# Patent

## Title
Thiophenylaminoimidazolines as IP antagonists

## Abstract

Methods for treatment of IP antagonist mediated diseases or conditions by administration to a subject in need thereof a compound of formula (I)




wherein R1, R2, A and X are as defined herein. Also disclosed are compounds and related compositions.

## Background
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims benefit under 35 U.S.C. 119(e) of U.S. Provisional Application No. 60/485,924, filed Jul. 9, 2003, which is hereby incorporated by reference in its entirety.


FIELD OF THE INVENTION
This invention relates to prostaglandin I2 (IP) receptor antagonists, and associated pharmaceutical compositions containing them, and methods for their use as therapeutic agents.
BACKGROUND OF THE INVENTION
Prostaglandins or prostanoids (PG's) are a group of bioactive compounds derived from membrane phospholipids and are formed from 20-carbon essential fatty acids containing three, four, or five double bonds, and a cyclopentane ring. They fall into several main classes designated by the letters D, E, F, G, H, or I, and are distinguished by substitutions to the cyclopentane ring. The main classes are further subdivided by subscripts 1, 2, or 3, which reflect their fatty acid precursors. Thus, PGI2 has a double ring structure, and the subscript 2 indicates that it is related to arachidonic acid.
PGI2 (also known as prostacyclin) acts on platelets and blood vessels to inhibit aggregation and to cause vasodilation, and is thought to be important for vascular homeostasis. It has been suggested that PGI2 may contribute to the antithrombogenic properties of the intact vascular wall. PGI2 is also thought to be a physiological modulator of vascular tone that functions to oppose the actions of vasoconstrictors. The importance of these vascular actions is emphasized by the participation of PGI2 in the hypotension associated with septic shock. Although prostaglandins do not appear to have direct effects on vascular permeability, PGI2 markedly enhances edema formation and leukocyte infiltration by promoting blood flow in the inflamed region. Therefore, IP receptor antagonists may relieve hypotension related to septic shock, may reduce edema formation, and may prevent conditions associated with excessive bleeding such as, but not limited to, hemophilia and hemorrhaging.
Several in vivo analgesia studies in rodents suggest that PGI2 plays a major role in the induction of hyperalgesia. Likewise, in vitro studies provide substantial evidence to suggest that “PGI2-preferring” (IP) receptors act as important modulators of sensory neuron function (K. Bley et al, Trends in Pharmacological Sciences 1998, 19(4):141–147). Since EP receptors in sensory neurons are coupled to activation of both adenylyl cyclase and phospholipase C, and hence, cAMP-dependent protein kinase and protein kinase C, these receptors can exert powerful effects on ion channel activity and thus neurotransmitter release. Evidence of a prominent role for IP receptors in inflammatory pain has been obtained from recent studies in transgenic mice lacking the IP receptor (T. Murata et al., Nature 1997, 388, 678–682).
In addition to being mediators of hyperalgesia, prostaglandins are known to be generated locally in the bladder in response to physiologic stimuli such as stretch of the detrusor smooth muscle, injuries of the vesical mucosa, and nerve stimulation (K. Anderson, Pharmacological Reviews 1993, 45(3), 253–308). PGI2 is the major prostaglandin released from the human bladder. There are suggestions that prostaglandins may be the link between detrusor muscle stretch produced by bladder filling and activation of C-fiber afferents by bladder distension. It has been proposed that prostaglandins may be involved in the pathophysiology of bladder disorders. Therefore, antagonists of prostaglandin IP receptors are expected to be useful in the treatment of such conditions.
Antagonists of IP receptors are also expected to find a utility in respiratory allergies wherein PGI2 production in response to an allergen is present or in respiratory conditions such as asthma.
Additional information relating to prostaglandins and their receptors is described in Goodman & Gillman's, The Pharmacological Basis of Therapeutics, ninth edition, McGraw-Hill, New York, 1996, Chapter 26, pages 601–616.
All publications, patents, and patent applications cited herein, whether supra or infra, are each hereby incorporated by reference their its entirety.
SUMMARY OF THE INVENTION
The invention provides methods for treating a disease or condition mediated by an IP antagonist, the methods comprising administering to a subject in need thereof an effective amount of a compound of the formula (I):




wherein:

    
    
        R1 is: alkyl; cycloalkyl; optionally substituted aryl; or optionally substituted heteroaryl;
        R2 is: hydrogen; alkyl; alkoxy; haloalkyl; or halogen;
        A is: —O—; —S(O)p— wherein p is from 0 to 2; —NR3— wherein R3 is hydrogen or alkyl; or a bond; and
        X is a group of formula i, ii, iii, iv, v, vi, vii or viii;
    
    






    
    
        herein:
        
            m is 0 or 1;
            n is from 1 to 3; and
            Ra, Rb, Rc, Rd, Re, Rf, Rg and Rh each independently is hydrogen or alkyl or pharmaceutically acceptable salts, solvates or prodrugs thereof.
        
        
    
    


Also provided are compounds and pharmaceutical compositions usable with the methods of the invention.


DETAILED DESCRIPTION OF THE INVENTION
Definitions
Unless otherwise stated, the following terms used in this Application, including the specification and claims, have the definitions given below. It must be noted that, as used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise.
“Acyl” (or “alkylcarbonyl”) means the radical —C(O)—Ra, wherein Ra is lower alkyl as defined herein. Examples of acyl radicals include, but are not limited to, formyl, acetyl, propionyl, butyryl, and the like.
“Alkyl” means the monovalent linear or branched saturated hydrocarbon radical, consisting solely of carbon and hydrogen atoms, having from one to twelve carbon atoms inclusive, unless otherwise indicated. Examples of alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, pentyl, n-hexyl, octyl, dodecyl, and the like.
“Alkylene” means the divalent linear or branched saturated hydrocarbon radical, consisting solely of carbon and hydrogen atoms, such as methylene, ethylene, isopropylene and the like.
“Lower alkyl” means the monovalent linear or branched saturated hydrocarbon radical, consisting solely of carbon and hydrogen atoms, having from one to six carbon atoms inclusive (i.e. “C1–C6alkyl”), unless otherwise indicated. Examples of lower alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, sec-butyl, tert-butyl, n-butyl, n-pentyl, n-hexyl, and the like.
“Alkoxy” means the radical —O—Rb, wherein Rb is a lower alkyl radical as defined herein. Examples of alkoxy radicals include, but are not limited to, methoxy, ethoxy, isopropoxy, and the like.
“Alkoxycarbonyl” means the radical —C(O)—ORc wherein Rc is a lower alkyl radical as defined herein. Examples of alkoxycarbonyl radicals include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, and the like.
“Alkylamino” means the radical —NHRd, wherein Rd is a lower alkyl radical as defined herein. Examples of alkylamino radicals include, but are not limited to, methylamino, ethylamino, butylamino, and the like.
“Alkylaminocarbonyl” means the radical —C(O)—NHRe wherein Re is a lower alkyl radical as defined herein. Examples of alkylaminocarbonyl radicals include, but are not limited to, methylaminocarbonyl, ethylaminocarbonyl, isopropylaminocarbonyl, and the like.
“Alkylenedioxy means a divalent radical —O(CH2)nO— wherein n is from 1 to 4. “Ethylenedioxy” means the radical —OCH2CH2O—. “Methylenedioxy” means the radical —OCH2O—.
Alkylsulfonyl” means the radical —SO2Rf wherein Rf is a lower alkyl radical as defined herein. Examples of alkylsulfonyl radicals include, but are not limited to, methanesulfonyl, ethanesulfonyl, propanesulfonyl, and the like.
“Aralkyl” means the radical —RgRh wherein Rg is an alkyl radical as defined herein, and Rh is a lower aryl radical as defined herein. Examples of aralkyl radicals include, but are not limited to, benzyl, phenylethyl, 3-phenylpropyl, and the like.
“Aralkyloxy” means the radical —O—Ri, wherein Ri is an aralkyl radical as defined herein. Examples of aralkyloxy radicals include, but are not limited to, benzyloxy, phenylethyloxy, and the like.
“Aryl” means a monovalent cyclic aromatic hydrocarbon moiety consisting of a mono-, bi- or tricyclic aromatic ring. The aryl group can be optionally substituted as defined herein. Examples of aryl moieties include, but are not limited to, optionally substituted phenyl, naphthyl, phenanthryl, fluorenyl, indenyl, pentalenyl, azulenyl, oxydiphenyl, biphenyl, methylenediphenyl, aminodiphenyl, diphenylsulfidyl, diphenylsulfonyl, diphenylisopropylidenyl, benzodioxanyl, benzofuranyl, benzodioxylyl, benzopyranyl, benzoxazinyl, benzoxazinonyl, benzopiperadinyl, benzopiperazinyl, benzopyrrolidinyl, benzomorpholinyl, methylenedioxyphenyl, ethylenedioxyphenyl, and the like, including partially hydrogenated derivatives thereof.
“Aryloxy” means the radical —O—Ri, wherein Rg is an aryl radical as defined herein. Examples of aryloxy radicals include, but are not limited to, phenoxy and the like.
“Cycloalkyl” means the monovalent saturated carbocyclic radical consisting of one or more rings, which can be optionally substituted with one or more substituents independently selected from hydroxy, cyano, lower alkyl, lower alkoxy, thioalkyl, halo, haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, dialkylamino, aminocarbonyl, carbonylamino, aminosulfonyl, sulfonylamino and/or trifluoromethyl, unless otherwise indicated. Examples of cycloalkyl radicals include, but are not limited to, cyclopropyl, cyclobutyl, 3-ethylcyclobutyl, cyclopentyl, cyclopentyl, cycloheptyl, and the like.
“Cycloalkyloxy” means the radical —O—Rk, wherein Rk is a cycloalkyl radical as defined herein.
“Cycloalkylalkyl” means the radical —R1Rm wherein R1 is alkylene as defined herein and Rm is cycloalkyl as defined herein.
“Cycloalkylalkyloxy” means the radical —O—R1Rm wherein R1 is alkylene as defined herein and Rm is cycloalkyl as defined herein.
“Dialkylamino” means the radical —NRnRo wherein Rn and Ro are each independently lower alkyl radicals as defined herein. Examples of dialkylamino radicals include, but are not limited to, dimethylamino, methyl ethylamino, diethylamino, methyl propylamino, and the like.
“Dialkylaminocarbonyl” means the radical —C(O)—NRpRq wherein Rp and Rq are each independently a lower alkyl radical as defined herein. Examples of dialkylaminocarbonyl radicals include, but are not limited to, dimethylamino-carbonyl, diethylaminocarbonyl, methyl propylaminocarbonyl, and the like.
“Halogen” or “halo” means the radical fluoro, bromo, chloro, and/or iodo.
“Haloalkyl” means alkyl as defined herein substituted in any position with one or more halogen atoms as defined herein. Examples of haloalkyl radicals include, but are not limited to, 1,2-difluoropropyl, 1,2-dichloropropyl, trifluoromethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, and the like.
“Haloalkyloxy” means a radical —O—Rr wherein Rr is haloalkyl as defined herein.
“Haloalkyloxyalkyl” means a radical —RsRt wherein Rs is alkylene as defined herein and Rt is haloalkoxy as defined
“Heteroaryl” means a monocyclic or bicyclic radical of 5 to 12 ring atoms having at least one aromatic ring containing one, two, or three ring heteroatoms selected from N, O, or S, the remaining ring atoms being C, with the understanding that the attachment point of the heteroaryl radical will be on an aromatic ring. The heteroaryl ring may be optionally substituted as defined herein. Examples of heteroaryl moieties include, but are not limited to, optionally substituted imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, thienyl, benzothienyl, thiophenyl, furanyl, pyranyl, pyridyl, pyrrolyl, pyrazolyl, pyrimidyl, quinolinyl, isoquinolinyl, benzofuiryl, benzothiophenyl, benzothiopyranyl, benzimidazolyl, benzooxazolyl, benzooxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzopyranyl, indolyl, isoindolyl, azaindolyl, indazolyl, triazolyl, triazinyl, quinoxalinyl, purinyl, quinazolinyl, quinolizinyl, naphthyridinyl, pteridinyl, carbazolyl, azepinyl, diazepinyl, acridinyl and the like, including partially hydrogenated derivatives thereof.
“Heterocyclyl” means a monovalent saturated moiety, consisting of one to three rings, incorporating one, two, or three or four heteroatoms (chosen from nitrogen, oxygen or sulfur). The heterocyclyl ring may be optionally substituted as defined herein. Examples of heterocyclyl moieties include, but are not limited to, optionally substituted piperidinyl, piperazinyl, homopiperazinyl, azepinyl, pyrrolidinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, pyridinyl, pyridazinyl, pyrimidinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, quinuclidinyl, quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazolylidinyl, benzothiazolidinyl, benzoazolylidinyl, dihydrofuryl, tetrahydrofuryl, dihydropyranyl, tetrahydropyranyl, thiamorpholinyl, thiamorpholinylsulfoxide, thiamorpholinylsulfone, dihydroquinolinyl, dihydrisoquinolinyl, tetrahydroquinolinyl, tetrahydrisoquinolinyl, and the like.
“Hydroxyalkyl” means alkyl as defined herein, substituted with one or more hydroxy groups. Examples of hydroxyalkyl radicals include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 1-(hydroxymethyl)-2-hydroxyethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl, and 2-(hydroxymethyl)-3-hydroxypropyl, and the like.
“Hydroxycarbonyl” means the radical —C(O)—OH.
“Optional” or “optionally” means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, “optional bond” means that the bond may or may not be present, and that the description includes single, double, or triple bonds.
“Optionally substituted”, when used in association with “aryl”, phenyl”, “heteroaryl” or “heterocyclyl”, means an aryl, phenyl, heteroaryl or heterocyclyl which is optionally substituted independently with one to four substituents, preferably one or two substituents selected from alkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, hydroxyalkyl, halo, nitro, cyano, hydroxy, alkoxy, amino, acylamino, mono-alkylamino, di-alkylamino, haloalkyl, haloalkoxy, heteroalkyl, —COR (where R is hydrogen, alkyl, phenyl or phenylalkyl), —(CR′R′′)n—COOR (where n is an integer from 0 to 5, R′ and R′′ are independently hydrogen or alkyl, and R is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl), or —(CR′R′′)n—CONRaRb (where n is an integer from 0 to 5, R′ and R′′ are independently hydrogen or alkyl, and Ra and Rb are, independently of each other, hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl).
“Isomer” means different compounds that have the same molecular formula, but differ in the nature or the sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”. Stereoisomers that are mirror images of each other and optically active are termed “enantiomers”, and stereoisomers that are not mirror images of one another are termed “diastereoisomers”.
“Atropic isomer” means the isomers owing their existence to restricted rotation caused by hindrance of rotation of large groups about a central bond.
“Chiral isomer” means a compound with one chiral center. It has two enantiomeric forms of opposite chirality and may exist either as an individual enantiomer or as a mixture of enantiomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is termed a “racemic mixture”. Compounds with more than one chiral center may exist as either an individual diastereomer or as a mixture of diastereomers, termed a “diastereomeric mixture”. When one chiral center is present, a stereoisomer may be characterized by the absolute configuration (R or S) of that chiral center. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center. The substituents attached to the chiral center under consideration are ranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog (Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahn et al., Angew. Chem. 1966, 78,413; Cahn and Ingold J. Chem. Soc. (London) 1951, 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem.Educ. 1964, 41, 116).
“Geometric isomer” means the diastereomers that owe their existence to hindered rotation about double bonds. These configurations are differentiated in their names by the prefixes cis- and trans-, or Z and E, which indicate that the groups are on the same or opposite side of the double bond in the molecule according to the Cahn-Ingold-Prelog rules.
“Leaving group” means the group with the meaning conventionally associated with it in synthetic organic chemistry, i.e., an atom or group displaceable under alkylating conditions. Examples of a leaving group include, but are not limited to, halogen, alkane- or arylenesulfonyloxy, such as methanesulfonyloxy, ethanesulfonyloxy, thiomethyl, benzenesulfonyloxy, tosyloxy, and thienyloxy, dihalophosphinoyloxy, optionally substituted benzyloxy, isopropyloxy, acyloxy, and the like.
“Protective group” or “protecting group” has the meaning conventionally associated with it in synthetic organic chemistry, i.e., a group which selectively blocks one reactive site in a multifunctional compound such that a chemical reaction can be carried out selectively at another unprotective reactive site. Certain processes of this invention rely upon the protecting groups to block reactive oxygen atoms present in the reactants. Acceptable protective groups for alcoholic or phenolic hydroxyl groups, which may be removed successively and selectively, include groups protected as acetates, haloalkyl carbonates, benzyl ethers, alkylsilyl ethers, heterocyclyl ethers, methyl or other alkyl ethers, and the like. Protective or blocking groups for carboxyl groups are similar to those described for hydroxyl groups, preferably tert-butyl, benzyl, or methyl esters. Examples of protecting groups can be found in T. W. Greene et al., Protective Groups in Organic Chemistry, 1999, J. Wiley, 2nd ed., and Harrison et al., Compendium of Synthetic Organic Methods, 1971–1996, Vols. 1–8, J. Wiley and Sons.
“Amino-protecting group” or “N-protecting group” means the protecting group that refers to those organic groups intended to protect the nitrogen atom against undesirable reactions during synthetic procedures and includes, but is not limited to, benzyl, benzyloxycarbonyl (carbobenzyloxy, CBZ), p-methoxybenzyl-oxycarbonyl, p-nitrobenzyloxycarbonyl, tert-butoxycarbonyl (BOC), trifluoroacetyl, and the like.
“Deprotection” or “deprotecting” is the process by which a protective group is removed after the selective reaction is completed. Certain protective groups may be preferred over others due to their convenience or relative ease of removal. Deprotecting reagents for protected hydroxyl or carboxyl groups include potassium or sodium carbonates, lithium hydroxyde in alcoholic solutions, zinc in methanol, acetic acid, trifluoroacetic acid, palladium catalysts, or boron tribromide, and the like.
“Inert organic solvent” or “inert solvent” means a solvent inert under the conditions of the reaction being described in conjunction therewith, including for example, benzene, toluene, acetonitrile, tetrahydrofuiran, N,N-dimethylformamide, chloroform, methylene chloride or dichloromethane, dichloroethane, diethyl ether, ethyl acetate, acetone, methyl ethyl ketone, methanol, ethanol, propanol, isopropanol, tert-butanol, dioxane, pyridine, and the like. Unless specified to the contrary, the solvents used in the reactions of the present invention are inert solvents.
“Pharmaceutically acceptable” means that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary as well as human pharmaceutical use.
“Pharmaceutically acceptable carrier” means a carrier that is useful in preparing a pharmaceutical composition that is generally compatible with the other ingredients of the composition, not deleterious to the recipient, and neither biologically nor otherwise undesirable, and includes a carrier that is acceptable for veterinary use or human pharmaceutical use. “A pharmaceutically acceptable carrier” as used in the specification and claims includes both one and more than one such carrier.
“Pharmaceutically acceptable salt” of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. Such salts, for example, include:
(1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxy-ethanesulfonic acid, benzenesulfonic acid, 2-napthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like;
(2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methyl-glucamine, and the like. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.
It should be understood that a reference to a pharmaceutically acceptable salt includes the solvent addition forms or crystal forms thereof, particularly solvates or polymorphs. Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and are often formed during the process of crystallization. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Polymorphs include the different crystal packing arrangements of the same elemental composition of a compound. Polymorphs usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Various factors such as the recrystallization solvent, rate of crystallization, and storage temperature may cause a single crystal form to dominate.
“Pharmacological effect” as used herein encompasses effects produced in the subject that achieve the intended purpose of a therapy. In one preferred embodiment, a pharmacological effect means the treatment of a subject in need of such treatment. For example, a pharmacological effect would be one that results in the prevention, alleviation, or reduction of a disease state associated with pain, inflammation, urinary tract disease state, or asthma in a subject in need of such treatment. In a preferred embodiment, a pharmacological effect means that the activation of the IP receptors is associated with therapeutic benefit in a subject having a disease state treatable by the administration of an IP receptor modulator, in particular an IP receptor antagonist.
“Subject” means mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the Mammalia class: humans, non-human primates such as chimpanzees and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs and cats; laboratory animals including rodents, such as rats, mice, and guinea pigs, and the like. Examples of non-mammals include, but are not limited to birds, and the like. The term does not denote a particular age or sex.
“Therapeutically effective amount” means an amount of a compound that, when administered to a subject for treating a disease state, is sufficient to effect such treatment for the disease state. The “therapeutically effective amount” will vary depending on the compound, and disease state being treated, the severity or the disease treated, the age and relative health of the subject, the route and form of administration, the judgement of the attending medical or veterinary practitioner, and other factors.
“Treating” or “treatment” of a disease state includes:
(1) preventing the disease state, i.e., causing the clinical symptoms of the disease state not to develop in a subject that may be exposed to or predisposed to the disease state, but does not yet experience or display symptoms of the disease state,
(2) inhibiting the disease state, i.e., arresting the development of the disease state or its clinical symptoms, or
(3) relieving the disease state, i.e., causing temporary or permanent regression of the disease state or its clinical symptoms.
Disease state” means any disease, disorder, condition, symptom, or indication.
“Disease state associated with the urinary tract” or “urinary tract disease state” or “uropathy” or “symptoms of the urinary tract”, used interchangeably, means the pathologic changes in the urinary tract, or dysfunction of urinary bladder smooth muscle or its innervation causing disordered urinary storage or voiding. Symptoms of the urinary tract include (also known as detrusor hyperactivity), outlet obstruction, outlet insufficiency, and pelvic hypersensitivity.
“Outlet insufficiency” includes, but is not limited to, urethral hypermobility, intrinsic sphincteric deficiency, or mixed incontinence. It is usually symptomatically manifested as stress incontinence.
“Outlet obstruction” includes, but is not limited to, benign prostatic hypertrophy (BPH), urethral stricture disease, tumors, and the like. It is usually symptomatically manifested as obstructive (low flow rates, difficulty in initiating urination, and the like), and irritative (urgency, suprapubic pain, and the like).
“Overactive bladder” or “detrusor hyperactivity” includes, but is not limited to, the changes symptomatically manifested as urgency, frequency, reduced bladder capacity, incontinence episodes, and the like; the changes urodynamically manifested as changes in bladder capacity, micturition threshold, unstable bladder contractions, sphincteric spasticity, and the like; and the symptoms usually manifested in detrusor hyperreflexia (neurogenic bladder), in conditions such as outlet obstruction, outlet insufficency, pelvic hypersensitivity, or in idiopathic conditions such as detrusor instability, and the like.
“Pelvic Hypersensitivity” includes, but is not limited to, pelvic pain, interstitial (cell) cystitis, prostadynia, prostatis, vulvadynia, urethritis, orchidalgia, and the like. It is symptomatically manifested as pain, inflammation or discomfort referred to the pelvic region, and usually includes symptoms of overactive bladder.
“Pain” means the more or less localized sensation of discomfort, distress, or agony, resulting from the stimulation of specialized nerve endings. There are many types of pain, including, but not limited to, lightning pains, phantom pains, shooting pains, acute pain, inflammatory pain, neuropathic pain, complex regional pain, neuralgia, neuropathy, and the like (Dorland's Illustrated Medical Dictionary, 28th Edition, W. B. Saunders Company, Philadelphia, Pa.). The goal of treatment of pain is to reduce the degree of severity of pain perceived by a treatment subject.
“Neuropathic pain” means the pain resulting from functional disturbances and/or pathological changes as well as noninflammatory lesions in the peripheral nervous system. Examples of neuropathic pain include, but are not limited to, thermal or mechanical hyperalgesia, thermal or mechanical allodynia, diabetic pain, entrapment pain, and the like.
“Modulator” means a molecule such as a compound that interacts with a target. The interactions include, but are not limited to, agonist, antagonist, and the like, as defined herein.
“Agonist” means a molecule such as a compound, a drug, an enzyme activator or a hormone that enhances the activity of another molecule or receptor site.
“Antagonist” means a molecule such as a compound, a drug, an enzyme inhibitor, or a hormone, that diminishes or prevents the action of another molecule or receptor site.
Nomenclature and Chemical Structures
In general, the nomenclature used in this Application is based on AutoNom®, a Beilstein Institute computerized system for the generation of IUPAC systematic nomenclature. Chemical structures shown herein were prepared using ISIS® version 2.2. Any open valency shown on a carbon, nitrogen or oxygen in the structures herein indicates the presence of a hydrogen.
As is well-known in the art, the imidazolin-2-ylamino group, in compounds such as the compounds of formula I, is in tautomeric equilibrium with the imidazolin-2-ylideneamino group:




For convenience, all the compounds of formula I are shown as having the imidazolin-2-ylamino structure, but it is to be understood that compounds of both tautomeric forms are intended to be within the scope of the invention.

Methods

The invention provides a method for treating a disease or condition mediated by an IP antagonist, the method comprising administering to a subject in need thereof an effective amount of a compound of the formula (I):




wherein:

    
    
        R1 is: alkyl; cycloalkyl; optionally substituted aryl; or optionally substituted heteroaryl;
        R2 is: hydrogen; alkyl; alkoxy; haloalkyl; or halogen;
        A is: —O—; —S(O)p— wherein p is from 0 to 2; —NR3— wherein R3 is hydrogen or alkyl; or a bond; and
        X is a group of formula i, ii, iii, iv, v, vi, vii or viii;
    
    






    
    
        herein:
        
            m is 0 or 1;
            n is from 1 to 3; and
            Ra, Rb, Rc, Rd, Re, Rf, Rg and Rh each independently is hydrogen or alkyl;

or pharmaceutically acceptable salts, solvates or prodrugs thereof.

        
        
    
    


Where any of R1, R2, R3, Ra, Rb, Rc, Rd, Re, Rf, Rg and Rh are alkyl, they are preferably lower alkyl, i.e. C1–C6 alkyl, and more preferably C1–C4alkyl.
In certain embodiments X may be of the formula i, and m may be 0 and n may be 1. In some embodiments Ra, Rb, Rc and Rd are hydrogen.
In many embodiments R1 is optionally substituted phenyl, such as phenyl optionally substituted with: alkyl; halo; alkoxy; haloalkyl; cycloalkyl; cycloalkylalkyl; cycloalkyloxy; cycloalkylalkyloxy; alkylenedioxy; carboxy; carboxyester; nitro; alkylsulfonylamino; hydroxyalkyl; phenoxy; alkanoyl; haloalkyloxyalkyl; phenylcarbonyl; or amido. In certain embodiments R1 may be 4-alkyl-phenyl; 4-halo-phenyl; 4-alkoxy-phenyl; 4-haloalkyl-phenyl; 4-cycloalkyl-phenyl; 4-cycloalkylalkyl-phenyl; 4-cycloalkyloxy-phenyl; 4-cycloalkylalkyloxy-phenyl; 4-alkylenedioxy-phenyl; 4-carboxy-phenyl; 4-carboxyester-phenyl; 4-nitro-phenyl; 4-alkylsulfonylamino-phenyl; 4-hydroxyalkyl-phenyl; 4-phenoxy-phenyl; 4-alkanoyl-phenyl; 4-haloalkyloxyalkyl-phenyl; 4-phenylcarbonyl-phenyl; or 4-amido-phenyl.
In certain embodiments the methods of the invention may utilize a compound of formula (II)




wherein:

    
    
        A is: —O; or —S—;
        R4 is: alkyl; halo; alkoxy; haloalkyl; cycloalkyl; cycloalkylalkyl; cycloalkyloxy; cycloalkylalkyloxy; alkylenedioxy; carboxy; carboxyester; nitro; alkylsulfonylamino; hydroxyalkyl; phenoxy; alkanoyl; haloalkyloxyalkyl; phenylcarbonyl; or amido;
        R5 is: hydrogen; alkyl; alkoxy; halo; or haloalkyl; or R4 and R5 together form an alkylene dioxy group; and
        m, n, R2, Ra, Rb, Rc and Rd are as defined herein.
    
    


In specific embodiments R4 may be: methyl; ethyl; isopropyl; tert-butyl; cyclohexyl; methoxy; ethoxy; isopropoxy; chloro; triflluoromethyl; ethoxycarbonyl; hydroxycarbonyl; nitro; methanesulfanyl-amino; hydroxymethyl; methoxycarbonyl-methyloxy; morpholin-4-yl-carbonyl-methyloxy; morpholin-4-yl-carbonyl; morpholin-4-yl-methyl; ethoxy-acetoacetamido; cyclohexyl-methyloxy; phenoxyethyl-carbonylamino; phenylethyl-carbonylamino; aminocarbonyl; isopropoxy-carbonyl; phenyl-carbonyl; phenylmethylamino-carbonyl; 2,2,2-trifluoroethyloxymethyl; phenoxy; hydroxycarbonyl-methyloxy; 2-(ethoxycarbonyl)-ethyl; 2-(ethoxycarbonyl)-ethenyl; morpholin-4-yl-carbonyloxy-methyl; 4-phenylpiperazin-1-yl-methyl; or dimethylaminocarbonyloxymethyl.
The methods of the invention may specifically utilize a compound of the formula (III):




wherein:

    
    
        R4 is: methyl; ethyl; isopropyl; tert-butyl; cyclohexyl; methoxy; ethoxy; isopropoxy; chloro; triflluoromethyl; ethoxycarbonyl; hydroxycarbonyl; nitro; methanesulfanyl-amino; hydroxymethyl; methoxycarbonyl-methyloxy; morpholin-4-yl-carbonyl-methyloxy; morpholin-4-yl-carbonyl; morpholin-4-yl-methyl; ethoxy-acetoacetamido; cyclohexyl-methyloxy; phenoxyethyl-carbonylamino; phenylethyl-carbonylamino; aminocarbonyl; isopropoxy-carbonyl; phenyl-carbonyl; phenylmethylamino-carbonyl; 2,2,2-trifluoroethyloxymethyl; phenoxy; hydroxycarbonyl-methyloxy; 2-(ethoxycarbonyl)-ethyl; 2-(ethoxycarbonyl)-ethenyl; morpholin-4-yl-carbonyloxy-methyl; 4-phenylpiperazin-1-yl-methyl; or dimethylaminocarbonyloxymethyl; and
        R2 and R5 are as defined herein.
    
    


By way of example and not of limitation, the disease or condition may comprise a urinary tract disease, respiratory disease, edema formation, a hypotensive vascular disease, pain or inflammation. The pain may be inflammatory pain, neuropathic pain, cancer pain, acute pain, chronic pain, surgical pain, dental pain, premenstrual pain, visceral pain, pain due to burns, migraine, cluster headaches, neuralgias, post traumatic injuries, pain associated with functional bowel disorders such as irritable bowel syndrome, hyperalgesia, or complex regional syndromes. The inflammation may be associated with bacterial infection, fungal infection, viral infection, idiopathic bladder inflammation, nutritional deficiency, prostatis, or conjunctivitis pain. The urinary tract disease may be bladder outlet obstruction, urinary incontinence, reduced bladder capacity, frequency of micturition, urge incontinence, stress incontinence, bladder hyperreactivity, benign prostatic hypertrophy (BPH), prostatitis, detrusor hyperreflexia, urinary frequency, nocturia, urinary urgency, overactive bladder, pelvic hypersensitivity, urge incontinence, urethritis, prostatitis, pelvic pain syndrome, prostatodynia, cystitis, or idiophatic bladder hypersensitivity. The respiratory disease may be allergy or asthma. The disease may further comprise edema formation or hypotensive vascular disease.
Representative compounds in accordance with the invention are shown in Table 1.









TABLE 1





#
Name
Structure

















1
N-Ethyl-N′-[4-(4-methoxy-phenylsulfanyl)-phenyl]-guanidine






 


2
N-[4-(4-Chloro-phenylsulfanyl)-phenyl]-N′-ethyl-guanidine






 


3
N,N′-Diethyl-N′′-[4-(4-methoxy-phenylsulfanyl)-phenyl]-guanidine






 


4
N-[4-(4-Chloro-phenylsulfanyl)-benzyl]-N′-ethyl-guanidine






 


5
(4,5-Dihydro-1H-imidazol-2-yl)-[4-(4-methoxy-phenylsulfanyl)-phenyl]-amine






 


6
[4-(4-Chloro-phenylsulfanyl)-phenyl]-(4,5-dihydro-1H-imidazol-2-yl)-amine






 


7
[4-(4-Methoxy-phenylsulfanyl)-phenyl]-(4-methyl-4,5-dihydro-1H-imidazol-2-yl)-amine






 


8
(4,4-Dimethyl-4,5-dihydro-1H-imidazol-2-yl)-[4-(4-methoxy-phenylsulfanyl)-phenyl]-amine






 


9
[4-(4-Chloro-phenylsulfanyl)-benzyl]-(4,5-dihydro-1H-imidazol-2-yl)-amine






 


10
[4-(4-Methoxy-phenylsulfanyl)-phenyl]-(1,4,5,6-tetrahydro-pyrimidin-2-yl)-amine






 


11
[4-(4-Methoxy-phenylsulfanyl)-phenyl]-(4,5,6,7-tetrahydro-1H-[1,3]diazepin-2-yl)-amine






 


12
2-[4-(4-Methoxy-phenylsulfanyl)-benzyl]-4,5-dihydro-1H-imidazole






 


13
4-(4-Methoxy-phenylsulfanyl)-benzamidine






 


14
2-[4-(4-Methoxy-phenylsulfanyl)-phenyl]-4,5-dihydro-1H-imidazole






 


15
2-[4-(4-Methoxy-phenylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine






 


16
2-[4-(4-Methoxy-phenylsulfanyl)-phenyl]-1H-imidazole






 


17
5-[4-(4-Methoxy-phenylsulfanyl)-benzyl]-1H-imidazole






 


18
1-[4-(4-Methoxy-phenylsulfanyl)-benzyl]-pyrrolidine






 


19
(4,5-Dihydro-1H-imidazol-2-yl)-[3-(4-methoxy-phenylsulfanyl)-phenyl]-amine






 


20
(4,5-Dihydro-1H-imidazol-2-yl)-[2-(4-methoxy-phenylsulfanyl)-phenyl]-amine






 


21
Dibenzothiophen-2-yl-(4,5-dihydro-1H-imidazol-2-yl)-amine






 


22
7-(4-Methoxy-phenylsulfanyl)-1,2,3,5-tetrahydro-imidazo[2,1-b]quinazoline






 


23
(4,5-Dihydro-1H-imidazol-2-yl)-(4-methylsulfanyl-phenyl)-amine






 


24
(4-Cyclohexylsulfanyl-phenyl)-(4,5-dihydro-1H-imidazol-2-yl)-amine






 


25
[4-(2,6-Dichloro-phenylsulfanyl)-phenyl]-(4,5-dihydro-1H-imidazol-2-yl)-amine






 


26
(4,5-Dihydro-1H-imidazol-2-yl)-(4-phenylsulfanyl-phenyl)-amine






 


27
(4,5-Dihydro-1H-imidazol-2-yl)-[4-(2-methoxy-phenylsulfanyl)-phenyl]-amine






 


28
(4,5-Dihydro-1H-imidazol-2-yl)-[4-(3-methoxy-phenylsulfanyl)-phenyl]-amine






 


29
(4,5-Dihydro-1H-imidazol-2-yl)-[4-(2,5-dimethoxy-phenylsulfanyl)-phenyl]-amine






 


30
[4-(2,3-Dihydro-benzo[1,4]dioxin-6-ylsulfanyl)-phenyl]-(4,5-dihydro-1H-imidazol-2-yl)-amine






 


31
(4,5-Dihydro-1H-imidazol-2-yl)-[4-(4-ethoxy-phenylsulfanyl)-phenyl]-amine






 


32
(4,5-Dihydro-1H-imidazol-2-yl)-[4-(4-isopropoxy-phenylsulfanyl)-phenyl]-amine






 


33
(4,5-Dihydro-1H-imidazol-2-yl)-(4-p-tolylsulfanyl-phenyl)-amine






 


34
(4,5-Dihydro-1H-imidazol-2-yl)-[4-(4-trifluoromethyl-phenylsulfanyl)-phenyl]-amine






 


35
(4,5-Dihydro-1H-imidazol-2-yl)-[4-(4-isopropyl-phenylsulfanyl)-phenyl]-amine






 


36
[4-(4-tert-Butyl-phenylsulfanyl)-phenyl]-(4,5-dihydro-1H-imidazol-2-yl)-amine






 


37
4-[4-(4,5-Dihydro-1H-imidazol-2-ylamino)-phenylsulfanyl]-benzoic acidethyl ester






 


38
4-[4-(4,5-Dihydro-1H-imidazol-2-ylamino)-phenylsulfanyl]-benzoic acid






 


39
(4,5-Dihydro-1H-imidazol-2-yl)-[4-(4-nitro-phenylsulfanyl)-phenyl]-amine






 


40
N-{4-[4-(4,5-Dihydro-1H-imidazol-2-ylamino)-phenylsulfanyl]-phenyl}-methanesulfonamide






 


41
(4,5-Dihydro-1H-imidazol-2-yl)-[4-(4-methoxy-phenoxy)-phenyl]-amine






 


42
(4,5-Dihydro-1H-imidazol-2-yl)-[4-(4-methoxy-benzenesulfonyl)-phenyl]-amine






 


43
N-(4,5-Dihydro-1H-imidazol-2-yl)-N′-(4-methoxy-phenyl)-N′-methyl-benzene-1,4-diamine






 


44
(4,5-Dihydro-1H-imidazol-2-yl)-(4′-methoxy-biphenyl-4-yl)-amine






 


45
(4,5-Dihydro-1H-imidazol-2-yl)-[4-(naphthalen-2-ylsulfanyl)-phenyl]-amine






 


46
{4-[4-(4,5-Dihydro-1H-imidazol-2-ylamino)-phenylsulfanyl]-phenyl}-methanol






 


47
{4-[4-(4,5-Dihydro-1H-imidazol-2-ylamino)-phenylsulfanyl]-phenoxy}-acetic acid methyl ester






 


48
2-{4-[4-(4,5-Dihydro-1H-imidazol-2-ylamino)-phenylsulfanyl]-phenoxy}-1-morpholin-4-yl-ethanone






 


49
{4-[4-(4,5-Dihydro-1H-imidazol-2-ylamino)-phenylsulfanyl]-phenyl}-morphohn-4-yl-methanone






 


50
(4,5-Dihydro-1H-imidazol-2-yl)-[4-(4-morpholin-4-ylmethyl-phenylsulfanyl)-phenyl]-amine






 


51
N{4-[4-(4,5-Dihydro-1H-imidazol-2-ylamino)-phenylsulfanyl]-phenyl}-malonamic acid ethyl ester






 


52
(4,5 -Dihydro-1H-imidazol-2-yl)-[4-(6-methoxy-pyridin-3-ylsulfanyl)-phenyl]-amine






 


53
[4-(4-Cyclohexylmethoxy-phenylsulfanyl)-phenyl]-(4,5-dihydro-1H-imidazol-2-yl)-amine






 


54
N-{4-[4-(4,5-Dihydro-1H-imidazol-2-ylamino)-phenylsulfanyl]-phenyl}-2-phenoxy-acetamide






 


55
N-{4-[4-(4,5-Dihydro-1H-imidazol-2-ylamino)-phenylsulfanyl]-phenyl}-3-phenyl-propionamide






 


56
4-[4-(4,5-Dihydro-1H-imidazol-2-ylamino)-phenylsulfanyl]-benzamide






 


57
4-[4-(4,5-Dihydro-1H-imidazol-2-ylamino)-phenylsulfanyl]-benzoic acidisopropyl ester






 


58
{4-[4-(4,5-Dihydro-1H-imidazol-2-ylamino)-phenylsulfanyl]-phenyl}-phenyl-methanone






 


59
N-Benzyl-4-[4-(4,5-dihydro-1H-imidazol-2-ylamino)-phenylsulfanyl]-N-methyl-benzamide






 


60
(4,5-Dihydro-1H-imidazol-2-yl)-[4-(4-ethoxymethyl-phenylsulfanyl)-phenyl]-amine






 


61
(4,5-Dihydro-1H-imidazol-2-yl)-[3-methoxy-4-(4-methoxy-phenylsulfanyl)-phenyl]-amine






 


62
[3-Chloro-4-(4-methoxy-phenylsulfanyl)-phenyl]-(4,5-dihydro-1H-imidazol-2-yl)-amine






 


63
(4,5-Dihydro-1H-imidazol-2-yl)-[4-(4-phenoxy-phenoxy)-phenyl]-amine






 


64
(5,5-Dimethyl-1,4,5,6-tetrahydro-pyrimidin-2-yl)-[4-(4-methoxy-phenylsulfanyl)-phenyl]-amine






 


65
[3-Chloro-4-(4-chloro-phenylsulfanyl)-phenyl]-(3,4,5,6-tetrahydro-pyridin-2-yl)-amine






 


66
[3-Chloro-4-(4-chloro-phenylsulfanyl)-phenyl]-(4,5-dihydro-3H-pyrrol-2-yl)-amine






 


67
{4-[4-(4,5-Dihydro-1H-imidazol-2-ylamino)-phenylsulfanyl]-phenoxy}-acetic acid






 


68
3-{4-[4-(4,5-Dihydro-1H-imidazol-2-ylamino)-phenylsulfanyl]-phenyl}-propionic acid ethyl ester






 


69
(E)-3-{4-[4-(4,5-Dihydro-1H-imidazol-2-ylamino)-phenylsulfanyl]-phenyl}-acrylicacid ethyl ester






 


70
Morpholine-4-carboxylic acid 4-[4-(4,5-dihydro-1H-imidazol-2-ylamino)-phenylsulfanyl]-benzyl ester






 


71
(4,5-Dihydro-1H-imidazol-2-yl)-{4-[4-(4-phenyl-piperazin-1-ylmethyl)-phenylsulfanyl]-phenyl}-amine






 


72
Dimethyl-carbamic acid 4-[4-(4,5-dihydro-1H-imidazol-2-ylamino)-phenylsulfanyl]-benzyl ester






 


73
[4-(4-Chloro-phenylsulfanyl)-phenyl]-(3,4,5,6-tetrahydro-pyridin-2-yl)-amine













General Synthetic Scheme
Compounds of the present invention may be made by the methods depicted in the illustrative synthetic reaction schemes shown and described below.
The starting materials and reagents used in preparing these compounds generally are either available from commercial suppliers, such as Aldrich Chemical Co., or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser's Reagents for Organic Synthesis; Wiley & Sons: New York, 1991, Volumes 1–20; Rodd's Chemistry of Carbon Compounds, Elsevier Science Publishers, 1989, Volumes 1–5 and Supplementals; and Organic Reactions, Wiley & Sons: New York, 1991, Volumes 1–40. The following synthetic reaction schemes are merely illustrative of some methods by which the compounds of the present invention may be synthesized, and various modifications to these synthetic reaction schemes may be made and will be suggested to one skilled in the art having referred to the disclosure contained in this Application.
The starting materials and the intermediates of the synthetic reaction schemes may be isolated and purified if desired using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography, and the like. Such materials may be characterized using conventional means, including physical constants and spectral data.
Unless specified to the contrary, the reactions described herein preferably take place at atmospheric pressure over a temperature range from about −78° C. to about 150° C., more preferably from about 0° C. to about 125° C., and most preferably and conveniently at about room (or ambient) temperature, e.g., about 20° C.
Scheme A illustrates one method for preparing compounds of the invention, wherein X is halo or other leaving group and may be the same or different in each occurrence, and R2, R4 and R5 are as described herein. The procedure of Scheme A is exemplary, and alternative synthetic routes to the compounds of the invention will suggest themselves to those skilled in the art.




In step 1 of Scheme A, thiophenol a is treated with strong base such as sodium hydride under dry polar solvent conditions, and then reacted with nitro compound b to provide a nitrophenylsulfanylbenzene compound c. Nitrophenylsulfanylbenzene c may then be treated with reducing agent such as sodium borohydride or SnCl2 under polar protic solvent conditions to in step 2 to afford the corresponding phenylsulfanyl aniline d. Aniline d in turn is reacted with an imidazoline e such as chloroimidazoline in step 3, to provide thiophenylaminoimidazoline compound f, which is a compound of formula (II) above where m is 0, A is —S—, and Ra, Rb and Rc are hydrogen.
As an alternative to step 3, step 4 may be carried out wherein phenylsulfanyl aniline d may be treated with acid followed by cyanide to afford a phenylsulfnanyl phenylguanidine compound g. Alternatively, step 5 may be carried out wherein phenylsulfanyl aniline d is reacted with lactam h to yield a phenylsulfanyl phenylpyrrolidine compound i.
Many variations on the procedure of Scheme A are possible and will be apparent to those skilled in the art. In one such variation, nitro compound b may be replaced with a corresponding protected aniline in step 1, with the protecting group being removed in step 2 (instead of nitro group reduction) to provide phenylsulfanyl aniline d. Many well-known protecting group schemes may be used in this regard. Exemplary protecting group strategies are described by, for example, by Greene et al. in Protecting Groups in Organic Synthesis, 3rd. Ed., Wiley & Sons, 1999. In other variations of Scheme A, imidazoline compound e (n=1) may be replaced with the corresponding trihydropyrimidine compound (n=2) or tetrahydrodiazepin compound (n=3). In yet another variation, the sulfanyl moiety may be partially or fully oxidized using meta chloro perbenzoic acid or OXON® to yield the corresponding sulfinyl or sulfonyl compounds.
Referring now to Scheme B, there is shown another procedure for making compounds of the invention, wherein X is halo or other leaving group and may be the same or different in each occurrence, and R2, R4 and R5 are as described herein. The procedure of Scheme B, like Scheme A, is exemplary and should not be considered as limiting.




In step 1 of Scheme B, thiophenol a is treated with strong base as in step 1 of Scheme A, and is then reacted with nitrile compound i to yield phenylsulfanylbenzene nitrile compound k. The phenylsulfanylbenzene nitrile may then in step 2 be reduced with a strong reducing agent such as lithium aluminum hydride to yield phenylsulfanyl benzylamine l. Benzylamine l may then be reacted with an imidazoline e in step 3 in the manner described above to provide thiophenyl methylaminoimidazoline compound m, which is a compound of formula (II) above where m is 1, A is —S—, and Ra, Rb and Rc are hydrogen. As in the procedure of Scheme A, step 4 may be substituted for step 3 to yield the corresponding guanidine compound n, or step 5 may be carried out to provide the corresponding pyrrolidine compound 0.
Numerous variations on the procedure of Scheme B are possible and will be apparent to those skilled in the art. Imidazoline compound e (n=1) may be replaced with the corresponding trihydropyrimidine compound (n=2) or tetrahydrodiazepin compound (n=3) in step 3 as noted above. In another variation, nitrile compound i may be replaced with a corresponding protected benzylamine in step 1, which would then be deprotected in step 2 to afford phenylsulfanyl benzylamine i. In yet another variation of the above procedure, phenylsulfanylbenzene nitrile compound k may be converted to the corresponding phenylsulfanyl-benzimidic acid ester, which may then be treated with ethylene diamine to afford a phenylsulfanyl-phenyl imidazoline, or propylene diamine to afford a phenylsulfanyl-phenyl trihydropyrimidine.
General Utility
The compounds of the present invention are IP receptor modulators, in particular, IP receptor antagonists, and as such possess selective antagonist activity at the IP receptor. These compounds (and compositions containing them) are expected to be useful in the prevention and treatment of a variety of diseases in mammals, especially humans.
In particular, the compounds of the invention possess anti-inflammatory and/or analgesic properties in vivo, and accordingly, are expected to find utility in the treatment of disease states associated with pain conditions from a wide variety of causes, including, but not limited to, inflammatory pain, surgical pain, visceral pain, dental pain, premenstrual pain, central pain, pain due to burns, migraine or cluster headaches, nerve injury, neuritis, neuralgias, poisoning, ischemic injury, interstitial cystitis, cancer pain, viral, parasitic or bacterial infection, post-traumatic injuries (including fractures and sports injuries), and pain associated with functional bowel disorders such as irritable bowel syndrome.
The compounds of the present invention are also useful in the treatment of inflammatory conditions from a variety of causes, including, but not limited to, bacterial, fungal or viral infections, rheumatoid arthritis, osteoarthritis, surgery, bladder infection or idiopathic bladder inflammation, over-use, old age, or nutritional deficiencies, prostatitis, and conjunctivitis.
The compounds of this invention are also useful in treating disease states associated with urinary tract disease states associated with bladder outlet obstruction and urinary incontinence conditions such as bladder outlet obstruction, urinary incontinence, reduced bladder capacity, frequency of micturition, urge incontinence, stress incontinence, bladder hyperreactivity, benign prostatic hypertrophy (BPH), prostatitis, detrusor hyperreflexia, urinary frequency, nocturia, urinary urgency, overactive bladder, pelvic hypersensitivity, urge incontinence, urethritis, prostatitits, pelvic pain syndrome, prostatodynia, cystitis, and idiophatic bladder hypersensitivity, and other symptoms related to overactive bladder.
The compounds of this invention may also find utility in the treatment of hypotensive vascular diseases such as hypotension associated with septic shock.
In addition, the compounds of this invention are useful in the treatment of respiratory diseases such as allergies and asthma.
These and other therapeutic uses are described, for example, in Goodman & Gilman 's, The Pharmacological Basis of Therapeutics, tenth edition, McGraw-Hill, New York, 2001, Chapter 26; and Coleman, R. A., Pharmacological Reviews, 1994, 46:205–229.
Testing
The anti-inflammatory/analgesic activity of the compounds of this invention may be assayed by in vivo assays such as the Rat Carrageenan-Induced Mechanical Hyperalgesia Paw Assay and the Rat Complete Freund's Adjuvant-Induced Mechanical Hyperalgesia Assay, as described in more detail in the following Examples. Activity in the inhibition of bladder contractions may be assayed by in vivo assays such as the Inhibition of Bladder Contractions Induced by Isovolumetric Bladder Distension Assay and the Inhibition of Volume-Induced Contracts in Rats Assay, as described in more detail in the Examples below. Activity in the inhibition of the septic shock may be assayed by in vivo assays such as the Rat Reversal of Endotoxin-Induced Hypotension Assay, as described in more detail in the Examples below. The level of HERG channel inhibition of the compounds of the invention were assayed according to the procedure described in the Examples.
Administration and Pharmaceutical Composition
The present invention includes pharmaceutical compositions comprising at least one compound of the present invention, or individual isomers, racemic or non-racemic mixtures of isomers, or pharmaceutically acceptable salts or solvates thereof, together with at least one pharmaceutically acceptable carrier and optionally other therapeutic and/or prophylactic ingredients.
In general, the compounds of the present invention will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities. Suitable dosage ranges are typically 1–500 mg daily, preferably 1–100 mg daily, and most preferably 1–30 mg daily, depending upon numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, the indication towards which the administration is directed, and the preferences and experience of the medical practitioner involved. One of ordinary skill in the art of treating such diseases will be able, without undue experimentation and in reliance upon personal knowledge and the disclosure of this Application, to ascertain a therapeutically effective amount of the compounds of the present invention for a given disease.
In general, compounds of the present invention will be administered as pharmaceutical formulations including those suitable for oral (including buccal and sub-lingual), rectal, nasal, topical, pulmonary, vaginal, or parenteral (including intramuscular, intraarterial, intrathecal, subcutaneous and intravenous) administration or in a form suitable for administration by inhalation or insufflation. The preferred manner of administration is generally oral using a convenient daily dosage regimen which can be adjusted according to the degree of affliction.
A compound or compounds of the present invention, together with one or more conventional adjuvants, carriers, or diluents, may be placed into the form of pharmaceutical compositions and unit dosages. The pharmaceutical compositions and unit dosage forms may be comprised of conventional ingredients in conventional proportions, with or without additional active compounds or principles, and the unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed. The pharmaceutical compositions may be employed as solids, such as tablets or filled capsules, semisolids, powders, sustained release formulations, or liquids such as solutions, suspensions, emulsions, elixirs, or filled capsules for oral use; or in the form of suppositories for rectal or vaginal administration; or in the form of sterile injectable solutions for parenteral use. Formulations containing about one (1) milligram of active ingredient or, more broadly, about 0.01 to about one hundred (100) milligrams, per tablet, are accordingly suitable representative unit dosage forms.
The compounds of the present invention may be formulated in a wide variety of oral administration dosage forms. The pharmaceutical compositions and dosage forms may comprise a compound or compounds of the present invention or pharmaceutically acceptable salts thereof as the active component. The pharmaceutically acceptable carriers may be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier may be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. In powders, the carrier generally is a finely divided solid which is a mixture with the finely divided active component. In tablets, the active component generally is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain from about one (1) to about seventy (70) percent of the active compound. Suitable carriers include but are not limited to magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term “preparation” is intended to include the formulation of the active compound with encapsulating material as carrier, providing a capsule in which the active component, with or without carriers, is surrounded by a carrier, which is in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges may be as solid forms suitable for oral administration.
Other forms suitable for oral administration include liquid form preparations including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions, or solid form preparations which are intended to be converted shortly before use to liquid form preparations. Emulsions may be prepared in solutions, for example, in aqueous propylene glycol solutions or may contain emulsifying agents, for example, such as lecithin, sorbitan monooleate, or acacia. Aqueous solutions can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing, and thickening agents. Aqueous suspensions can be prepared by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well known suspending agents. Solid form preparations include solutions, suspensions, and emulsions, and may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
The compounds of the present invention may be formulated for parenteral administration (e.g., by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, for example solutions in aqueous polyethylene glycol. Examples of oily or nonaqueous carriers, diluents, solvents or vehicles include propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate), and may contain formulatory agents such as preserving, wetting, emulsifying or suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilisation from solution for constitution before use with a suitable vehicle, e.g., sterile, pyrogen-free water.
The compounds of the present invention may be formulated for topical administration to the epidermis as ointments, creams or lotions, or as a transdermal patch. Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also containing one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents. Formulations suitable for topical administration in the mouth include lozenges comprising active agents in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
The compounds of the present invention may be formulated for administration as suppositories. A low melting wax, such as a mixture of fatty acid glycerides or cocoa butter is first melted and the active component is dispersed homogeneously, for example, by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and to solidify.
The compounds of the present invention may be formulated for vaginal administration. Pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
The compounds of the present invention may be formulated for nasal administration. The solutions or suspensions are applied directly to the nasal cavity by conventional means, for example, with a dropper, pipette or spray. The formulations may be provided in a single or multidose form. In the latter case of a dropper or pipette, this may be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension. In the case of a spray, this may be achieved for example by means of a metering atomizing spray pump.
The compounds of the present invention may be formulated for aerosol administration, particularly to the respiratory tract and including intranasal administration. The compound will generally have a small particle size for example of the order of five (5) microns or less. Such a particle size may be obtained by means known in the art, for example by micronization. The active ingredient is provided in a pressurized pack with a suitable propellant such as a chlorofluorocarbon (CFC), for example, dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, or carbon dioxide or other suitable gas. The aerosol may conveniently also contain a surfactant such as lecithin. The dose of drug may be controlled by a metered valve. Alternatively the active ingredients may be provided in a form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidine (PVP). The powder carrier will form a gel in the nasal cavity. The powder composition may be presented in unit dose form for example in capsules or cartridges of e.g., gelatin or blister packs from which the powder may be administered by means of an inhaler.
When desired, formulations can be prepared with enteric coatings adapted for sustained or controlled release administration of the active ingredient.
The pharmaceutical preparations are preferably in unit dosage forms. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
Other suitable pharmaceutical carriers and their formulations are described in Remington: The Science and Practice of Pharmacy 1995, edited by E. W. Martin, Mack Publishing Company, 19th edition, Easton, Pa. Representative pharmaceutical formulations containing a compound of the present invention are described in Examples 1 to 17.
The following preparations and examples are given to enable those skilled in the art to more clearly understand and to practice the present invention. They should not be considered as limiting the scope of the invention, but merely as being illustrative and representative thereof.
Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperatures, etc.), but some experimental error and deviation should, of course, be allowed for as well as due to differences such as, for example, in calibration, rounding of numbers, and the like.
EXAMPLES
The following preparations and examples are given to enable those skilled in the art to more clearly understand and to practice the present invention. They should not be considered as limiting the scope of the invention, but merely as being illustrative and representative thereof.
Example 1
(4,5-Dihydro-1H-imidazol-2-yl)-[4-(4-methoxy-phenylsulfanyl)-phenyl]-amine




The synthetic procedures used in this Example are outlined in Scheme C.




Step 1

4-(4-Methoxy-phenylsulfanyl)-nitrobenzene





To a suspension of NaH (4.2 g) in 100 mL of dry DMF under nitrogen was slowly added 14.02 g of 4-methoxythiophenol. The reaction mix was stirred until no further gas evolution occurred (circa 20 minutes). To this solution was added 15.76 g of 4-chloronitrobenzene dissolved in 100 ml of dry DMF, after which the mixture was heated to 120° C. for one hour. The reaction mix became red in colour during this time. The mixture was then cooled to room temperature and poured over 1000 g of crushed ice. The resulting yellow solid was filtered, washed several times with water, and dried to afford 25.29 g (96%) of 4-(4-methoxy-phenylsulfanyl)-nitrobenzene as a yellow solid. MS M+H; 264.
Step 2
4-(4-Methoxy-phenylsulfanyl)-phenylamine




To a solution of 13.06 g of 4-(4-methoxy-phenylsulfanyl)-nitrobenzene from step 1 in 100 mL of ethanol was added 33.85 g of SnCl2−2H2O. The resulting mixture was stirred for 30 minutes at room temperature, then heated to reflux for 2 hours. The mixture was then cooled to room temperature, concentrated in vacuo, and treated with 20% aqueous NaOH. The solution was extracted three times with ethyl acetate, and the combined extracts were washed with water followed by brine, dried (MgSO4), after which the ethyl acetate was removed in vacuo. The resulting solid was chromatographed on SiO2 (70%/30% dichloromethane/hexanes) to afford 7.87 g (68%) of 4-(4-methoxy-phenylsulfanyl)-phenylamine. Mp: 91–92° C. MS M+H: 232.
Step 3
(4,5-Dihydro-1H-imidazol-2-yl)-[4-(4-methoxy-phenylsulfanyl)-phenyl]-amine




Chloroimidazoline sulfuric acid salt (4.06 g) was partitioned between 50 mL of 10% aqueous NaOH (cooled to ice bath temperature) and 50 mL of Et2O. The aqueous layer was extracted twice more with Et2O (2×10 mL), and the combined ether layers were washed with cold water, brine, and dried (Na2SO4). 2.31 g of 4-(4-methoxy-phenylsulfanyl)-phenylamine was then added, and dissolved by stirring. The solvent was removed in vacuo, and 20 mL of isobutanol was added to the residue. The resulting residue was heated to reflux for 2 hours, concentrated to 1⁄2 of its original volume (approximately 10 mL), and then cooled to room temperature. The resulting crystals that formed upon cooling were collected by filtration to provided 2.874 g of (4,5-Dihydro-1H-imidazol-2-yl)-[4-(4-methoxy-phenylsulfanyl)-phenyl]-amine hydrochloride salt (96%). Mp: 149–150° C. MS M+H: 300.
Using the above procedure, but replacing in step 1 the 4-methoxythiophenol with the appropriate thiophenol, provided several additional compounds which are shown in Table 1.
Example 2
N-[4-(4-Methoxy-phenylsulfanyl)-phenyl]-guanidine




4-(4-Methoxy-phenylsulfanyl)-phenylamine from Example 1 (0.693 g), bis-Boc thiourea (N,N-di-(tert-butoxycarbonyl)-thiourea, 0.828 g), and pyridine (0.475 g) were dissolved in 8 mL of dry DMF and stirred under nitrogen in an ice bath. To the stirring solution was added 0.896 g of HgCl2. The mixture was stirred for 1 hour at ice bath temperature, and then allowed to warm up to room temperature with stirring for an additional 4 hours. The mixture was diluted with 50 mL ethyl acetate and filtered through a celite pad. The filtrate was washed with water, then with brine, and was dried with Na2SO4. Removal of solvent in vacuo yielded a yellow oil that was eluted on a silica column (EtOAc/Hexanes 20%/80%). Recrystallization from hexanes afforded 0.626 g of N-[4-(4-methoxy-phenylsulfanyl)-phenyl]-N,N-di-(tert-butoxycarbonyl)-guanidine as a white solid (44%). Mp: 101–102° C. The N-[4-(4-methoxy-phenylsulfanyl)-phenyl]-N,N-di-(tert-butoxycarbonyl)-guanidine was dissolved in 3 mL of methylene chloride, and 1.5 mL of trifluoracetic acid and stirred for 1 hour at room temperature. The mixture was then concentrated in vacuo, diluted with cold water, basified with 10% NaOH solution, and extracted with methylene chloride. The combined methylene chloride layers were washed with brine, dried (K2CO3), and the solvent was removed in vacuo. The residue was recrystallized to provide N-[4-(4-methoxy-phenylsulfanyl)-phenyl]-guanidine. Mp: 140–141° C.
Example 3
[4-(4-Chloro-phenylsulfanyl)-benzyl]-(4,5-dihydro-1H-imidazol-2-yl)-amine




The synthetic procedures used in this Example are outlined in Scheme D.




Step 1

4-(4-Chloro-phenylsulfanyl)-benzonitrile





A mixture of 4-methoxy-benzenethiol (4.89 g), 4-fluorobenzonitrile (4.24 g) and powdered anhydrous potassium carbonate were added to 50 mL of dry DMSO, and the mixture was heated at 100° C. under nitrogen for 6 hours, then allowed to remain at room temperature for 48 hours. The reaction mixture was diluted with ethyl acetate (400 mL) and washed three times with cold water, followed by brine, and then dried (K2CO3). The solvent was removed in vacuo to yield 8.41 g of 4-(4-chloro-phenylsulfanyl)-benzonitrile as a white solid. MS M+H: 247.
Step 2
4-(4-Chloro-phenylsulfanyl)-benzylamine




To a solution of 4-(4-chloro-phenylsulfanyl)-benzonitrile (4.91 g) in 100 mL of dry THF under nitrogen stirring at room temperature was added 40 mL of lithium aluminum hydride solution (1.0 M in THF) via syringe. The reaction mix was allowed to stir for 3.5 hours at room temperature, and was then heated to reflux for 4.5 hours, and then allowed to sit at room temperature overnight. The reaction mix was then cooled in an ice bath and quenched by addition of 10 mL water, followed by 1 mL of 15% aqueous NaOH solution and an additional 30 mL of water. Anhydrous sodium sulfate was added, and the mixture was filtered. The resulting filter cake was washed several times with Et2O. The combined ether filtrates were concentrated in vacuo to yield 4.67 g of 4-(4-chloro-phenylsulfanyl)-benzylamine as a white solid. MS M+H: 250.
Step 3
[4-(4-Chloro-phenylsulfanyl)-benzyl]-(4,5-dihydro-1H-imidazol-2-yl)-amine




Chloroimidazoline sulfuric acid salt (0.92 g) was partitioned between ice cold 15% aqueous NaOH solution (25 mL) and Et2O (25 mL). The organic layer was separated, and the aqueous layer was extracted twice with 15 mL of Et2O. The combined ether layers were dried (sodium sulfate), and the ether filtrate was added to a solution of 4-(4-chloro-phenylsulfanyl)-benzylamine in 20 mL of isopropanol. The resulting mixture was concentrated in vacuo to remove approximately 90% of the solvent. The remaining residue was refluxed under nitrogen for 4.5 hours and left overnight at room temperature. The residue was eluted on neutral alumina (MeOH:methylene chloride:NH4OH 10%:89.99%:0.01%) to afford a resinous solid that was recrystallized from acetone to yield 0.33 g of [4-(4-chloro-phenylsulfanyl)-benzyl]-(4,5-dihydro-1H-imidazol-2-yl)-amine hydrochloride salt (47%) as a white solid. Mp: 127–130° C. MS M+H: 318.
Example 4
[4-(4-Chloro-phenylsulfanyl)-phenyl]-(3,4,5,6-tetrahydro-pyridin-2-yl)-amine




To a solution of 0.555 g delta valerolactam in 10 mL of benzene was added 0.383 g of POCl3. The mixture was stirred under nitrogen at room temperature for 4 hours. 4-(4-Chloro-phenylsulfanyl)-benzylamine (0.624 g) was then added and the mixture was allowed to stir at room temperature for 17 hours. The reaction mix was then brought to reflux for 1 hour and cooled to room temperature. The reaction mix was quenched with water, basified with ammonium hydroxide solution, and extracted thoroughly with ethyl acetate. The combined organic layers were evaporated in vacuo, and the resulting solid was eluted on neutral alumina (MeOH:dichloromethane 10%:90%). The resulting product was recrystallized from ethyl acetate to yield 0.408 g (49.3%) of [4-(4-chloro-phenylsulfanyl)-phenyl]-(3,4,5,6-tetrahydro-pyridin-2-yl)-amine hydrochloride salt as a white solid. Mp: 148–152° C. MS M+H: 317.
Example 5
Formulations
Pharmaceutical preparations for delivery by various routes are formulated as shown in the following Tables. “Active ingredient” or “Active compound” as used in the Tables means one or more of the Compounds of Formula I.










Composition for Oral Administration










Ingredient
% wt./wt.














Active ingredient
20.0%



Lactose
79.5%



Magnesium stearate
0.5%










The ingredients are mixed and dispensed into capsules containing about 100 mg each; one capsule would approximate a total daily dosage.










Composition for Oral Administration










Ingredient
% wt./wt.














Active ingredient
20.0%



Magnesium stearate
0.5%



Crosscarmellose sodium
2.0%



Lactose
76.5%



PVP (polyvinylpyrrolidine)
1.0%










The ingredients are combined and granulated using a solvent such as methanol. The formulation is then dried and formed into tablets (containing about 20 mg of active compound) with an appropriate tablet machine.










Composition for Oral Administration










Ingredient
Amount







Active compound
 1.0 g



Fumaric acid
 0.5 g



Sodium chloride
 2.0 g



Methyl paraben
 0.15 g



Propyl paraben
 0.05 g



Granulated sugar
 25.5 g



Sorbitol (70% solution)
12.85 g



Veegum K (Vanderbilt Co.)
 1.0 g



Flavoring
0.035 ml



Colorings
 0.5 mg



Distilled water
q.s. to 100 ml










The ingredients are mixed to form a suspension for oral administration.










Parenteral Formulation










Ingredient
% wt./wt.







Active ingredient
0.25 g



Sodium Chloride
qs to make isotonic



Water for injection
100 ml










The active ingredient is dissolved in a portion of the water for injection. A sufficient quantity of sodium chloride is then added with stirring to make the solution isotonic. The solution is made up to weight with the remainder of the water for injection, filtered through a 0.2 micron membrane filter and packaged under sterile conditions.










Suppository Formulation










Ingredient
% wt./wt.














Active ingredient
1.0%



Polyethylene glycol 1000
74.5%



Polyethylene glycol 4000
24.5%










The ingredients are melted together and mixed on a steam bath, and poured into molds containing 2.5 g total weight.










Topical Formulation










Ingredients
grams







Active compound
0.2–2



Span 60
2



Tween 60
2



Mineral oil
5



Petrolatum
10



Methyl paraben
0.15



Propyl paraben
0.05



BHA (butylated hydroxy anisole)
0.01



Water
q.s. 100










All of the ingredients, except water, are combined and heated to about 60° C. with stirring. A sufficient quantity of water at about 60° C. is then added with vigorous stirring to emulsify the ingredients, and water then added q.s. about 100 g.
Nasal Spray Formulations
Several aqueous suspensions containing from about 0.025–0.5 percent active compound are prepared as nasal spray formulations. The formulations optionally contain inactive ingredients such as, for example, microcrystalline cellulose, sodium carboxymethylcellulose, dextrose, and the like. Hydrochloric acid may be added to adjust pH. The nasal spray formulations may be delivered via a nasal spray metered pump typically delivering about 50–100 microliters of formulation per actuation. A typical dosing schedule is 2–4 sprays every 4–12 hours.
Example 6
Carrageenan-Induced Mechanical Hyperalgesia Assay
The anti-inflammatory/analgesic activity of compounds of this invention was determined by the Carrageenan-Induced Mechanical Hyperalgesia Assay by measuring the inhibition of carrageenan-induced paw hyperalgesia in the rat, using a modification of the method described in L. O. Randall and J. J. Selitto, Archives of International Pharmacodynamics, 1957, 11, 409–419, and Vinegar et al., Journal of Pharmacology and Experimental Therapeutics, 1969, 166, 96–103.
Male Sprague-Dawley rats (130–150 g) were weighed and randomly assigned to treatment groups (n=10). To induce mechanical hyperalgesia, rats were lightly anesthetized with halothane and administered 1% carrageenan or vehicle 1 (100 μl) in the plantar surface of the left hindpaw. Rats were administered vehicle (10 ml/kg, p.o.or 1 ml/kg, i.v) or compounds of this invention (at 1, 3, 10, 30 and 100 mg/kg, p.o.) or (0.3, 1.0, 3.0 and 10 mg/kg, i.v.) one hour before testing. Mechanical hyperalgesia was measured using an Analgesy-meter (UGO BASILE, Biological Research Apparatus, Comerio, Italy). The vehicle- or carrageenan-treated hindpaw was placed on the dome of the apparatus, plantar surface facing down. A constantly increasing force was then applied to the dorsal surface of the paw. The force at which the rat withdrew its paw, struggled, or vocalized was considered the end point.
Treatment groups were compared using a one-way analysis of variance on the paw withdrawal force (RESP). Pairwise comparisons for the drug-treated groups to the vehicle group were made using Fisher's LSD strategy and Dunn's procedure. Percent inhibition of mechanical hyperalgesia was calculated for each animal, and the average ID50 value was estimated using the following sigmoidal model:

% inhibition=100/(1+exp((ID50−dose)/N))

where ID50 is the dose of the compound needed to inhibit half of the maximum response (i.e., 100% in this model) and N is a curvature parameter. The compounds of this invention were active in this assay.

Example 7
Complete Freund's Adjuvant-Induced Mechanical Hyperalpesia Assay
The anti-inflammatory/analgesic activity of compounds of this invention may also be determined using an adjuvant-induced arthritis pain model in the rat, where pain is assessed by the animal's response to the squeezing of the inflamed foot, using a modification of the method described in J. Hylden et al., Pain 1989, 37, 229–243. The modification includes the assessment of hyperalgesia instead of changes in activity of spinal cord neurons.
Briefly, rats were weighed and randomly assigned to treatment groups. To induce mechanical hyperalgesia, rats were lightly anesthetized with halothane and 100 μl of Complete Freund's Adjuvant or saline was administered into the plantar surface of the left hindpaw. Twenty-four hours later, water (vehicle) or compounds of this invention were orally administered to the rats one hour before testing. Mechanical hyperalgesia was measured using an Analgesy-meter (UGO BASILE, Biological Research Apparatus, Comerio, Italy). The saline or carrageenan-treated hindpaw was placed on the dome of the apparatus, plantar surface facing down. A constantly increasing force was then applied to the dorsal surface of the paw, and the force at which the rat withdrew its paw, struggled, or vocalized was considered the end point. The treatment groups were compared using a one-way analysis of variance on the paw withdrawal force. Percent inhibition was calculated for each animal in the form:

100×((c/d−c/v)÷(s/v−c/v))

where c/d is the paw withdrawal force for the carrageenan-treated paw in an animal to which drug has been administered; c/v is the paw withdrawal force for the carrageenan-treated paw in an animal to which vehicle has been administered; and s/v is the paw withdrawal force for the saline-treated paw in an animal to which vehicle has been administered. Significance was determined using Student's t-test. The compounds of the invention were active in this assay.

Example 8
Inhibition of Bladder Contractions Induced by Isovolumetric Bladder Distension in Rats
The inhibition of bladder contractions was determined by an assay using a modification of the method described in C. A. Maggi et al., J. Pharm. and Exper. Therapeutics, 1984, 230, 500–513.
Briefly, male Sprague-Dawley rats (200–250 g) were weighed and randomly assigned to treatment groups. A catheter was inserted through the urethra into the bladder to induce bladder contractions, and a warm saline solution (5 mL) was infused. Rhythmic contractions were produced in about 30% of the animals. The compounds of the invention (0.1, 0.3 or 1 mg/kg) were administered intravenous at the onset of regular rhythmic contractions. The effects on rhythmic contracts were then measured. The compounds of this invention were active in this assay.
Example 9
Inhibition of Volume-Induced Contractions in Rats
The inhibition of bladder contractions was determined by an assay using a modification of the method described in S. S. Hegde et al., Proceedings of the 26th Annual Meeting of the International Continence Society (August 27th-30th) 1996, Abstract 126.
Female Sprague-Dawley rats were anesthetized with urethane and instrumented for intravenous administration of drugs and, in some cases, measurement of arterial pressure, heart rate and intra-bladder pressure. The effect of test compounds on volume-induced bladder contractions was determined in separate groups of animals. Volume-induced reflex bladder contractions were induced by filling the bladder with saline.
The test compounds were administered intravenously in a cumulative manner at 10-minute intervals. Atropine (0.3 mg/kg, iv) was administered at the end of the study as a positive control. The compounds of this invention were active in this assay.
Example 10
Reversal of Endotoxin-Induced Hypotension in Rats
Septic shock, sometimes referred to as endotoxic shock, is caused by the presence of infectious agents, particularly bacterial endotoxins, in the bloodstream and is characterized by hypotension and organ dysfunction. Many symptoms of septic shock, in particular, hypotension, are induced in the rat by the administration of bacterial endotoxins. The ability of a compound to inhibit endotoxin-induced hypotension is therefore predictive of the utility of the compound in the treatment of septic or endotoxic shock.
The activity of the compounds of the invention in the treatment of septic or endotoxic shock was determined by measuring the reversal of endotoxin-induced hypotension in the rat, using a modification of the method described in M. Giral et al., British Journal of Pharmacology, 1969, 118, 1223–1231.
Briefly, adult rats (>200 g) were anesthetized with an inhalation anesthetic and femoral arteries and veins were cannulated for insertion of blood pressure transducers and drug administration lines, respectively. They were placed in Mayo restrainers while still under the influence of the anesthetic. After recovery from anesthesia and stabilization of heart rate and blood pressure (which typically required about 30 minutes), endotoxin (50 mg/kg E. coli and 25 mg/kg Salmonella) was administered intravenously. Changes in blood pressure and heart rate were monitored. After one hour, compounds of this invention or vehicle were also administered intravenously, and cardiovascular parameters were continuously monitored for the next three hours. Responses are represented as percentage return to initial diastolic blood pressure. Significance was determined using Student's t-test. The compounds of this invention were active in this assay.
While the present invention has been described with reference to the specific embodiments thereof, it should be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the invention. In addition, many modifications may be made to adapt a particular situation, material, composition of matter, process, process step or steps, to the objective spirit and scope of the present invention. All such modifications are intended to be within the scope of the claims appended hereto.

## Claims

1. A compound of the formula (II):




wherein:
A is: —O—; or —S—;
m is 0 or 1;
n is from 1 to 3;
R2 is: hydrogen; alkyl; alkoxy; haloalkyl; or halogen;
R4 is: isopropoxy; trifluoromethyl; ethoxycarbonyl; hydroxycarbonyl; nitro;

methanesulfanyl-amino; hydroxymethyl; methoxycarbonyl-methyloxy; morpholin-4-yl-carbonyl-methyloxy; morpholin-4-yl-carbonyl; morpholin-4-yl-methyl; ethoxy-acetoacetamido; cyclohexyl-methyloxy; phenoxyethyl-carbonylamino; phenylethyl-carbonylamino; aminocarbonyl; isopropoxy-carbonyl; phenyl-carbonyl; phenylmethylamino-carbonyl; 2,2,2-trifluoroethyloxymethyl; phenoxy; hydroxycarbonyl-methyloxy; 2-(ethoxycarbonyl)-ethyl; 2-(ethoxycarbonyl)-ethenyl; morpholin-4-yl-carbonyloxy-methyl; 4-phenylpiperazin-1-yl-methyl; or dimethylaminocarbonyloxymethyl; and
R5 is: hydrogen; alkyl; alkoxy;
halo; or haloalkyl; or R4 and R5 together form an alkylene dioxy group; and
Ra, Rb, Rc and Rd each independently is hydrogen or alkyl; or pharmaceutically acceptable salts, solvates or prodrugs thereof.

2. The compound of claim 1, wherein m is 0.

3. The compound of claim 2, wherein Ra, Rb, Rc and Rd are hydrogen.

4. The compound of claim 3, wherein n is 1.

5. The compound of claim 4, wherein A is —S—.

6. The compound of claim 4, wherein said compound is selected from:
(4,5-Dihydro-1H-imidazol-2-yl)-[4-(4-isopropoxy-phenylsulfanyl)-phenyl]-amine;
(4,5-Dihydro-1H-imidazol-2-yl)-[4-(4-trifluoromethyl-phenylsulfanyl)-phenyl]-amine;
4-[4-(4,5-Dihydro-1H-imidazol-2-ylamino)-phenylsulfanyl]-benzoic acid ethyl ester;
4-[4-(4,5-Dihydro-1H-imidazol-2-ylamino)-phenylsulfanyl]-benzoic acid;
(4,5-Dihydro-1H-imidazol-2-yl)-[4-(4-nitro-phenylsulfanyl)-phenyl]-amine;
N-{4-[4-(4,5-Dihydro-1H-imidazol-2-ylamino)-phenylsulfanyl]-phenyl}-methanesulfonamide;
{4-[4-(4,5-Dihydro-1H-imidazol-2-ylamino)-phenylsulfanyl]-phenyl}-methanol;
{4-[4-(4,5-Dihydro-1H-imidazol-2-ylamino)-phenylsulfanyl]-phenoxy}-acetic acid methyl ester;
2-{4-[4-(4,5-Dihydro-1H-imidazol-2-ylamino)-phenylsulfanyl]-phenoxy}-1-morpholin-4-yl-ethanone;
{4-[4-(4,5-Dihydro-1H-imidazol-2-ylamino)-phenylsulfanyl]-phenyl}-morpholin-4-yl-methanone;
(4,5-Dihydro-1H-imidazol-2-yl)-[4-(4-morpholin-4-ylmethyl-phenylsulfanyl)-phenyl]-amine;
N-{4-[4-(4,5-Dihydro-1H-imidazol-2-ylamino)-phenylsulfanyl]-phenyl}-malonamic acid ethyl ester;
[4-(4-Cyclohexylinethoxy-phenylsulfanyl)-phenyl]-(4,5-dihydro-1H-imidazol-2-yl)-amine;
N-{4-[4-(4,5-Dihydro-1H-imidazol-2-ylamino)-phenylsulfanyl]-phenyl}-2-phenoxy-acetamide;
N-{4-[4-(4,5-Dihydro-1H-imidazol-2-ylamino)-phenylsulfanyl]-phenyl}-3-phenyl-propionamide;
4-[4-(4,5-Dihydro-1H-imidazol-2-ylamino)-phenylsulfanyl]-benzamide;
4-[4-(4,5-Dihydro-1H-imidazol-2-ylamino)-phenylsulfanyl]-benzoic acid isopropyl ester;
{4-[4-(4,5-Dihydro-1H-imidazol-2-ylamino)-phenylsulfanyl]-phenyl}-phenyl-methanone;
N-Benzyl-4-[4-(4,5-dihydro-1H-imidazol-2-ylamino)-phenylsulfanyl]-N-methyl-benzamide;
(4,5-Dihydro-1H-imidazol-2-yl)-[4-(4-ethoxymethyl-phenylsulfanyl)-phenyl]-amine;
(4,5-Dihydro-1H-imidazol-2-yl)-[4-(4-phenoxy-phenoxy)-phenyl]-amine;
{4-[4-(4,5-Dihydro-1H-imidazol-2-ylamino)-phenylsulfanyl]-phenoxy}-acetic acid;
3-{4-[4-(4,5-Dihydro-1H-imidazol-2-ylamino)-phenylsulfanyl]-phenyl}-propionic acid ethyl ester;
(E)-3-{4-[4-(4,5-Dihydro-1H-imidazol-2-ylamino)-phenylsulfanyl]-phenyl}-acrylic acid ethyl ester;
Morpholine-4-carboxylic acid 4-[4-(4,5-dihydro-1H-imidazol-2-ylamino)-phenylsulfanyl]-benzyl ester,
(4,5-Dihydro-1H-imidazol-2-yl)-{4-[4-(4-phenyl-piperazin-1-ylmethyl)-phenylsulfanyl]-phenyl}-amine; and
Dimethyl-carbamic acid 4-[4-(4,5-dihydro-1H-imidazol-2-ylamino)-phenylsulfanyl]-benzyl ester.

7. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound of claim 1 in admixture with at least one pharmaceutically acceptable carrier.