WO1997016187A1 - Muscarine antagonists - Google Patents

Muscarine antagonists Download PDF

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Publication number
WO1997016187A1
WO1997016187A1 PCT/US1996/017214 US9617214W WO9716187A1 WO 1997016187 A1 WO1997016187 A1 WO 1997016187A1 US 9617214 W US9617214 W US 9617214W WO 9716187 A1 WO9716187 A1 WO 9716187A1
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WIPO (PCT)
Prior art keywords
animal
dihydro
benzimidazol
receptors
cyclohex
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PCT/US1996/017214
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French (fr)
Inventor
Wayne J. Thompson
Richard W. Ransom
Pierre Mallorga
Michael F. Sugrue
Peter M. Munson
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Merck & Co., Inc.
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Publication date
Priority claimed from GBGB9603835.1A external-priority patent/GB9603835D0/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to AU74784/96A priority Critical patent/AU7478496A/en
Publication of WO1997016187A1 publication Critical patent/WO1997016187A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • This invention relates to control of ocular development in general and, more particularly, to the treatment of the eye to prevent and/or arrest the development of myopia (nearsightedness).
  • myopia nearsightedness
  • myopia Approximately one of every four persons suffer from myopia, i.e., an elongation of the eye along the visual axis.
  • myopia afflicts 10% to 75% of the youth of the world, depending upon race, geographic distribution and level of education.
  • Myopia is not a trivial maldevelopment of the eye. In its pathologic form, the sclera continues to grow and as result the retina stretches and degenerates resulting in permanent blindness.
  • Cyclop legics are topically administered drugs that relax the ciliary muscle of the eye, which is the muscle that focuses the eye by controlling lens dimensions.
  • the classic cycloplegic drug is the belladonna alkaloid atropine, available for over a century.
  • Atropine is a long-acting non-specific antimuscarinic agent that antagonizes the action of the neurotransmitter acetylcholine (ACh) at autonomic effector cells innervated by postganglionic cholinergic nerves of the parasympathetic nervous system.
  • ACh neurotransmitter acetylcholine
  • Atropine is impractical in that it causes mydriasis (increase of pupil size) and its action on the ciliary muscle to inhibit ocular focusing impairs near visual work like reading.
  • the receptors in the iris and ciliary muscle responsible for the side effects of atropine are of the m3 subtype.
  • studies have shown that muscarinic receptors in the retina of a variety of non-human species are comprised of ml, m2 and m4 subtypes. Accordingly, a muscarinic antagonist with low m3 activity would be efficacious in prevention of the development of myopia without the undesirable side effects associated with the u,se of atropine.
  • the phenomenon of an animal's vision process apparently contributes to the feedback mechanism by which postnatal ocular growth is normally regulated and refractive error is determined. This indicates that this mechanism is neural and likely originates in the retina.
  • R. A. Stone, et al. have found a method of controlling the abnormal postnatal growth of the eye of a maturing animal. The method comprises controlling the presence of a neurochemical, its agonist or antagonist, which neurochemical is found to be changed under conditions during maturation leading to abnormal axial length. See U.S. Pat. No. 4,066,772 and 5,284,843.
  • retinal concentrations of dopamine were found to be reduced during such image deprivation and the ocular administration of a dopamine-related agent, e.g., apomorphine, a dopamine agonist, was found to inhibit or actually prevent the axial enlargement of the eye under conditions ordinarily leading to such enlargement.
  • a dopamine-related agent e.g., apomorphine, a dopamine agonist
  • Cholinergic receptors are proteins embedded in the wall of a cell that respond to the chemical acetylcholine. Particularly, it is now known that the cholinergic receptors are subdivided into nicotinic and muscarinic receptors and that the muscarinic receptors are not all of the same type. Recent literature indicates that there are at least five types of cholinergic muscarinic receptors (types ml through m5). Receptors of type ml are those present in abundance and thought to be enriched in the brain neural tissue and neural ganglia. The other receptors are concentrated in other tissues such as the heart, smooth muscle tissue or glands.
  • pirenzepine (Gastrozepin, LS 519) 5, 1 1 -Dihydro- 1 l-[4-methyl-l -piperazinyl) acetyl] -6H-pyrido[2,3-b] benzodiazepin-6-one, and its dihydrochloride are anticholinergic, antimuscarinic, and relatively selective for ml receptors. See U.S. Pat. No. 5,122,522 and WO9015604-A.
  • 4-DAMP (4-diphenylacetoxy- N-methylpiperadine methiodide) is a relatively selective antagonist for smooth muscle (ordinarily called m3 type but variously called type m2 or m3, as the current classification of receptors is in flux).
  • Pirenzepine being primarily an ml antagonist, inhibits axial elongation, but is far less effective at pupil dilation than atropine or another cycloplegic agent. This makes it possible to suppress the development of myopia without dilating the pupil and paralyzing the accommodation activity of the ciliary muscle. Additionally, the administration of a drug topically into the eye of a developing child for a long period of time makes it desirable to have a minimal likelihood of sensitization of the eye. Pirenzepine and atropine test positive in sensitization assays and this is an undesirable side effect.
  • This invention is concerned with novel 1 , 3 -dihydro- 1-[1-(1 - heteroarylpiperazin-4-yl)cyclohex-4-yl]-2H-benzimidazolones, their compositions and method of use.
  • the novel compounds are selective muscarinic antagonists of the ml , m2, and m4 subtypes with low activity at the m3 subtype.
  • the compounds have good ocular penetration (bioavailability) when dosed as a 0.1 - 4% aqueous solution, preferably a 0.5-2% solution.
  • the compounds are effective for the treatment and/or prevention of myopia.
  • novel compounds of this invention are represented by the structural formula I:
  • R2 - R9 are independently H, alkyl, halo, alkoxy, OH, HOCH2-, aryl, 3-pyridyl, 5-pyrimidinyl, alkoxycarbonyl, amino, dialkylamino, alkene, thioalkyl, or alkylamino; alternatively, R4 and R7 or R2 and R9 may be connected as an ethylene bridge to form a bicyclic heterocycle;
  • Y l is H, alkyl, halo, alkylamino, dialkylamino, alkoxy, alkoxyamino, or amino;
  • Y2 is heterocycle, or heterocyclyl
  • A is H, CHRl , C(R l)2 or carbonyl
  • Rl is alkyl, alkoxy, aryl, heteroaryl, heterocyclyl or heterocycle.
  • heterocycle or heterocyclic represents a stable 5- to 7- membered monocyclic heterocyclic ring, which is either saturated or unsaturated, and which consists of carbon atoms and from one to three heteroatoms selected from the group consisting of N, O and S, and including any bicyclic group in which any of the above defined heterocyclic rings is fused to a benzene ring.
  • the heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure.
  • heterocyclic rings examples include pyridine, pyrazine, pyrimidine, pyridazine, triazine, imidazole, pyrazole, triazole, quinoline, isoquinoline, quinazoline, quinoxaline, phthalazine, oxazole, isoxazole, thiazole, isothiazole, thiadiazole, oxadiazole, pyrrole, furan, thiophene, hydrogenated derivatives of these heterocyles such as piperidine, pyrrolidine, azetidine, tetrahydrofuran, and N-oxide derivatives of heterocyles containing basic nitrogen.
  • heterocyclic rings Any fused combinations of any of these above-defined heterocyclic rings is also a part of this definition. Attached to the heterocyclic ring can be substituents such as alkyls, amines, alkylamino, or halogens (F, Cl, Br, I).
  • alkyl is intended to include branched, cyclic and straight chain saturated aliphatic hydrocarbon groups having 1 to 15 carbon atoms, unless otherwise defined.
  • Preferred straight or branched alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, t-butyl and the like.
  • Preferred cycloalkyi groups include cyclopentyl and cyclohexyl.
  • alkoxy represents an alkyl group of indicated carbon atoms attached through an oxygen linkage.
  • alkylamino represents an alkyl group of indicated carbon atoms attached through a nitrogen atom linkage.
  • dialkylamino represents two alkyl groups of indicated carbon atoms attached through a nitrogen atom linkage.
  • small alkyl is intended to indicate those alkyls with Cl to C6 carbon atoms, either branched or linear in connection.
  • halo represents fluoro, chloro, bromo or iodo.
  • aryl refers to aromatic rings e.g., phenyl, substituted phenyl and the like groups as well as rings which are fused e.g., naphthyl and the like.
  • Aryl thus contains at least one ring having at least 6 atoms, with up to two such rings being present, containing up to 10 atoms therein, with alternating (resonating) double bonds between adjacent carbon atoms.
  • the preferred aryl groups are phenyl and naphthyl.
  • Aryl groups may likewise be substituted with 1-3 groups such as alkyl, halo, carboxyalkyl, alkylamino, dialkylamino, alkoxy, alkoxyamino and the like.
  • heteroaryl refers to a monocyclic aromatic hydrocarbon group having 5 or 6 ring atoms, or a bicyclic aromatic group having 8 to 10 atoms, containing at least one heteroatom, O, S, or N, in which a carbon or nitrogen atom is the point of attachment, and in which one additional carbon atom is optionally replaced by a heteroatom selected from O or S, an in which from 1 to 3 additional carbon atoms are optionally replaced by nitrogen heteroatoms.
  • the heteroaryl group is optionally substituted with up to three groups. Heteroaryl thus includes aromatic and partially aromatic groups which contain one or more heteroatoms. Examples of this type are pyrrol, pyridine, oxazole, thiazole and oxazine. Additional nitrogen atoms may be present together with the first nitrogen and oxygen or sulfur, giveing e.g., thiadizaole.
  • R2 - R9 are independently H, alkyl, or halo
  • Y l is H, alkyl, or halo
  • Y2 is 5-pyrimidinyl, 3-pyridyl, or l -methyl-5-imidazolyl
  • Rl is alkyl, alkoxy, phenyl, 5-pyrimidinyl, 3-pyridyl, or l -methyl-5- imidazolyl.
  • the pharmaceutically acceptable salts of the compounds of formula I include the conventional non-toxic salts or the quartemary ammonium salts of the compounds of formula I formed e.g. from non-toxic inorganic or organic acids.
  • such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the compounds of formula I which contain a basic or acidic moiety by conventional chemical methods. Generally, the salts are prepared by reacting the free base or acid with stoichiometric amounts or with an excess of the desired salt- forming inorganic or organic acid or base in a suitable solvent or various combinations of solvents.
  • the compounds of the present invention may have asymmetric centers and occur as racemates, racemic mixtures, and as individual diastereomers, with all possible isomers, including optical isomers, being included in the present invention.
  • the reaction is preferably carried out at room temperature (20-30°C) at a pH in the range of 2-7 (acidic) by the addition of glacial acetic acid or hydrochloric acid.
  • Deprotection by the usual methods hydrogenation or acidic hydrolysis followed by basification ) provides the free amine compound which can be acylated or alkylated by standard procedures. By this route the most preferred compounds can be obtained after isolation and purification.
  • the selectivity of the compounds can be measured by radioligand displacement from ml-m5 receptors expressed in Chinese hamster ovary cells (CHO) as described in the Examples section.
  • the functional activity of the compounds can be assessed by measuring the agonist induced contractile response on muscle tissue from rabbit vas deferens (Ml), the guinea pig left atria (M2), or the guinea pig ileum (M3) as described in the Examples section.
  • the functional activity at the human muscarinic receptors can be assessed by measuring agonist induced phosphoinositide hydrolysis in CHO cells expressing the human m 1 and m3 receptors or agonist inhibition of foskolin-stimulated adenylate cyclase activity in CHO cells expressing the human m2 receptor as described in the Examples section.
  • the instant compounds of this invention are useful in treating and/or preventing the development of myopia.
  • Therapy to inhibit axial-elongation myopia during maturation can be administered by the use of the agent in eye drops. Indeed, in the vast majority of cases, treatment agents are administered to human eyes by the application of eye drops. Eye drops are typically made up at a concentration of active agent between about 0.1 and 4% in the ophthalmic medium. A 0.5%-2% solution of the instant muscarinic antagonist in water would be a likely concentration for clinical use. A pH of about 4.5 to about 7.5 is expected to be acceptable as an ophthalmic drop and practical in terms of known solubility and stability of piperidines. Phosphate buffering is also common for eye drops and is compatible with the instant muscarinic antagonist.
  • a common regimen for application of eye drops is one to three times a day spaced evenly throughout waking hours. More effective agents may require fewer applications or enable the use of more dilute solutions. Alternatively, ointments and solid inserts are now coming into increased use in clinical practice. These aid the ocular penetration of the drug. It is, of course, also possible to administer the above-described active agents in therapeutically effective amounts and dosages in pills, capsules, or other preparations of systemic administration.
  • amblyopia was also experimentally and coincidentally induced in primates. Amblyopia is evidenced by poor visual acuity in the eye resulting in poor visual performance. Normally, visual acuity improves during maturation. It is known that amblyopia may occur in humans from unknown causes or as part of strabismus. Accordinly, it is expected that administration of therapeutically effective amounts and dosages of the instant muscarinic antagonist might prevent or inhibit the development of permanent or persistent amblyopia in maturing humans with decreased likelihood of sensitization of the eye. It is expected that humans who have already developed amblyopia from other or even unknown causes might be aided by similar therapeutic treatment with the aforementioned agents.
  • Step 1 A mixture of 10 g of 1 ,4-cyclohexanedione mono-ethyleneketal, 13.8 g of 1 ,2-phenylenediamine, 180 mL of 1 ,2-dichloroethane, 4 mL of glacial acetic acid and 19 g of sodium triacetoxyborohydride was stirred at room temperature for 48 h. The reaction mixture was poured into 200 mL chloroform and 200 mL saturated IN NaOH and the layers separated. The aqueous layer was extracted with 2 X 50 mL of chloroform and the combined organic layers dried over MgS04 and concentrated to dryness under reduced pressure.
  • Step 2 A mixture of 7 g of the ethylene ketal of 1 ,3 -dihydro- 1 -(4- oxocyclohexyl)-2H-benzimidazol-2-one, 100 mL of glacial acetic acid, 50 mL of water and 50 mL of cone. HCl was heated under reflux for 12 h. The mixture was concentrated under reduced pressure, diluted with 100 mL of water and extracted into 3 X 200 mL of CHCI3. The combined organic extracts were washed with 100 mL of water, 100 mL of saturated Na2C ⁇ 3, dried over MgS ⁇ 4 and concentrated under reduced pressure.
  • Step 1 A mixture of 1.5 g of l,3-dihydro-l-(4-oxocyclohexyl)- 2H-benzimidazol-2-one, 1.21 g of tert-butyl 1 -piperazinecarboxylate, 20 mL of 1 ,2-dichloroethane, 0.40 mL of glacial acetic acid and 1.79 g of sodium triacetoxyborohydride was stirred at room temperature for 48 h. The reaction mixture was poured into 50 mL chloroform and 50 mL saturated aqueous Na2C03 and the layers separated.
  • Step 2 A stirred solution of 0.52 g of l -4-[4- (tert -butylcarbonyl)piperazin- 1 -yl]- 1 -cyclohexyl ⁇ -2H-benzimidazol-2- one in 15 mL of 1 N HCl was heated to reflux for 1 h, cooled and basified with 6N NaOH. The basic mixture was extracted with 2 X 50 mL portions of chloroform. The combined organic extracts were dried over MgS04 and concentrated under reduced pressure.
  • Step 3 To a stirred solution of 0.044 g of l ,3-dihydro-l- ⁇ rr ⁇ ti5 -4-[ l-piperazinyl]-l -cyclohexyl ⁇ -2H-benzimidazol-2-one and 0.2 mL of triethylamine in 3 mL of dichloromethane was added 0.030 g of pyrimidine-5 -carboxylic acid chloride. After 2 h, 5 mL of dilute aqueous ammonia was added and the mixture stirred for an additional 30 min.
  • muscarinic antagonists for ml-m5 receptors expressed in Chinese hamster ovary cells were determined using the technique described by Dorje et al., J. Pharmacol. Exp. Ther. 256: 727-733 (1991 ).
  • CHO cells When 80-100% confluent, CHO cells were harvested, and transferred to centrifuge tubes containing CHO buffer (20 mM HEPES at pH 7.4 containing 5mM MgCl2). The cells were homogenized, using a Brinkman Polytron homogenizer for 30 seconds at a setting of 5, on ice. The homogenate was centrifuged at 40,000 x g for 15 minutes at 4°C in a Beckman J2-21M centrifuge. The supernatant was discarded and the homogenization/centrifugation step repeated once.
  • Pelleted membranes were resuspended in CHO buffer to a concentration of one flask harvested (75 cm 2 ) per mL of buffer, mixed well and aliquoted in cryovials (lmL/vial). The vials were stored at -70°C until used in the assay.
  • the binding incubation was done in polypropylene macrowell tube strips in a final volume of 0.5 mL of HEPES buffer (20 mM; pH 7.4 containing 5 mM MgC ) containing 0.1 mL of cell membrane suspension, 3H-N-methylscopolamine (NEN Co ⁇ oration, NET-636, 70-87 /mmole) at a final concentration of approximately 0.2 nM and the competing drug in a varying range of concentrations or vehicle. After the addition of the cell homogenate the tubes were agitated on a vortex mixer and then placed in a water bath at 32°C.
  • the membranes were harvested on a Skatron filtermat (#1 1734) or a Wallac filtermat (#205-404) using three washes of HEPES buffer (4°C). The radioactivity on the filters was counted in a Packard 2200CA scintillation counter or in a Wallac 1205 Betaplate scintillation counter. Specific binding was defined as the difference in binding observed in the presence and absence of 10 micromolar atropine and accounted for at least 80% of total binding. Kj values were calculated using the program LIGAND. Compounds displayed Ki values at ml , m2 and m4 in the range of InM to 5,000 nM. All compounds described herein displayed typically greater than 300- fold less potency at the m3 receptor subtype, in the range of 300 nM to 1 14,000 nM.
  • tissue is cut into three 2-cm segments: proximal to the prostate, a middle section, and distal to the prostate. Only the first two segments are used. Tissue segments are attached to platinum electrodes with 4-0 surgical silk and placed in a 10 mL jacketed tissue bath containing
  • Each atria is attached to platinum electrodes with 4-0 surgical silk and placed in a 10 mL jacketed tissue bath containing Krebs buffer at 37°C, bubbled with 5% CO2 / 95% O2.
  • the tissues are connected to a Statham-Gould force transducer; 0.75 gram of tension is applied and the tissues are electrically stimulated. [EFS parameters are 3 Hz; 4 ms duration; voltage is set to 5 V.]
  • the contractions are recorded on a Gould strip chart recorder.
  • the tissues are washed every 20 minutes and allowed to equilibrate.
  • a concentration response curve to the agonist carbachol is determined. Tissues are washed every 20 minutes for 60 minutes.
  • the lumen of the remainder is flushed with oxygenated Krebs solution [NaCl, 1 18 mM; KCI, 4.7 mM; CaC , 2.5 mM; KH2PO4, 1.2 mM; MgS04, 1.2 mM; NaHC ⁇ 3, 25 mM; dextrose, 1 1 mM] warmed to 30°C.
  • the ileum is cut into 2.5 cm segments and each segment is mounted on a glass pipette.
  • a scalpel is used to lightly cut the surface of the tissue and a cotton swab used to tease the longitudinal muscle free from the underlying circular muscle.
  • Antagonist dissociation constants are calculated by the dose-ratio method. Compounds displayed Kb values at M3 in the range of 3900 to 24000 nM. EXAMPLE 10 ml and m3 receptor antagonist activity on the human muscarinic receptors expressed in CHO cells
  • Preconfluent CHO cells were labeled for 24 hours with 4 ⁇ Ci/mL of [ 3 H] myo-inositol (specific activity 15-20 Ci /mmole).
  • the cells were detached from flasks using 1 mM EDTA in phosphate buffer saline, centrifuged for 5 minutes at 200x g, and resuspended in assay buffer (1 16 mM NaCl; 10 mM LiCl; 4.7 mM KCI; 1.2 mM MgS ⁇ 4; 2.5 mM CaCb; 1.2 mM KH2PO4; 5 mM NaHC ⁇ 3; 11 mM dextrose, 20 mM HEPES; pH 7.4 at 37°C) to the desired volume.
  • Preconfluent CHO cells were harvested using 1 mM EDTA in phosphate buffer saline and washed one time by centrifugation in a HEPES buffered physiological salt solution. The cell concentration was adjusted to 3.3 X 10 ⁇ cells / mL in the HEPES buffer containing 1.3 micromolar isobuty lmethy Ixanthine. Three hundred microiiters of the cell suspension was added to tubes containing compound and incubated for 15 minutes at room temperature. Muscarinic agonist (50 microiiters of carbachol; 1 micromolar final concentration) was then added followed by 20 microiiters of 200 ⁇ M forskolin and the tubes were incubated at 30°C for an additional 15 minutes.
  • Muscarinic agonist 50 microiiters of carbachol; 1 micromolar final concentration

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Abstract

This invention is concerned with novel 1,3-dihydro-1-[1-(1-heteroarylpiperazin-4-yl)cyclohex-4-yl]-2H-benzimidazolones, derivatives thereof, their preparation, method of use and pharamceutical compositions. These compounds are endowed with antimuscarinic activity and are useful in the treatment and/or prevention of myopia (commonly known as nearsightedness).

Description

TITLE OF THE INVENTION MUSCARINE ANTAGONISTS
BACKGROUND OF THE INVENTION
This invention relates to control of ocular development in general and, more particularly, to the treatment of the eye to prevent and/or arrest the development of myopia (nearsightedness). Approximately one of every four persons suffer from myopia, i.e., an elongation of the eye along the visual axis. In particular, myopia afflicts 10% to 75% of the youth of the world, depending upon race, geographic distribution and level of education. Myopia is not a trivial maldevelopment of the eye. In its pathologic form, the sclera continues to grow and as result the retina stretches and degenerates resulting in permanent blindness.
Inheritance, environmental forces such as diet, sun intake, and substantial eye use, etc., are but a few theories that have been postulated to explain the on-set of myopia. In that regard, preventive measures such as eye rest, eye exercise, eye glasses, contact lens and drug and surgical therapies have been proposed. However, these measures are neither ideal nor risk-free. The surgical therapies (e.g. corneal surgery using excimer lasers or conventional knives) attempted for this condition are drastic and often unsuccessful. Moreover, neither of the therapies (excimer lasers or conventional knives) are easily reversed or sufficiently predictable in their results. Complications from contact lens wear range from allergic reactions to permanent loss of vision due to corneal ulceration. Even with the complications associated with contact lens wear, there are roughly 24 million wearers in the United States, with the number expected to double in the next 3 years. While eyeglasses eliminate most of the medical risks listed above, they are not an acceptable option as evidenced by the contact lens wearers who tolerate the frustration of contact lens wear.
One particular drug therapy utilized in the treatment of myopia involves the use of cycloplegics. Cyclop legics are topically administered drugs that relax the ciliary muscle of the eye, which is the muscle that focuses the eye by controlling lens dimensions. The classic cycloplegic drug is the belladonna alkaloid atropine, available for over a century. Atropine is a long-acting non-specific antimuscarinic agent that antagonizes the action of the neurotransmitter acetylcholine (ACh) at autonomic effector cells innervated by postganglionic cholinergic nerves of the parasympathetic nervous system. However, use of atropine, is impractical in that it causes mydriasis (increase of pupil size) and its action on the ciliary muscle to inhibit ocular focusing impairs near visual work like reading. There is strong evidence that the receptors in the iris and ciliary muscle responsible for the side effects of atropine are of the m3 subtype. Additionally, studies have shown that muscarinic receptors in the retina of a variety of non-human species are comprised of ml, m2 and m4 subtypes. Accordingly, a muscarinic antagonist with low m3 activity would be efficacious in prevention of the development of myopia without the undesirable side effects associated with the u,se of atropine.
There is now substantial evidence to link the posterior part of the eye, specifically image quality at the retina and hence an extension of the nervous system, to the postnatal regulation of ocular growth. There is significant evidence of myopia in an eye that is subjected to retinal image impairment. It has been shown that axial myopia can be experimentally induced, in either birds or primates, in an eye in which the retina is deprived of formed images, e.g., by suturing the eyelids or wearing an image diffusing goggle. The experimental myopia induced in birds or primates such as monkeys mimics, in many respects, the axial myopia of humans.
Thus, the phenomenon of an animal's vision process apparently contributes to the feedback mechanism by which postnatal ocular growth is normally regulated and refractive error is determined. This indicates that this mechanism is neural and likely originates in the retina. R. A. Stone, et al. have found a method of controlling the abnormal postnatal growth of the eye of a maturing animal. The method comprises controlling the presence of a neurochemical, its agonist or antagonist, which neurochemical is found to be changed under conditions during maturation leading to abnormal axial length. See U.S. Pat. No. 4,066,772 and 5,284,843. Therein it is disclosed that retinal concentrations of dopamine were found to be reduced during such image deprivation and the ocular administration of a dopamine-related agent, e.g., apomorphine, a dopamine agonist, was found to inhibit or actually prevent the axial enlargement of the eye under conditions ordinarily leading to such enlargement.
There have also been recent advances made in the understanding of the cholinergic nervous system and the receptors thereto. Cholinergic receptors are proteins embedded in the wall of a cell that respond to the chemical acetylcholine. Particularly, it is now known that the cholinergic receptors are subdivided into nicotinic and muscarinic receptors and that the muscarinic receptors are not all of the same type. Recent literature indicates that there are at least five types of cholinergic muscarinic receptors (types ml through m5). Receptors of type ml are those present in abundance and thought to be enriched in the brain neural tissue and neural ganglia. The other receptors are concentrated in other tissues such as the heart, smooth muscle tissue or glands. While many pharmacological agents interacting with muscarinic receptors influence several types of receptors, some agents are known to have a major effect on a single type of receptor with relative selectivity. Still other agents may have a significant effect on more than one or even all types of receptors.
It is known, for example, that pirenzepine, (Gastrozepin, LS 519) 5, 1 1 -Dihydro- 1 l-[4-methyl-l -piperazinyl) acetyl] -6H-pyrido[2,3-b] benzodiazepin-6-one, and its dihydrochloride are anticholinergic, antimuscarinic, and relatively selective for ml receptors. See U.S. Pat. No. 5,122,522 and WO9015604-A. It is also known that 4-DAMP (4-diphenylacetoxy- N-methylpiperadine methiodide) is a relatively selective antagonist for smooth muscle (ordinarily called m3 type but variously called type m2 or m3, as the current classification of receptors is in flux). Pirenzepine, being primarily an ml antagonist, inhibits axial elongation, but is far less effective at pupil dilation than atropine or another cycloplegic agent. This makes it possible to suppress the development of myopia without dilating the pupil and paralyzing the accommodation activity of the ciliary muscle. Additionally, the administration of a drug topically into the eye of a developing child for a long period of time makes it desirable to have a minimal likelihood of sensitization of the eye. Pirenzepine and atropine test positive in sensitization assays and this is an undesirable side effect.
It is therefore an object of this invention to provide a muscarinic antagonist which is effective in the treatment and prevention of myopia without many side effects.
SUMMARY OF THE INVENTION
This invention is concerned with novel 1 , 3 -dihydro- 1-[1-(1 - heteroarylpiperazin-4-yl)cyclohex-4-yl]-2H-benzimidazolones, their compositions and method of use. The novel compounds are selective muscarinic antagonists of the ml , m2, and m4 subtypes with low activity at the m3 subtype. The compounds have good ocular penetration (bioavailability) when dosed as a 0.1 - 4% aqueous solution, preferably a 0.5-2% solution. The compounds are effective for the treatment and/or prevention of myopia.
DETAILED DESCRIPTION OF THE INVENTION
The novel compounds of this invention are represented by the structural formula I:
Figure imgf000007_0001
I
or pharmaceutically acceptable salts thereof, or diastereomers, enantiomers or mixtures thereof; wherein:
R2 - R9 are independently H, alkyl, halo, alkoxy, OH, HOCH2-, aryl, 3-pyridyl, 5-pyrimidinyl, alkoxycarbonyl, amino, dialkylamino, alkene, thioalkyl, or alkylamino; alternatively, R4 and R7 or R2 and R9 may be connected as an ethylene bridge to form a bicyclic heterocycle;
Y l is H, alkyl, halo, alkylamino, dialkylamino, alkoxy, alkoxyamino, or amino;
Y2 is heterocycle, or heterocyclyl;
A is H, CHRl , C(R l)2 or carbonyl; and
Rl is alkyl, alkoxy, aryl, heteroaryl, heterocyclyl or heterocycle.
The term heterocycle or heterocyclic, as used herein except where noted, represents a stable 5- to 7- membered monocyclic heterocyclic ring, which is either saturated or unsaturated, and which consists of carbon atoms and from one to three heteroatoms selected from the group consisting of N, O and S, and including any bicyclic group in which any of the above defined heterocyclic rings is fused to a benzene ring. The heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure. Examples of such heterocyclic rings include pyridine, pyrazine, pyrimidine, pyridazine, triazine, imidazole, pyrazole, triazole, quinoline, isoquinoline, quinazoline, quinoxaline, phthalazine, oxazole, isoxazole, thiazole, isothiazole, thiadiazole, oxadiazole, pyrrole, furan, thiophene, hydrogenated derivatives of these heterocyles such as piperidine, pyrrolidine, azetidine, tetrahydrofuran, and N-oxide derivatives of heterocyles containing basic nitrogen. Any fused combinations of any of these above-defined heterocyclic rings is also a part of this definition. Attached to the heterocyclic ring can be substituents such as alkyls, amines, alkylamino, or halogens (F, Cl, Br, I).
The term alkyl is intended to include branched, cyclic and straight chain saturated aliphatic hydrocarbon groups having 1 to 15 carbon atoms, unless otherwise defined. Preferred straight or branched alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, t-butyl and the like. Preferred cycloalkyi groups include cyclopentyl and cyclohexyl.
The term alkoxy represents an alkyl group of indicated carbon atoms attached through an oxygen linkage.
The term alkylamino represents an alkyl group of indicated carbon atoms attached through a nitrogen atom linkage.
The term dialkylamino represents two alkyl groups of indicated carbon atoms attached through a nitrogen atom linkage.
The term small alkyl is intended to indicate those alkyls with Cl to C6 carbon atoms, either branched or linear in connection.
The term halo as used herein, represents fluoro, chloro, bromo or iodo.
The term aryl refers to aromatic rings e.g., phenyl, substituted phenyl and the like groups as well as rings which are fused e.g., naphthyl and the like. Aryl thus contains at least one ring having at least 6 atoms, with up to two such rings being present, containing up to 10 atoms therein, with alternating (resonating) double bonds between adjacent carbon atoms. The preferred aryl groups are phenyl and naphthyl. Aryl groups may likewise be substituted with 1-3 groups such as alkyl, halo, carboxyalkyl, alkylamino, dialkylamino, alkoxy, alkoxyamino and the like.
The term heteroaryl refers to a monocyclic aromatic hydrocarbon group having 5 or 6 ring atoms, or a bicyclic aromatic group having 8 to 10 atoms, containing at least one heteroatom, O, S, or N, in which a carbon or nitrogen atom is the point of attachment, and in which one additional carbon atom is optionally replaced by a heteroatom selected from O or S, an in which from 1 to 3 additional carbon atoms are optionally replaced by nitrogen heteroatoms. The heteroaryl group is optionally substituted with up to three groups. Heteroaryl thus includes aromatic and partially aromatic groups which contain one or more heteroatoms. Examples of this type are pyrrol, pyridine, oxazole, thiazole and oxazine. Additional nitrogen atoms may be present together with the first nitrogen and oxygen or sulfur, giveing e.g., thiadizaole.
A preferred embodiment of the novel compounds of this invention is realized when:
R2 - R9 are independently H, alkyl, or halo;
Y l is H, alkyl, or halo;
Y2 is 5-pyrimidinyl, 3-pyridyl, or l -methyl-5-imidazolyl; and
Rl is alkyl, alkoxy, phenyl, 5-pyrimidinyl, 3-pyridyl, or l -methyl-5- imidazolyl.
The pharmaceutically acceptable salts of the compounds of formula I include the conventional non-toxic salts or the quartemary ammonium salts of the compounds of formula I formed e.g. from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
The pharmaceutically acceptable salts of the present invention can be synthesized from the compounds of formula I which contain a basic or acidic moiety by conventional chemical methods. Generally, the salts are prepared by reacting the free base or acid with stoichiometric amounts or with an excess of the desired salt- forming inorganic or organic acid or base in a suitable solvent or various combinations of solvents.
The compounds of the present invention may have asymmetric centers and occur as racemates, racemic mixtures, and as individual diastereomers, with all possible isomers, including optical isomers, being included in the present invention.
Examples of the novel compounds of this invention are as follows: trans - 1 ,3-dihydro-l - { 1 '-[4"-(3'"-pyridinecarbonyl)piperazin- 1 "- yl]cyclohex-4'-yl } -2H-benzimidazol-2-one;
cis - 1 ,3-dihydro- 1 -{ 1 '-[4"-(3"'-pyridinecarbonyl)piperazin- 1 "- yl]cyclohex-4'-yl } -2H-benzimidazol-2-one;
trans - 1 ,3-dihydro- 1 - { 1 '-[4"-(5'"-pyrimidinecarbonyl)piperazin- 1 "- yl]cyclohex-4'-yl } -2H-benzimidazol-2-one;
(1 *"R) trans - l ,3-dihydro- l -{ r-[4π-( r"-(5,,"-pyrimidinyl)-r"- ethyl)piperazin- 1 "-yl]cyclohex-4'-yl } -2H-benzimidazol-2-one; ( 1 , S) trans - 1 ,3-dihydro- 1 - { 1 '-[4"-( 1 -(5""-pyrimidiny 1)- 1 "'- ethyl)piperazin-l"-yl]cyclohex-4'-yl}-2H-benzimidazol-2-one;
( 1 'R) trans - 1 ,3-dihydro- 1 - { 1 '-[4"-( 1 ,"-(3""-pyridinyl)- 1 "'- ethyl)piperazin-l"-yl]cyclohex-4'-yl}-2H-benzimidazol-2-one;
trans - 1 ,3-dihydro- 1 -{ 1 '-[4"-(3"'-pyridinylmethyl)piperazin- 1" - yl]cyclohex-4'-yl } -2H-benzimidazol-2-one;
(1"'S) trans -l,3-dihydro-l-{ ^-[4,■-(l -(3' -pyridinyl)-l,"- ethyl)piperazin-l "-yl]cyclohex-4'-yl } -2H-benzimidazol-2-one;
trans -l,3-dihydro-l-{ l'-[4"-(3 -pyridinecarbonyl)-2"- methy lpiperazin- 1 "-yl]cyclohex-4'-yl } -2H-benzimidazol-2-one;
trans -l,3-dihydro-l-{ l'-[4"-(3"'-pyridinecarbonyl)-3"- methylpiperazin- 1 "-yl]cyclohex-4'-y 1 } -2H-benzimidazol-2-one;
trans -l,3-dihydro-l-{ l'-[4"-(3",-pyridinecarbonyl)-2"- hydroxymethylpiperazin- 1 "-yl]cyclohex-4'-yl } -2H-benzimidazol-2-one;
trans -l,3-dihydro-l-{ r-[4"-(l'"-methylimidazol-5"'- ylcarbonyl)piperazin-l"-yl]cyclohex-4'-yl}-2H-benzimidazol-2-one;
1 ,3-dihydro- 1 - { 1 '-[4"-(3 -pyridinecarbonyl)piperazin- 1 "-yl]-3'- methylcyclohex-4'-yl }-2H-benzimidazol-2-one; and
trans -l,3-dihydro-l-{ r-[8"-(3*"-pyridinecarbonyl)-3,8- diazabicyclo[3.2.1 ]octanyI]cyclohex-4'-yl } -2H-benzimidazol-2-one. The novel compounds of this invention are prepared by the following non-limiting procedures:
Figure imgf000012_0001
X = F, Cl or Br
Figure imgf000012_0002
and Y2
Figure imgf000012_0003
The reaction is preferably carried out at room temperature (20-30°C) at a pH in the range of 2-7 (acidic) by the addition of glacial acetic acid or hydrochloric acid. A suitably protected monoprotected piperazine such as A-Y2 = Cθ2Et, Cθ2CH2Ph, or Cθ2C(CH3)3 can be used as an intermediate. Deprotection by the usual methods (hydrogenation or acidic hydrolysis followed by basification ) provides the free amine compound which can be acylated or alkylated by standard procedures. By this route the most preferred compounds can be obtained after isolation and purification.
The starting materials are either commercially available or can be obtained by conventional procedures such as those described in the Examples section. Compound II (l -(4-oxocyclohexyl) benzimidazolones) is obtained from Compound UI (4-aminocyclohexanols) as shown above.
The selectivity of the compounds can be measured by radioligand displacement from ml-m5 receptors expressed in Chinese hamster ovary cells (CHO) as described in the Examples section. The functional activity of the compounds can be assessed by measuring the agonist induced contractile response on muscle tissue from rabbit vas deferens (Ml), the guinea pig left atria (M2), or the guinea pig ileum (M3) as described in the Examples section. The functional activity at the human muscarinic receptors can be assessed by measuring agonist induced phosphoinositide hydrolysis in CHO cells expressing the human m 1 and m3 receptors or agonist inhibition of foskolin-stimulated adenylate cyclase activity in CHO cells expressing the human m2 receptor as described in the Examples section.
The instant compounds of this invention are useful in treating and/or preventing the development of myopia. Therapy to inhibit axial-elongation myopia during maturation can be administered by the use of the agent in eye drops. Indeed, in the vast majority of cases, treatment agents are administered to human eyes by the application of eye drops. Eye drops are typically made up at a concentration of active agent between about 0.1 and 4% in the ophthalmic medium. A 0.5%-2% solution of the instant muscarinic antagonist in water would be a likely concentration for clinical use. A pH of about 4.5 to about 7.5 is expected to be acceptable as an ophthalmic drop and practical in terms of known solubility and stability of piperidines. Phosphate buffering is also common for eye drops and is compatible with the instant muscarinic antagonist. A common regimen for application of eye drops is one to three times a day spaced evenly throughout waking hours. More effective agents may require fewer applications or enable the use of more dilute solutions. Alternatively, ointments and solid inserts are now coming into increased use in clinical practice. These aid the ocular penetration of the drug. It is, of course, also possible to administer the above-described active agents in therapeutically effective amounts and dosages in pills, capsules, or other preparations of systemic administration.
In experiments in animals where axial myopia has been experimentally induced by depriving the retina of foimed images, it has been noted that amblyopia was also experimentally and coincidentally induced in primates. Amblyopia is evidenced by poor visual acuity in the eye resulting in poor visual performance. Normally, visual acuity improves during maturation. It is known that amblyopia may occur in humans from unknown causes or as part of strabismus. Accordinly, it is expected that administration of therapeutically effective amounts and dosages of the instant muscarinic antagonist might prevent or inhibit the development of permanent or persistent amblyopia in maturing humans with decreased likelihood of sensitization of the eye. It is expected that humans who have already developed amblyopia from other or even unknown causes might be aided by similar therapeutic treatment with the aforementioned agents.
The following examples are provided in order that this invention might be more fully understood; they are not to be construed as limitative of the invention. The compounds are characterized analytically using techniques such as nuclear magnetic resonance, mass spectrometry, chromatography and the like. EXAMPLE 1
1 ,3-dihydro-l -(4-oxocyclohexyl)-2H-benzimidazol-2-one
Step 1 : A mixture of 10 g of 1 ,4-cyclohexanedione mono-ethyleneketal, 13.8 g of 1 ,2-phenylenediamine, 180 mL of 1 ,2-dichloroethane, 4 mL of glacial acetic acid and 19 g of sodium triacetoxyborohydride was stirred at room temperature for 48 h. The reaction mixture was poured into 200 mL chloroform and 200 mL saturated IN NaOH and the layers separated. The aqueous layer was extracted with 2 X 50 mL of chloroform and the combined organic layers dried over MgS04 and concentrated to dryness under reduced pressure. To an ice cold, vigorously stirred solution of the resulting crude 4-(2-aminoanilino)- cyclohexan-1-one ethylene ketal in 200 mL of ethyl acetate was added 200 mL of saturated sodium carbonate followed by 10 mL of 1.9 M phosgene in toluene dropwise over 30 min. After stirring overnight at room temperature, the layers were separated and the organic layer dried over MgSθ4 and concentrated to dryness. Chromatography over silica gel, eluting with 5% methanol in dichloromethane gave 7 g of the ethylene ketal of l,3-dihydro-l-(4-oxocyclohexyl)-2H-benzimidazol-2- one as a solid. *H NMR (400 MHz, CDCI3) 9.58 (s, IH), 7.28 (m, IH), 7.07-7.15 (m, 3H), 4.5 (m, IH), 4.03 (m, 4H), 2.5 (m, 2H), 1.8-1.93 (m, 6H).
Step 2: A mixture of 7 g of the ethylene ketal of 1 ,3 -dihydro- 1 -(4- oxocyclohexyl)-2H-benzimidazol-2-one, 100 mL of glacial acetic acid, 50 mL of water and 50 mL of cone. HCl was heated under reflux for 12 h. The mixture was concentrated under reduced pressure, diluted with 100 mL of water and extracted into 3 X 200 mL of CHCI3. The combined organic extracts were washed with 100 mL of water, 100 mL of saturated Na2Cθ3, dried over MgSθ4 and concentrated under reduced pressure. Drying under vacuum gave 5 g of l ,3-dihydro-l -(4- oxocyclohexyl)-2H-benzimidazol-2-one as a tan solid: iH NMR (400 MHz, CDCI3) 9.52 (s, IH), 7.14-7.03 (m, 4H), 4.82 (m, IH), 2.8-2.6 (m, 4H), 2.2 (m, 2H). EXAMPLE 2
1 ,3-dihydro- 1 - { trans -4-[4-(5-pyrimidinecarbonyl)piperazin- 1 -yl]- 1 - cyclohexyl } -2H-benzimidazol-2-one
Step 1 : A mixture of 1.5 g of l,3-dihydro-l-(4-oxocyclohexyl)- 2H-benzimidazol-2-one, 1.21 g of tert-butyl 1 -piperazinecarboxylate, 20 mL of 1 ,2-dichloroethane, 0.40 mL of glacial acetic acid and 1.79 g of sodium triacetoxyborohydride was stirred at room temperature for 48 h. The reaction mixture was poured into 50 mL chloroform and 50 mL saturated aqueous Na2C03 and the layers separated. The aqueous layer was extracted with 2 X 25 mL of chloroform and the combined organic layers dried over MgS04 and concentrated under reduced pressure. Chromatography of the crude product on silica gel, eluting with 10% methanol in choroform gave, firstly, 0.63 g of l,3-dihydro-l -{ c s -4-[4- (tert -butylcarbonyl)piperazin-l -yl]- 1 -cyclohexyl } -2H-benzimidazol-2- one: iH NMR (400 MHz, CDCI3) 7.47 (m, IH), 7.25 (m, IH), 7.05 (m, 2H), 4.55 (m, IH), 3.54 (m, 4H), 2.49 (m, 6H), 2.27 (s, 0.8H), 2.15 (d, 2H), 1.97 (m, 0.2H), 1.57 (m, 4H), 1.49 (s, 9H). Later fractions gave 1 ,3-dihydro- 1 - { trans -4-[4-(tert -butylcarbonyl)piperazin- 1 -yl]- 1 - cyclohexyl }-2H-benzimidazol-2-one: iH NMR (400 MHz, CDCI3) 7.15 (m, 2H), 7.06 (m, 2H), 4.28 (m, IH), 3.46 (m, 4H), 2.56 (m, 4H), 2.5 (m, IH), 2.26 (m, 2H), 2.03 (m, 6H), 1.47 (s, 9H).
Step 2: A stirred solution of 0.52 g of l
Figure imgf000016_0001
-4-[4- (tert -butylcarbonyl)piperazin- 1 -yl]- 1 -cyclohexyl } -2H-benzimidazol-2- one in 15 mL of 1 N HCl was heated to reflux for 1 h, cooled and basified with 6N NaOH. The basic mixture was extracted with 2 X 50 mL portions of chloroform. The combined organic extracts were dried over MgS04 and concentrated under reduced pressure. After drying overnight under vacuum, there was obtained 0.28 g of 1 , 3 -dihydro- 1 - [ trans -4-[ l -piperazinyl]- 1 -cyclohexyl }-2H-benzimidazol-2-one as a white solid: l U NMR (400 MHz, CDCI3) 7.16-7.03 (m, 4H), 4.27 (m, IH), 2.94 (m, 4H), 2.61 (m, 4H), 2.25 (m, 2H), 2.1 (d, 2H), 1.97 (d, 2H), 1.54 (m, 2H). Step 3: To a stirred solution of 0.044 g of l ,3-dihydro-l-{ rrαti5 -4-[ l-piperazinyl]-l -cyclohexyl }-2H-benzimidazol-2-one and 0.2 mL of triethylamine in 3 mL of dichloromethane was added 0.030 g of pyrimidine-5 -carboxylic acid chloride. After 2 h, 5 mL of dilute aqueous ammonia was added and the mixture stirred for an additional 30 min. The organic layer was separated, the aqueous layer extracted with two addtional 20 mL portions of chloroform and the combined organic extracts dried over MgS04 and concentrated under reduced pressure. Chromatography over silica gel eluting with 10% methanol in ethyl acetate gave 0.030 g of l ,3-dihydro-l -{ rrαti5 -4-[4-(5- pyrimidinecarbonyl)piperazin- 1 -yl]-l -cyclohexyl } -2H-benzimidazol-2- one as a white solid: *H NMR (400 MHz, CDCI3) 9.76 (s, IH), 9.29 (s, IH), 8.83 (s, 2H), 7.16-7.04 (m, 4H), 4.27 (m, IH), 3.84 (s, 2H), 3.48 (s, 2H), 2.72 (s, 2H), 2.61 (s, 2H), 2.56 (m, IH), 2.30 (q, 2H), 2.05 (m, 4H), 1.86 (br s, IH), 1.5 (q, 2H). The dihydrochloride salt was precipitated from chloroform/ethyl acetate: Analysis calculated for C22H26N6θ2*2HCl«0.65 CHCI3 C: 48.84, H: 5.18, N: 15.09 found C: 48.85, H: 5.36, N: 14.72.
EXAMPLE 3
trans - l ,3-dihydro-l -{ r-[4"-(3'"-pyridinecarbonyl)piperazin- l "- yl]cyclohex-4'-yl } -2H-benzimidazol-2-one;
From 1 ,3 -dihydro- \-{ trans -4-[ 1 -piperazinyl]- 1 -cyclohexyl }-2H- benzimidazol-2-one and nicotinoylchloride hydrochloride using the procedure described for Example 1 , Step 3 there was obtained 1,3- dihydro- 1 - { trans -4-[4-(3-pyridinecarbonyl)piperazin-l -yl]- 1 - cyclohexyl }-2H-benzimidazol-2-one as a white solid: iH NMR (400 MHz, CDC13) 9.51 (s, IH), 8.68 (s, 2H), 7.77 (m, IH), 7.38 (m, IH), 7.12-7.04 (m, 4H), 4.26 (m, IH), 3.83 (s, 2H), 3.47 (s, 2H), 2.71 (s, 2H), 2.58 (s, 2H), 2.53 (m, 2H), 2.30 (q, 2H), 2.0 (q, 4H), 1.53 (m, 2H), 1.26 (m, 2H). The citrate salt was precipitated from ethyl acetate/methanol: Analysis calculated for C23H27N5θ2« 1.2 C6H θ7»1.0 H3O C: 55.45, H: 5.95, N: 10.71 ; found C: 55.83, H: 6.22, N: 10.33. EXAMPLE 4
cis - 1 ,3-dihydro- 1 - { 1 '-[4"-(3"'-pyridinecarbony l)piperazin- 1 "- yl]cyclohex-4'-yl } -2H-benzimidazol-2-one
From l,3-dihydro-l-{ct5 -4-[ 1 -piperazinyl] -1 -cyclohexyl }-2H- benzimidazol-2-one and nicotinoylchloride hydrochloride using the procedure described for Example 1 , Step 3 there was obtained 1,3- dihydro-l-{ cis -4-[4-(3-pyridinecarbonyl)piperazin-l-yl]-l- cyclohexyl]-2H-benzimidazol-2-one as a white solid: ^H NMR (400 MHz, CDC13) 9.82 (s, IH), 8.72 (s, IH), 8.68 (s, IH), 7.77 (m, IH), 7.38 (m, IH), 7.12-7.04 (m, 4H), 4.5 (m, IH), 3.9 (s, 2H), 3.57 (s, 2H), 2.65 (s, 2H), 2.58 (m, 2H), 2.34 (s, IH), 2.15 (d, 2H), 1.8 (m, IH), 1.62 (m, 3H), 1.26 (m, IH). The hydrochloride salt was precipitated from chloroform/toluene: Analysis calculated for C23H27N5θ2*HCl»0.4 C7H8-0.2 CHC13 C: 57.99, H: 6.43, N: 12.83; found C: 58.04, H: 6.36, N: 12.75.
EXAMPLE 5
trans - l ,3-dihydro- l -{ -[4"-(3'"-pyridinylmethyl)piperazin-l "- yl]cyclohex-4'-yl } -2H-benzimidazol-2-one
A mixture of 0.033 g 1 ,3 -dihydro- \ -{ trans -4-[ 1 -piperazinyl]- 1 - cyclohexyl }-2H-benzimidazol-2-one, 0. 12 g of 3- pyridinecarboxaldehyde, 5 mL of 1 ,2-dichloroethane, 0.01 mL of glacial acetic acid and 0.5 g of sodium triacetoxyborohydride was stirred at room temperature for 48 h. The reaction mixture was poured into 100 mL chloroform and 25 mL saturated aqueous Na2C03 and the layers separated. The aqueous layer was extracted with 2 X 25 mL of chloroform and the combined organic layers dried over MgS04 and concentrated under reduced pressure. Purification of the residue by low pressure chromatography on silica gel eluting with a gradient of 100:1 CHCl3:MeOH to 10: 1 CHCl3:MeOH gave trans - 1 ,3 -dihydro- 1 - { 1 ,-[4"-((3,"-pyridinyl)methyl)piperazin- 1 "-yl]cyclohex-4'-yl } -2H- benzimidazol-2-one as a white solid: *H NMR (400 MHz, CDCI3) 9.7 (s, IH), 8.56 (s, I H), 8.52 (s, 2H), 7.67 (d, I H), 7.26 (m, 2H), 7.0- 7.15 (m, 2H), 4.26 (br m, IH), 3.5 (s, 2H), 2.7 (br s, 4H), 2.5 (br s, 5H), 2.27 (q, 2H), 2.1 (d, 2H), 1.95 (d, 2H), 1.5 (br q, 2H. The hydrochloride salt (0.030 g) precipitated from ethyl ether/choroform: Analysis calculated for C23H29N5O-3.0 HC1-0.8 CHCI3: C: 47.93, H: 5.54, N: 1 1.74; found C: 48.08, H: 5.80, N: 1 1.40.
EXAMPLE 6 Radioligand Binding Studies
The affinity of muscarinic antagonists for ml-m5 receptors expressed in Chinese hamster ovary cells (CHO) were determined using the technique described by Dorje et al., J. Pharmacol. Exp. Ther. 256: 727-733 (1991 ).
When 80-100% confluent, CHO cells were harvested, and transferred to centrifuge tubes containing CHO buffer (20 mM HEPES at pH 7.4 containing 5mM MgCl2). The cells were homogenized, using a Brinkman Polytron homogenizer for 30 seconds at a setting of 5, on ice. The homogenate was centrifuged at 40,000 x g for 15 minutes at 4°C in a Beckman J2-21M centrifuge. The supernatant was discarded and the homogenization/centrifugation step repeated once. Pelleted membranes were resuspended in CHO buffer to a concentration of one flask harvested (75 cm2) per mL of buffer, mixed well and aliquoted in cryovials (lmL/vial). The vials were stored at -70°C until used in the assay. The binding incubation was done in polypropylene macrowell tube strips in a final volume of 0.5 mL of HEPES buffer (20 mM; pH 7.4 containing 5 mM MgC ) containing 0.1 mL of cell membrane suspension, 3H-N-methylscopolamine (NEN Coφoration, NET-636, 70-87 /mmole) at a final concentration of approximately 0.2 nM and the competing drug in a varying range of concentrations or vehicle. After the addition of the cell homogenate the tubes were agitated on a vortex mixer and then placed in a water bath at 32°C. After 90 minutes of incubation, the membranes were harvested on a Skatron filtermat (#1 1734) or a Wallac filtermat (#205-404) using three washes of HEPES buffer (4°C). The radioactivity on the filters was counted in a Packard 2200CA scintillation counter or in a Wallac 1205 Betaplate scintillation counter. Specific binding was defined as the difference in binding observed in the presence and absence of 10 micromolar atropine and accounted for at least 80% of total binding. Kj values were calculated using the program LIGAND. Compounds displayed Ki values at ml , m2 and m4 in the range of InM to 5,000 nM. All compounds described herein displayed typically greater than 300- fold less potency at the m3 receptor subtype, in the range of 300 nM to 1 14,000 nM.
EXAMPLE 7 ml receptor antagonist activity on the rabbit vas deferens
The technique described by Feifel et al., Brit. J.
Pharmacol. 99: 455-460 (1990) was used as follows: Male Hazelton
New Zealand White rabbits weighing 1.5-3 kg, are euthanized
(phenobarbital sodium, 85 mg/kg. i. v.). An abdominal incision is made and the vas deferens are removed. The tissues are placed in a
Petri dish containing oxygenated Krebs solution [NaCl, 1 18 mM;
KCI, 4.7 mM; CaCtø, 2.5 mM; KH2PO4, 1.2 mM; MgS04, 1.2 mM;
NaHCθ3, 25 mM; dextrose, 1 1 mM] warmed to 30°C. Each tissue is cut into three 2-cm segments: proximal to the prostate, a middle section, and distal to the prostate. Only the first two segments are used. Tissue segments are attached to platinum electrodes with 4-0 surgical silk and placed in a 10 mL jacketed tissue bath containing
Krebs buffer at 30°C, bubbled with 5% CO2 / 95% O2. The tissues are connected to a Statham-Gould force transducer; 0.75 gram of tension is applied and the tissues are electrically stimulated. [EFS parameters are 0.05 Hz; 0.5 ms duration; voltage is set to 30% of 50
V at 25 ohms and increased until a supramaximal voltage is achieved.] The contractions are recorded on a Gould strip chart recorder. The tissues are washed every 20 minutes and allowed to equilibrate. A concentration response curve to the selective ml receptor agonist McN-A-343 is determined. Tissues are washed every 20 minutes for 60 minutes. The vehicle or compound is added to the bath and the tissues are incubated for 30 minutes, then the McN-A-343 concentration response is repeated. EC50 values are determined for both vehicle and tissues treated with the compound before and after treatment. Antagonist dissociation constants (Kb) are calculated by the dose-ratio method. Compounds displayed Kb values at ml in the range of 5 to 100 nM.
EXAMPLE 8 m2 receptor antagonist activity on the guinea pig left atria
The technique described by Feifel et al., Brit. J. Pharmacol. 99: 455-460 (1990) was used as follows: Duncan- Hartley guinea pigs (Hazelton) weighing 300-600 g, are asphyxiated with CO2. The abdomen is opened and the left atria is rapidly removed. The tissues are placed in a Petri dish containing oxygenated Krebs solution [NaCl, 1 18 mM; KCI, 4.7 mM; CaCh, 2.5 mM; KH2PO4, 1.2 mM; MgSθ4, 1.2 mM; NaHCθ3, 25 mM; dextrose, 1 1 mM] warmed to 37°C. Each atria is attached to platinum electrodes with 4-0 surgical silk and placed in a 10 mL jacketed tissue bath containing Krebs buffer at 37°C, bubbled with 5% CO2 / 95% O2. The tissues are connected to a Statham-Gould force transducer; 0.75 gram of tension is applied and the tissues are electrically stimulated. [EFS parameters are 3 Hz; 4 ms duration; voltage is set to 5 V.] The contractions are recorded on a Gould strip chart recorder. The tissues are washed every 20 minutes and allowed to equilibrate. A concentration response curve to the agonist carbachol is determined. Tissues are washed every 20 minutes for 60 minutes. The vehicle or compound is added to the bath and the tissues are incubated for 30 minutes, then the carbachol concentration response is repeated. EC50 values are determined for both vehicle and compound treated tissues before and after treatment. Antagonist dissociation constants (Kb) are calculated by the dose-ratio method. Compounds displayed K values at M2 in the range of 5 to 100 nM. EXAMPLE 9 M3 receptor antagonist activity on the guinea pig ileum longitudinal muscle
The technique described by Feifel et al., Brit. J. Pharmacol. 29: 455-460 (1990) was used as follows: Duncan- Hartley guinea pigs (Hazelton) weighing 300-600 g, are asphyxiated with CO2. The abdomen is opened and the caecum and the distal end of the ileum are identified. The ileum is removed and 5 cm of the terminal end (proximal to the caecum) is discarded. The lumen of the remainder is flushed with oxygenated Krebs solution [NaCl, 1 18 mM; KCI, 4.7 mM; CaC , 2.5 mM; KH2PO4, 1.2 mM; MgS04, 1.2 mM; NaHCθ3, 25 mM; dextrose, 1 1 mM] warmed to 30°C. The ileum is cut into 2.5 cm segments and each segment is mounted on a glass pipette. A scalpel is used to lightly cut the surface of the tissue and a cotton swab used to tease the longitudinal muscle free from the underlying circular muscle. Longitudinal muscle segments are attached to glass tissue holders with 4-0 surgical silk and placed in a 10 mL jacketed tissue bath containing Krebs buffer at 30°C, bubbled with 5% CO2 / 95% O2. The tissues are connected to a Statham- Gould force transducer. One gram of tension is applied and the contractions are recorded on a Gould strip chart recorder. The tissues are washed every 20 minutes and allowed to equilibrate. A concentration response curve to the agonist carbachol is determined. Tissues are washed every 20 minutes for 60 minutes. The vehicle or compound is added to the bath and the tissues are incubated for 30 minutes, then the carbachol concentration response is repeated. EC50 values are determined for both vehicle and tissues treated with the compound before and after treatment. Antagonist dissociation constants (Kb) are calculated by the dose-ratio method. Compounds displayed Kb values at M3 in the range of 3900 to 24000 nM. EXAMPLE 10 ml and m3 receptor antagonist activity on the human muscarinic receptors expressed in CHO cells
Preconfluent CHO cells were labeled for 24 hours with 4 μCi/mL of [3H] myo-inositol (specific activity 15-20 Ci /mmole). The cells were detached from flasks using 1 mM EDTA in phosphate buffer saline, centrifuged for 5 minutes at 200x g, and resuspended in assay buffer (1 16 mM NaCl; 10 mM LiCl; 4.7 mM KCI; 1.2 mM MgSθ4; 2.5 mM CaCb; 1.2 mM KH2PO4; 5 mM NaHCθ3; 11 mM dextrose, 20 mM HEPES; pH 7.4 at 37°C) to the desired volume. Four hundred microiiters of the cell suspension (approximately 2 X 10^ cells) was added to tubes containing buffer or compound and left at room temperature for 30 minutes. Muscarinic agonist (carbachol) was then added and the cells incubated for 30 minutes at 37°C. The reaction was stopped using an acid solution (12% perchloric acid / 3 mM EDTA / 1 mM diethylenetriamine pentaacetic acid) and the tubes placed on ice for 15 minutes. The samples were then neutralized with 3M KOH / 0.25 M 2-(N-morpholino)ethane sulfonic acid / 0.25 M 3-(N-morpholino) propane sulfonic acid and centrifuged at 3000x g for 15 minutes. Five hundred microiiters of each supernatant was diluted to 5.5 mL with water and the entire tube contents applied to anion exchange columns. The columns are sequentially washed with 5 mL of H2O, 15 mL of 60 mM ammonium formate / 5 mM borax and 8 mL of 200 mM ammonium formate / 5 mM borax. The radioactivity in the last eluate was determined by liquid scintillation counting and taken as the amount of [3H] -inositol monophosphate formed during the incubation. Two different types of experiments were performed: IC50 values for compounds where calculated using a fixed concentration of carbachol , or Kb values were generated by performing carbachol concentration-response curves in the absence and presence of a fixed concentration of compound. Compounds displayed Kb values at m 1 and m3 in the range of 1 to 100 nM at ml and 4,000 to 20,000 at m3. EXAMPLE 11 m2 receptor antagonist activity on the human muscarinic receptors expressed in CHO cells
Preconfluent CHO cells were harvested using 1 mM EDTA in phosphate buffer saline and washed one time by centrifugation in a HEPES buffered physiological salt solution. The cell concentration was adjusted to 3.3 X 10^ cells / mL in the HEPES buffer containing 1.3 micromolar isobuty lmethy Ixanthine. Three hundred microiiters of the cell suspension was added to tubes containing compound and incubated for 15 minutes at room temperature. Muscarinic agonist (50 microiiters of carbachol; 1 micromolar final concentration) was then added followed by 20 microiiters of 200 μM forskolin and the tubes were incubated at 30°C for an additional 15 minutes. The reaction was stopped by placing the tubes in boiling water for 5 minutes. The tubes were cooled on ice and then centrifuged at 12,000 xg for 10 minutes. Fifty microiiters of each supematant was then analyzed for cAMP using a commercially available radioimmunoassay kit following the manufacturer's instmctions. Two different types of experiments were performed: IC50 values for compounds where calculated using a fixed concentration of carbachol , or Kb values were generated by performing carbachol concentration-response curves in the absence and presence of a fixed concentration of compound. Compounds displayed Kb values at m2 in the range of 1 to 100 nM.

Claims

WHAT IS CLAIMED IS:
1. A compound of structural formula I
Figure imgf000025_0001
I
or pharmaceutically acceptable salts thereof, or diastereomers, enantiomers or mixtures thereof; wherein:
R2 - R9 are independently H, alkyl, halo, alkoxy, OH, HOCH2-, aryl, 3-pyridyl, 5-pyrimidinyl, alkoxycarbonyl, amino, dialkylamino, alkene, thioalkyl, or alkylamino; alternatively, R4 and R7 or R2 and R9 may be connected as an ethylene bridge to form a bicyclic heterocycle;
Yl is H, alkyl, halo, alkylamino, dialkylamino, alkoxy, alkoxyamino, or amino;
Y2 is heterocycle, or heterocyclyl;
A is H, CHR l , C(Rl )2 or carbonyl; and
R l is alkyl, alkoxy, aryl, heteroaryl, heterocyclyl or heterocycle.
2. The compound of Claim 1 wherein:
R2 - R9 are independently H, alkyl, or halo;
Yl is H, alkyl, or halo; Y2 is 5-pyrimidinyl, 3-pyridyl, or l-methyl-5-imidazolyl; and
Rl is alkyl, alkoxy, phenyl, 5-pyrimidinyl, 3-pyridyl, or l-methyl-5- imidazolyl.
3. The compound: trans -l,3-dihydro-l-{ -[4"-(3'"-pyridinecarbonyl)piperazin-l"- yl]cyclohex-4'-yl } -2H-benzimidazol-2-one;
cis - 1 ,3-dihydro- 1 - { 1 '-[4"-(3'"-pyridinecarbonyl)piperazin- 1 "- yl]cyclohex-4'-yl } -2H-benzimidazol-2-one;
trans - 1 ,3-dihydro- 1 - { 1 '-[4"-(5'"-pyrimidinecarbony l)piperazin- 1 "- yl]cyclohex-4'-yl } -2H-benzimidazol-2-one;
(1"'R) trans -l,3-dihydro-l-{ l'-[4M-(r,,-(5""-pyrimidinyl)-r"- ethyl)piperazin-l "-yl]cyclohex-4'-yl } -2H-benzimidazol-2-one;
(l'"S) trans -l,3-dihydro-l-{ r-[4"-(l -(5' -pyrimidinyl)-r"- ethyl)piperazin-l"-yl]cyclohex-4'-yl}-2H-benzimidazol-2-one;
(1"'R) trans -l,3-dihydro-l-{ r-[4"-(r"-(3m'-pyridinyl)-lm- ethyl)piperazin- 1 M-yl]cyclohex-4'-y 1 } -2H-benzimidazol-2-one;
trans -l,3-dihydro-l-{ r-[4"-(3'"-pyridinylmethyl)piperazin-l"- yl]cyclohex-4'-yl } -2H-benzimidazol-2-one;
(1"'S) trans -l,3-dihydro-l-{ 1 '-[4"-(l "'-(3""-pyridinyl)-l "'- ethyl)piperazin-l"-yl]cyclohex-4'-yl}-2H-benzimidazol-2-one;
trans -l,3-dihydro-l-{ l'-[4"-(3'"-pyridinecarbonyl)-2"- methylpiperazin- 1 "-yl]cyclohex-4'-yl } -2H-benzimidazol-2-one; trans -l ,3-dihydro- l -{ l '-[4"-(3"'-pyridinecarbonyl)-3"- methylpiperazin-l "-yl]cyclohex-4'-yl }-2H-benzimidazol-2-one;
trans -l ,3-dihydro-l -{ l '-[4"-(3,"-pyridinecarbonyl)-2"- hydroxymethylpiperazin- 1 "-yl]cyclohex-4'-y 1 } -2H-benzimidazol-2-one;
trans -l ,3-dihydro-l -{ r-[4"-(l "'-methylimidazol-5, - ylcarbonyl)piperazin- 1 "-yl]cyclohex-4'-yl }-2H-benzimidazol-2-one;
1 ,3-dihydro- 1 - { 1 '-[4"-(3'"-pyridinecarbonyl)piperazin- 1 "-yl]-3'- methylcyclohex-4'-yl }-2H-benzimidazol-2-one; and
trans -l ,3-dihydro-l -{ l ,-[8"-(3"'-pyridinecarbonyl)-3,8- diazabicyclo[3.2.1 ]octanyl]cyclohex-4'-yl } -2H-benzimidazol-2-one.
4. A method for the treatment of abnormal increase in eye axial length in an animal in need thereof, which comprises the step of ocularly administering to said animal a pharmacologically effective amount of a muscarinic pharmacological agent known to be selective for ml , m2 and m4 receptors, but less active at m3 receptors.
5. A method for the treatment of abnormal increase in eye axial length in an animal in need thereof, which comprises the step of ocularly administering to said animal a pharmacologically effective amount of a muscarinic pharmacological agent of Claim 1.
6. A method for the treatment of abnormal increase in eye axial length in an animal in need thereof, which comprises the step of ocularly administering to said animal a pharmacologically effective amount of a muscarinic pharmacological agent according to Claim 1 known to be selective for ml , m2 and m4 receptors, but less active at m3 receptors.
7. A method for the prevention of abnormal increase in eye axial length in an animal in need thereof, which comprises the step of ocularly administering to said animal a pharmacologically effective amount of a muscarinic pharmacological agent known to be selective for ml , m2 and m4 receptors, but less active at m3 receptors.
8. A method for the prevention of abnormal increase in eye axial length in an animal in need thereof, which comprises the step of ocularly administering to said animal a pharmacologically effective amount of a muscarinic pharmacological agent according to Claim 1.
9. A method for the prevention of abnormal increase in eye axial length in an animal in need thereof, which comprises the step of ocularly administering to said animal a pharmacologically effective amount of a muscarinic pharmacological agent according to Claim 1 known to be selective for ml , m2 and m4 receptors, but less active at m3 receptors.
10. A method of alleviating the development of amblyopia in the eye of an animal in need thereof, which comprises administering to such an animal a pharmacologically effective amount of a compound of Claim 1.
1 1. A method of controlling the development of amblyopia in the eye of an animal in need thereof, which comprises administering to such an animal a pharmacologically effective amount of a compound of Claim 1.
12. A composition useful for the prevention of abnormal increase in eye axial length in an animal in need thereof, which comprises a pharmacologically effective amount of a muscarinic pharmacological agent, known to be selective for ml , m2 and m4 receptors, but less active at m3 receptors, in a carrier or diluent buffered to a pH suitable for ocular administration.
13. A composition useful for the treatment of abnormal increase in eye axial length in an animal in need thereof, which comprises a pharmacologically effective amount of a muscarinic pharmacological agent, known to be selective for ml , m2 and m4 receptors, but less active at m3 receptors, in a carrier or diluent buffered to a pH suitable for ocular administration.
14. A composition useful for the treatment of abnormal increase in eye axial length in an animal in need thereof, which comprises a pharmacologically effective amount of a muscarinic pharmacological agent of Claim 1 in a carrier or diluent buffered to a pH suitable for ocular administration.
15. A composition useful for the prevention of abnormal increase in eye axial length in an animal in need thereof, which comprises a pharmacologically effective amount of a muscarinic pharmacological agent of Claim 1 , in a carrier or diluent buffered to a pH suitable for ocular administration.
16. A composition useful for the treatment of abnormal increase in eye axial length in an animal in need thereof, which comprises a pharmacologically effective amount of a muscarinic pharmacological agent of Claim 1 , known to be selective for ml , m2 and m4 receptors, but less active at m3 receptors, in a carrier or diluent buffered to a pH suitable for ocular administration.
17. A composition useful for the prevention of abnormal increase in eye axial length in an animal in need thereof, which comprises a pharmacologically effective amount of a muscarinic pharmacological agent of Claim 1 , known to be selective for ml , m2 and m4 receptors, but less active at m3 receptors, in a carrier or diluent buffered to a pH suitable for ocular administration.
PCT/US1996/017214 1995-10-31 1996-10-28 Muscarine antagonists WO1997016187A1 (en)

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Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6951849B2 (en) 2001-10-02 2005-10-04 Acadia Pharmaceuticals Inc. Benzimidazolidinone derivatives as muscarinic agents
US7087593B2 (en) 2001-10-02 2006-08-08 Acadia Pharmaceuticals Inc. Benzimidazolidinone derivatives as muscarinic agents
US8557835B2 (en) 1997-12-12 2013-10-15 Warner-Lambert Company, Llc Statin-carboxyalkylether combinations
US9849104B2 (en) 2015-11-06 2017-12-26 Gemphire Therapeutics Inc. Treatment of NASH with gemcabene
US10259787B2 (en) 2016-10-14 2019-04-16 Heptares Therapeutics Limited Substituted cyclohexanes as muscarinic M1 receptor and/or M4 receptor agonists
CN109996792A (en) * 2016-10-14 2019-07-09 赫普泰雅治疗有限公司 With the active heterocyclic compound in treatment CNS disease and pain as the regulator of muscarinic M 1 and/or M4 receptor
US11046658B2 (en) 2018-07-02 2021-06-29 Incyte Corporation Aminopyrazine derivatives as PI3K-γ inhibitors
US11773090B2 (en) 2018-06-22 2023-10-03 Heptares Therapeutics Limited Pharmaceutical compounds
US11793817B2 (en) 2011-11-18 2023-10-24 Heptares Therapeutics Limited Muscarinic M1 receptor agonists
US11926616B2 (en) 2018-03-08 2024-03-12 Incyte Corporation Aminopyrazine diol compounds as PI3K-γ inhibitors
US11945801B2 (en) 2018-12-07 2024-04-02 Heptares Therapeutics Limited Bicyclic aza compounds as muscarinic M1 and/or M4 receptor agonists
US11999745B2 (en) 2020-12-18 2024-06-04 Heptares Therapeutics Limited Pharmaceutical compounds
US12024499B2 (en) 2015-08-03 2024-07-02 Heptares Therapeutics Limited Muscarinic agonists

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5576318A (en) * 1991-07-30 1996-11-19 Boehringer Ingelheim Italia S.P.A. Benzimidazolone derivatives

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5576318A (en) * 1991-07-30 1996-11-19 Boehringer Ingelheim Italia S.P.A. Benzimidazolone derivatives

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US8557835B2 (en) 1997-12-12 2013-10-15 Warner-Lambert Company, Llc Statin-carboxyalkylether combinations
US6951849B2 (en) 2001-10-02 2005-10-04 Acadia Pharmaceuticals Inc. Benzimidazolidinone derivatives as muscarinic agents
US7087593B2 (en) 2001-10-02 2006-08-08 Acadia Pharmaceuticals Inc. Benzimidazolidinone derivatives as muscarinic agents
US7273857B2 (en) 2001-10-02 2007-09-25 Acadia Pharmaceuticals Inc. Benzimidazolidinone derivatives as muscarinic agents
US7291611B2 (en) 2001-10-02 2007-11-06 Acadia Pharmaceuticals Inc. Benzimidazolidinone derivatives as muscarinic agents
US7300928B2 (en) 2001-10-02 2007-11-27 Acadia Pharmaceuticals, Inc. Benzimidazolidinone derivatives as muscarinic agents
US11793817B2 (en) 2011-11-18 2023-10-24 Heptares Therapeutics Limited Muscarinic M1 receptor agonists
US12024499B2 (en) 2015-08-03 2024-07-02 Heptares Therapeutics Limited Muscarinic agonists
US9849104B2 (en) 2015-11-06 2017-12-26 Gemphire Therapeutics Inc. Treatment of NASH with gemcabene
US10449154B2 (en) 2015-11-06 2019-10-22 Gemphire Therapeutics Inc. Treatment of NASH with Gemcabene
CN109996792B (en) * 2016-10-14 2023-02-17 赫普泰雅治疗有限公司 Heterocyclic compounds having activity as modulators of muscarinic M1 and/or M4 receptors in the treatment of CNS diseases and pain
US11014880B2 (en) 2016-10-14 2021-05-25 Heptares Therapeutics Limited Substituted cyclohexanes as muscarinic M1 receptor and/or M4 receptor agonists
US10259787B2 (en) 2016-10-14 2019-04-16 Heptares Therapeutics Limited Substituted cyclohexanes as muscarinic M1 receptor and/or M4 receptor agonists
US10759751B2 (en) 2016-10-14 2020-09-01 Heptares Therapeutics Limited Substituted spirocyclohexanes as muscarinic M1 receptor and/or M4 receptor agonists
US11834407B2 (en) 2016-10-14 2023-12-05 Heptares Therapeutics Limited Substituted cyclohexanes as muscarinic M1 receptor and/or M4 receptor agonists
CN109996792A (en) * 2016-10-14 2019-07-09 赫普泰雅治疗有限公司 With the active heterocyclic compound in treatment CNS disease and pain as the regulator of muscarinic M 1 and/or M4 receptor
US11926616B2 (en) 2018-03-08 2024-03-12 Incyte Corporation Aminopyrazine diol compounds as PI3K-γ inhibitors
US11773090B2 (en) 2018-06-22 2023-10-03 Heptares Therapeutics Limited Pharmaceutical compounds
US11046658B2 (en) 2018-07-02 2021-06-29 Incyte Corporation Aminopyrazine derivatives as PI3K-γ inhibitors
US11945801B2 (en) 2018-12-07 2024-04-02 Heptares Therapeutics Limited Bicyclic aza compounds as muscarinic M1 and/or M4 receptor agonists
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