10 4 ) were injected intravenously into the tail veins of C57B1/6 mice.
  • the mice were given intraperitoneal (i.p.) treatments of either 1.0 ml 2.8% DMSO alone (control), 1.0 ml (5.0 mg/ml) DL-2-methyl-2- phthalimidinoglutaric acid (racemate) in 2.8% DMSO, 1.0 ml (5.0 mg/ml) (R)-(+)-2-methyl-2-phthalimidinoglutaric acid (JS-2-13- Pl) in 2.8% DMSO, or (S)-(-)-2-methyl-2-phthalimidinoglutaric acid (JS-2-13-P2) in 2.8% DMSO four times a day beginning 72 hours after injection of the tumor cells.
  • B16-BL6 melanoma cells (5 x 10 4 ) were injected intravenously into the tail veins of C57B1/6 mice.
  • the mice were given intraperitoneal (i.p.) treatments of one of the following solutions four times a day beginning 72 hours after injection of the tumor cells.
  • a T/C is defined as the ratio of lung metastases of treated (T) animals vs. non-treated or control (C) animals.

Abstract

La présente invention concerne des analogues nouveaux et utiles de l'acide 2-phthalimidinoglutarique. Les analogues comprennent l'acide DL-2- méthyl-2- phthalimidinoglutarique et des analogues hydroxylés de 2-phthalimidinoglutarique. L'invention englobe également des procédés de fabrication de ces analogues. Elle concerne également les deux enantiomères de l'acide DL-2- méthyl-2- phthalimidinoglutarique, l'acide (R)-(+)-2- méthyl-2- phthalimidinoglutarique et l'acide (S)-(-)-2-méthyl-2-phthalimidinoglutarique ainsi que les procédés permettant de séparer ces énantiomères individuels du racémique vrai. De plus, cette invention, s'intéresse à des méthodes permettant d'inhiber l'angiogenèse et de traiter des affections en rapport avec l'angiogenèse, dont le cancer et la dégénérescence maculaire, par administration d'un ou de plusieurs de ces composés.
EP99925585A 1998-05-11 1999-05-11 Analogues de l'acide 2-phthalimidinoglutarique Withdrawn EP1091726A2 (fr)

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US108037P 1998-11-12
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US7776907B2 (en) 2002-10-31 2010-08-17 Celgene Corporation Methods for the treatment and management of macular degeneration using cyclopropyl-N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-3-oxoisoindoline-4-yl}carboxamide
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CA2808646C (fr) 2003-09-17 2016-08-23 The Government Of The United States Of America, As Represented By The Secretary Of The Department Of Health And Human Services Analogues de la thalidomide comme modulateurs tnf-alpha
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US9617212B2 (en) 2013-12-17 2017-04-11 Controlled Chemicals, Inc. Isoindolin-1-ones as macrophage migration inhibitory factor (MIF) inhibitors
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KR100699968B1 (ko) 2007-03-28
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