WO1991015206A1 - Treatment of glaucoma and ocular hypertension with imidazole angiotensin-ii receptor antagonists - Google Patents

Treatment of glaucoma and ocular hypertension with imidazole angiotensin-ii receptor antagonists Download PDF

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Publication number
WO1991015206A1
WO1991015206A1 PCT/US1991/002119 US9102119W WO9115206A1 WO 1991015206 A1 WO1991015206 A1 WO 1991015206A1 US 9102119 W US9102119 W US 9102119W WO 9115206 A1 WO9115206 A1 WO 9115206A1
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Prior art keywords
carbon atoms
alkyl
methyl
imidazole
tetrazol
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PCT/US1991/002119
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French (fr)
Inventor
Arthur A. Patchett
Ronald Duane Smith
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E.I. Du Pont De Nemours And Company
Merck & Co., Inc.
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Publication of WO1991015206A1 publication Critical patent/WO1991015206A1/en

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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
    • A61K31/495—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
    • 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
    • A61K31/435—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
    • A61K31/535—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

Definitions

  • Glaucoma is an ocular disease complex associated with an elevated pressure within the eye, i.e., elevated intraocular pressure (IOP).
  • IOP intraocular pressure
  • Ocular hypertension i.e., a condition of elevated IOP, without optic nerve damage or
  • Glaucoma is among the leading causes of blindness in the U.S. today.
  • renin inhibitor identified as Abbott-64662 was found to decrease aqueous humor formation and lower the IOP in rabbits following topical application (Stein et al .
  • beta-blockers useful as antiglaucoma agents are disclosed in commonly-assigned U.S. Patent Application Publication No. 20110060600A1
  • U.S. Patent Application Publication No. 20110060600A1 discloses that beta-blockers useful as antiglaucoma agents are disclosed in commonly-assigned U.S. Patent Application Publication No. 20110060600A1
  • Timolol a group consisting of beta-blockers that are administered to the eye several times daily.
  • beta-blockers useful as antiglaucoma agents are disclosed in commonly-assigned U.S. Patent Application Publication
  • angiotensin II antagonist compound having the formula (I):
  • R 1 is 4-CO 2 H; 4-CO 2 R 9 ; -OSO 3 H; -SO 3 H; -C(CF 3 ) 2 OH;
  • R 2 is H; Cl; Br; I; F; NO 2 ; CN; alkyl of 1 to 4 carbon atoms; acyloxy of 1 to 4 carbon atoms; alkoxy of
  • R 3 is H; Cl, Br, I or F; alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms;
  • R 4 is CN, NO 2 or CO 2 R 11 ;
  • R 5 is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, alkenyl or alkynyl of 2 to 4 carbon atoms;
  • R 6 is alkyl of 2 to 10 carbon atoms, alkenyl or alkynyl of 3 to 10 carbon atoms or the same groups substituted with F or CO 2 R 14 ; cycloalkyl of 3 to 8 carbon atoms, cycloalkylalkyl of 4 to 10 carbon atoms; cycloalkylalkenyl or cycloalkylalkynyl of 5 to 10 carbon atoms; (CH 2 ) s z (CH 2 ) m R 5 optionally substituted with F or
  • phenyl or phenylalkyl where alkyl is 1 to 3 carbon atoms; or substituted phenyl or substituted phenylalkyl, where alkyl is 1 to 3 carbon atoms, substituted with one or two substituents selected from alkyl of 1 to 4 carbon atoms, F, Cl, Br, OH, OCH 3 , CF 3 , and COOR, where R is H, alkyl of 1 to 4 carbon atoms, or phenyl; vinyl; alkynyl of 2-10 carbon atoms; phenylalkynyl where the alkynyl portion is 2-6 carbon atoms; heteroaryl selected from 2-and 3-thienyl, 2- and 3-furyl, 2-, 3-, and 4-pyridyl, 2-pyrazinyl, 2-, 4-, and 5-pyrimidinyl, 3- and
  • 5-selenazolyl, 2-, 4-, and 5-oxazolyl 2- or 3-pyrrolyl, 3-, 4- or 5-pyrazolyl, and 2-, 4- or 5-imidazolyl; o-, m- or p-biphenylyl; o-, m- or p-phenoxyphenyl;
  • subsituents selected from halogen, alkoxy of 1-5 carbon atoms, alkyl of 1-5 carbon atoms, -NO 2 , -CN, -CF 3 ,
  • 2-naphthyl or substituted alkyl of 1 to 10 carbon atoms, alkenyl or alkynyl of 2 to 10 carbon atoms substituted with a substituted or unsubstituted
  • R 8 is H, CN, alkyl of 1 to 10 carbon atoms, alkenyl of 3 to 10 carbon atoms, or the same groups substituted with F; phenylalkenyl wherein the aliphatic portion is 2 to 6 carbon atoms; - (CH 2 ) m -imidazol-1-yl; - (CH 2 ) m -1,2,3-triazolyl optionally substituted with one or two groups selected from CO 2 CH 3 or alkyl of 1 to 4 carbon atoms; - (CH 2 ) s -tetrazolyl;
  • -CH CH(CH 2 ) 2 OCR 11 ; -(CH 2 ) s -CH-COR 16 ; -(CH 2 ) n CR 16 ;
  • R 10 is alkyl of 1 to 6 carbon atoms or
  • R 11 is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl or benzyl;
  • R 12 is H, methyl or benzyl
  • R 13 is -CO 2 H; -CO 2 R 9 ; -CH 2 CO 2 H, -CH 2 CO 2 R 9 ;
  • R 14 is H, alkyl or perfluoroalkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl or benzyl;
  • R 15 is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl, benzyl, acyl of 1 to 4 carbon atoms, phenacyl;
  • R 16 is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, (CH 2 ) p C 6 H 5 , OR 17 , or NR 18 R 19 ;
  • R 17 is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl or benzyl;
  • R 18 and R 19 independently are H, alkyl of 1 to 4 carbon atoms, phenyl, benzyl, ⁇ -methylbenzyl, or taken together with the nitrogen form a ring of the formula
  • Q is NR 20 , O or CH 2 ;
  • R 20 is H, alkyl of 1-4 carbon atoms, or phenyl
  • R 21 is alkyl of 1 to 6 carbon atoms, -NR 22 R 23 , or
  • NH 2 R 22 and R 23 independently are H, alkyl of 1 to 6 carbon atoms, benzyl, or are taken together as (CH 2 ) u where u is 3-6;
  • R 24 is H, CH 3 or -C 6 H 5 ;
  • R 25 is NR 27 R 28 , OR 28 , NHCONH 2 , NHCSNH 2 ,
  • R 26 is hydrogen, alkyl with from 1 to 6 carbon atoms, benzyl, or allyl;
  • R 27 and R 28 are independently hydrogen, alkyl with from 1 to 5 carbon atoms, or phenyl;
  • R 29 and R 30 are independently alkyl of 1-4 carbon atoms or taken together are -(CH 2 ) q -;
  • R 32 is H, NO 2 , NH 2 , OH or OCH 3 ;
  • X is a carbon-carbon s ingle bond, -CO-, -CH 2 - , -O-,
  • Y is O or S
  • Z is O, NR 11 , or S
  • n 1 to 5;
  • n 1 to 10;
  • p 0 to 3
  • r 0 to 2
  • s 0 to 5
  • t is 0 or 1;
  • X is a single bond, and R 13 is CO 2 H, or
  • R 13 must be in the ortho or meta position; or when R 1 and X are as above and R 13 is NHSO 2 CF 3 or NHSO 2 CH 3 , R 13 must be ortho;
  • R 13 must be ortho or meta ;
  • R 6 when R 1 is 4-CO 2 H or a salt thereof, R 6 cannot be S-alkyl;
  • X is -OCH 2 -, and R 13 is 2-CO 2 H, and R 7 is H then R 6 is not C 2 H 5 S;
  • R 6 is n-hexyl, then R 7 and R 8 are not both hydrogen;
  • R 6 is not methoxybenzyl
  • the R 6 group is not -F-CHCH 2 CH 2 CH 3 or CH 2 OH;
  • X is a single bond, R 7 is Cl, and R 8 is -CHO, then R 13 is not 3-(tetrazol-5-yl);
  • X is a single bond, R 7 is Cl, and R 8 is -CHO, then R 13 is not 4-(tetrazol-5-yl).
  • Preferred in the method of this invention are compounds having the formula (II):
  • R 1 is -CO 2 H; -NHSO 2 CF 3 ;
  • R 6 is alkyl of 3 to 10 carbon atoms, alkenyl of 3 to 10 carbon atoms, alkynyl of 3 to 10 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, benzyl substituted on the phenyl ring with up to two groups selected from alkoxy of 1 to 4 carbon atoms, halogen, alkyl of 1 to 4 carbon atoms, and nitro;
  • R 16 is H, alkyl of 1 to 5 carbon atoms, OR 17 , or NR 18 R 19 ;
  • X is carbon-carbon single bond, -CO-, CH 2 CH 2 -,
  • R 2 is H, alkyl of 1 to 4 carbon atoms, halogen, or alkoxy of 1 to 4 carbon atoms;
  • R 6 is alkyl, alkenyl or alkynyl of 3 to 7 carbon atoms
  • R 7 is heteroaryl selected from 2- and 3-thienyl, 2- and 3-furyl, 2-, 3-, and 4-pyridyl, p-biphenylyl; H, Cl,
  • R 10 is CF 3 , alkyl of 1 to 6 carbon atoms or phenyl;
  • R 11 is H, or alkyl of 1 to 4 carbon atoms;
  • R 13 is CO 2 H; CO 2 CH 2 OCOC(CH 3 ) 3 ; NHSO 2 CF 3 ;
  • R 14 is H, or alkyl of 1 to 4 carbon atoms
  • R 15 is H, alkyl of 1 to 4 carbon atoms, or acyl of 1 to 4 carbon atoms;
  • R 16 is H, alkyl of 1 to 5 carbon atoms; OR 17 ; or
  • n 1 to 5;
  • X single bond, -O-; -CO-; -NHCO-; or -OCH 2 -; and pharmaceutically acceptable salts.
  • compositions include both the metallic (inorganic) salts and organic salts; a list of which is given in Remington's Pharmaceutical Sciences,
  • a radical when a radical can be a substituent in more than one previously defined radical, that first radical can be selected independently in each previously defined radical.
  • R 1 , R 2 and R 3 can each be CONHOR 12 .
  • R 12 need not be the same substituent in each of R 1 , R 2 and R 3 but can be selected independently for each of them.
  • the invention is also concerned with the use of combinations of the compounds of the foregoing
  • a ⁇ -blocker such as timolol maleate or betaxalol
  • a carbonic anhydrase inhibitor such as 5,6-dihydro-4-ethylamino-4H- 6-methylthieno[2,3-b]-thiophene-2-sulfonamide-7,7- dioxide
  • a para-sympathomimetic agent such as- pilocarpine
  • an angiotensin converting enzyme (ACE) inhibitor such as enalaprilat.
  • the invention is also concerned with an
  • opthalmological formulation for the treatment of ocular hypertension and glaucoma and the promotion of retinal blood flow comprising as active ingredient a compound of the foregoing formulae, either alone or in admixture with one or more of: a ⁇ -blocker such as timolol maleate; a carbonic anhydrase inhibitor such as
  • a para-sympathomimetic agent such as pilocarpine
  • an ACE inhibitor such as enalaprilat
  • novel pharmaceutical formulation of this invention is a topical ophthalmologically acceptable composition for the treatment of glaucoma, and ocular hypertension associated therewith and the promotion of retinal blood flow which comprises an effective ocular antihypertensive amount of an A-II antagonist, either alone or in combination with a topically effective CA inhibitor or ⁇ -blocker and an ophthalmologically
  • the A-II antagonist preferably is selected from the previously described compounds.
  • novel method of treatment of this invention comprises the topical ocular administration of an effective ocular antihypertensive, retinal blood flow promoting amount of an A-II antagonist either alone or in combination with a topically effective CA inhibitor or ⁇ -blocker to a patient in need of such treatment.
  • the A-II antagonist is selected from the previously described compounds.
  • Formulations may contain the active compound, preferably in the form of a soluble acid addition salt, in amounts ranging from about 0.01% to about 10% by weight, preferably from about 0.5% to about 5% by weight.
  • Unit dosages of the active compound can range from about 0.001 to about 5.0 mg, preferably from about 0.05 to about 2.0 mg, and especially 0.1 to 1.0 mg. The dosage administered to a patient will depend upon the patient's needs and the particular compounds employed.
  • the active compounds may be conveniently admixed with a non-toxic pharmaceutically acceptable carrier suitable for topical ophthalmologic administration.
  • a non-toxic pharmaceutically acceptable carrier suitable for topical ophthalmologic administration.
  • pharmaceutically acceptable carriers are, for example, water, mixtures of water and water miscible solvents such as lower alkanols or vegetable oils, petroleum based jelly, or including also from 0.5 to 5% by weight of water soluble polymers such as cellulose derivatives such as methyl cellulose, alkali metal carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyImethyl cellulose; acrylates such as polyacrylic acids salts, ethylacrylates;
  • polyacrylamides polyacrylamides
  • natural products such as gelatin, alginates, pectins, tragacanth, karaya, chondrus, agar, acacia
  • the starch derivatives such as starch acetate, hydroxyethyl starch ethers, hydroxypropyl starch, as well as other synthetic derivatives such as polyvinyl alcohol, polyvinyl pyrrolidone polyvinyl methyl ether, polyethylene oxide, neutralized carbopol and gums such as gellan, rhamson and xanthan gum and mixtures of these polymers.
  • the pharmaceutical preparation may also contain non-toxic auxiliary substances such as
  • emulsifying, preserving, wetting, bodying agents and the like as for example, polyethylene glycols, carbowaxes, antibacterial preservative components commonly employed in ophthalmic formulations; buffering ingredients; and other conventional ingredients.
  • Formulations for eye drops preferably include the active compound as a soluble acid addition salt in a properly buffered, sterile, aqueous isotonic solution.
  • the pharmaceutical preparation may also be in the form of a solid insert.
  • a solid water soluble polymer as the carrier for the medicament. Inserts that are known in the art that are suitable for this use include those described in United States Patents 3,993,071; 3,986,510; 3,868,445; and 3,867,510. Solid water insoluble inserts, such as those prepared from ethylene vinyl acetate copolymer, may also be utilized.
  • compositions of the invention may include additional therapeutic agents in addition to the A-II antagonist.
  • antibiotics for example antibiotics, antiinflammatory steroids, and anesthetics as well as other IOP lowering agents such as a carbonic anhydrase inhibitor (CAI), ACE inhibitor or ⁇ -blocker may be present.
  • CAI carbonic anhydrase inhibitor
  • ACE inhibitor ACE inhibitor
  • ⁇ -blocker may be present.
  • the preferred CAI is 5,6-dihydro-4-ethylamino-4H- 6methyl-thieno[2,3-b]thiopyran-2-sulfonamido-7,7- dioxide
  • the preferred ⁇ -blocker is timolol
  • the preferred ACE inhibitor is enalaprilat.
  • the A-II antagonist is used in a concentration of about one-half that employed if it were the sole active ingredient, and the CAI, ACE inhibitor or ⁇ -blocker is used in a pharmacologically equivalent concentration.
  • each of the A-II antagonists, CAI, ACE inhibitor and ⁇ -Blocker in the ophthalmic formulation is present at a concentration of about 0.005 to 2.5% and especially about 0.125 to 1%.
  • As a unit dosage form 0.005 to 1.25 mg, preferably 0.025 to 1.25 mg, and especially 0.05 to 0.5 mg of each active ingredient is applied to the human eye, generally on a daily basis and preferably in divided doses.
  • A-II antagonist 0.5 mg 7.5 mg
  • A-II antagonist 0.5 mg 7.5 mg
  • Benzalkonium chloride 0.10 mg 0.10 mg Water for injection q.s. ad. 1.0 ml 1.0 ml
  • the active ingredient (s), phosphate buffer salts and benzalkonium chloride are added to and dissolved in water.
  • the pH of the composition is adjusted to 5-6 and diluted to volume.
  • the composition is rendered sterile by exposure to ionizing radiation.
  • intraocular pressure was tested by topical ocular administration of 0.2% and 2% solutions of 2-butyl-4- chloro-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)-methyl]- 5-(hydroxymethyl)imidazole (hereafter referred to as DuP753) to African Green Monkeys.
  • the intraocular pressure was reduced approximately 1.5-2.5 mm Hg for about 2 hours.
  • Applanation Pneumatonagraph which has both a digital output and recorder for maintaining permanent records. Three consecutive readings per eye were made (duration 10 sec. each) until a constant IOP was recorded. In some instances the peripheral ear artery was cannulated and systemic blood pressure recorded on a physiograph.
  • Test drugs were applied locally to one eye, either in topical form, or through intracameral administration. Measurements of IOP were made on both the treated eye and vehicle control. A dose comparable to the ocular hypotensive action found in a pilot study was selected as the starting dose and the dose was increased or decreased logarithmically and the effects on IOP were observed. Two to four log doses were tested in order to construct a log dose effect curve, which provided information on efficacy as well as potency. A time course for the drug effect was monitored by measuring the IOP of untreated animals for 60 minutes at 15 minute intervals, to obtain a baseline, and following drug addition (single dose), the IOP was measured at 30 minute intervals for six hours, or until recovery of the

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Abstract

Substituted imidazoles such as 2-butyl-4-chloro-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-5-(hydroxymethyl)imidazole and 2-butyl-4-chloro-1-[(2'-carboxybiphenyl-4-yl)-methyl]-5-(hydroxymethyl)imidazole and pharmaceutically acceptable salts thereof are useful for treating glaucoma and ocular hypertension.

Description

TITLE
Treatment of Glaucoma and Ocular Hypertension With Imidazole Angiotensin-II Receptor Antagonists BACKGROUND OF THE INVENTION
Glaucoma is an ocular disease complex associated with an elevated pressure within the eye, i.e., elevated intraocular pressure (IOP). As a result of the elevated IOP, damage to the optic nerve, resulting in
irreversible loss of visual function, may ensue.
Untreated, this condition may eventually lead to blindness. Ocular hypertension, i.e., a condition of elevated IOP, without optic nerve damage or
characteristic glaucomatous visual field loss, is now believed by the majority of ophthalmologists to
represent the earliest phase in the onset of glaucoma. Glaucoma is among the leading causes of blindness in the U.S. today.
Drugs currently available for the control of the symptoms of glaucoma and to halt the progressive optic nerve damage are only marginally effective (Yorio (1985) J. Ocular Pharmacol, 1:397-422). Recently, the renin- angiotensin system (RAS) has been suggested as possibly playing a role in the maintenance of intraocular
pressure, as the angiotensin-converting enzyme (ACE) inhibitors, captopril and SCH 33861, have been shown to lower IOP in ocular normotensive rabbits (Watkins et al.
(1987) J. Ocular Pharmacol, 3:295-307) and in humans with elevated intraocular pressures (Constad et al.
(1988) Am. J. Opthalmol, 105:674-677). More recently, a renin inhibitor identified as Abbott-64662 was found to decrease aqueous humor formation and lower the IOP in rabbits following topical application (Stein et al .
(1989) The Pharmacologist 31: 124).
The use of certain angiotensin (All) receptor antagonists in the treatment of elevated intraocular pressure and glaucoma has been disclosed in South
African Patent Application 871653, to Schering, filed March 6, 1987.
Conventional therapy for glaucoma has involved topical administration of pilocarpine and/or
epinephrine, and more recently beta-blockers, such as Timolol, administered to the eye several times daily. For example, beta-blockers useful as antiglaucoma agents are disclosed in commonly-assigned U.S. Patent
Application 07/285007, filed 12/15/88 (CC-0747).
SUMMARY OF INVENTION
According to the present invention there is provided a method of treating glaucoma and intraocular hypertension and promoting retinal blood flow in a mammal comprising the topical ocular administration of an angiotensin II antagonist compound having the formula (I):
Figure imgf000004_0001
wherein
R1 is 4-CO2H; 4-CO2R9; -OSO3H; -SO3H; -C(CF3)2OH;
-OPO3H2; -PO3H2; -NH-PO3H2;
4-NHSO2CH3; -4-NHSO2CF3; -CONHOR12;
Figure imgf000005_0001
Figure imgf000006_0001
R2 is H; Cl; Br; I; F; NO2; CN; alkyl of 1 to 4 carbon atoms; acyloxy of 1 to 4 carbon atoms; alkoxy of
1 to 4 carbon atoms; CO2H; CO2R9; NHSO2CH3; NHSO2CF3;
CONHOR12; SO2NH2;
Figure imgf000006_0002
; aryl; or furyl;
R3 is H; Cl, Br, I or F; alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms;
R4 is CN, NO2 or CO2R11;
R5 is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, alkenyl or alkynyl of 2 to 4 carbon atoms;
R6 is alkyl of 2 to 10 carbon atoms, alkenyl or alkynyl of 3 to 10 carbon atoms or the same groups substituted with F or CO2R14; cycloalkyl of 3 to 8 carbon atoms, cycloalkylalkyl of 4 to 10 carbon atoms; cycloalkylalkenyl or cycloalkylalkynyl of 5 to 10 carbon atoms; (CH2)s z (CH2)mR5 optionally substituted with F or
CO2R14; benzyl or benzyl substituted on the phenyl ring with 1 or 2 halogens, alkoxy of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms or nitro;
R7 is H, F, Cl, Br, I, NO2, CvF2v+1, where v = 1-6;
C6F5; CN;
Figure imgf000007_0001
straight or branched alkyl of 1 to 6 carbon atoms;
phenyl or phenylalkyl, where alkyl is 1 to 3 carbon atoms; or substituted phenyl or substituted phenylalkyl, where alkyl is 1 to 3 carbon atoms, substituted with one or two substituents selected from alkyl of 1 to 4 carbon atoms, F, Cl, Br, OH, OCH3, CF3, and COOR, where R is H, alkyl of 1 to 4 carbon atoms, or phenyl; vinyl; alkynyl of 2-10 carbon atoms; phenylalkynyl where the alkynyl portion is 2-6 carbon atoms; heteroaryl selected from 2-and 3-thienyl, 2- and 3-furyl, 2-, 3-, and 4-pyridyl, 2-pyrazinyl, 2-, 4-, and 5-pyrimidinyl, 3- and
4-pyridazinyl, 2-, 4- and 5-thiazolyl, 2-, 4-, and
5-selenazolyl, 2-, 4-, and 5-oxazolyl; 2- or 3-pyrrolyl, 3-, 4- or 5-pyrazolyl, and 2-, 4- or 5-imidazolyl; o-, m- or p-biphenylyl; o-, m- or p-phenoxyphenyl;
substituted phenylalkynyl, heteroaryl, biphenylyl or phenoxphenyl as defined above substituted on ring carbon with 1 or 2 substituents selected from halogen, alkoxy of 1-5 carbon atoms, alkyl of 1-5 carbon atoms, -NO2, -CN, -CF3, -COR16, -CH2OR17, -NHCOR17, CONR18R19,
S(O)rR17, and SO2NR18R19; pyrollyl, pyrazolyl or
imidazolyl as defined above substituted on ring nitrogen with alkyl of 1-5 carbon atoms or benzyl; or substituted alkyl, alkenyl, or alkynyl of 1 to 10 carbon atoms substituted with a substituted or unsubstituted heteroaryl, biphenylyl or phenoxyphenyl group as defined above; 1- or 2- naphthyl; 5- or 6-naphthσquinonyl; 3-, 4-, or 5-acenaphthyl; 3-, 4-, or 5-acenaphthenyl; 1-, 2-or 9-anthracenyl; 1- or 2-anthraquinonyl; 1-, 2-, 3-, 4-, or 9-phenanthrenyl; 2-, 3-, 4-, 5-, 6-, 7- or 8- quinolinyl; 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinonyl; 2-, 3- ,4-, 5-, 6- or 7-indolyl which can be substituted on ring nitrogen with lower alkyl of 1 to 5 carbon atoms or benzyl; 4-, 5-, 6- or 7-indenyl; 2-, 3-, 4-, 5-, 6- or 7-benzofuryl; 2-, 3-, 4-, 5-, 6- or 7-benzothienyl; 1-, 2-, 3- or 4-dibenzofuryl; 1-, 2-, 3- or 4-dibenzo- thienyl; 1-, 2-, 3- or 4-fluoenyl; any of the foregoing polycyclic aryl groups substituted with 1 or 2
subsituents selected from halogen, alkoxy of 1-5 carbon atoms, alkyl of 1-5 carbon atoms, -NO2, -CN, -CF3,
-COR16, -CH2OR17, -NHCOR17, CONR18R19, S(O)rR17, and SO2NR18R19; the anhydride of 4,5-dicarboxyl-1- or
2-naphthyl; or substituted alkyl of 1 to 10 carbon atoms, alkenyl or alkynyl of 2 to 10 carbon atoms substituted with a substituted or unsubstituted
polycyclic aryl group as defined above;
R8 is H, CN, alkyl of 1 to 10 carbon atoms, alkenyl of 3 to 10 carbon atoms, or the same groups substituted with F; phenylalkenyl wherein the aliphatic portion is 2 to 6 carbon atoms; - (CH2)m-imidazol-1-yl; - (CH2)m-1,2,3-triazolyl optionally substituted with one or two groups selected from CO2CH3 or alkyl of 1 to 4 carbon atoms; - (CH2)s-tetrazolyl;
Figure imgf000009_0002
-(CH2)n-1CH-R11; -(CH2)nOCR14; -(CH2)nSR15;
Figure imgf000009_0001
OR17
R14
-
Figure imgf000009_0003
Figure imgf000009_0004
Figure imgf000009_0005
CH=CH(CH2)sCHOR15; -CH=CH(CH2)sCR16; -CR16;
O O
Figure imgf000009_0006
Figure imgf000009_0007
-CH=CH(CH2)2OCR11; -(CH2)s-CH-COR16; -(CH2)nCR16;
Figure imgf000009_0008
CH3
Y Y
Figure imgf000009_0009
Figure imgf000009_0010
-(CH2)nOCNHR10; -(CH2)nNR11COR10;
Figure imgf000009_0011
-(CH2)nNR11CNHR10; -(CH2)nNR11SO2R10;
Y
Figure imgf000009_0012
-(CH2)nNR11CR10; -(CH2)mF; -(CH2)mONO2; -CH2N3;
Figure imgf000010_0001
-(CH2)n-1CH-R11 ; -(CH2)nOCR14 ; -(CH2)nSR15 ;
OR17
Figure imgf000011_0002
Figure imgf000011_0003
-CH=CH(CH2)sCHOR15; -CH=CH(CH2)sCR16; -CR16;
Figure imgf000011_0001
-CH=CH(CH2)sOCR11 ; -(CH2)m-tetrazolyl ;
Figure imgf000011_0004
Figure imgf000011_0005
-(CH2)s-CH-COR16 ; -(CH2)nCR16 ; -(CH2)nOCHNR10;
Figure imgf000011_0006
CH3
Y O
Figure imgf000011_0007
Figure imgf000011_0008
-(CH2)nNR11(COR10; -(CH2)nNR11CNHR10 ; -(CH2)nNR11SO2R10 ;
Y
Figure imgf000011_0009
or, -(CH2)nNR11CR10;
R9 is
Figure imgf000011_0010
-OH-OCR21;
R10 is alkyl of 1 to 6 carbon atoms or
perfluoroalkyl of 1 to 6 carbon atoms, 1-adamantyl,
1-naphthyl, 1-(1-naphthyl)ethyl, or (CH2)pC6H5;
R11 is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl or benzyl;
R12 is H, methyl or benzyl;
R13 is -CO2H; -CO2R9; -CH2CO2H, -CH2CO2R9;
Figure imgf000011_0011
-O-S-OH; -O-P-OH; -SO3H2; -NHP-OH;
Figure imgf000011_0012
-PO3H2; -C(CF3)2OH; -NHSO2CH3; -NHSO2CF3; -NHCOCF3;
-CONHOR12; -SO2NH2;
Figure imgf000012_0001
R14 is H, alkyl or perfluoroalkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl or benzyl;
R15 is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl, benzyl, acyl of 1 to 4 carbon atoms, phenacyl;
R16 is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, (CH2)pC6H5, OR17, or NR18R19;
R17 is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl or benzyl;
R18 and R19 independently are H, alkyl of 1 to 4 carbon atoms, phenyl, benzyl, α-methylbenzyl, or taken together with the nitrogen form a ring of the formula
Figure imgf000013_0001
Q is NR20, O or CH2;
R20 is H, alkyl of 1-4 carbon atoms, or phenyl;
R21 is alkyl of 1 to 6 carbon atoms, -NR22R23, or
-CHCH2CO2CH3;
Figure imgf000013_0003
NH2 R22 and R23 independently are H, alkyl of 1 to 6 carbon atoms, benzyl, or are taken together as (CH2)u where u is 3-6;
R24 is H, CH3 or -C6H5;
R25 is NR27R28, OR28, NHCONH2, NHCSNH2,
Figure imgf000013_0002
R26 is hydrogen, alkyl with from 1 to 6 carbon atoms, benzyl, or allyl;
R27 and R28 are independently hydrogen, alkyl with from 1 to 5 carbon atoms, or phenyl;
R29 and R30 are independently alkyl of 1-4 carbon atoms or taken together are -(CH2)q-;
R31 is H, alkyl of 1 to 4 carbon atoms, -CH2CH=CH2 or -CH2C6H4R32;
R32 is H, NO2, NH2, OH or OCH3;
X is a carbon-carbon s ingle bond, -CO-, -CH2- , -O-,
-S-, -NH- ,
-N-, -CON- , -NCO- I I I
R26 R23 R23 -OCH2-, -CH2O-, -SCH2-, -CH2S-, NHC(R27) (R28), NR23SO2~, -SO2NR23-, -C(R27) (R28)NH-, -CH=CH-, -CF=CF-, -CH=CF-, CF=CH-, -CH2CH2-, -CF2CF2-,
Figure imgf000014_0001
Y is O or S;
Z is O, NR11, or S;
m is 1 to 5;
n is 1 to 10;
p is 0 to 3,
q is 2 to 3,
r is 0 to 2,
s is 0 to 5,
t is 0 or 1;
and pharmaceutically acceptable salts of these
compounds; provided that:
(1) the R1 group is not in the ortho position;
(2) when R1 is
Figure imgf000014_0002
X is a single bond, and R13 is CO2H, or
Figure imgf000014_0003
then R13 must be in the ortho or meta position; or when R1 and X are as above and R13 is NHSO2CF3 or NHSO2CH3, R13 must be ortho;
Figure imgf000015_0001
and X is other than a single bond, then R13 must be ortho except when X = NR23CO and R13 is NHSO2CF3 or
NHSO2CH3 , then R13 must be ortho or meta ;
(4) when R1 is 4-CO2H or a salt thereof, R6 cannot be S-alkyl;
(5) when R1 is 4-CO2H or a salt thereof, the substituent on the 4-position of the imidazole cannot be
CH2OH, CH2OCOCH3, or CH2CO2H;
Figure imgf000015_0002
X is -OCH2-, and R13 is 2-CO2H, and R7 is H then R6 is not C2H5S;
Figure imgf000015_0003
and R6 is n-hexyl, then R7 and R8 are not both hydrogen;
(8) when R1 is
Figure imgf000016_0001
R6 is not methoxybenzyl;
(9) the R6 group is not -F-CHCH2CH2CH3 or CH2OH;
Figure imgf000016_0002
X is -NH-C=O, R13 is 2-NHSO2CF3, and R6 is n-propyl, then R7 and R8 are not -CO2CH3;
Figure imgf000016_0003
X is NH-C=O, R13 is 2-COOH, and R6 is n-propyl, then R7 and R8 are not -CO2CH3;
Figure imgf000016_0004
X is a single bond, R7 is Cl, and R8 is -CHO, then R13 is not 3-(tetrazol-5-yl);
(13) when r=1, R1=
Figure imgf000017_0002
X is a single bond, R7 is Cl, and R8 is -CHO, then R13 is not 4-(tetrazol-5-yl).
Preferred in the method of this invention are compounds having the formula (II):
Figure imgf000017_0001
wherein
R1 is -CO2H; -NHSO2CF3;
Figure imgf000017_0003
R6 is alkyl of 3 to 10 carbon atoms, alkenyl of 3 to 10 carbon atoms, alkynyl of 3 to 10 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, benzyl substituted on the phenyl ring with up to two groups selected from alkoxy of 1 to 4 carbon atoms, halogen, alkyl of 1 to 4 carbon atoms, and nitro;
R8 is
Figure imgf000018_0003
-(CH2)s-tetrazolyl. -(CH2)nOR11; -(CH2)n OOR 14;
Figure imgf000018_0002
Figure imgf000018_0004
R14
-CH=CH(CH2)sCR16, -CH=CH(CH2)sCHOR15;
Figure imgf000018_0006
Figure imgf000018_0005
-(CH2)nCR16; -(CH2)nNHCOR10; -(CH2)nNHSO2R10;
Figure imgf000018_0007
-(CH2)mF; or -OR16; phenylalkenyl wherein the aliphatic portion is 2 to 4 carbon atoms; - (CH2)m-imidazol-1-yl; or - (CH2)m-1,2,3- triazolyl optionally substituted with one or two groups selected from -CO2CH3 or alkyl of 1 to 4 carbon atoms; R13 is -CO2H, -CO2R9, NHSO2CF3; SO3H; or
Figure imgf000018_0001
R16 is H, alkyl of 1 to 5 carbon atoms, OR17, or NR18R19;
X is carbon-carbon single bond, -CO-, CH2CH2-,
Figure imgf000019_0001
-OCH2-, -CH2O-, -O-, -SCH2-, -CH2S-, -NH-CH2-, -CH2NH- or -CH=CH-; and pharmaceutically acceptable salts of these compounds.
More preferred in the process of the invention are compounds of the preferred scope where:
R2 is H, alkyl of 1 to 4 carbon atoms, halogen, or alkoxy of 1 to 4 carbon atoms;
R6 is alkyl, alkenyl or alkynyl of 3 to 7 carbon atoms;
R7 is heteroaryl selected from 2- and 3-thienyl, 2- and 3-furyl, 2-, 3-, and 4-pyridyl, p-biphenylyl; H, Cl,
Figure imgf000019_0003
Br, I; CvF2v+1, where v=1-3; CR16 ; straight or branched chain alkyl of 1 to 6 carbon atoms; or phenyl;
R8 is
Figure imgf000019_0004
Figure imgf000019_0005
-(CH2)mOR11; -(CH2)mOCR14; -CH=CH-CHOR15;
Figure imgf000019_0006
Figure imgf000019_0007
-(CH2)mCR16; -CH2NHCOR10; -(CH2)mNHSO2R10;
Figure imgf000019_0002
R10 is CF3, alkyl of 1 to 6 carbon atoms or phenyl; R11 is H, or alkyl of 1 to 4 carbon atoms;
R13 is CO2H; CO2CH2OCOC(CH3)3; NHSO2CF3;
Figure imgf000020_0001
R14 is H, or alkyl of 1 to 4 carbon atoms;
R15 is H, alkyl of 1 to 4 carbon atoms, or acyl of 1 to 4 carbon atoms;
R16 is H, alkyl of 1 to 5 carbon atoms; OR17; or
Figure imgf000020_0002
m is 1 to 5;
X = single bond, -O-; -CO-; -NHCO-; or -OCH2-; and pharmaceutically acceptable salts.
More preferred in the method of the invention are compounds of Formula II, wherein R1 is
Figure imgf000020_0003
and X is a single bond; and pharmaceutically suitable salts thereof.
Most preferred in the method of the invention are compounds of formula II selected from the following, and pharmaceutically acceptable salts thereof.
• 2-Butyl-4-chloro-1-[(2'-(1H-tetrazol-5- yl)biphenyl-4-yl)methyl]-5-(hydroxymethyl)imidazole. • 2-Butyl-4-chloro-1-[(2'-carboxybiphenyl-4- yl)-methyl]-5-(hydroxymethyl)imidazole.
• 2-Butyl-4-chloro-1-[(2'-carboxybiphenyl-4- yl)-methyl]-5-[(methoxycarbonyl)aminomethyl] imidazole. • 2-Butyl-4-chloro-1-[(2'-carboxybiphenyl-4-yl) methyl]-5-[(propoxycarbonyl)aminomethyl] imidazole.
• 2-Butyl-4-chloro-1-[(2'-carboxybiphenyl-4-yl) methyl]imidazole-5-carboxaldehyde.
• 2-Butyl-1-[(2'-carboxybiphenyl-4-yl)methyl]- imidazole-5-carboxaldehyde.
• 2-(1E-Butenyl)-4-chloro-1-[(2'-carboxybi- phenyl-4-yl)methyl]-5-(hydroxymethyl)imidazole.
• 2-(1E-Butenyl)-4-chloro-1-[(2'-carboxybi- ρhenyl-4-yl)methyl]imidazole-5-carboxaldehyde.
• 2-Propyl-4-chloro-1-[(2'-(1H-tetrazol-5- yl)biphenyl-4-yl)methyl]-5-(hydroxymethyl) imidazole. • 2-Propyl-4-chloro-1-[(2'-(1H-tetrazol-5- yl)biphenyl-4-yl)methyl]imidazole-5-carboxaldehyde.
• 2-Butyl-4-chloro-1-[2'-(1H-tetrazol-5- yl)biphenyl-4-yl)methyl]imidazole-5-carboxaldehyde.
• 2-(1E-Butenyl)-4-chloro-1-[(2'-(1H-tetrazol-5- yl)biphenyl-4-yl)methyl]-5-hydroxymethyl)imidazole.
• 2-(1E-Butenyl)-4-chloro-1-[(2'-(1H-tetrazol-5- yl)bipheny1-4-yl)methyl]imidazole-5-carboxaldehyde.
• 2-Butyl-4-chloro-1-[(2'-(1H-tetrazol-5-yl)- biphenyl-4-yl)methyl]imidazole-5-carboxylic acid.
• 2-Propyl-4-chloro-1-[(2'-(lH-tetrazol-5-yl)- biρhenyl-4-yl)methyl]imidazole-5-carboxylic acid.
• 2-Propyl-4-trifluoromethyl-l-[(2'-(lH- tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole-5- carboxylic acid.
• 2-Propyl-4-trifluoromethyl-1-[(2'-(1H- tetrazol-5-yl)bipheny1-4-yl)methyl]-5-(hydroxyImethyl)- imidazole.
• 2-Butyl-4-trifluoromethyl-1-[(2'-(1H-tetrazol- 5-yl)biphenyl-4-yl)methyl]imidazole-5-carboyxlic acid. • 2-Propyl-4-trifluoromethyl-1-[(2'- (carboxybiphenyl-4-yl)methyl]imidazole-5-carboxaldehyde. • 2-Propyl-4-pentafluoroethyl-1-[(2'-(1H- tetrazol-5-yl)biphenyl-4-yl)methyl]-5-(hydroxymethyl)- imidazole.
• 2-Propyl-4-pentafluoroethyl-1-[(2'-(1H- tetrazol-5-yl)bipheny1-4-yl)methyl]imidazole-5- carboxylic acid.
• 2-Propyl-4-pentafluoroethyl-[(2'-(1H-tetrazol- 5-yl)biphenyl-4-yl)methyl]imidazole-5-carboxaldehyde. • 1-[(2'-(1H-Tetrazol-5-yl)biphenyl-4- yl)methyl]-4-phenyl-2-propylimidazole-5-carboxaldehyde. • 1-[(2'-Carboxybiphenyl-4-yl)methyl]-4-phenyl- 2-propylimidazole-5-carboxaldehyde.
Throughout the text when an alkyl substituent is mentioned, the normal alkyl structure is meant (i.e., butyl is n-butyl) unless otherwise specified.
Pharmaceutically suitable salts include both the metallic (inorganic) salts and organic salts; a list of which is given in Remington's Pharmaceutical Sciences,
17th Edition, pg. 1418 (1985). It is well known to one skilled in the art that an appropriate salt form is chosen based on physical and chemical stability, flowability, hydroscopicity and solubility. Prefered salts of this invention for the reasons cited above include potassium, sodium, calcium and ammonium salts.
In the foregoing structural formulae, when a radical can be a substituent in more than one previously defined radical, that first radical can be selected independently in each previously defined radical. For example, R1, R2 and R3 can each be CONHOR12. R12 need not be the same substituent in each of R1, R2 and R3 but can be selected independently for each of them. The invention is also concerned with the use of combinations of the compounds of the foregoing
structural formulae with one or more of: a β-blocker such as timolol maleate or betaxalol; a carbonic anhydrase inhibitor such as 5,6-dihydro-4-ethylamino-4H- 6-methylthieno[2,3-b]-thiophene-2-sulfonamide-7,7- dioxide; or a para-sympathomimetic agent such as- pilocarpine; or an angiotensin converting enzyme (ACE) inhibitor such as enalaprilat.
The invention is also concerned with an
opthalmological formulation for the treatment of ocular hypertension and glaucoma and the promotion of retinal blood flow comprising as active ingredient a compound of the foregoing formulae, either alone or in admixture with one or more of: a β-blocker such as timolol maleate; a carbonic anhydrase inhibitor such as
5,6-dihydro-4-ethylamino-4H-6-methylthieno- [2,3-b]thiopyran-2-sulfonamide-7,7-dioxide;
a para-sympathomimetic agent such as pilocarpine; or an ACE inhibitor such as enalaprilat.
DETAILED DESCRIPTION OF THE INVENTION
The compounds of the foregoing formulae are
described in and prepared by methods set forth in
European Patent Application EP 0 324 377, published 7/19/89, (page 17, line 5 through page 212, line 32), copending commonly-assigned U.S. patent application USSN 07/375069, filed 6/30/89, (page 16, line 21 through page 133, line 35), and copending commonly-assigned U.S.
patent application USSN 07/373,755, filed 6/30/89, (page 16, line 21 through page 153, line 15), the disclosures of which are hereby incorporated by reference. The novel pharmaceutical formulation of this invention is a topical ophthalmologically acceptable composition for the treatment of glaucoma, and ocular hypertension associated therewith and the promotion of retinal blood flow which comprises an effective ocular antihypertensive amount of an A-II antagonist, either alone or in combination with a topically effective CA inhibitor or β-blocker and an ophthalmologically
acceptable carrier. The A-II antagonist preferably is selected from the previously described compounds.
The novel method of treatment of this invention comprises the topical ocular administration of an effective ocular antihypertensive, retinal blood flow promoting amount of an A-II antagonist either alone or in combination with a topically effective CA inhibitor or β-blocker to a patient in need of such treatment.
The A-II antagonist is selected from the previously described compounds.
The compounds of the foregoing formulae are
advantageously administered topically to the eye in the form of a solution, ointment, or solid insert, such as is described in U.S. Patent 4,195,085. Formulations may contain the active compound, preferably in the form of a soluble acid addition salt, in amounts ranging from about 0.01% to about 10% by weight, preferably from about 0.5% to about 5% by weight. Unit dosages of the active compound can range from about 0.001 to about 5.0 mg, preferably from about 0.05 to about 2.0 mg, and especially 0.1 to 1.0 mg. The dosage administered to a patient will depend upon the patient's needs and the particular compounds employed.
To prepare suitable dosage forms, the active compounds may be conveniently admixed with a non-toxic pharmaceutically acceptable carrier suitable for topical ophthalmologic administration. Typical of such
pharmaceutically acceptable carriers are, for example, water, mixtures of water and water miscible solvents such as lower alkanols or vegetable oils, petroleum based jelly, or including also from 0.5 to 5% by weight of water soluble polymers such as cellulose derivatives such as methyl cellulose, alkali metal carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyImethyl cellulose; acrylates such as polyacrylic acids salts, ethylacrylates;
polyacrylamides; natural products such as gelatin, alginates, pectins, tragacanth, karaya, chondrus, agar, acacia, the starch derivatives such as starch acetate, hydroxyethyl starch ethers, hydroxypropyl starch, as well as other synthetic derivatives such as polyvinyl alcohol, polyvinyl pyrrolidone polyvinyl methyl ether, polyethylene oxide, neutralized carbopol and gums such as gellan, rhamson and xanthan gum and mixtures of these polymers. The pharmaceutical preparation may also contain non-toxic auxiliary substances such as
emulsifying, preserving, wetting, bodying agents and the like, as for example, polyethylene glycols, carbowaxes, antibacterial preservative components commonly employed in ophthalmic formulations; buffering ingredients; and other conventional ingredients.
The method of treatment of this invention
advantageously involves the topical administration of eye drops containing the active compound. Formulations for eye drops preferably include the active compound as a soluble acid addition salt in a properly buffered, sterile, aqueous isotonic solution.
The pharmaceutical preparation may also be in the form of a solid insert. For example, one may use a solid water soluble polymer as the carrier for the medicament. Inserts that are known in the art that are suitable for this use include those described in United States Patents 3,993,071; 3,986,510; 3,868,445; and 3,867,510. Solid water insoluble inserts, such as those prepared from ethylene vinyl acetate copolymer, may also be utilized.
The compositions of the invention may include additional therapeutic agents in addition to the A-II antagonist. For example antibiotics, antiinflammatory steroids, and anesthetics as well as other IOP lowering agents such as a carbonic anhydrase inhibitor (CAI), ACE inhibitor or β-blocker may be present.
The preferred CAI is 5,6-dihydro-4-ethylamino-4H- 6methyl-thieno[2,3-b]thiopyran-2-sulfonamido-7,7- dioxide, the preferred β-blocker is timolol and the preferred ACE inhibitor is enalaprilat.
If combined with a CAI, ACE inhibitor or β-blocker in a novel formulation of this invention, the A-II antagonist is used in a concentration of about one-half that employed if it were the sole active ingredient, and the CAI, ACE inhibitor or β-blocker is used in a pharmacologically equivalent concentration. In other words each of the A-II antagonists, CAI, ACE inhibitor and β-Blocker in the ophthalmic formulation is present at a concentration of about 0.005 to 2.5% and especially about 0.125 to 1%. As a unit dosage form 0.005 to 1.25 mg, preferably 0.025 to 1.25 mg, and especially 0.05 to 0.5 mg of each active ingredient is applied to the human eye, generally on a daily basis and preferably in divided doses. EXAMPLE 1
Formulations
A-II antagonist 1 mg 15 mg
Monobasic Sodium phosphate•2H2O 9.38 mg 6.10 mg
Dibasic Sodium phosphate•12H2O 28.48 mg 16.80 mg
Benzalkonium chloride 0.10 mg 0.10 mg
Water for injection q.s. ad. 1.0 ml 1.0 ml
EXAMPLE 2
Formulations
A-II antagonist 0.5 mg 7.5 mg
CA Inhibitor 0.5 mg 7.5 mg
Monobasic Sodium phosphate•2H2O 9.38 mg 6.10 mg
Dibasic Sodium phosphate•12H2O 28.48 mg 16.80 mg
Benzalkonium chloride 0.10 mg 0.10 mg
Water for injection q.s. ad. 1.0 ml 1.0 ml
EXAMPLE 3
Formulations
A-II antagonist 0.5 mg 7.5 mg
B-blocker 0.5 mg 7.5 mg
Monobasic Sodium phosphate•2H2O 9.38 mg 6.10 mg
Dibasic Sodium phosphate•12H2O 28.48 mg 16.80 mg
Benzalkonium chloride 0.10 mg 0.10 mg Water for injection q.s. ad. 1.0 ml 1.0 ml
The active ingredient (s), phosphate buffer salts and benzalkonium chloride are added to and dissolved in water. The pH of the composition is adjusted to 5-6 and diluted to volume. The composition is rendered sterile by exposure to ionizing radiation.
The ability of A-II antagonists to lower
intraocular pressure was tested by topical ocular administration of 0.2% and 2% solutions of 2-butyl-4- chloro-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)-methyl]- 5-(hydroxymethyl)imidazole (hereafter referred to as DuP753) to African Green Monkeys. The intraocular pressure was reduced approximately 1.5-2.5 mm Hg for about 2 hours.
The effect of DuP753 on intraocular pressure was also determined in the following Conscious Rabbit Model:
Adult New Zealand white rabbits were placed in a restrainer and their IOP measured using an Alcon
Applanation Pneumatonagraph, which has both a digital output and recorder for maintaining permanent records. Three consecutive readings per eye were made (duration 10 sec. each) until a constant IOP was recorded. In some instances the peripheral ear artery was cannulated and systemic blood pressure recorded on a physiograph.
Test drugs were applied locally to one eye, either in topical form, or through intracameral administration. Measurements of IOP were made on both the treated eye and vehicle control. A dose comparable to the ocular hypotensive action found in a pilot study was selected as the starting dose and the dose was increased or decreased logarithmically and the effects on IOP were observed. Two to four log doses were tested in order to construct a log dose effect curve, which provided information on efficacy as well as potency. A time course for the drug effect was monitored by measuring the IOP of untreated animals for 60 minutes at 15 minute intervals, to obtain a baseline, and following drug addition (single dose), the IOP was measured at 30 minute intervals for six hours, or until recovery of the
IOP. In addition, once a dose-effect curve was
generated, the effects of agents on systemic blood pressure (BP) following topical administration was assessed by selecting the ED50 dose for testing. Thus, both changes in IOP and BP were monitored for each agent.
Table 1 shows results obtained with DuP753 as compared to captopril, an antihypertensive inhibitor of angiotensin-converting enzyme (ACE), in reducing the IOP of ocular normotensive rabbits (N=4). As shown in
Table 1, whereas captopril was ineffective in lowering IOP in the present model, DuP753 significantly lowered IOP.
Figure imgf000029_0001

Claims

CLAIMS :
1. A method of reducing intraocular pressure and increasing retinal blood flow in a mammal in need of such treatment which comprises topically administering to the eye, in an amount effective to achieve such results, a compound having the formula (I):
Figure imgf000030_0001
(I)
wherein
R1 is 4-CO2-H; 4-CO2R9;
Figure imgf000030_0002
Figure imgf000030_0003
Figure imgf000030_0004
-O-S-OH; -SO3H; -C(CF3)2OH; -O-P-OH2; -PO3H2; -NH-P-OH;
Figure imgf000030_0007
Figure imgf000030_0006
Figure imgf000030_0005
4-NHSO2CH3; -4-NHSO2CF3; -CONHOR12;
Figure imgf000031_0001
R2 is H; Cl; Br; I; F; NO2; CN; alkyl of 1 to 4 carbon atoms; acyloxy of 1 to 4 carbon atoms; alkoxy of
1 to 4 carbon atoms; CO2H; CO2R9; NHSO2CH3; NHSO2CF3;
CONHOR12; SO2NH2;
Figure imgf000032_0001
; a;yl; or furyl;
R3 is H; Cl, Br, I or F; alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms;
R4 is CN, NO2 or CO2R11;
R5 is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, alkenyl or alkynyl of 2 to 4 carbon atoms; R6 is alkyl of 2 to 10 carbon atoms, alkenyl or alkynyl of 3 to 10 carbon atoms or the same groups substituted with F or CO2R14; cycloalkyl of 3 to 8 carbon atoms, cycloalkylalkyl of 4 to 10 carbon atoms; cycloalkylalkenyl or cycloalkylalkynyl of 5 to 10 carbon atoms; (CH2)sZ (CH2)mR5 optionally substituted with F or CO2R14; benzyl or benzyl substituted on the phenyl ring with 1 or 2 halogens, alkoxy of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms or nitro; R7 is H, F, Cl, Br, I, NO2, CvF2v+1, where v = 1-6; C6F5; CN;
Figure imgf000032_0002
-OR16 ;
straight or branched alkyl of 1 to 6 carbon atoms;
phenyl or phenylalkyl, where alkyl is 1 to 3 carbon atoms; or substituted phenyl or substituted phenylalkyl, where alkyl is 1 to 3 carbon atoms, substituted with one or two substituents selected from alkyl of 1 to 4 carbon atoms, F, Cl, Br, OH, OCH3, CF3, and COOR, where R is H, alkyl of 1 to 4 carbon atoms, or phenyl; vinyl; alkynyl of 2-10 carbon atoms; phenylalkynyl where the alkynyl portion if 2-6 carbon atoms; heteroaryl selected from 2-and 3-thienyl, 2- and 3-furyl, 2-, 3-, and 4-pyridyl, 2-pyrazinyl, 2-, 4-, and 5-pyrimidinyl, 3- and
4-pyridainyl, 2-, 4- and 5-thiazolyl, 2-, 4-, and
5-selenazolyl, 2-, 4-, and 5-oxazolyl; 2- or 3-pyrrolyl, 3-, 4- or 5-pyrazolyl, and 2-, 4- or 5-imidazolyl; o-, m- or p-biphenylyl; o-, m- or p-phenoxyphenyl;
substituted phenylalkynyl, heteroaryl, biphenylyl or phenoxphenyl as defined above substituted on ring carbon with 1 or 2 substituents selected from halogen, alkoxy of 1-5 carbon atoms, alkyl of 1-5 carbon atoms, -NO2, -CN, -CF3, -COR16, -CH2OR17, -NHCOR17, CONR18R19,
S(O)rR17, and SO2NR18R19; pyrollyl, pyrazolyl or
imidazolyl as defined above substituted on ring nitrogen with alkyl of 1-5 carbon atoms or benzyl; or substituted alkyl, alkenyl, or alkynyl of 1 to 10 carbon atoms substituted with a substituted or unsubstituted
heteroaryl, biphenylyl or phenoxyphenyl group as defined above; 1- or 2- naphthyl; 5- or 6-naphthoquinonyl; 3-, 4-, or 5-acenaphthyl; 3-, 4-, or 5-acenaphthenyl; 1-, 2-or 9-anthracenyl; 1- or 2-anthraquinonyl; 1-, 2-, 3-,
4-, or 9-phenanthrenyl; 2-, 3-, 4-, 5-, 6-, 7- or 8- quinolinyl; 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinonyl; 2-, 3- ,4-, 5-, 6- or 7-indolyl which can be substituted on ring nitrogen with lower alkyl of 1 to 5 carbon atoms or benzyl; 4-, 5-, 6- or 7-indenyl; 2-, 3-, 4-, 5-, 6- or
7-benzofuryl; 2-, 3-, 4-, 5-, 6- or 7-benzothienyl; 1-, 2-, 3- or 4-dibenzofuryl; 1-, 2-, 3- or 4-dibenzo- thienyl; 1-, 2-, 3- or 4-fluoenyl; any of the foregoing polycyclic aryl groups substituted with 1 or 2 subsituents selected from halogen, alkoxy of 1-5 carbon atoms, alkyl of 1-5 carbon atoms, -Nθ2, -CN, -CF3, -COR16, -CH2OR17, -NHCOR17, CONR18R19, S(O)rR17, and SO2NR18R19; the anhydride of 4, 5-dicarboxyl-1- or
2-naphthyl; or substituted alkyl of 1 to 10 carbon atoms, alkenyl or alkynyl of 2 to 10 carbon atoms substituted with a substituted or unsubstituted
polycyclic aryl group as defined above; R8 is H, CN, alkyl of 1 to 10 carbon atoms alkenyl of 3 to 10 carbon atoms, or the same groups substituted with F; phenylalkenyl wherein the aliphatic portion is 2 to 6 carbon atoms; - (CH2)m-imidazol-1-yl; - (CH2)m-1,2,3-triazolyl optionally substituted with one or two groups selected from CO2CH3 or alkyl of 1 to 4 carbon atoms; - (CH2)s-tetrazolyl;
Figure imgf000034_0001
-(CH2)n- 1CH-R11; -(CH2)nOCR14; -(CH2)nSR15;
Figure imgf000034_0002
OR17
R4
Figure imgf000034_0003
Figure imgf000034_0007
Figure imgf000034_0008
-CH=CH(CH2)sCHOR15; -CH=CH(CH2)sCR16; -CR16;
Figure imgf000034_0004
Figure imgf000034_0006
-CH=CH(CH2)2OCR11; -(CH2)s--CH-COR16; -(CH2)nCR16;
Figure imgf000034_0005
3
Figure imgf000035_0002
Figure imgf000035_0003
-(CH2)nOCNHR10; -(CH2)nNR11COR10;
Figure imgf000035_0004
-(CH2)nNR11CNHR10; -(CH2)nNR11SO2R10.
Figure imgf000035_0005
(CH2)nNR11CR10; -(CH2)mF; -(CH2)mONO2; -CH2N3;
Figure imgf000035_0001
-(CH2)n-1CH-R11 ; -(CH2)nOCR14 ; -(CH2)nSR15 ;
Figure imgf000036_0011
OR17
O
Figure imgf000036_0012
Figure imgf000036_0001
Figure imgf000036_0002
-CH=CH(CH2)sCHOR15; -CH=CH(CH2)sCR16; -CR16;
Figure imgf000036_0003
-CH=CH(CH2)sOCR11 ; -(CH2)m-tetrazolyl ;
Figure imgf000036_0005
-(CH2)s-CH-COR16 ; -(CH2)n
Figure imgf000036_0004
CR16 ; -(CH2)nOCHNR10;
CH3
Figure imgf000036_0006
Figure imgf000036_0007
-(CH2)nNR11COR10; -(CH2)nNR11ONHR10 ; -(CH2)nNR11SO2R10 ;
Figure imgf000036_0008
or, -( (CH2)nNR11CR10;
R9 is
Figure imgf000036_0010
Figure imgf000036_0009
-OH-OCR21;
R10 is alkyl of 1 to 6 carbon atoms or
perfluoroalkyl of 1 to 6 carbon atoms, 1-adamantyl, 1- naphthyl, 1-(1-naphthyl)ethyl, or (CH2)pC6-H5;
R11 is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl or benzyl;
R12 is H, methyl or benzyl;
R13 is -CO2H; -CO2R9; -CH2CO2H, -CH2CO2R9;
Figure imgf000037_0002
-O-S-OH; -O-P-OH; -SO3H2; -NHP-OH;
Figure imgf000037_0003
-PO3H2; -C(CF3)2OH; -NHSO2CH3; -NHSO2CF3; -NHCOCF3; -CONHOR12; -SO2NH2;
Figure imgf000037_0001
R14 is H, alkyl or perfluoroalkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl or benzyl;
R15 is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl, benzyl, acyl of 1 to 4 carbon atoms, phenacyl; R16 is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, (CH2)pC6H5, OR17, or NR18R19; R17 is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl or benzyl;
R18 and R19 independently are H, alkyl of 1 to 4 carbon atoms, phenyl, benzyl, α-methylbenzyl, or taken together with the nitrogen form a ring of the formula
Figure imgf000038_0001
Q is NR20, O or CH2;
R20 is H, alkyl of 1-4 carbon atoms, or phenyl;
R21 is alkyl of 1 to 6 carbon atoms, -NR22R23, or -CHCH2CO2CH3;
Figure imgf000038_0003
NH2
R22 and R23 independently are H, alkyl of 1 to 6 carbon atoms, benzyl, or are taken together as (CH2)u where u is 3-6;
R24 is H, CH3 or -C6H5; R25 is NR27R28, OR28, NHCONH2, NHCSNH2,
Figure imgf000038_0002
R26 is hydrogen, alkyl with from 1 to 6 carbon atoms, benzyl, or allyl; R27 and R28 are independently hydrogen, alkyl with from 1 to 5 carbon atoms, or phenyl;
R29 and R30 are independently alkyl of 1-4 carbon atoms or taken together are -(CH2)q-;
R31 is H, alkyl of 1 to 4 carbon atoms, -CH2CH=CH2 or -CH2C6H4R32; R32 is H, NO2, NH2, OH or OCH3;
X is a carbon-carbon single bond, -CO-, -CH2-, -O-, -S-, -NH-,
-N-, -CON-, -NCO-
Figure imgf000039_0002
R26 R23 R23
-OCH2-, -CH2O-, -SCH2-, -CH2S-, NHC(R27) (R28),
-NR23SO2-, -SO2NR23-, -C(R27) (R28)NH-, -CH=CH-, -CF=CF-, -CH=CF-, -CF=CH-, -CH2CH2-, -CF2CF2-,
Figure imgf000039_0001
Y is O or S;
z is O, NR11, or S;
m is 1 to 5;
n is 1 to 10;
P is 0 to 3;
q is 2 to 3;
r is 0 to 2;
s is 0 to 5;
t is 0 or 1; or a pharmaceutically acceptable salt thereof; provided that:
(1) the R1 group is not in the ortho position;
(2) when R1 is
Figure imgf000040_0001
X is a single bond, and R13 is CO2H, or
Figure imgf000040_0002
then R13 must be in the ortho or meta position; or when
R1 and X are as above and R13 is NHSO2CF3 or NHSO2CH3,
R13 must be ortho;
(3) when R1 is
Figure imgf000040_0003
and X is other than a single bond, then R13 must be ortho except when X = NR23CO and R13 is NHSO2CF3 or NHSO2CH3, then R13 must be ortho or meta;
(4) when R1 is 4-CO2H or a salt thereof, R6 cannot be S-alkyl;
(5) when R1 is 4-CO2H or a salt thereof, the substituent on the 4-position of the imidazole cannot be CH2OH, CH2OCOCH3, or CH2CO2H;
(6) when R1 is
Figure imgf000041_0001
X is -OCH2-, and R13 is 2-CO2H, and R7 is H then R6 is not C2H5S;
Figure imgf000041_0002
and R6 is n-hexyl, then R7 and R8 are not both hydrogen;
Figure imgf000041_0003
R6 is not methoxybenzyl;
(9) the R6 group is not -F-CHCH2CH2CH3 or CH2OH;
Figure imgf000041_0004
X is -NH-C=O, R13 is 2-NHSO2CF3, and R6 is n-propyl, then R7 and R8 are not -CO2CH3;
(11) when r=0, R1 is
Figure imgf000042_0001
X is NH-C=O, R13 is 2-COOH, and R6 is n-propyl, then R7 and R8 are not -CO2CH3;
Figure imgf000042_0002
X is a single bond, R7 is Cl, and R8 is -CHO, then R13 is not 3-(tetrazol-5-yl);
Figure imgf000042_0003
X is a single bond, R7 is Cl, and R8 is -CHO, then R13 is not 4-(tetrazol-5-yl).
2. Method of claim 1 wherein the compound of formula (I) is a compound of formula (II):
Figure imgf000043_0001
wherein R1 is -CO2H ; -NHSO2CF3 ;
Figure imgf000043_0002
R6 is alkyl of 3 to 10 carbon atoms, alkenyl of 3 to 10 carbon atoms, alkynyl of 3 to 10 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, benzyl substituted on the phenyl ring with up to two groups selected from alkoxy of 1 to 4 carbon atoms, halogen, alkyl of 1 to 4 carbon atoms, and nitro;
R8 is
Figure imgf000044_0001
-(CH2)s-tetrazolyl, -(CH2)nOR11; -(CH2)n OCR14;
Figure imgf000044_0003
Figure imgf000044_0002
-CH=CH(CH2)sCR16, -CH=CH(CH2)sCHOR15;
Figure imgf000044_0004
Figure imgf000044_0005
-(CH2)nCR16; -(CH2)nNHCOR10; -(CH2)nNHSO2R10;
Figure imgf000044_0006
-(CH2)mF; or -OR16;
phenylalkenyl wherein the aliphatic portion is 2 to 4 carbon atoms; - (CH2) m-imidazol-1-yl; or - (CH2)m-1,2,3- triazolyl optionally substituted with one or two groups selected from -CO2CH3 or alkyl of 1 to 4 carbon atoms;
R13 is -CO2H, -CO2R9, NHSO2CF3; SO3H; or
Figure imgf000044_0007
R16 is H, alkyl of 1 to 5 carbon atoms, OR17, or NR18R19;
X is carbon-carbon single bond, -CO-, CH2CH2-,
Figure imgf000044_0008
-OCH2-, -CH2O-, -O-, -SCH2-, -CH2S-, -NH-CH2-, -CH2NH- or -CH=CH-; or a pharmaceutically acceptable salt thereof.
3. Method of claim 2 wherein the compound of formula (II) is a compound wherein:
R2 is H, alkyl of 1 to 4 carbon atoms, halogen, or alkoxy of 1 to 4 carbon atoms;
R6 is alkyl, alkenyl or alkynyl of 3 to 7 carbon atoms;
R7 is heteroaryl selected from 2- and 3-thienyl, 2- and 3-furyl, 2-, 3-, and 4-pyridyl, p-biphenylyl; H, Cl,
Figure imgf000045_0005
Br, I; CvF2v+1, where v=1-3; CR16; straight or branched chain alkyl of 1 to 6 carbon atoms; or phenyl;
R8 is
Figure imgf000045_0003
Figure imgf000045_0004
-(CH2)mOR11 ; -(CH2)mOCR14; -CH=CH-CΗOR15;
Figure imgf000045_0006
Figure imgf000045_0007
-(CH2)mC R16; -CH2NHCOR10; -(CH2)mNHSO2R10;
: or -COR1 6;
Figure imgf000045_0001
R10 is CF3, alkyl of 1 to 6 carbon atoms or phenyl; R11 is H, or alkyl of 1 to 4 carbon atoms;
R13 is CO2H; CO2CH2OCOC (CH3)3; NHSO2CF3;
Figure imgf000045_0002
R14 is H, or alkyl of 1 to 4 carbon atoms;
R15 is H, alkyl of 1 to 4 carbon atoms, or acyl of 1 to 4 carbon atoms;
R16 is H, alkyl of 1 to 5 carbon atoms; OR17; or
Figure imgf000046_0001
m is 1 to 5;
X = single bond, -O-; -CO-; -NHCO-; or -OCH2-; or a pharmaceutically acceptable salt thereof.
4. Method of claim 3 wherein the compound of formula (II) is a compound wherein R1 is
Figure imgf000046_0002
and X is a single bond; or a pharmaceutically suitable salt thereof.
5. Method of claim 4 wherein the compound of formula II is:
• 2-Butyl-4-chloro-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4- yl)methyl]-5-(hydroxymethyl)imidazole
• 2-Butyl-4-chloro-1-[(2'-carboxybiphenyl-4-yl)-methyl]- 5-(hydroxymethyl)imidazole
• 2-Butyl-4-chloro-1-[(2'-carboxybiphenyl-4-yl)-methyl]- 5-[(methoxycarbonyl)aminomethyl] imidazole • 2-Butyl-4-chloro-1-[(2'-carboxybiphenyl-4-yl)-methyl]- 5-[(propoxycarbonyl)aminomethyl] imidazole
• 2-Butyl-4-chloro-1-[(2'-carboxybiphenyl-4- yl)methyl]imidazole-5-carboxaldehyde
• 2-Butyl-1-[(2'-carboxybiphenyl-4-yl)methyl]-imidazole- 5-carboxaldehyde
• 2-(1E-Butenyl)-4-chloro-1-[(2'-carboxybiphenyl-4- yl)methyl]-5-(hydroxymethyl) imidazole
• 2-(1E-Butenyl)-4-chloro-1-[(2'-carboxybiphenyl-4- yl)methyl]imidazole-5-carboxaldehyde
• 2-Propyl-4-chloro-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4- yl)methyl]-5-(hydroxymethyl) imidazole
• 2-Prσpyl-4-chloro-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4- yl)methyl]imidazole-5-carboxaldehyde
• 2-Butyl-4-chloro- - [2'-(1H-tetrazol-5-yl)biphenyl-4- yl)methyl]imidazole-5-carboxaldehyde
• 2-(1E-Butenyl)-4-chloro-l-[(2'-(1H-tetrazol-5- yl)biphenyl-4-yl)methyl]-5-hydroxymethyl) imidazole • 2-(1E-Butenyl)-4-chloro-1-[(2'-(1H-tetrazol-5- yl)biphenyl-4-yl)methyl]imidazole-5-carboxaldehyde • 2-Butyl-4-chloro-1-[(2'-(1H-tetrazol-5-yl)-biphenyl-4- yl)methyl]imidazole-5-carboxylic acid
• 2-Propyl-4-chloro-1-[(2'-(1H-tetrazol-5-yl)-biphenyl- 4-yl)methyl]imidazole-5-carboxylic acid
• 2-Propyl-4-trifluoromethyl-1-[(2'-(1H-tetrazol-5- yl)biphenyl-4-yl)methyl]imidazole-5-carboxylic acid • 2-Propyl-4-trifluoromethyl-1-[(2'-(1H-tetrazol-5- yl)biphenyl-4-yl)methyl]-5-(hydroxyImethyl)-imidazole • 2-Butyl-4-trifluoromethyl-1-[(2'-(1H-tetrazol-5- yl) biphenyl-4-yl)methyl]imidazole-5-carboyxlic acid • 2-Propyl-4-trifluoromethyl-1-[(2'-(carboxybiphenyl-4- yl)methyl]imidazole-5-carboxaldehyde
• 2-Propyl-4-pentafluoroethyl-1-[(2'-(1H-tetrazol-5- yl)biphenyl-4-yl)methyl]-5-(hydroxymethyl)-imidazole • 2-Propyl-4-pentafluoroethyl-1-[(2'-(1H-tetrazol-5- yl)biphenyl-4-yl)methyl]imidazole-5-carboxylic acid
• 2-Propyl-4-pentafluoroethyl-[(2'-(1H-tetrazol-5- yl)biphenyl-4-yl)methyl]imidazole-5-carboxaldehyde
• 1-[(2 ' -(1H-Tetrazol-5-yl)biphenyl-4-yl)methyl]-4- phenyl-2-propylimidazole-5-carboxaldehyde
• 1-[(2'-Carboxybiρhenyl-4-yl)methyl]-4-phenyl-2- propylimidazole-5-carboxaldehyde.
6. An ophthalmological formulation for the treatment of ocular hypertension and increasing retinal blood flow comprising an ophthalmologically acceptable carrier and 0.01% to 5% (w/v) of a compound of formula (ll):
Figure imgf000048_0001
(II)
wherein
R1 is -CO2H4; -NHSO2CF3;
Figure imgf000049_0001
R6 is alkyl of 3 to 10 carbon atoms, alkenyl of 3 to 10 carbon atoms, alkynyl of 3 to 10 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, benzyl substituted on the phenyl ring with up to two groups selected from alkoxy of 1 to 4 carbon atoms, halogen, alkyl of 1 to 4 carbon atoms, and nitro; R7 is H, F, Cl, Br, I, NO2, CvF2v+1, where v = 1-6,
Figure imgf000049_0002
C6F5; CN; -CR16 ; straight or branched alkyl of 1 to 6 carbon atoms; phenyl or phenylalkyl, where alkyl is 1 to 3 carbon atoms; or substituted phenyl or substituted phenylalkyl, where alkyl is 1 to 3 carbon atoms, substituted on the phenyl with one or two substituents selected from alkyl of 1 to 4 carbon atoms, F, Cl, Br, OH, OCH3, CF3, and COOR, where R is H, alkyl of 1 to 4 carbon atoms, or phenyl; R8 is phenylalkenyl wherein the aliphatic portion is 2 to 4 carbon atoms, - (CH2)m-imidazol-1-yl, -(CH2)m- 1,2,3-triazolyl optionally substituted with one or two groups selected from CO2CH3 or alkyl of 1 to 4 carbon atoms (CH2)m-tetrazolyl, -(CH2)nOR11;
Figure imgf000050_0002
-(CH2)n OCR14;
Figure imgf000050_0003
Figure imgf000050_0004
-CH=CH(CH2)sCR16, -CH=CH(CH2)sCHOR15;
Figure imgf000050_0005
Figure imgf000050_0006
-(CH2)nCR16; -(CH2)nNHCOR10; -(CH2)nNHSO2R10;
Figure imgf000050_0007
-(CH2)mF; or -CR16;
R2 is H; Cl; Br; I; F; NO2; CN; alkyl of 1 to 4 carbon atoms; acyloxy of 1 to 4 carbon atoms; alkoxy of 1 to 4 carbon atoms; CO2H; CO2R9; NHSO2CH3; NHSO2CF3; CONHOR12; SO2NH2;
aryl; or furyl; R9 is
Figure imgf000050_0001
R10 is alkyl of 1 to 6 carbon atoms or
perfluoroalkyl of 1 to 6 carbon atoms, 1-adamantyl, 1- naphthyl, 1-(1-naphthyl) ethyl, or (CH2)pC6H5;
R11 is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl or benzyl; R12 is H, methyl or benzyl; R13 is -CO2H; -CO2R9; -CH2CO2H, -CH2CO2R9;
Figure imgf000051_0002
II II II
-O-S-OH; -O-P-OH; -SO3H2; -NHP-OH;
Figure imgf000051_0003
-PO3H2; -C(CF3)2OH; -NHSO2CH3; -NHSO2CF3; -NHCOCF3; -CONHOR12; -SO2NH2;
Figure imgf000051_0001
R4 is -CN, NO2 or CO2R"; R14 is H, alkyl or perfluoroalkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl or benzyl;
R15 is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl, benzyl, acyl of 1 to 4 carbon atoms, phenacyl; R16 is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, (CH2)pC6H5, OR17, or NR18R19; R17 is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl or benzyl;
R18 and R19 independently are H, alkyl of 1 to 4 carbon atoms, phenyl, benzyl, α-methylbenzyl, or taken together with the nitrogen form a ring of the formula
Figure imgf000052_0001
Q is NR20, O or CH2;
R20 is H, alkyl of 1-4 carbon atoms, or phenyl;
R21 is alkyl of 1 to 6 carbon atoms, -NR22R23, or
-CHCH2CO2CH3;
Figure imgf000052_0003
NH2
R22 and R23 independently are H, alkyl of 1 to 6 carbon atoms, benzyl, or are taken together as (CH2)u where u is 3-6; R24 is H, CH3 or -C6H5;
R25 is NR27R28, OR28, NHCONH2, NHCSNH2,
Figure imgf000052_0002
R26 is hydrogen, alkyl with from 1 to 6 carbon atoms, benzyl, or allyl;
R27 and R28 are independently hydrogen, alkyl with from 1 to 5 carbon atoms, or phenyl;
R29 and R30 are independently alkyl of 1-4 carbon atoms or taken together are -(CH2)q-; R31 is H, alkyl of 1 to 4 carbon atoms, -CH2CH=CH2 or -CH2C6H4R32;
R32 is K, NO2, NH2, OH or OCH3; X is a carbon-carbon single bond, -CO-, -CH2-, -O-,
-S-, -NH-,
-N-, -CON-, -NCO-
Figure imgf000053_0004
R26 R23 R23
-OCH2-, -CH2O-, -SCH2-, -CH2S-, NHC(R27) (R28), NR23SO2~, -SO2NR23-, -C(R27) (R28)NH-, -CH=CH-, -CF=CF-, -CH=CF-, CF=CH-, -CH2CH2-, -CF2CF2-,
OR14, OCOR17, NR25 R29O OR30
Figure imgf000053_0001
Figure imgf000053_0002
-CH- -CH- -C- or
Figure imgf000053_0003
V m is 1 to 5;
n is 1 to 10;
p is 0 to 3,
q is 2 to 3,
r is 0 to 2,
s is 0 to 5,
t is 0 or 1,
or a pharmaceutically acceptable salt thereof.
7. The formulation of Claim 6 wherein:
R2 is H, alkyl of 1 to 4 carbon atoms, halogen, or alkoxy of 1 to 4 carbon atoms;
R6 is alkyl, alkenyl or alkynyl of 3 to 7 carbon atoms;
R7 is H, Cl, Br, I; CvF2v+1, where v=1-3; or
Figure imgf000054_0001
R8 is
Figure imgf000054_0004
R14
-(CH2)mOR11; -(CH2)mOCR14; -CH=CH-CHOR15;
Figure imgf000054_0005
Figure imgf000054_0006
"(CH2)mCR16; -CH2NHCOR10; -(CH2)mNHSO2R10;
- or -COR16;
Figure imgf000054_0002
R10 is CF3, alkyl of 1 to 6 carbon atoms or phenyl;
R11 is H, or alkyl of 1 to 4 carbon atoms; R13 is CO2H; CO2CH2OCOC(CH3)3; NHSO2CF3;
Figure imgf000054_0003
R14 is H, or alkyl of 1 to 4 carbon atoms; R15 is H, alkyl of 1 to 4 carbon atoms, or acyl of 1 to 4 carbon atoms;
R16 is H, alkyl of 1 to 5 carbon atoms; OR17; or
Figure imgf000055_0001
m is 1 to 5; X = single bond, -O-; -CO-; -NHCO-; or -OCH2-;
or a pharmaceutically acceptable salt thereof.
8. The formulation of Claim 7 wherein
R2 is H, alkyl of 1 to 4 carbon atoms, halogen, or alkoxy of 1 to 4 carbon atoms;
R6 is alkyl, alkenyl or alkynyl of 3 to 7 carbon atoms;
Figure imgf000055_0002
R7 is CvF2 v+ 1 , where v=1-3 ; -CR 16 ; or Cl ;
R8 is
-(CH2)mOR11 ; -(CH2)mOC-R14; -COOH or CHO;
R
Figure imgf000056_0004
Figure imgf000056_0005
Figure imgf000056_0006
-CH-CH-CHOR15; -(CH2)mdR16; -CH2NHCOR10;
-(CH2)mNHSO2R10; or -COR16;
Figure imgf000056_0003
R10 is CF3, alkyl of 1 to 6 carbon atoms or phenyl; R11 is H, or alkyl of 1 to 4 carbon atoms;
R13 is CO2H; CO2CH2OCOC (CH3)3; NHSO2CF3.
Figure imgf000056_0002
R14 is H, or alkyl of 1 to 4 carbon atoms;
R15 is H, alkyl of 1 to 4 carbon atoms, or acyl of1 to 4 carbon atoms; R16 is H, alkyl of 1 to 5 carbon atoms; OR17; or
Figure imgf000056_0001
m is 1 to 5; X = single bond, -O-; -CO-; -NHCO-; or -OCH2-;
or a pharmaceutically acceptable salt thereof.
9. The formulation of Claim 8 wherein the compound is:
• 2-Butyl-4-chloro-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4- yl)methyl]-5-(hydroxymethyl)imidazole
• 2-Butyl-4-chloro-1-[(2'-carboxybiphenyl-4-yl)-methyl]- 5-(hydroxymethyl)imidazole
• 2-Butyl-4-chloro-1-[(2'-carboxybiphenyl-4-yl)-methyl]- 5-[(methoxycarbonyl)aminomethyl] imidazole
• 2-Butyl-4-chloro-1-[(2'-carboxybiphenyl-4-yl)-methyl]- 5-[(propoxycarbonyl)aminomethyl] imidazole
• 2-Butyl-4-chloro-1-[(2'-carboxybiphenyl-4- yl)methyl]imidazole-5-carboxaldehyde
• 2-Butyl-1-[(2'-carboxybiphenyl-4-yl)methyl]-imidazole- 5-carboxaldehyde
• 2-(1E-Butenyl)-4-chloro-1-[(2'-carboxybiphenyl-4- yl)methyl]-5-(hydroxymethyl)imidazole
• 2-(1E-Butenyl)-4-chloro-1-[(2'-carboxybipheny1-4- yl)methyl]imidazole-5-carboxaldehyde
• 2-Propyl-4-chloro-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4- yl)methyl]-5-(hydroxymethyl) imidazole
• 2-Propyl-4-chloro-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4- yl)methyl]imidazole-5-carboxaldehyde
• 2-Butyl-4-chloro-1-[2'-(1H-tetrazol-5-yl)biphenyl-4- yl)methyl]imidazole-5-carboxaldehyde
• 2-(1E-Butenyl)-4-chloro-1-[(2'-(1H-tetrazol-5- yl)biphenyl-4-yl)methyl]-5-hydroxymethyl) imidazole• 2-(1E-Butenyl)-4-chloro-1-[(2'-(1H-tetrazol-5- yl)biphenyl-4-yl)methyl]imidazole-5-carboxaldehyde• 2-Butyl-4-chloro-1-[(2'-(1H-tetrazol-5-yl)-biphenyl-4- yl)methyl]imidazole-5-carboxylic acid
• 2-Propyl-4-chloro-1-[(2'-(1H-tetrazol-5-yl)-biphenyl- 4-yl)methyl]imidazole-5-carboxylic acid • 2-Propyl-4-trifluoromethyl-1-[(2'-(1H-tetrazol-5- yl)biphenyl-4-yl)methyl]imidazole-5-carboxylic acid • 2-Propyl-4-trifluoromethyl-1-[(2'-(1H-tetrazol-5- yl)biphenyl-4-yl)methyl]-5-(hydroxylmethyl)-imidazole • 2-Butyl-4-trifluoromethyl-1-[(2'-(1H-tetrazol-5- yl)bipheny1-4-yl)methyl]imidazole-5-carboyxlic acid • 2-Propyl-4-trifluoromethyl-1-[(2'-(carboxybiphenyl-4- yl)methyl]imidazole-5-carboxaldehyde
• 2-Propyl-4-pentafluoroethyl-1-[(2'-(1H-tetrazol-5- yl)biphenyl-4-yl)methyl]-5-(hydroxymethyl)-imidazole • 2-Propyl-4-pentafluoroethyl-1-[(2'-(1H-tetrazol-5- yl)biphenyl-4-yl)methyl]imidazole-5-carboxylic acid • 2-Propyl-4-pentafluoroethyl-[(2'-(1H-tetrazol-5- yl)biphenyl-4-yl)methyl]imidazole-5-carboxaldehyde • 1-[(2'-(1H-Tetrazol-5-yl)biphenyl-4-yl)methyl]-4- phenyl-2-propylimidazole-5-carboxaldehyde
• 1-[(2'-Carboxybiphenyl-4-yl)methyl]-4-phenyl-2- propylimidazole-5-carboxaldehyde.
PCT/US1991/002119 1990-04-05 1991-04-02 Treatment of glaucoma and ocular hypertension with imidazole angiotensin-ii receptor antagonists WO1991015206A1 (en)

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EP0631780A1 (en) * 1993-07-02 1995-01-04 Takeda Chemical Industries, Ltd. Use of an angiotensin II antagonist as an ocular hypotensive agent
WO1996040258A2 (en) * 1995-06-07 1996-12-19 G.D. Searle & Co. Spironolactone and angiotensin ii antagonist combination therapy for treatment of congestive heart failure
WO1996040255A2 (en) * 1995-06-07 1996-12-19 G.D. Searle & Co. Method to treat cardiofibrosis with a combination therapy of an angiotensin ii antagonist and an epoxy-steroidal aldosterone antagonist
EP0795326A1 (en) * 1994-03-16 1997-09-17 Sankyo Company Limited Ocular tension depressant
WO2000076543A1 (en) * 1999-06-11 2000-12-21 Sankyo Company, Limited Ocular tension lowering composition for topical adminstration
WO2001039805A1 (en) * 1999-12-01 2001-06-07 Sankyo Company, Limited Concomitant drugs for treating glaucoma
WO2002045748A1 (en) * 2000-12-05 2002-06-13 Sankyo Company, Limited Ocular tension-lowering compositions for topical administration
US7531560B2 (en) 2004-11-10 2009-05-12 Boehringer Ingelheim Pharmaceuticals, Inc. Anti-cytokine heterocyclic compounds
WO2011069038A2 (en) 2009-12-03 2011-06-09 Synergy Pharmaceuticals, Inc. Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia, atherosclerosis, coronary heart disease, gallstone, obesity and other cardiovascular diseases
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WO2014151200A2 (en) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Compositions useful for the treatment of gastrointestinal disorders
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WO2014197720A2 (en) 2013-06-05 2014-12-11 Synergy Pharmaceuticals, Inc. Ultra-pure agonists of guanylate cyclase c, method of making and using same
EP2998314A1 (en) 2007-06-04 2016-03-23 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders
EP3241839A1 (en) 2008-07-16 2017-11-08 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase useful for the treatment of gastrointestinal, inflammation, cancer and other disorders

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US5639773A (en) * 1993-07-02 1997-06-17 Senju Pharmaceutical Co., Ltd. Ocular hypotensive agent
WO1995001176A1 (en) * 1993-07-02 1995-01-12 Senju Pharmaceutical Co., Ltd. Use of an angiotensin ii antagonist as an ocular hypotensive agent
EP0631780A1 (en) * 1993-07-02 1995-01-04 Takeda Chemical Industries, Ltd. Use of an angiotensin II antagonist as an ocular hypotensive agent
EP1110551A2 (en) * 1994-03-16 2001-06-27 Sankyo Company Limited Ocular tension lowering agent
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US5925664A (en) * 1994-03-16 1999-07-20 Sankyo Company, Limited Method for treating ocular hypertension and glaucoma
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WO1996040255A3 (en) * 1995-06-07 1997-01-23 Searle & Co Method to treat cardiofibrosis with a combination therapy of an angiotensin ii antagonist and an epoxy-steroidal aldosterone antagonist
WO1996040258A3 (en) * 1995-06-07 1997-01-23 Searle & Co Spironolactone and angiotensin ii antagonist combination therapy for treatment of congestive heart failure
WO1996040255A2 (en) * 1995-06-07 1996-12-19 G.D. Searle & Co. Method to treat cardiofibrosis with a combination therapy of an angiotensin ii antagonist and an epoxy-steroidal aldosterone antagonist
WO1996040258A2 (en) * 1995-06-07 1996-12-19 G.D. Searle & Co. Spironolactone and angiotensin ii antagonist combination therapy for treatment of congestive heart failure
US6984633B2 (en) 1995-06-07 2006-01-10 G.D Searle & Co. Method to treat cardiofibrosis with a combination therapy of an angiotensin II antagonist and epoxymexrenone
WO2000076543A1 (en) * 1999-06-11 2000-12-21 Sankyo Company, Limited Ocular tension lowering composition for topical adminstration
CZ300553B6 (en) * 1999-06-11 2009-06-17 Sankyo Company Limited Locally administered preparations for reduction of intraocular pressure
US6777436B2 (en) 1999-06-11 2004-08-17 Sankyo Company, Limited Intraocular tension lowering compositions for topical administration
EP1344534A3 (en) * 1999-12-01 2004-01-02 Sankyo Company, Limited Combined angiotensin II antagonists and carbonic anhydrase inhibitors for treatment of glaucoma
EP1234582A4 (en) * 1999-12-01 2003-05-07 Sankyo Co Concomitant drugs for treating glaucoma
EP1344535A3 (en) * 1999-12-01 2004-01-28 Sankyo Company, Limited Combined angiotensin II antagonists and adrenaline receptor blockers for treatment of glaucoma
AU773110B2 (en) * 1999-12-01 2004-05-20 Sankyo Company Limited Concomitant drugs for treating glaucoma
EP1234582A1 (en) * 1999-12-01 2002-08-28 Sankyo Company, Limited Concomitant drugs for treating glaucoma
US7307096B2 (en) 1999-12-01 2007-12-11 Sankyo Company, Limited Combined agents for treatment of glaucoma
WO2001039805A1 (en) * 1999-12-01 2001-06-07 Sankyo Company, Limited Concomitant drugs for treating glaucoma
EP1344534A2 (en) * 1999-12-01 2003-09-17 Sankyo Company, Limited Combined angiotensin II antagonists and carbonic anhydrase inhibitors for treatment of glaucoma
WO2002045748A1 (en) * 2000-12-05 2002-06-13 Sankyo Company, Limited Ocular tension-lowering compositions for topical administration
US7531560B2 (en) 2004-11-10 2009-05-12 Boehringer Ingelheim Pharmaceuticals, Inc. Anti-cytokine heterocyclic compounds
EP2998314A1 (en) 2007-06-04 2016-03-23 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders
EP2810951A2 (en) 2008-06-04 2014-12-10 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders
EP3241839A1 (en) 2008-07-16 2017-11-08 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase useful for the treatment of gastrointestinal, inflammation, cancer and other disorders
EP2923706A1 (en) 2009-12-03 2015-09-30 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia
WO2011069038A2 (en) 2009-12-03 2011-06-09 Synergy Pharmaceuticals, Inc. Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia, atherosclerosis, coronary heart disease, gallstone, obesity and other cardiovascular diseases
WO2013138352A1 (en) 2012-03-15 2013-09-19 Synergy Pharmaceuticals Inc. Formulations of guanylate cyclase c agonists and methods of use
EP3708179A1 (en) 2012-03-15 2020-09-16 Bausch Health Ireland Limited Formulations of guanylate cyclase c agonists and methods of use
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