[go: up one dir, main page]

WO1996035424A1 - Aryl-imidazolines et aryl-imidazoles utiles en tant qu'agents agonistes adrenergiques alpha-2 n'entrainant pas d'effets secondaires cardio-vasculaires - Google Patents

Aryl-imidazolines et aryl-imidazoles utiles en tant qu'agents agonistes adrenergiques alpha-2 n'entrainant pas d'effets secondaires cardio-vasculaires Download PDF

Info

Publication number
WO1996035424A1
WO1996035424A1 PCT/US1996/006633 US9606633W WO9635424A1 WO 1996035424 A1 WO1996035424 A1 WO 1996035424A1 US 9606633 W US9606633 W US 9606633W WO 9635424 A1 WO9635424 A1 WO 9635424A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
mammal
formula
pharmaceutical agent
oxo group
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US1996/006633
Other languages
English (en)
Inventor
Stephen A. Munk
James A. Burke
Ronald K. Lai
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Allergan Inc
Original Assignee
Allergan 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 Allergan Inc filed Critical Allergan Inc
Priority to EP96913983A priority Critical patent/EP0828491A1/fr
Priority to JP8534262A priority patent/JPH11505224A/ja
Priority to AU56785/96A priority patent/AU715350B2/en
Publication of WO1996035424A1 publication Critical patent/WO1996035424A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

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
    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/12—Antidiarrhoeals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present invention relates to meta-substituted aryl linked imidazolines and imidazoles. More particularly, the invention relates to such compounds which have oc 2 adrenergic agonist activity.
  • Aryl-2-amino-imidazolines are well-known in the art. Compounds such as moxonidine, para-aminoclonidine, brimonidine and tramazoline are but a few of the compounds which contain this basic structural feature that have also found use as therapeutic agents.
  • adrenergic receptors see R. Ruffolo, Jr. (ed.) in ⁇ - Adrenoreceptors: Molecular Biology, Biochemistry and Pharmacology, Prog. Basic Clin. Pharmacol. (Basel, Karger), 8 pp. 75-114 (1991).
  • moxonidine A compound of similar structure is moxonidine.
  • moxonidine has been identified pharmacologically as a selective imidazoline receptor agonist, with utility as a centrally-acting antihypertensive agent.
  • the pharmacological investigation of imidazoline agents independent of adrenoceptors started in the mid- 1980's.
  • Two major subtypes, tentatively designated I t and I 2 are recognized. I ⁇ sites are labeled with nanomolar affinity by clonidine analogs whereas I 2 sites have micromolar affinity for clonidine and are usually labeled by tritiated idazoxan.
  • the T designation (for imidazoline) has been intended to encompass not only imidazolines, imidazoles, and imidazolidines, but also such related structures as guanidines and oxazolines, all of which are potential ligands at these sites.
  • imidazoline-preferring receptors A recent review of imidazoline-preferring receptors has been published by M.C. Michel and P. Ernsberger in TiPS, 13, pp. 369-379 (Oct. 1992).
  • the rilmenidine structure substitutes an oxazolidine ring for imidazoline.
  • Such heterocyclic ring substitutions are noted in the Ruffolo monograph on page 99 to reduce or abolish activity at ⁇ 2 receptors.
  • Harron, D.W. Am. J. Hypertens., 5(4, Pt. 2) pp. 91S-98S (Apr.
  • rilmenidine differs from clonidine in that it is more selective for imidazoline receptors than for ⁇ 2 -adrenoceptors; at equihypotensive doses, rilmenidine causes less bradycardia and reduction in cardiac output, less sedation, and little or no antinociceptive action compared to clonidine.
  • Rilmendine A few aryl-2-amino-imidazole derivatives are known in the pharmaceutical arts: Jen, et al in T. Med. Chem.. 18(1). 90-99 (1975) made and tested a clonidine analog, among a few other related structures for antihypertensive and gastric antisecretory activity.
  • U.S. Patent number 3,459,763 which discloses a variety of substituted imidazole compounds, the two classes of compounds disclosed are regioisomers of the general structures: phenyl-2-amino-imidazole and N-l-phenyl-2-amino-imidazole. These structures wet disclosed as having cardiovascular and anti-inflammatory activities.
  • adrenoceptors were first divided in ⁇ and ⁇ types by Ahlquist in 1948. This division was based on pharmacological characteristics. Later, ⁇ -adrenoceptors were subdivided into ⁇ j and ⁇ 2 subtypes, again based on a pharmacological definition by comparison of the relative potencies of 12 agonists. The ⁇ -adrenoceptors were also subdivided into ⁇ , and ⁇ 2 subtypes, initially based on a presumed localization of oC j receptors postsynaptically and ⁇ 2 presynaptically.
  • SUBSTITUTE SHEET (RULE 26 initial work was done with various tissue aken from various species. While receptor heterogeneity among species is considered to be important, the term 'subtype' is usually reserved by pharmacologists for heterogeneity which can be demonstrated within the same species and ideally within a single tissue. Bylund and coworkers have later demonstrated that some regions of the human and rat brain contain two populations of ⁇ 2 -adrenoceptors sites which differ in their affinity for prazosin by 30- to 40- fold.
  • alpha2 (0:2) adrenergic receptor agonists are:
  • Clonidine is clinically useful as a hypotensive agent, and has been studied as a nasal decongestant and as an ocular hypotensive agent and as an anesthetic adjunct.
  • the mechanism of action of clonidine has been described as a centrally acting ⁇ 2 adrenergic partial agonist, however, clonidine also has hypotensive cardiovascular effects. It was
  • SUBSTITUTE SHEET (RULE 26; reported that clonidine binds to both ⁇ 2 and imidazoline receptors and that the binding to the imidazoline receptors mediates the blood pressure lowering side effects of clonidine. [See e.g. Codd, E.E., et al. Life Sci., 56 (2) p. 63-74 (2 Dec. 94) and Ernsberger, P., et al., Cardiovasc. Drugs Ther., 8 (Suppl. 1) pp. 27-41 (Mar.
  • Brimonodine (UK 14,304) is a newer ⁇ 2 adrenergic agent which possesses superior therapeutic action as an ocular hypotensive, and has been tested in other ⁇ 2 agonist responsive conditions.
  • Brimonidine as is shown by the data in table I at Example 4 also shows significant imidazoline receptor binding affinity.
  • Other activities inferred by I-receptor studies are stimulation of insulin release from pancreatic ⁇ -cells via coupling to ATP-sensitive K+ channels and inhibition of sodium reabsorption in the tubules of the kidneys. It has now been suggested by the present inventors that the imidazoline receptor is a nonfunctional binding site. [See Munk, S.A., et al. T. Med. Chem.. 39 (6) 1193-1195(1996).]
  • ⁇ 2A receptors have been identified in the ciliary body of the eye, and so are postulated to have a controlling mechanism in ocular hypertension and symptomatology of glaucoma (see Jin, Y. et al, T. Ocul. Pharmacol. 10(1) pp. 359-69 (1994).
  • Alpha 2A receptors have also been studied in pain perception, or alternatively, pain alleviation (see Millan, M. J., Eur. T. Pharmacol..215(2-3) pp. 355-6 (1992).
  • a selective or subtype selective agonist as the term is used in this invention indicates a compound that binds to, and activates, a specific receptor subtype in preference to other receptors of related but different subtype(s).
  • a compound that binds to and activates the ⁇ 2A subtype receptor in preference to the ⁇ 2B or ⁇ 2C subtype receptors is an ⁇ 2A selective agonist.
  • Activation means that the receptor is induced to initiate a biochemical event that is controlled or operated by that particular receptor. Activation can further be thought of in terms of a signal transduction process which mediates the signal triggered by receptor activation to intracellular effector structures.
  • This invention covers methods of using compounds of formula I selective agonism of ⁇ 2 adrenoceptors
  • each R j is independently H, alkyl of 1 to 4 carbon atoms or a halogen atom
  • each R 2 is independently H or an atom or functional group chosen from the group consisting of -N(R 4 ) 3 , -OR 4 , F, Cl, Br and -SR 4
  • each R 4 is independently chosen from the group consisting of hydrogen, alkyl of 1 to 4 carbon atoms and alkylcarbonyl of 1 to 5 carbon atoms
  • R 3 is independently chosen from the group of values for R j and R ; ,, or R 2 and R 3 together can form a 5 or 6 membered ring, which can optionally bear methyl, ethyl or oxo substituents, fused to the aryl ring, provided that in either case at least one R 2 is -N(R 4 ) 3 , -OR 4
  • the present invention provides a method of treating elevated intraocular pressure, nasal congestion or diarrhea in a mammal comprising administering to said mammal a therapeutically effective amount of a compound of the formula II
  • R j is H, alkyl of 1 to 4 carbon atoms or a halogen atom
  • X is O or NH
  • A is H or an oxo group and wherein said compound does not cause a concomitant reduction in blood pressure of said mammal.
  • the compound of formula II has the structure
  • R represents methyl or bromine and A is hydrogen or an oxo group.
  • the compound of formula II has the structure
  • Pharmaceutically acceptable salts of the compounds of formula I are also within the scope of the present invention.
  • Pharmaceutically acceptable acid addition salts of the compounds of the invention are those formed from acids which form non-toxic addition salts containing pharmaceutically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, phosphate or acid phosphate, acetate, maleate, fumarate, oxalate, lactate, tartrate, citrate, gluconate, saccharate, or_p_-toluenesulfonate salts.
  • a pharmaceutically acceptable salt may be any salt which retains the activity of the parent compound and does not impart any deleterious or untoward effect on the subject to which it is administered and in the context in which it is administered.
  • Organic amine salts may be made with amines, particularly ammonium salts such as mono-, di- and trialkyl amines or ethanol amines. Salts may also be formed with caffeine, tromethamine, and similar molecules. Where there is a nitrogen sufficiently basic as to be capable of forming acid addition salts such may be formed with any inorganic or organic acids or alkylating agent such as methyl iodide. Any of a number of simple organic acids such as mono-, di-, or tri-acid may also be used.
  • a pharmaceutically acceptable salt may be prepared for any compound of the invention having a functionality capable of forming such a salt, e.g., an acid salt of an amine group.
  • esters and amide as used here refer to and cover any compound falling within the definition of those terms as classically used in organic chemistry.
  • Some compounds of the present invention contain the (2-imidazolyl) amino structure which is represented as:
  • SUBSTITUTE SHEET (RULE 26) These compounds exist as tautomers (formally equivalent isomers capable of interchanging double bond positions and a proton between the heteroatoms) wherein the double bond can shift from one nitrogen to another either within or without the ring but always terminating at the 2-carbon of the ring.
  • the chemical nomenclature of these compounds is: 2-amino-imidazolines for the forms where the double bond is positioned within the ring and 2-imino-imidazolidines when the double bond is positioned outside the ring. No tautomeric form of these compounds places a double bond at the 4-5 position of the imidazole ring.
  • a further group of the present invention involves compounds which have in imidazoline ring but not an exocyclic amino group, but rather a methylene group in its place. Compounds of this type can tautomerize to give different double bond position within the ring only as shown below.
  • Hydrogen-bond acceptors are well-defined in the art [see for example, Wilson and Gisvold's Textbook of Organic Medicinal and Pharmaceutical Chemistry., R.F. Doerge (ed.) J.B. Lipincott Co. 1982, pp. 41-43 or Physical Organic Chemistry, N.S. Isaacs Universities Press (Belfast) Ltd., 1987 pp. 62-67].
  • a hydrogen bond is a bond in which a hydrogen atom serves to hold two other atoms together. These "other atoms" must themselves be capable of forming hydrogen bonds. Atoms with hydrogen bond forming capability have at least one unshared electron pair together with a complete octet of electrons.
  • a list of atoms contemplated by the invention includes: F, O, N, Cl, Br and S.
  • the H- bond consists of an attractive force which exists between a hydrogen atom covalently bound to an atom from the list given above (e.g. a hydroxy group, -O-H) and a second atom, not necessarily the same, from the list.
  • the lone pair atom which has the covalent bond to hydrogen is called the hydrogen bond donor.
  • the other atom which hydrogen bonds with this donated hydrogen is called the hydrogen bond acceptor.
  • Some groups such as hydroxy or primary or secondary amine can act as both hydrogen bond donors and hydrogen bond acceptors.
  • Groups such as ethers or tertiary amines are hydrogen bond acceptors only. The valence of quaternary amines which have no free lone pair are incapable of being hydrogen bond acceptors.
  • Hydrogen bond acceptor groups specifically contemplated by the present invention are primary, secondary, and tertiary amines, hydroxyl and ethers functions, amides and esters, fluoro, chloro and bromo groups and thiols and thioethers.
  • alkyl refers to and includes normal and branch chained alkyl groups.
  • lower alkyl unless specifically stated otherwise, includes normal alkyl of 1 to 4 carbons, branch chained alkyl of 3 or 4 carbons.
  • alkenyl and alkynyl include normal and branch chained groups having 2 to 4 carbons when the chains are normal, and 3 or 4 carbons when the chains are branched.
  • Figure I compares the effect of clonidine and a representative compound of this invention for lowering intraocular pressure (IOP).
  • Figure II compares the effect of clonidine and a representative compound of this invention for lowering blood pressure.
  • the present compounds may be prepared in a manner analogous to the procedures in: Commonly assigned PCT application 95/US/01150 filed on 25 January, 1995 by Munk, et al. discloses certain phenyl-2-amino- imidazoles which have subtype selected ⁇ 2A activity and methods for making them. The contents of this PCT application are hereby incorporated by reference in their entirety.
  • U.S. Patent No. 5,091,528 by Gluchowski and commonly assigned with the present application discloses methods of making (2-amino-imidazolinyl)-benzoxazine compounds encompassed by the methods of the present invention. The content of US 5,091,528 is hereby incorporated by reference in its entirety.
  • the desired therapeutic effects are an alteration, preferably a decrease in the rate of fluid transport in the gastrointestinal tract of a mammal, a reduction in or maintenance of the intraocular pressure in at least one eye of a mammal; and an increase in the renal fluid flow in at least one kidney of a mammal, or a decrease in nasal congestion in the air passages of a mammal.
  • the present compounds may be used as a anti-diarrhea agent, a medication for use in the treatment or management of glaucoma, a medication for use in the treatment or management of kidney disease and /or a treatment for congested nasal passages.
  • One important feature of many of the present compounds is that the desired therapeutic effect is achieved with reduced or absent side effects, in particular, lacking effects on the blood pressure or the mammal to which the present compound or compounds is/are administered.
  • Preferred compounds of the invention with reference to the Examples 1- 24 in Table 1 are those compounds which show high affinity for ⁇ 2 receptors (low Ki values) in the binding assays. Particularly preferred are those compounds in which the Ki (binding affinity) value for the ⁇ 2 receptors is from 0.0001 to 10.
  • the elements which are preferred in providing the desired binding respect to the structural features which are preferred in the present invention are the presence of a fused ring at R 2 and R 3 , more preferably with a nitrogen atom bonding to the aryl ring at R 2 and even more preferably with a nitrogen atom bonding to the ary ring at R 2 , and even more preferably with a nitrogen or oxygen atom bonding to the aryl ring at R 3 .
  • Other preferred embodiments include compounds of formula 1 wherein both R j S are methyl, one R 2 is hydroxy or methoxy, the other R 2 is hydrogen, and R 3 is t-butyl.
  • any suitable method of admi istering the present compound or compounds to me mammal to be treated may be used.
  • the particular method of administration chosen is preferably one which allows the present compound or compounds to have the desired therapeutic effect in an effective manner, e.g., low medication concentration and low incidence of side effects.
  • the present compound or compounds are administered to a mammal in a manner substantially similar to the used to administer ⁇ 2 agonists, to obtain the same or similar therapeutic effect.
  • Tissue preparation Membrane suspensions were prepared from human cerebral cortex (HDD, for ⁇ l receptors) obtained from the UCI Organ and Tissue Bank. Briefly, tissues (lg) were homogenized in 25 mL of ice-cold 5 mM Tris, pH 7.4 with a Polytron homogenizer for 30 sec at setting #7, and centrifuged for
  • CHO cells expressing the human ⁇ 2A and human ⁇ 2C (CHO-C10 and CHO-C4 respectively) receptors and CHO cells (CHO-RNG) expressing the rat ⁇ 2B adrenoceptor were grown to near confluence in Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum using standard cell culture methods.
  • Cells were harvested by scraping and placed into cold buffer of the following composition: 50 mM Tris-HCl, 5 mM EDTA, pH 7.4). Cells were then homogenized with a Polytron homogenizer for 2 x 10 sec at setting #7, and centrifuged for 20 minutes at 49,000 x g. The pellet fraction was washed (resuspended in Tris-HCl, pH 8 buffer and centrifuged for 15-20 minutes at 49,000 x g) 2 times and stored at -100 ° until binding assay.
  • radioligands [ 3 H]rauwolscine (specific activity 80 Ci/mmol) and [ 3 H)prazosin (specific activity 76 Ci/mmol) were obtained from New England Nuclear, Boxton, MA. Frozen membrane pellet was resuspended in 25 mM glycine/ gly cine, pH 7.5 and incubated with radioligand under the following conditions: CHO-C10, CHO-RNG, CHO-C4-[ 3 H]rauwolscine, 22°C, 30 minutes; RKC-[ 3 H]rauwolscine, 0°C, 120 minutes; and, HCC-[ 3 H]prazosin, 22°C, 30 minutes in a final volume of 500 ul.
  • the samples were filtered through glass filters (Whatman GF/B) in a 96 well cell harvester and rapidly washed four times with 4 mL of iced-cold 50 mM Tris-HCl buffer. The filters were then oven dried and transferred to scintillation vials containing 10 mL of Beckman's Ready Protein® scintillation cocktail for counting.
  • glass filters Whatman GF/B
  • CHO cells expressing the human ⁇ 2A (CHO-C10) and the rate ⁇ 2B (CHO-RNG) human ⁇ 2A adrenoceptors were grown to near confluence in Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum using standard cell culture methods.
  • Cells were harvested by scraping and placed into cold buffer of the following composition: 50 mM Tris-HCl, 5 mM EDTA, pH 7.4). Cells were then homogenized with a Polytyron homogenizer for 2 x 10 sec at setting #7, and centrifuged for 20 minutes at 49,000 x g. The pellet fraction was washed (resuspended in Tris-HCl, pH 8 buffer and centrifuged for 15-20 minutes at 49,000 x g) 2 times and stored at 100 ° C until binding assay.
  • radioligands [ 3 H] rauwolscine (specific activity 80 Ci/mmol) and [ 3 H] prazosin (specific activity 76 Ci/mmol) were obtained from New England Nuclear, Boston, MA. Frozen membrane pellet was resuspended in 25 mM glycine/ gly cine, pH 7.4 and incubated with radioligand under the following conditions: CHO-C10, CHO-RNG, CHO-C4-[ 3 H]rauwolscine, 22° C, 30 min.; and, HCC-[ 3 H]prazowsin, 22°C, 30 minutes in a final volume of 500 ul.
  • the samples were filtered through glass fiber filters (Whatman GF/B) in a 96 well cell harvester and rapidly washed four times with 4 mL of iced-cold 50 mM Tris-CHl buffer. The filters were then oven dried and transferred to scintillation vials containing 5 mL of Beckman's Ready Protein® scintillation cocktail for counting.
  • glass fiber filters Whatman GF/B
  • Specific binding defined by 10 uM phentolamine for competition studies were as follows: 0.3 nM[ 3 H]rauwolscine-CHO-C10 99%; 0.4 nM[ 3 H]rauwolscine-CHO-RNG 99%, and 0.3 nM [ 3 H]prazosin-HCC 87%. Protein concentrations were determined with a protein assay kit from Bio Rad. Binding isotherms, equilibrium dissociation and affinity constants were analyzed and determined by the non-linear least squares curve fitting programs AccuFit Competition/Saturation by Beckman.
  • Fresh bovine brain stems were obtained from a local slaughter house. After removal of pia-arachnoid, the medulla was isolated by dissecting the brain stem about 1 cm posterior and 1 cm caudal to the obex. The ventral quadrants of the medulla excluding the pyramids were used as the VLM. For each preparation, 30 to 40 VLM were used. Initial homogenization was performed in 20 volumes of 5 mM HEPES buffer (pH 7.4 at 4°C) containing 250 mM sucrose, 50 uM Calpain I inhibitor (Boehginer Mannheim, Indianapolis, IN), 100 uM 1,10-phenanthroline (Sigma, St.
  • the pellets obtained were resuspended in a teflon-glass homogenizer in 50 mM Tris-HCl with 5 mM EDTA (pH 7.7 at 4°C), centrifuged, and resuspended in 50 mM Tris- HC1 with 25 mM NaCl, pH 7.7 at room temp. To remove endogenous ligands, the homogenate was incubated 30 min at room temp before it was centrifuged for 20 min at 48000xg. The pellets were then washed with 50 mM Tris-HCl buffer, (pH 7.4 at 4°C) and loaded on top of 5 mM HEPES/0.85 M sucrose (pH 7.4 at 4°C).
  • imidazoline receptor binding assay Example 28: I ⁇ imidazoline receptor binding affinity was determined from radioligand binding of 3 H-clonidine (NEN, Boston, MA) to bovine VLM membranes. Specific activity of 3 H-clonidine was 43 Ci/mmol. Kd of 3 H-clonidine binding to the imidazoline receptor was determined by saturation experiments and Ki of other ligands studied were determined by competition experiments. The radioligand binding assay was performed in Teflon 96-wells with the Biomek-1000 robotics (Beckman Instruments, Fullerton, CA).
  • Each well contained 4 mN 3 H-Clonidine and 0.3 to 0.5 mg of bovine VLM protein in 5 mM HEPES buffer containing 0.5 mM EGTA and 0.5 mM MgCl 2 , pH 7.4 (0.1 mM ascorbic acid was added just before the protein). After 50 min of incubation at 25 °C, the reaction was terminated by rapid filtration over Whatman GF/B filters treated with 0.1% polyethyleneimine and washed with 12 ml ice cold 50 mM Tris-HCl, pH 7.4 at 4°C in a Brandel Harvester (Brandel, Gaithersburg, M.D.). Both 'hot' and 'cold' saturation experiments were performed.
  • Radioactivity was counted in a Beckman LS-3801 scintillation counter. Data were captured and analyzed with Accufit saturation and competition softwares modeled both for one-site and two-site fits (Beckman Instruments, Fullerton, CA) using an IBM compatible computer. All experiments were repeated at least twice.
  • the compound of Example 16 was compared to clonidine for lowering intraocular pressure (IOP) by topical administration of a single drop of 0.001% of the compound in an ophthalmically acceptable vehicle to one eye of a rabbit.
  • the untreated eye was used as the control.
  • the results are reported in Figure 1.
  • clonidine shows a systemic effect, in that the IOP of the untreated eye is lowered to the same extent as the treated eye.
  • the eye treated with the compound of Example 16 showed a greater effect in lowering IOP than clonidine without lowering IOP in the untreated eye.
  • Example 16 The compound of Example 16 and clonidine were tested for systemic effect by injecting 10 ug/kg of each compound into a rabbit. In comparison to a saline control, the clonidine lowered the mean arterial blood pressure, substantially, while the compound of Example 16 did not effectively lower the mean arterial blood pressure.

Landscapes

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

Abstract

Cette invention concerne des procédés permettant de traiter un mammifère dont l'état justifie un traitement d'agent agoniste alpha-2, et ce sans induire d'effets secondaires cardio-vasculaires. Ces procédés font usage de composé représenté par la formule (II) dans laquelle R1 est H, alkyle ayant de 1 à 4 atomes de carbone ou un atome d'halogène, X est O ou NH et A est H ou un groupe oxo, ce composé ne provoquant aucune réduction concomitante de la pression sanguine chez le mammifère traité.
PCT/US1996/006633 1995-05-12 1996-05-09 Aryl-imidazolines et aryl-imidazoles utiles en tant qu'agents agonistes adrenergiques alpha-2 n'entrainant pas d'effets secondaires cardio-vasculaires Ceased WO1996035424A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP96913983A EP0828491A1 (fr) 1995-05-12 1996-05-09 Aryl-imidazolines et aryl-imidazoles utiles en tant qu'agents agonistes adrenergiques alpha-2 n'entrainant pas d'effets secondaires cardio-vasculaires
JP8534262A JPH11505224A (ja) 1995-05-12 1996-05-09 心臓血管系副作用を伴わないα▲下２▼アドレナリン作動剤として有用なアリール−イミダゾリンおよびアリール−イミダゾール
AU56785/96A AU715350B2 (en) 1995-05-12 1996-05-09 Aryl-imidazolines and aryl-imidazoles useful as alpha-2 adrenergic agonists without cardiovascular side effects

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US44003095A 1995-05-12 1995-05-12
US08/440,030 1995-05-12

Publications (1)

Publication Number Publication Date
WO1996035424A1 true WO1996035424A1 (fr) 1996-11-14

Family

ID=23747133

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1996/006633 Ceased WO1996035424A1 (fr) 1995-05-12 1996-05-09 Aryl-imidazolines et aryl-imidazoles utiles en tant qu'agents agonistes adrenergiques alpha-2 n'entrainant pas d'effets secondaires cardio-vasculaires

Country Status (5)

Country Link
EP (1) EP0828491A1 (fr)
JP (1) JPH11505224A (fr)
AU (1) AU715350B2 (fr)
CA (1) CA2220517A1 (fr)
WO (1) WO1996035424A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2001524542A (ja) * 1997-12-04 2001-12-04 アラーガン・セイルズ・インコーポレイテッド α２Ｂまたは２Ｂ／２Ｃアドレナリン受容体において作動剤様活性を示す置換イミダゾール誘導体
WO2001060347A3 (fr) * 2000-02-15 2002-02-28 Allergan Sales Inc Methode de traitement des douleurs oculaires
US8815923B2 (en) 2007-08-15 2014-08-26 Allergan, Inc. Therapeutic compounds

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP3360073B2 (ja) * 2001-02-22 2002-12-24 花王株式会社 飲 料
US20050058696A1 (en) * 2003-09-12 2005-03-17 Allergan, Inc. Methods and compositions for the treatment of pain and other alpha 2 adrenergic-mediated conditions
CN101855213B (zh) * 2007-08-15 2014-09-10 阿勒根公司 治疗性化合物
US8815861B2 (en) * 2011-07-25 2014-08-26 Allergan, Inc. N-(imidazolidin-2-ylidene)quinoline derivatives as modulators of alpha 2 adrenergic receptors

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5091528A (en) * 1990-09-12 1992-02-25 Allergan, Inc. 6- or 7- (2-imino-2-imidazolidine)-1,4-benzoxazines as α adrenergic agents
US5112822A (en) * 1989-10-12 1992-05-12 Allergan, Inc. (2-imidazolin-2-ylamino) quinoxaline derivatives and methods for using same
WO1995019968A1 (fr) * 1994-01-24 1995-07-27 Allergan DERIVES AROMATIQUES 2-AMINO-IMIDAZOLE UTILISES COMME AGONISTES DE L'ADRENORECEPTEUR α-2A

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5112822A (en) * 1989-10-12 1992-05-12 Allergan, Inc. (2-imidazolin-2-ylamino) quinoxaline derivatives and methods for using same
US5091528A (en) * 1990-09-12 1992-02-25 Allergan, Inc. 6- or 7- (2-imino-2-imidazolidine)-1,4-benzoxazines as α adrenergic agents
WO1995019968A1 (fr) * 1994-01-24 1995-07-27 Allergan DERIVES AROMATIQUES 2-AMINO-IMIDAZOLE UTILISES COMME AGONISTES DE L'ADRENORECEPTEUR α-2A

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
MUNK: "Analogs of UK-14304: structural features responsible for alpha-2 adrenoceptor activity", BIOORG.MED.CHEM.LETT., vol. 5, no. 15, 1995, XP000600833 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2001524542A (ja) * 1997-12-04 2001-12-04 アラーガン・セイルズ・インコーポレイテッド α２Ｂまたは２Ｂ／２Ｃアドレナリン受容体において作動剤様活性を示す置換イミダゾール誘導体
WO2001060347A3 (fr) * 2000-02-15 2002-02-28 Allergan Sales Inc Methode de traitement des douleurs oculaires
US8815923B2 (en) 2007-08-15 2014-08-26 Allergan, Inc. Therapeutic compounds

Also Published As

Publication number Publication date
AU715350B2 (en) 2000-01-20
CA2220517A1 (fr) 1996-11-14
EP0828491A1 (fr) 1998-03-18
JPH11505224A (ja) 1999-05-18
AU5678596A (en) 1996-11-29

Similar Documents

Publication Publication Date Title
US6087361A (en) Aryl-imidazolines and aryl-imidazoles useful as α-2 adrenergic agonists without cardiovascular side effects
FI114983B (fi) Menetelmä bentsimidatsoli-7-karboksylaatin C-tyyppiä olevan kiteen valmistamiseksi
JP3883205B2 (ja) アンギオテンシン▲ｉｉ▼レセプタ遮断イミダゾールによるアテローム性動脈硬化症の治療
DK2616068T3 (en) ESTER prodrugs of the [3- (1- (1H-imidazol-4-yl) ethyl) -2-methyl-phenyl] -methanol for lowering intraocular pressure
JP2011256195A (ja) 虚血後腎不全の予防および処置並びに虚血腎臓の保護のためのａｔ１−レセプターアンタゴニスト
US11331306B2 (en) Pharmaceutical compositions comprising 4-[1-(2,3-dimethylphenyl)ethyl]-3H-imidazole derivatives for treating retinal diseases
WO2005087750A1 (fr) Modulateurs de canaux ioniques
CA2724293A1 (fr) Quinolynylmethylimidizoles en tant qu'agents therapeutiques
CN101284818B (zh) (e)-1-(4-((1r,2s,3r)-1,2,3,4-四羟基丁基)-1h-咪唑-2-基)乙酮肟的固体形式
AU715350B2 (en) Aryl-imidazolines and aryl-imidazoles useful as alpha-2 adrenergic agonists without cardiovascular side effects
Caillard et al. Hypotensive activity of PAF-acether in rats
Gentili et al. Agonists and antagonists targeting the different α2-adrenoceptor subtypes
AU744018B2 (en) Aryl-imidazolines and aryl-imidazoles useful as alpha-2 adrenergic agonists without cardiovascular side effects
AU2011329209B8 (en) Pharmaceutical compositions comprising (3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl) methanol
US20060293359A1 (en) Methods and compositions for the treatment of diabetes
RU2420280C2 (ru) Терапевтическое средство против кератоконъюнктивального расстройства

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AL AM AT AU AZ BB BG BR BY CA CH CN CZ DE DK EE ES FI GB GE HU IS JP KE KG KP KR KZ LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK TJ TM TR TT UA UG UZ VN AM AZ BY KG KZ MD RU TJ

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): KE LS MW SD SZ UG AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 1996913983

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 2220517

Country of ref document: CA

Ref country code: CA

Ref document number: 2220517

Kind code of ref document: A

Format of ref document f/p: F

ENP Entry into the national phase

Ref country code: JP

Ref document number: 1996 534262

Kind code of ref document: A

Format of ref document f/p: F

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

WWP Wipo information: published in national office

Ref document number: 1996913983

Country of ref document: EP