WO2002040018A1 - Traitement du glaucome et de l'hypertension oculaire - Google Patents

Traitement du glaucome et de l'hypertension oculaire Download PDF

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Publication number
WO2002040018A1
WO2002040018A1 PCT/US2000/031151 US0031151W WO0240018A1 WO 2002040018 A1 WO2002040018 A1 WO 2002040018A1 US 0031151 W US0031151 W US 0031151W WO 0240018 A1 WO0240018 A1 WO 0240018A1
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WO
WIPO (PCT)
Prior art keywords
imidazole
trichlorotrityl
chlorotrityl
mmol
steroidal glucocorticoid
Prior art date
Application number
PCT/US2000/031151
Other languages
English (en)
Inventor
Abbot F. Clark
Raymond E. Conrow
Original Assignee
Alcon, Inc.
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Alcon, Inc. filed Critical Alcon, Inc.
Priority to AU2001216038A priority Critical patent/AU2001216038A1/en
Priority to PCT/US2000/031151 priority patent/WO2002040018A1/fr
Publication of WO2002040018A1 publication Critical patent/WO2002040018A1/fr

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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • 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
    • 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

Definitions

  • This invention is directed to the use of non-steroidal glucocorticoid antagonists for treating glaucoma and ocular hypertension.
  • lOP intraocular pressure
  • beta- blockers and carbonic anhydrase inhibitors lower lOP by decreasing aqueous humor production. It would be advantageous to control lOP without decreasing aqueous humor production as the aqueous humor is the fluid that nourishes the anterior parts of the eye that are devoid of blood vessels, such as, the cornea and the lens.
  • Non-steroidal glucocorticoid antagonists and their pharmaceutical formulations are useful for treating glaucoma and ocular hypertension.
  • the invention is also directed to methods for controlling glaucoma and ocular hypertension using NSGAs, some of which are novel.
  • Glaucomatous damage to vision is usually due to elevated lOP in a pressure sensitive eye.
  • TM trabecular meshwork
  • Glucocorticoids have been associated w ' ⁇ th the development of ocular hypertension and primary open angle glaucoma (Kass, et al., Corticosteroid-induced glaucoma, In Ritch, R., Shields, M. B., Krupin, T. (eds.), The Glaucomas, The C. V. Mosby Company, St. Louis, MO, pp.
  • Glaucoma patients have also been reported to have higher levels of the endogenous glucocorticoid, cortisol (Rozsival, et al., Aqueous humour and plasma cortisol levels in glaucoma and cataract patients, Current Eye Research 1: 391-396 (1981); Ray, et al., Plasma cortisol in glaucoma, Ann. Ophthalmol. 9: 1151-1154 (1977); and Schwartz, Increased plasma free cortisol in ocular hypertension and open angle glaucoma, Arch. Ophthalmol. 105: 1060-1065 (1987)).
  • trabecular meshwork cells have glucocorticoid receptors and that glucocorticoid binding with these receptors causes a change in trabecular meshwork cell gene expression.
  • Known manifestations of this change include a reorganization of the cytoskeleton (Wilson, et al., Dexamethasone induced ultrastructural changes in cultured human trabecular meshwork cells, Cur. Eye Res. 12: 783-793 (1993) and Clark, et al., Glucocorticoid-induced formation of cross-linked actin networks in cultured human trabecular meshwork cells, Invest. Ophthalmol. Vis. Sci.
  • the trabecular meshwork becomes "clogged" and unable to perform one of its most critical functions, that is, serving as a gateway for aqueous humor flow from the anterior chamber of the eye.
  • the intraocular pressure of the eye rises. If this state of elevated intraocular pressure is maintained or frequently occurs, the optic nerve head can be damaged resulting in the loss of visual field. Loss of visual field is the hallmark symptom associated with glaucoma.
  • Endogenous glucocorticoids may be responsible for producing the changes in the trabecular meshwork that lead to ocular hypertension and glaucoma. It is believed that non-steroidal glucocorticoid antagonists bind to the glucocorticoid receptor in trabecular meshwork cells, and thereby prevent binding of endogenous glucocorticoids to the glucocorticoid receptor. They may also displace endogenous glucocorticoids which are bound to glucocorticoid receptors.
  • Use of the compounds of the present invention is advantageous over existing therapies in that the compounds function at the disease site, that is, at the trabecular meshwork cell level, rather than indirectly addressing elevated intraocular pressure by suppressing aqueous humor formation.
  • Ketoconazole and clotrimazole are known glucocorticoid antagonists. (Loose, et al., Ketoconazole Binds to Glucocorticoid Receptors and Exhibits Glucocorticoid Antagonist Activity in Cultured Cells, J. Clin. Invest. 72: 404-408 (1983)). They are not known to be useful in treating or controlling glaucoma.
  • Non-steroidal glucocorticoid antagonists which are particularly useful in treating glaucoma or ocular hypertension have the following structure:
  • n 0,1 ,2;
  • R1 H, F, Cl, Br, R2, OR2, N(R2) 2 , COOH, CONH 2 , CONHR2, CON(R2) 2 , CH 2 N(CH 2 CH 2 )O;
  • R2 C Ce alkyl
  • Y N-imidazolyl, N-pyrrolidinyl, N-(2-hydroxymethyl)pyrrolidinyl, N-triazolyl, N-pyrazolyl each optionally substituted with CH 3 , SH or S-C(4-CI-C 6 H ) 3 ; OH, O(CH 2 ) 2 N(CH 2 CH 2 ) 2 O, O(CH 2 ) 2 N(CH 2 CH 2 ) 2 N(CH 2 ) 2 OH;
  • Most preferred compounds include the following specific compounds:
  • Topical formulations contain about 0.05 to 5 wt.% of a non-steroidal glucocorticoid antagonist.
  • Systemic formulations contain about 10 to 1000 mg.
  • the formulations can be administered systemically or topically, preferably topically, one to four times daily according to the discretion of a skilled clinician.
  • N-(r2-Fluoro-9-phenyl.fluorenyl)imidazole (3) To a stirred, ice-cooled solution of 2-fluorofluorenone (2.0 g, 10 mmol) in 15 mL of dry THF under N 2 was added 10 mL of 2.4 M phenyllithium solution in cyclohexane-Et 2 O (7:3), keeping T ⁇ 20°C. The mixture was quenched with water and the product isolated with EtOAc and purified by flash chromatography (7% EtOAc-hexanes) to give 2.52 g (90%) of 2-fluoro-9-phenylfluoren-9-ol. b.
  • Example 5(b) The procedure of Example 5(b) was followed, using 1.26 g (3.47 mmol) of tris(4-chlorophenyl)methanol, 0.52 g (5.1 mmol) of 1 ,2,4-triazole-3-thioI, 4.0 mL of CH 2 CI 2 and 1.25 mL (10 mmol) of BF 3 etherate. Isolation followed by flash chromatography (75 g SiO 2 , 40% EtOAc-hexanes) gave 0.51 g of the title compound, followed by 0.71 g of an unstable product that turned into the title compound up on standing in solution. A 0.44 g sample of the first-eluted material was recrystallized from MeOH giving 0.18 g of (15), m.p.
  • the procedure described for (13) was followed, using 1.47 g (4.7 mmol) of the chloride of Example 7(b), 0.55 g (5.5 mmol) of L-prolinol, 1.1 mL (6.3 mmol) of ethyldiisopropylamine and 10 mL of dry DMF. After 24 h, the crude product was isolated with EtOAc and purified by flash chromatography giving 0.84 g of a foam (major rotamer).
  • N-(2-[4,4'.4''-Trichlorotrityl.oxyethyl)morpholine (5.. a. Dry DMSO (20 mL) was added to 14 mmol of hexane-washed KH under Ar with stirring at RT. After H 2 evolution ceased, a solution of tris-(p-chlorophenyl) methanol (3.63 g, 10 mmol) in 25 mL dry DMSO was added, giving a deep red anion solution. After 5 min, 1-bromo-3-methyl-2-butene (2.0 mL, 19 mmol) was added and stirring continued for 1 h.
  • a solution of (2,6-dichloro-3-methylphenyl)diphenylmethanol (0.40 g, 1.2 mmol) and imidazole (0.50 g, 7.4 mmol) in 2 mL of acetic acid was heated to reflux for 0 2 h and then allowed to stand at RT for two days. The product was isolated by EtOAc/H 2 O partition followed by chromatography (75 g SiO 2 , 50% EtOAc- hexane) to give 0.40 g (87%) of (16) as a white foam.
  • Tablet 10-1000 mg of non-steroidal glucocorticoid antagonist with inactive ingredients such as cornstarch, lactose, colloidal silicon dioxide, microcrystalline cellulose, and magnesium stearate can be formulated according to procedures known to those skilled in the art of tablet formulation.

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des compositions d'antagonistes glucocorticoïdes non-stéroïdiens permettant de traiter un glaucome ou une hypertension oculaire, ainsi que des méthodes permettant d'utiliser ces compositions.
PCT/US2000/031151 2000-11-14 2000-11-14 Traitement du glaucome et de l'hypertension oculaire WO2002040018A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU2001216038A AU2001216038A1 (en) 2000-11-14 2000-11-14 Treatment of glaucoma and ocular hypertension
PCT/US2000/031151 WO2002040018A1 (fr) 2000-11-14 2000-11-14 Traitement du glaucome et de l'hypertension oculaire

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/US2000/031151 WO2002040018A1 (fr) 2000-11-14 2000-11-14 Traitement du glaucome et de l'hypertension oculaire

Publications (1)

Publication Number Publication Date
WO2002040018A1 true WO2002040018A1 (fr) 2002-05-23

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PCT/US2000/031151 WO2002040018A1 (fr) 2000-11-14 2000-11-14 Traitement du glaucome et de l'hypertension oculaire

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WO (1) WO2002040018A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994018967A1 (fr) * 1993-02-18 1994-09-01 President And Fellows Of Harvard College Traitements de maladies caracterisees par la neovascularisation
WO1999011605A1 (fr) * 1997-08-28 1999-03-11 Novartis Ag Certains acides 5-alkyl-2-arylaminophenylacetiques et leurs derives
WO1999032101A1 (fr) * 1997-12-19 1999-07-01 Alcon Laboratories, Inc. Traitement du glaucome glc1a par des antagonistes non steroidiens des glucocorticoides
WO2000007972A1 (fr) * 1998-08-05 2000-02-17 Karo Bio Ab Ligands du recepteur d'hormones thyroidienne et glucocorticoide utilises pour le traitement des troubles du metabolisme

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994018967A1 (fr) * 1993-02-18 1994-09-01 President And Fellows Of Harvard College Traitements de maladies caracterisees par la neovascularisation
WO1999011605A1 (fr) * 1997-08-28 1999-03-11 Novartis Ag Certains acides 5-alkyl-2-arylaminophenylacetiques et leurs derives
WO1999032101A1 (fr) * 1997-12-19 1999-07-01 Alcon Laboratories, Inc. Traitement du glaucome glc1a par des antagonistes non steroidiens des glucocorticoides
WO2000007972A1 (fr) * 1998-08-05 2000-02-17 Karo Bio Ab Ligands du recepteur d'hormones thyroidienne et glucocorticoide utilises pour le traitement des troubles du metabolisme

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AU2001216038A1 (en) 2002-05-27

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