WO2000009115A1 - Grp receptor ligands - Google Patents

Grp receptor ligands Download PDF

Info

Publication number
WO2000009115A1
WO2000009115A1 PCT/US1999/018008 US9918008W WO0009115A1 WO 2000009115 A1 WO2000009115 A1 WO 2000009115A1 US 9918008 W US9918008 W US 9918008W WO 0009115 A1 WO0009115 A1 WO 0009115A1
Authority
WO
WIPO (PCT)
Prior art keywords
methoxyphenyl
cyano
ynyl
guanidine
cyclopentyloxy
Prior art date
Application number
PCT/US1999/018008
Other languages
French (fr)
Inventor
Jia-Ning Xiang
Irennegbe Kelly Osifo
Joseph M. Karpinski
Siegfried B. Christensen, Iv
Original Assignee
Smithkline Beecham Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Smithkline Beecham Corporation filed Critical Smithkline Beecham Corporation
Priority to AU56716/99A priority Critical patent/AU5671699A/en
Publication of WO2000009115A1 publication Critical patent/WO2000009115A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
    • C07D271/107—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles with two aryl or substituted aryl radicals attached in positions 2 and 5
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/70—Compounds containing any of the groups, e.g. isoureas
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/28—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to cyano groups, e.g. cyanoguanidines, dicyandiamides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/44—Acylated amino or imino radicals
    • C07D277/46—Acylated amino or imino radicals by carboxylic acids, or sulfur or nitrogen analogues thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated

Definitions

  • the present invention relates to novel GRP receptor ligands, pharmaceutical compositions comprising these compounds and methods of using these compounds to treat chronic kidney disease and prostate cancer.
  • Chronic renal disease is the progressive loss of renal function due to irreversible and progressive glomerular, tubular or interstitial disease.
  • Current therapy includes treatment of underlying disease, control of hypertension, protein restriction and use of angiotensin converting enzyme (ACE) inhibitor, all of which have limited efficacy.
  • ACE angiotensin converting enzyme
  • captopril is the only approved drug for chronic renal failure and its effects are modest. Data from clinical trials on angiotensin II receptor antagonists indicate some degree of effect, however, it is unclear whether they will provide a dramatic improvement over the ACE inhibitors.
  • Carcinoma of the prostate is the most common malignant disease of men in the U.S., and the second most common cause of cancer-related death in men of all ages.
  • Current therapy for prostate cancer involves radical prostatectomy, radiation therapy, and either surgical (orchiectomy) or medical (leuprolide) castration. Surgical or medical castration have had variable success, and cytotoxic chemotherapy is generally not effective. Anti-androgenic therapy has significant side effects, and relapse can occur as a result of the development of hormone- insensitive cells.
  • GRP Gastrin releasing peptide
  • GRP receptors are present in the kidney, and that GRP stimulates mesangial cell proliferation and the expression of extracellular matrix.
  • a peptide receptor antagonist to GRP attenuates these effects.
  • GRP is recognized as an autocrine factor in some cancer cells (Dietrich,
  • GRP GRP stimulates lipid surfactant secretion by pneumocytes, indicating a role for GRP in development (Asokananthan and Cake, 1996).
  • GRP stimulates proliferation of lung (Cuttitta et al., 1985), breast (Nelson et al., 1991) and prostate (Bologna et al., 1989) carcinoma cells in vitro.
  • GRP neuromedin B
  • NMB neuromedin B
  • GRP and NMB are mammalian peptides which have homology to the amphibian peptide, bombesin. conserveed amino acids are indicated by solid vertical lines. Peptide sequence of GRP-like peptides
  • pGlu denotes pyroglutamate
  • NH2 denotes amidated carboxy-terminal residue
  • GRP GRP
  • NMB NMB
  • BRS3 mammalian bombesin receptor
  • BRS3-deficient mice generated by target disruption were obese, and developed diabetes and hypertension (Ohki-Hamazaki et al., 1997).
  • the natural ligand for this receptor is not known, the synthetic analogue of bombesin, [D- Phe6, ⁇ -Alal l,Phel3,Nlel4]Bn(6-14), has been identified as a high affinity agonist for this receptor (Mantey et al., 1997).
  • the natural ligand as well as the involvement of this receptor in renal and prostate diseases are yet to be identified.
  • GRP/NMB Potent nonselective
  • the present invention involves compounds represented by Formula (I) hereinbelow, pharmaceutical compositions comprising such compounds and methods of antagonizing the GRP receptor using these compounds.
  • the present invention further provides novel methods for the synthesis of the present compounds and novel intermediates involves therein.
  • R is selected from the group consisting of C2-C12 alkyl, heteroalkyl and arylalkyl, R is selected from the group consisting of hydrogen, OH, halogen, CN, NO2, CF3, CF 2 H, Ci-CiQ alkoxy and NR4R5;
  • R2 is aryl which may be unsubstituted or substituted by one or more substituents selected from the group consisting of C ⁇ -Cg alkyl, CF3, CF2H, halogen, CO2R6 > COR ⁇ , O(CH 2 ) n CO 2 R6, C ⁇ -C 6 alkoxy, CN, NO , OH, and NR4R5, aryl may be further substituted by a substituent selected from the group consisting of pyrrolyl, thiazolyl, oxadiazolyl, all of which may be unsubstituted or substituted by Rg, R3 is selected from the group consisting of hydrogen, C2-Cg aminoalkyl
  • R4 and R5 are independently selected from the group consisting of hydrogen, C2- Cj2 alkyl, heteroalkyl and arylalkyl;
  • Rg is selected from the group consisting of hydrogen, and Cj-Cg alkyl;
  • X is selected from the group consisting of NCN, O, S and NH;
  • m is an interger from 1 to 4; and
  • n is an integer from 1 to5.
  • aryl substituents of R are selected from the group consisting of C1-C2 alkoxy, C 1 -C4 alkyl, CF3, CI, and F.
  • Rj is hydogen or C1-C2 alkoxy.
  • R2 is phenyl
  • R3 is hydrogen
  • alkyl refers to an optionally substituted hydrocarbon group joined together by single carbon-carbon bonds.
  • the alkyl hydrocarbon group may be linear, branched or cyclic, saturated or unsaturated.
  • the group is saturated linear or cyclic.
  • aryl may be phenyl, naphthyl, pyridyl, indolyl, thienyl, pyrimidyl.
  • Preferred compounds useful in the present invention include: (R)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(3-methoxyphenyl)but- 3-ynyl]guanidine
  • More preferred compounds useful in the present invention include: (R)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(3-methoxyphenyl)but- 3-ynyl]guanidine
  • the most preferred compounds useful in the present invention include: (R)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(3-methoxyphenyl)but- 3-ynyl]guanidine
  • (+/-)-N-cyano-N'-[2-(3-decyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]guanidine may contain one or more asymmetric carbon atoms and may exist in racemic and optically active forms. All of these compounds and diastereomers are contemplated to be within the scope of the present invention.
  • the present compounds can also be formulated as pharmaceutically acceptable salts and complexes thereof.
  • Pharmaceutically acceptable salts are non- toxic salts in the amounts and concentrations at which they are administered.
  • Pharmaceutically acceptable salts include acid addition salts such as those containing sulfate, hydrochloride, fumarate, maleate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p- toluenesulfonate, cyclohexylsulfamate and quinate.
  • Pharmaceutically acceptable salts can be obtained from acids such as hydrochloric acid, maleic acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p- toluenesulfonic acid, cyclohexylsulfamic acid, fumaric acid, and quinic acid.
  • acids such as hydrochloric acid, maleic acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p- toluenesulfonic acid, cyclohexylsulfamic acid, fumaric acid, and quinic acid.
  • Pharmaceutically acceptable salts also include basic addition salts such as those containing benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, ammonium, alkylamine, and zinc, when acidic functional groups, such as carboxylic acid or phenol are present.
  • the present compounds are prepared using the following novel process: which can be prepared by a process comprising: treating a hydroxy aryl aldehyde of Formula (2)
  • a halide such as cyclopentyl bromide in the presence of a base such as potassium carbonate in a suitable solvent such as N,N-dimethylformamide at 90°C to afford a cyclopentyl aryl ether of Formula (3).
  • a compound of Formula (13) is treated with a base such as sodium hydride followed by addition of di-t-butyl dicarbonate to afford a compound of Formula (14).
  • an amine of Formula (8) can be reacted with diphenyl cyanocarbonimidate to form a compound of Formula (17).
  • a compound of Formula (I) or a pharmaceutically acceptable salt thereof for the treatment of humans and other mammals, it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
  • the present ligands can be administered by different routes including intravenous, intraperitoneal, subcutaneous, intramuscular, oral, topical, transdermal, or transmucosal administration.
  • oral administration is preferred.
  • the compounds can be formulated into conventional oral dosage forms such as capsules, tablets and liquid preparations such as syrups, elixirs and concentrated drops.
  • injection parenteral administration
  • the compounds of the invention are formulated in liquid solutions, preferably, in physiologically compatible buffers or solutions, such as saline solution, Hank's solution, or Ringer's solution.
  • the compounds may be formulated in solid form and redissolved or suspended immediately prior to use. Lyophilized forms can also be produced.
  • Systemic administration can also be by transmucosal or transdermal means.
  • penetrants appropriate to the barrier to be permeated are used in the formulation.
  • penetrants are generally known in the art, and include, for example, for transmucosal administration, bile salts and fusidic acid derivatives.
  • detergents may be used to facilitate permeation.
  • Transmucosal administration may be through nasal sprays, rectal suppositories, or vaginal suppositories.
  • the compounds of the invention can be formulated into ointments, salves, gels, or creams, as is generally known in the art.
  • the amounts of various compounds to be administered can be determined by standard procedures taking into account factors such as the compound IC50, EC50, the biological half-life of the compound, the age, size and weight of the patient, and the disease or disorder associated with the patient. The importance of these and other factors to be considered are known to those of ordinary skill in the art.
  • Amounts administered also depend on the routes of administration and the degree of oral bioavailability. For example, for compounds with low oral bioavailability, relatively higher doses will have to be administered.
  • the composition is in unit dosage form.
  • a tablet, or capsule may be administered, for nasal application, a metered aerosol dose may be administered, for transdermal application, a topical formulation or patch may be administered and for transmucosal delivery, a buccal patch may be administered. In each case, dosing is such that the patient may administer a single dose.
  • Each dosage unit for oral administration contains suitably from 0.01 to 500 mg/Kg, and preferably from 0.1 to 50 mg/Kg, of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, calculated as the free base.
  • the daily dosage for parenteral, nasal, oral inhalation, transmucosal or transdermal routes contains suitably from 0.01 mg to 100 mg/Kg, of a compound of Formula(I).
  • a topical formulation contains suitably 0.01 to 5.0% of a compound of Formula (I).
  • the active ingredient may be administered from 1 to 6 times per day. preferably once, sufficient to exhibit the desired activity, as is readily apparent to one skilled in the art.
  • treatment includes, but is not limited to prevention, retardation and prophylaxis of the disease.
  • compositions of Formula (I) and their pharmaceutically acceptable salts which are active when given orally can be formulated as syrups, tablets, capsules and lozenges.
  • a syrup formulation will generally consist of a suspension or solution of the compound or salt in a liquid carrier for example, ethanol, peanut oil. olive oil, glycerine or water with a flavoring or coloring agent.
  • a liquid carrier for example, ethanol, peanut oil. olive oil, glycerine or water with a flavoring or coloring agent.
  • any pharmaceutical carrier routinely used for preparing solid formulations may be used.
  • any routine encapsulation is suitable, for example using the aforementioned carriers in a hard gelatin capsule shell.
  • any pharmaceutical carrier routinely used for preparing dispersions or suspensions may be considered, for example aqueous gums, celluloses, silicates or oils, and are incorporated in a soft gelatin capsule shell.
  • Typical parenteral compositions consist of a solution or suspension of a compound or salt in a sterile aqueous or non-aqueous carrier optionally containing a parenterally acceptable oil, for example polyethylene glycol, polyvinylpyrrolidone, lecithin, arachis oil or sesame oil.
  • a parenterally acceptable oil for example polyethylene glycol, polyvinylpyrrolidone, lecithin, arachis oil or sesame oil.
  • compositions for inhalation are in the form of a solution, suspension or emulsion that may be administered as a dry powder or in the form of an aerosol using a conventional propellant such as dichlorodifluoromethane or trichlorofluoromethane.
  • a typical suppository formulation comprises a compound of Formula (I) or a pharmaceutically acceptable salt thereof which is active when administered in this way, with a binding and/or lubricating agent, for example polymeric glycols, gelatins, cocoa-butter or other low melting vegetable waxes or fats or their synthetic analogs.
  • Typical dermal and transdermal formulations comprise a conventional aqueous or non-aqueous vehicle, for example a cream, ointment, lotion or paste or are in the form of a medicated plaster, patch or membrane.
  • the composition is in unit dosage form, for example a tablet, capsule or metered aerosol dose, so that the patient may administer a single dose.
  • HEK 293 Human embryonic kidney (HEK 293) cells transfected with rhGRP receptor clone were washed two times with DPBS and scraped in the same buffer. After pelleting by centrifugation, the cells were frozen in liquid nitrogen and thawed on ice. The cell pellet was resuspended in 20 mM Tris HC1, pH 7.5, 5 mM EDTA, 0.5 mM phenylmethylsulfonyl fluoride, 5 ug/mL leupeptin, and 0.1 U/mL aprotinin, and the suspension was homogenized 20 times using a glass dounce homogenizer and centrifuged at 800 x g for 10 min to remove unbroken cells and nuclei. The supernatant was centrifuged at 40,000 x g for 30 min and the pellet was resuspended in 50 mM Tris HC1, pH 7.5 and 10 mM MgCl 2 . Binding
  • Binding of [125j]-bombesin to the membrane preparation was performed in 50 uL assay volume containing 50 mM Tris HC1, pH 7.5, 10 mM MgCl2, and 0.05% bovine serum albumin. Saturation binding experiments were performed with increasing concentrations of [125 ⁇ ]-bombesin and 1-2 ug of the membrane protein in the absence (total binding) and presence (non-specific binding) 1 uM unlabelled GRP. Incubations were carried out at 30 °C for 30 min and terminated by rapid vacuum filtration through GF/C filters, and the filters were counted using a gamma counter with 75% efficiency.
  • Inositol phosphates measurement HEK293 cells transfected with rhGRP receptors grown in T-150 flasks were labeled with [3j-[]-myoinositol (1 uCi/mL) for 24 hr in inositol-free DMEM without serum. Before the experiment, the radioactive medium was removed and the cells were washed once with DPBS++ (DPBS containing 5 mM glucose, 0.2% bovine serum albumin and 10 mM MgCl2) and incubated in 10-15 mL of DPBS ++ containing 10 mM LiCl for 10 min at 37 °C.
  • DPBS++ DPBS containing 5 mM glucose, 0.2% bovine serum albumin and 10 mM MgCl2
  • cells (2xl0 5 ) were pipetted into 12x75 glass tubes which contained indicated concentrations of antagonists or agonists or antagonists plus agonists and the reaction continued for 20 min. The reaction was stopped by adding 50 uL of 100% trichloroacetic acid. Samples were centrifuged, 0.4 mL of supernatant were withdrawn and neutralized with 10 uL of 1 M Tris base and 2 ml of 5 mM Na tetraborate, containing 0.5 mM EDTA. Total inositol phosphates were separated from free inositol using ion exchange chromatography.
  • Example 1 is illustrative of the present invention but not intended to be limiting in any way.
  • Example 1 is illustrative of the present invention but not intended to be limiting in any way.
  • Example 1(d) The compound from Example 1(d) (0.1 g, 0.3 mmol) was partitioned between 10% NaOH and EtOAc. The organic phase was dried (K2CO3) and was evaporated. The residue was dissolved in DMF (0.2 mL) and di-boc-thiourea (0.1 g, 0.36 mmol), prepared according the procedure described by Iwanowicz et.al., Synthetic Communications, 23(10), 1993, 1443-5, was added. 2-Chloro-l -methyl pyridinium iodide (0.09 g, 0.36 mmol) and triethylamine (0.09 mL, 0.66 mmol) were added and the mixture was stirred 18 h.
  • (+/-)-N-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]thiourea 3(a) (+/-)-N-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]-N'- benzoylthiourea
  • Example 5 To a solution of the compound from Example 4(a) (0.03 g, 0.05 mmol) in CH2CI2 (1 mL) was added TFA (0.5 mL). The mixture was stirred for 0.4 h and neutralized with solid NaHCO3. The mixture was diluted with CH2CI2 and was washed with 10% aqueous NaOH. The organic extract was dried (MgSO4) and was evaporated. The residue was purified by flash chromatography (silica gel, 2% MeOH/CH2Cl2) to provide the title compound as a yellow foam, 0.019 g (74%). MS(ES) m/e 493 [M+H]+.
  • Example 5 To a solution of the compound from Example 4(a) (0.03 g, 0.05 mmol) in CH2CI2 (1 mL) was added TFA (0.5 mL). The mixture was stirred for 0.4 h and neutralized with solid NaHCO3. The mixture was diluted with CH2CI2 and was washed with 10% aque
  • Example 44(b) The compound from Example 44(b) (12.5 g, 37.6 mmol) was dissolved in a mixture of MeOH (75 mL) and H2O (40 mL) and treated with 10% aqueous NaOH (90 mL). The reaction was stirred 1 h at room temperature, was diluted with H2O (200 mL) and was treated with activated carbon. The mixture was filtered and the filtrate was acidified, and extracted with ether. The extracts were washed with H2O, dried (MgSO4), and the solvent evaporated. The residue was crystallized from 1 : 1 he anes/CH2Cl2 (200 ml) providing the titled compound (6.5 g, 60%). mp 128- 131°C.
  • Me2CO 300 mL was cooled to 0°C and treated with Et3N (4.5 mL, 32 mmol) and then isobutyl chloroformate (4.2 mL, 32 mmol) dropwise.
  • Et3N 4.5 mL, 32 mmol
  • isobutyl chloroformate 4.2 mL, 32 mmol
  • a solution of NaN3 (4.2 g, 64 mmol) in H2O (25 mL) was added dropwise to the cold solution, and stirring continued for 0.25 h.
  • the reaction was diluted with H2O, and extracted with Et2 ⁇ .
  • (+/-)-4-Amino-3-(3-cyclopentyloxy-4-methoxyphenyl)- 1 -phenyl- 1 -butyne hydrochloride (10.0 g, 26.9 mmol), isopropanol (600 mL), triethylamine (4.0 g, 40.3 mmol) and diphenylcyanocarbonimidate (8.0 g, 33.6 mmol) were combined and stirred at 25 °C for 1 hour. The precipitate material was filtered and washed with isopropanol to afford 6.2 g (48%) of white crystalline: mp 159 -161°C.
  • (+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl] -O-(phenyl)isourea (6.2 g 12.93 mmol), isopropanol (400 mL) and anhydrous ammonia were combined in a sealed tube and stirred overnight at 25°C. Most of the isopropanol was evaporated in vacuo, water was added, the mixture was extracted with ethyl acetate (3 x 100 mL) and the combined extracts was concentrated to afford 5.0 g (96.0%) of white solid: mp 68-69°C; MS ES+ m/z 403.4 (MH+).
  • (+/-)-N-cyano-N'-[2-(3-hydroxy-4-methoxyphenyl)-4-phenylbut-3-ynyl] guanidine To a solution of (+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)- 4-phenylbut-3-ynyl]guanidine (3.6 g 8.94 mmol) in methylene chloride (160 mL) was cooled to -78 °C and borontribromide (4.5 g 17.9 mmol) was added slowlly and the resulting mixture was stirred for 15 min.
  • (+/-)-N-cyano-N'-[2-(3-hydroxy-4-methoxyphenyl)-4- phenylbut-3-ynyl]guanidine 70 mg 0.21 mmol
  • dimethylformamide 50 mL
  • 1-iododecane 62 mg 0.23 mmol
  • potassium carbonate 32 mg 0.23 mmol
  • Formulations for pharmaceutical use incorporating compounds of the present invention can be prepared in various forms and with numerous excipients. Examples of such formulations are given below:
  • a compound of Formula (I), (1 mg to 100 mg) is aerosolized from a metered dose inhaler to deliver the desired amount of drug per use.
  • Ingredients 1, 2, 3 and 4 are blended in a suitable mixer/blender. Sufficient water is added portion-wise to the blend with careful mixing after each addition until the mass is of a consistency to permit its conversion to wet granules.
  • the wet mass is converted to granules by passing it through an oscillating granulator using a No. 8 mesh (2.38 mm) screen.
  • the wet granules are then dried in an oven at 140°F (60°C) until dry.
  • the dry granules are lubricated with ingredient No. 5, and the lubricated granules are compressed on a suitable tablet press.
  • a pharmaceutical composition for parenteral administration is prepared by dissolving an appropriate amount of a compound of formula I in polyethylene glycol with heating. This solution is then diluted with water for injections (to 100 mL). The solution is then rendered sterile by filtration through a 0.22 micron membrane filter and sealed in sterile containers.

Abstract

Novel GRP receptor antagonists are provided. Methods of using the present compounds to antagonize GRP receptors are also provided. The present invention further involves the synthesis of the present compounds.

Description

GRP RECEPTOR LIGANDS
FIELD OF THE INVENTION
The present invention relates to novel GRP receptor ligands, pharmaceutical compositions comprising these compounds and methods of using these compounds to treat chronic kidney disease and prostate cancer.
BACKGROUND OF THE INVENTION
Chronic renal disease is the progressive loss of renal function due to irreversible and progressive glomerular, tubular or interstitial disease. Currently, over 200,000 people in the U.S. have end-stage renal disease with the majority on dialysis. There are an estimated 675,000 people with pre-dialysis chronic renal failure and a further 3 million at risk. Current therapy includes treatment of underlying disease, control of hypertension, protein restriction and use of angiotensin converting enzyme (ACE) inhibitor, all of which have limited efficacy. The ACE inhibitor, captopril, is the only approved drug for chronic renal failure and its effects are modest. Data from clinical trials on angiotensin II receptor antagonists indicate some degree of effect, however, it is unclear whether they will provide a dramatic improvement over the ACE inhibitors.
Carcinoma of the prostate is the most common malignant disease of men in the U.S., and the second most common cause of cancer-related death in men of all ages. Current therapy for prostate cancer involves radical prostatectomy, radiation therapy, and either surgical (orchiectomy) or medical (leuprolide) castration. Surgical or medical castration have had variable success, and cytotoxic chemotherapy is generally not effective. Anti-androgenic therapy has significant side effects, and relapse can occur as a result of the development of hormone- insensitive cells.
Gastrin releasing peptide ("GRP") is a 27 amino acid peptide which is normally produced in neuroendocrine cells of the gastrointestinal tract, lung and central nervous system. It acts by binding to a specific G-protein-coupled seven transmembrane spanning receptor and has diverse physiological effects, including stimulation of cell proliferation, hormone section, gastric motility, immune cell activation, and modulation of neurotransmission. Blockade of GRP for 4 weeks by systemic administration of a GRP antibody, however, failed to reveal any adverse behavioral, clinical or pathological effects. Although the role of GRP in pathophysiology has not been fully explored, there are indications that it may have a significant effect on cell growth. It has been established that GRP receptors are present in the kidney, and that GRP stimulates mesangial cell proliferation and the expression of extracellular matrix. In addition, a peptide receptor antagonist to GRP attenuates these effects. GRP is recognized as an autocrine factor in some cancer cells (Dietrich,
1994; Cuttitta et al., 1985). Furthermore, the effects of GRP on cell proliferation and differentiation have been explored in a number of organ systems. In the lung, GRP stimulates lipid surfactant secretion by pneumocytes, indicating a role for GRP in development (Asokananthan and Cake, 1996). In addition, GRP stimulates proliferation of lung (Cuttitta et al., 1985), breast (Nelson et al., 1991) and prostate (Bologna et al., 1989) carcinoma cells in vitro. Several lung and prostate cancer cells which proliferate in response to GRP in vitro are inhibited by treatment with GRP antibodies (Maruno and Said, 1993; Shimoda, 1992) and peptide receptor antagonists (Moody et al., 1995). In addition, the growth of prostate and breast cancer cell xenografts in a nude mouse host are inhibited by treatment of the mice with peptide antagonists (Pinski et al., 1993a,b; Shirahige et al., 1994) or GRP antibodies (Shimoda, 1992).
The amino acid structure of GRP, neuromedin B (NMB), and bombesin are depicted below. GRP and NMB are mammalian peptides which have homology to the amphibian peptide, bombesin. Conserved amino acids are indicated by solid vertical lines. Peptide sequence of GRP-like peptides
1 10 13 GRP(27)
Figure imgf000005_0001
bombesin pGlu-Gln-Arg-Leu-Gly-Asn-Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH2
I I I I I I I neuromedin B (NMB) Gly-Asn-Leu-Trp-Ala-Thr-Gly-His-Phe-Met-NH2
pGlu denotes pyroglutamate; NH2 denotes amidated carboxy-terminal residue
To date, two mammalian receptor subtypes have been cloned, and they are named GRP (BB2) and NMB (BB 1) receptors. While bombesin binds to both receptors with equal affinity, GRP receptor binds GRP with high affinity, whereas NMB receptor binds neuromedin B with high affinity.
Recently, a third type of mammalian bombesin receptor [BRS3 (BB3)] has been identified and cloned (Pathi et al., 1993; Gorbulev et al., 1992) which shares 51% and 47% amino acid sequence homology to the GRP and NMB receptor, respectively. While GRP and NMB demonstrate a widespread tissue distribution (Battey et al., 1991; Vigna et al., 1987), BRS3 is present in pregnant uterus (Gorbulev et al., 1992), a few brain regions (Gorbulev et al., 1992), human lung (Pathi et al., 1993), breast and epidermal cancer lines (Gorbulev et al., 1994). BRS3-deficient mice generated by target disruption were obese, and developed diabetes and hypertension (Ohki-Hamazaki et al., 1997). Although the natural ligand for this receptor is not known, the synthetic analogue of bombesin, [D- Phe6,β-Alal l,Phel3,Nlel4]Bn(6-14), has been identified as a high affinity agonist for this receptor (Mantey et al., 1997). In addition, this agonist stimulated inositol phosphate accumulation (EC50 = 25-30 nM) and tyrosine phosphorylation of pl25FAK (EC50 = 0.2-0.7 nM) in hBRS3-transfected BALB 3T3 cells and NCI- HI299 cell lines (Ryan et al., 1998). The natural ligand as well as the involvement of this receptor in renal and prostate diseases are yet to be identified.
It is believed that selective inhibition of GRP receptor in kidney and prostate will have therapeutic utility in chronic renal diseases and prostate as well as other cancels Potent nonselective (GRP/NMB) antagonists will have additional therapeutic utility in treating lung cancer
Based on the foregoing, there is a need to identify a potent nonpeptide GRP receptor antagonist for the treatment of chronic renal disease and prostate cancer
SUMMARY OF THE INVENTION
The present invention involves compounds represented by Formula (I) hereinbelow, pharmaceutical compositions comprising such compounds and methods of antagonizing the GRP receptor using these compounds The present invention further provides novel methods for the synthesis of the present compounds and novel intermediates involves therein.
DETAILED DESCRIPTION OF THE INVENTION The present invention provides compounds of Formula (I), hereinbelow:
Figure imgf000006_0001
Formula (I) or a pharmaceutically acceptable salt thereof, wherein:
R is selected from the group consisting of C2-C12 alkyl, heteroalkyl and arylalkyl, R is selected from the group consisting of hydrogen, OH, halogen, CN, NO2, CF3, CF2H, Ci-CiQ alkoxy and NR4R5; R2 is aryl which may be unsubstituted or substituted by one or more substituents selected from the group consisting of C^-Cg alkyl, CF3, CF2H, halogen, CO2R6> CORβ, O(CH2)nCO2R6, Cι -C6 alkoxy, CN, NO , OH, and NR4R5, aryl may be further substituted by a substituent selected from the group consisting of pyrrolyl, thiazolyl, oxadiazolyl, all of which may be unsubstituted or substituted by Rg, R3 is selected from the group consisting of hydrogen, C2-Cg aminoalkyl and C2-C hydroxy alkyl;
R4 and R5 are independently selected from the group consisting of hydrogen, C2- Cj2 alkyl, heteroalkyl and arylalkyl; Rg is selected from the group consisting of hydrogen, and Cj-Cg alkyl; X is selected from the group consisting of NCN, O, S and NH; m is an interger from 1 to 4; and n is an integer from 1 to5.
Preferably, aryl substituents of R are selected from the group consisting of C1-C2 alkoxy, C 1 -C4 alkyl, CF3, CI, and F.
Preferably, Rj is hydogen or C1-C2 alkoxy.
Preferably, R2 is phenyl.
Preferably, R3 is hydrogen.
Preferably, X is NCN. As used herein, "alkyl" refers to an optionally substituted hydrocarbon group joined together by single carbon-carbon bonds. The alkyl hydrocarbon group may be linear, branched or cyclic, saturated or unsaturated. Preferably, the group is saturated linear or cyclic.
As used herein, "aryl" may be phenyl, naphthyl, pyridyl, indolyl, thienyl, pyrimidyl.
Preferred compounds useful in the present invention include: (R)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(3-methoxyphenyl)but- 3-ynyl]guanidine
(+/-)-N-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]guanidine, (+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3- ynyljguanidine,
(+/-)-N-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]thiourea,
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]-N"-
(benzyl)guanidine, (+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]-N"-
(N.N-dimethylaminopropyl)guanidine,
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]-N"-
(piperidin- 1 -ylethyl)guanidine, (+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]-N"-
(3-hydroxypropyl)guanidine,
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]-N"-
(2-hydroxyethyl)guanidine,
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]-N"- (2-aminoethyl)guanidine,
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]-N"-
(3-aminopropyl)guanidine,
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]-N"-
(4-aminobutyl)guanidine, (+/-)-N-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]urea,
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(3-chlorophenyl)but-3- ynyl]guanidine,
(-l-/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(4-chlorophenyl)but-3- ynyl]guanidine, (+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-t-butylphenyl)but-3- ynyl]guanidine,
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(3- carboxymethylphenyl)but-3-ynyl]guanidine, (+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(4- methoxycarbonylmethoxyphenyl)but-3-ynyl]guanidine,
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-[3-(5-methyl- [ 1 ,3 ,4]thiadiazol-2-yl)phenyl]but-3-ynyl]guanidine, (+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(4- carboxymethoxyphenyl)but-3-ynyl]guanidine, (+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(4-fluoro-3- chlorophenyl)but-3-ynyl]guanidine,
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(4-chloro-3- fluorophenyl)but-3-ynyl]guanidine, (+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(3,4- difluorophenyl)but-3-ynyl]guanidine,
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(3-methoxyphenyl)but- 3-ynyl]guanidine,
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(4- trifluoromethoxyphenyl)but-3-ynyl]guanidine,
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-[3-(5-methyl- [l,3,4]oxadiazol-2-yl)phenyl]but-3-ynyl]guanidine,
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(3- trifluoromethylphenyl)but-3-ynyl]guanidine, (+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(4-N- pyrrolylphenyl)but-3-ynyl]guanidine,
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(naphthalen-2-yl)but-3- ynyl]guanidine,
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(4-methoxyphenyl)but- 3-ynyl]guanidine,
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(3-acetylphenyl)but-3- ynyl]guanidine,
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(4-methoxyphenyl)but-
3-ynyl]guanidine, (- /-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(3-carboxyphenyl)but-
3-ynyl]guanidine,
(+/-)-N-cyano-N'-[2-(3-hydroxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]guanidine,
(+/-)-N-cyano-N'-[2-(3-decyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]guanidine,
(+/-)-N-cyano-N'-[2-(3-ethyloxy-4-metoxyphenyl)-4-phenylbut-3-ynyl]guanidine, (+/-)-N-cyano-N'-[2-(3-butyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]guanidine, (+/-)-N-cyano-N'-[2-(3-(4-(ethylcarbonylmethyl)thiazolyl-2-aminocarbonyl- methyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]guanidine, (+/-)-N-cyano-N'-[2-(3-cyclobutylmethoxy-4-methoxyphenyl)-4-phenylbut-3- ynyl]guanidine, (+/-)-N-cyano-N'-[2-(3-(4-ethyoxycarbonylbutyloxy)-4-methoxyphenyl)-4- phenylbut-3-ynyl]guanidine,
(+/-)-N-cyano-N'-[2-(3-cyclohexylcarbonylmethyloxy)-4-methoxyphenyl-4- phenylbut-3-ynyl]guanidine,
(+/-)-N-cyano-N'-[2-(3-(cyclohexylethoxy)-4-methoxyphenyl)-4-phenylbut-3- ynyljguanidine, and
(+/-)-N-cyano-N'-[2-(3-(2-ethylhexyloxy)-4-methoxyphenyl)-4-phenylbut-3- ynyl]guanidine.
More preferred compounds useful in the present invention include: (R)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(3-methoxyphenyl)but- 3-ynyl]guanidine
(+/-)-N-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]guanidine,
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3- ynyl]guanidine,
(+/-)-N-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]thiourea, (+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]-N"-
(2-hydroxyethyl)guanidine,
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]-N"-
(2-aminoethyl)guanidine,
(+/-)-N-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]urea, (+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(3-chlorophenyl)but-3- ynyljguanidine,
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(4-chlorophenyl)but-3- ynyljguanidine,
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(4- methoxycarbonylmethoxyphenyl)but-3-ynyl]guanidine, (+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(4-fluoro-3- chlorophenyl)but-3-ynyl]guanidine,
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(4-chloro-3- fluorophenyl)but-3-ynyl]guanidine, (+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(3,4- difluorophenyl)but-3-ynyl]guanidine,
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(3-methoxyphenyl)but- 3-ynyl]guanidine,
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(4- trifluoromethoxyphenyl)but-3-ynyl]guanidine,
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(3- trifluoromethylphenyl)but-3-ynyl]guanidine,
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(4-methoxyphenyl)but- 3-ynyl]guanidine, (+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(3-acetylphenyl)but-3- ynyl]guanidine,
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(4-methoxyphenyl)but- 3-ynyl]guanidine,
(+/-)-N-cyano-N'-[2-(3-hydroxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]guanidine, (+/-)-N-cyano-N'-[2-(3-decyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]guanidine, (+/-)-N-cyano-N'-[2-(3-ethyloxy-4-metoxyphenyl)-4-phenylbut-3-ynyl]guanidine, (+/-)-N-cyano-N'-[2-(3-butyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]guanidine, (+/-)-N-cyano-N'-[2-(3-(4-(ethylcarbonylmethyl) thiazolyl-2-aminocarbonyl- methyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]guanidine, (+/-)-N-cyano-N'-[2-(3-cyclobutylmethoxy-4-methoxyphenyl)-4-phenylbut-3- ynyl]guanidine,
(+/-)-N-cyano-N'-[2-(3-cyclohexylcarbonylmethyloxy)-4-methoxyphenyl-4- phenylbut-3-ynyl]guanidine,
(+/-)-N-cyano-N'-[2-(3-(cyclohexylethoxy)-4-methoxyphenyl)-4-phenylbut-3- ynyljguanidine, and (+/-)-N-cyano-N'-[2-(3-(2-ethylhexyloxy)-4-methoxyphenyl)-4-phenylbut-3- ynyljguanidine.
The most preferred compounds useful in the present invention include: (R)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(3-methoxyphenyl)but- 3-ynyl]guanidine
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(3-chlorophenyl)but-3- ynyl]guanidine,
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(4-chlorophenyl)but-3- ynyl]guanidine, (+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(4-fluoro-3- chlorophenyl)but-3-ynyl]guanidine,
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(4-chloro-3- fluorophenyl)but-3-ynyl]guanidine,
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(3,4- difluorophenyl)but-3-ynyl]guanidine,
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(3-methoxyphenyl)but-
3-ynyl]guanidine,
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(4- trifluoromethoxyphenyl)but-3-ynyl]guanidine, (+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(3- trifluorornethylphenyl)but-3-ynyl]guanidine, and
(+/-)-N-cyano-N'-[2-(3-decyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]guanidine. The compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic and optically active forms. All of these compounds and diastereomers are contemplated to be within the scope of the present invention.
The present compounds can also be formulated as pharmaceutically acceptable salts and complexes thereof. Pharmaceutically acceptable salts are non- toxic salts in the amounts and concentrations at which they are administered. Pharmaceutically acceptable salts include acid addition salts such as those containing sulfate, hydrochloride, fumarate, maleate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p- toluenesulfonate, cyclohexylsulfamate and quinate. Pharmaceutically acceptable salts can be obtained from acids such as hydrochloric acid, maleic acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p- toluenesulfonic acid, cyclohexylsulfamic acid, fumaric acid, and quinic acid.
Pharmaceutically acceptable salts also include basic addition salts such as those containing benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, ammonium, alkylamine, and zinc, when acidic functional groups, such as carboxylic acid or phenol are present.
The present compounds are prepared using the following novel process: which can be prepared by a process comprising: treating a hydroxy aryl aldehyde of Formula (2)
Figure imgf000013_0001
with a halide such as cyclopentyl bromide in the presence of a base such as potassium carbonate in a suitable solvent such as N,N-dimethylformamide at 90°C to afford a cyclopentyl aryl ether of Formula (3).
Figure imgf000014_0001
Knoevenagel reaction of an aryl aldehyde of Formula (3) with Meldrum's acid (4)
Figure imgf000014_0002
in the presence of an ammonium salt such as piperidinium acetate in an appropriate solvent such as refluxing benzene provides a Meldrum's acid adduct of Formula (5).
Figure imgf000014_0003
Addition of trimethylsilylacetylide or phenylacetylide resulting from treatment of trimethylsilylacetylene or phenylacetylene with n-BuLi in THF to a Meldrum's acid adduct of Formula (5) affords a 1,4-addition product of Formula (6).
Figure imgf000015_0001
Hydrolysis of the isopropylidine group of a compound of Formula (6) with, e.g., aqueous hydrochloric acid in dioxane followed by decarboxylation in a suitable solvent such as N,N-dimethylacetamide under heat (when R = trimethylsilyl, the resulting compound is further treated with aqueous base such as aqueous NaOH in methanol) provides a mono-acid of Formula (7).
Figure imgf000015_0002
Upon treatment of an acid chloride derived from an acid of Formula (7) with sodium azide in a solvent such as toluene, the resulting intermediate is then treated with aqueous hydrochloride in dioxane to afford a Curtius rearrangement product of Formula (8).
Figure imgf000015_0003
Reaction of an amine of Formula (8) with dimethylcyanodithioiminocarbonate in a suitable solvent such as pyridine under heat provides a compound of Formula (9).
Figure imgf000016_0001
Alternatively, reaction of an amine of Formula (8) with an isocyanate (10) or isothiocyanate (1 1)
R-NC0 ( 10)
or
Figure imgf000016_0002
provides an urea or thiourea of Formula (I).
Alternatively, treatment of an amine of Formula (8) with di-Boc-thiourea in a solvent such as N,N-dimethylformamide in presence of 2-chloro-l- methylpyridinium iodide and an amine such as triethylamine gave a protected guanidine of Formula (12)
Figure imgf000016_0003
Treatment of a compound of Formula (12) with trifluoroacetic acid in a solvent such as dichloromethane affords a guanidine of Formula (I).
Treatment of a compound of Formula (9) with cyanodithioiminocarbonate provides a compound of Formula (13).
Figure imgf000017_0001
A compound of Formula (13) is treated with a base such as sodium hydride followed by addition of di-t-butyl dicarbonate to afford a compound of Formula (14).
Figure imgf000017_0002
Reaction of a compound of Formula (14) with ammonia or an amine of Formula (15)
R~ NH2 ( 15)
followed by deprotection with an acid such as trifluoroacetic acid gave a cyanoguanidine of Formula (16).
Figure imgf000018_0001
Alternatively, an amine of Formula (8) can be reacted with diphenyl cyanocarbonimidate to form a compound of Formula (17).
Figure imgf000018_0002
Treatment of a compound of Formula (17) with ammonia or an amine (15) in a suitable solvent such as isopropyl alcohol also provides a compound of Formula (16).
Palladium-catalyzed coupling of a compound of Formula (14), where R2 = H, with aryl iodide in the presence of copper iodide and a suitable base such as triethylamine in a solvent such as N,N-dimethylformamide affords a compound of Formula (I), wherein R represents cyclopentyl, R2 represents aryl, and X represents NCN.
Treatment of a compound of Formula (18) with a Lewis acid such as tribromoborane in a suitable solvent such as dichloromethane at low temperature affords a phenol of Formula (19).
Figure imgf000019_0001
Alkylation of a phenol of Formula ( 16) with a halide of Formula (20)
R— X (20)
in presence of a base such as potassium carbonate in a suitable solvent such as N,N- dimethylformamide provides a compound of Formula (I), wherein R3 represents H. Alternatively, Mitsunobu reaction of a phenol of Formula (19) with an alcohol of Formula (21)
R— OH (21)
in presence of activating agents such as tri-n-butylphosphine and diethyl azodicarboxylate in an appropriate solvent such as tetrahydrofuran affords a compound of Formula (I).
Esterification of an acid of Formula (7) in methanol in presence of catalytic amount of concentrated hydrochloric acid afforded a methyl ester of Formula (22).
Figure imgf000019_0002
O
O,
O
R;'
(22) Resolution of a methyl ester of Formula (22) with chiral HPLC column provided two enantiomers of Formula (23) and Formula (24), respectively.
R~
Figure imgf000020_0001
Rl (23) Rl (24)
Basic hydrolysis of a methyl ester of Formula (23) or Formula (24) followed by acidic work up afforded the corresponding enantiomer pure acid of Formula (25) or Formula (26).
R2 R2
Figure imgf000020_0002
Conversion of an acid of Formula (25) or Formula (26) to a compound of Formula (I) can be achieved following the procedure described above.
With appropriate manipulation and protection of any chemical functionality, synthesis of the remaining compounds of Formula (I) is accomplished by methods analogous to those above and those described in the Experimental section hereinafter. Novel intermediates represented by the present invention include:
Figure imgf000021_0001
In order to use a compound of Formula (I) or a pharmaceutically acceptable salt thereof for the treatment of humans and other mammals, it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
The present ligands can be administered by different routes including intravenous, intraperitoneal, subcutaneous, intramuscular, oral, topical, transdermal, or transmucosal administration. For systemic administration, oral administration is preferred. For oral administration, for example, the compounds can be formulated into conventional oral dosage forms such as capsules, tablets and liquid preparations such as syrups, elixirs and concentrated drops.
Alternatively, injection (parenteral administration) may be used, e.g., intramuscular, intravenous, intraperitoneal, and subcutaneous. For injection, the compounds of the invention are formulated in liquid solutions, preferably, in physiologically compatible buffers or solutions, such as saline solution, Hank's solution, or Ringer's solution. In addition, the compounds may be formulated in solid form and redissolved or suspended immediately prior to use. Lyophilized forms can also be produced.
Systemic administration can also be by transmucosal or transdermal means.
For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, bile salts and fusidic acid derivatives. In addition, detergents may be used to facilitate permeation.
Transmucosal administration, for example, may be through nasal sprays, rectal suppositories, or vaginal suppositories. For topical administration, the compounds of the invention can be formulated into ointments, salves, gels, or creams, as is generally known in the art.
The amounts of various compounds to be administered can be determined by standard procedures taking into account factors such as the compound IC50, EC50, the biological half-life of the compound, the age, size and weight of the patient, and the disease or disorder associated with the patient. The importance of these and other factors to be considered are known to those of ordinary skill in the art.
Amounts administered also depend on the routes of administration and the degree of oral bioavailability. For example, for compounds with low oral bioavailability, relatively higher doses will have to be administered. Preferably the composition is in unit dosage form. For oral application, for example, a tablet, or capsule may be administered, for nasal application, a metered aerosol dose may be administered, for transdermal application, a topical formulation or patch may be administered and for transmucosal delivery, a buccal patch may be administered. In each case, dosing is such that the patient may administer a single dose.
Each dosage unit for oral administration contains suitably from 0.01 to 500 mg/Kg, and preferably from 0.1 to 50 mg/Kg, of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, calculated as the free base. The daily dosage for parenteral, nasal, oral inhalation, transmucosal or transdermal routes contains suitably from 0.01 mg to 100 mg/Kg, of a compound of Formula(I). A topical formulation contains suitably 0.01 to 5.0% of a compound of Formula (I). The active ingredient may be administered from 1 to 6 times per day. preferably once, sufficient to exhibit the desired activity, as is readily apparent to one skilled in the art.
As used herein, "treatment" of a disease includes, but is not limited to prevention, retardation and prophylaxis of the disease.
As used herein, "diseases" treatable using the present compounds include, but are not limited to: prostate cancer, small-cell and non-small-cell lung carcinomas, breast cancer, gastric-carcinoma, glioblastoma, colon cancer, thyroid cancer, and pituitary tumor. Composition of Formula (I) and their pharmaceutically acceptable salts which are active when given orally can be formulated as syrups, tablets, capsules and lozenges. A syrup formulation will generally consist of a suspension or solution of the compound or salt in a liquid carrier for example, ethanol, peanut oil. olive oil, glycerine or water with a flavoring or coloring agent. Where the composition is in the form of a tablet, any pharmaceutical carrier routinely used for preparing solid formulations may be used. Examples of such carriers include magnesium stearate, terra alba, talc, gelatin, acacia, stearic acid, starch, lactose and sucrose. Where the composition is in the form of a capsule, any routine encapsulation is suitable, for example using the aforementioned carriers in a hard gelatin capsule shell. Where the composition is in the form of a soft gelatin shell capsule any pharmaceutical carrier routinely used for preparing dispersions or suspensions may be considered, for example aqueous gums, celluloses, silicates or oils, and are incorporated in a soft gelatin capsule shell.
Typical parenteral compositions consist of a solution or suspension of a compound or salt in a sterile aqueous or non-aqueous carrier optionally containing a parenterally acceptable oil, for example polyethylene glycol, polyvinylpyrrolidone, lecithin, arachis oil or sesame oil.
Typical compositions for inhalation are in the form of a solution, suspension or emulsion that may be administered as a dry powder or in the form of an aerosol using a conventional propellant such as dichlorodifluoromethane or trichlorofluoromethane. A typical suppository formulation comprises a compound of Formula (I) or a pharmaceutically acceptable salt thereof which is active when administered in this way, with a binding and/or lubricating agent, for example polymeric glycols, gelatins, cocoa-butter or other low melting vegetable waxes or fats or their synthetic analogs.
Typical dermal and transdermal formulations comprise a conventional aqueous or non-aqueous vehicle, for example a cream, ointment, lotion or paste or are in the form of a medicated plaster, patch or membrane.
Preferably the composition is in unit dosage form, for example a tablet, capsule or metered aerosol dose, so that the patient may administer a single dose.
No unacceptable toxological effects are expected when compounds of the present invention are administered in accordance with the present invention.
The biological activity of the compounds of Formula (I) are demonstrated by the tests indicated hereinbelow. Membrane preparation:
Human embryonic kidney (HEK 293) cells transfected with rhGRP receptor clone were washed two times with DPBS and scraped in the same buffer. After pelleting by centrifugation, the cells were frozen in liquid nitrogen and thawed on ice. The cell pellet was resuspended in 20 mM Tris HC1, pH 7.5, 5 mM EDTA, 0.5 mM phenylmethylsulfonyl fluoride, 5 ug/mL leupeptin, and 0.1 U/mL aprotinin, and the suspension was homogenized 20 times using a glass dounce homogenizer and centrifuged at 800 x g for 10 min to remove unbroken cells and nuclei. The supernatant was centrifuged at 40,000 x g for 30 min and the pellet was resuspended in 50 mM Tris HC1, pH 7.5 and 10 mM MgCl2. Binding studies:
Binding of [125j]-bombesin to the membrane preparation was performed in 50 uL assay volume containing 50 mM Tris HC1, pH 7.5, 10 mM MgCl2, and 0.05% bovine serum albumin. Saturation binding experiments were performed with increasing concentrations of [125τ]-bombesin and 1-2 ug of the membrane protein in the absence (total binding) and presence (non-specific binding) 1 uM unlabelled GRP. Incubations were carried out at 30 °C for 30 min and terminated by rapid vacuum filtration through GF/C filters, and the filters were counted using a gamma counter with 75% efficiency. Inositol phosphates measurement: HEK293 cells transfected with rhGRP receptors grown in T-150 flasks were labeled with [3j-[]-myoinositol (1 uCi/mL) for 24 hr in inositol-free DMEM without serum. Before the experiment, the radioactive medium was removed and the cells were washed once with DPBS++ (DPBS containing 5 mM glucose, 0.2% bovine serum albumin and 10 mM MgCl2) and incubated in 10-15 mL of DPBS++ containing 10 mM LiCl for 10 min at 37 °C. At the end of incubation, cells (2xl05) were pipetted into 12x75 glass tubes which contained indicated concentrations of antagonists or agonists or antagonists plus agonists and the reaction continued for 20 min. The reaction was stopped by adding 50 uL of 100% trichloroacetic acid. Samples were centrifuged, 0.4 mL of supernatant were withdrawn and neutralized with 10 uL of 1 M Tris base and 2 ml of 5 mM Na tetraborate, containing 0.5 mM EDTA. Total inositol phosphates were separated from free inositol using ion exchange chromatography.
The following examples are illustrative of the present invention but not intended to be limiting in any way. Example 1
(+/-)-N-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]guanidine 1 (a) 2,2-dimethyl-5-(3-cyclopentyloxy-4-methoxybenzylidenyl)- 1 ,3-dioxane-4,6- dione
A mixture of 3-cyclopentyloxy-4-methoxybenzaldehyde (12.8 g, 0.058 mol), 2,2-dimethyl-l,3-dioxane-4,6-dione (8.3 g, 0.058 mol), piperidine (1 mL) and HO Ac (0.5 mL) in benzene (150 mL) was refluxed for 2h, using a Dean-Stark trap to remove the water that was formed. Hexane (75 mL) was added, the mixture was cooled, and the crystalline product filtered and dried (18.7 g, 93%). mp 1 16-119°C. 1(b) (+/-)-2,2-dimethyl-5-( [ l-(3-cyclopentyloxy-4-methoxyphenyl)-3-phenyl]prop- 2-yne)-l,3-dioxane-4,6-dione A solution of phenylacetylene (2.66 g, 0.026 mol) in THF (50mL) at 0°C was treated slowly with a solution of n-BuLi (0.026 mol) in hexane (16.4 mL). After the addition, the reaction was stirred for 15 min at 23°C, and then cooled to - 78°C. A solution of the compound of Example 1 (a) (8.0 g, 0.022 mol) in THF (125 mL) was added over 5 min, and stirring was continued at -78°C for 30 min. The reaction was quenched with water (500 mL) and 3N HCl (20 mL), and extracted with ether. The extracts were washed with water, dried (CaSO4), and the solvent evaporated. The residue was recrystallized from a mixture of CH2CI2 and cyclohexane, and gave the titled compound (8.31 g, 84%). mp 108-1 14°C. 1(c) (+/-)-3-(3-cyclopentyloxy-4-methoxyphenyl)-3-phenylethynylpropionic acid A solution of the compound of Example 1 (b) (4.2 g, 9.4 mmol) in dioxane (70 mL), water ( 3mL) and 3N HCl (5 mL) was heated at 100°C for 90 min. The reaction was cooled, diluted with water (200 mL), and extracted with ether. The extracts were washed with water, dried (CaSO4), and the solvent evaporated. The residue was dissolved in dimethylacetamide (10 mL), and the solution was heated at 135°C for 30 min. The reaction was cooled, diluted with water (200 mL) and extracted with ether. The extracts were washed well with water, dried (CaSO4), and the solvent evaporated. The residue was recrystallized from a mixture of CH2CI2 and hexane, and gave the titled compound (2.8 g, 82%). mp 86-88°C. 1 (d) (+/-)-4-amino-3-(3-cyclopentyloxy-4-methoxyphenyl)- 1 -phenyl- 1 -butyne hydrochloride
A solution of the compound from Example 1(c) (1.2 g, 3.3 mmol) in Me2CO (40 mL) was cooled to OoC and treated with Et3N (0.5 mL, 3.3mmol) and then ethyl chloroformate (0.35 mL, 3,63 mmol) dropwise. A solution of NaN3 (0.47 g, 7.25 mmol) in H2O (2 mL) was added dropwise to the cold solution, and stirring continued for 0.25 h. The reaction was diluted with H2O, and extracted with Et2θ. The organic phase was washed with water, was dried (Na2SO4), and was filtered. The ether extract was slowly added to refluxing toluene (100 mL), and the solution was heated at 1 lOoC for 0.5 h, and was evaporated. The residue was dissolved in a mixture of dioxane (5 mL), water (3 mL), and cone. HCl (3 mL), was refluxed for 0.2 h, was cooled and the solid was filtered. Recrystallization from a mixture of isopropanol and ether gave the titled compound as the HCl salt, 1.03 g (84%). mp 212-215"C.
1(f) (+/-)-N-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]-N',N"-bis- (t-butoxycarbonyl)guanidine
The compound from Example 1(d) (0.1 g, 0.3 mmol) was partitioned between 10% NaOH and EtOAc. The organic phase was dried (K2CO3) and was evaporated. The residue was dissolved in DMF (0.2 mL) and di-boc-thiourea (0.1 g, 0.36 mmol), prepared according the procedure described by Iwanowicz et.al., Synthetic Communications, 23(10), 1993, 1443-5, was added. 2-Chloro-l -methyl pyridinium iodide (0.09 g, 0.36 mmol) and triethylamine (0.09 mL, 0.66 mmol) were added and the mixture was stirred 18 h. The reaction mixture was diluted with water and was extracted with CH2CI2. The organic extract was dried (Na2SO4) and was evaporated. Purification by flash chromatography (silica gel, 0.15 EtOAc/hexanes) provided the title compound as a white solid, 0.13 g (75%). mp 63- 66°C. 1(g) (+/-)-N-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]guanidine
A solution of the compound from Example 1(f) (0.12 g, 0.2 mmol) in CH2CI2 (4 mL) was treated with TFA (4 mL). The solution was stirred for 4 h and solid NaHCO3 was added to pH 7. The mixture was diluted with water, was extracted with CH2CI2. The organic extract was dried (Na2SO4) and was evaporated to provide the title compound as a brown solid, 0.04 g (50%). Anal. (C23H27N3O2.O.9TFA) calcd: C, 62.04; H, 5.86; N, 8.75 found: C, 62.11; H, 6.18; N, 8.39. Example 2
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3- ynyl]guanidine
2(a) (+/-)-N-cyano-N'-[2-(3-cycloρentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]- S-methylisothiourea A mixture of the compound from Example 1(d) (0.22 g, O.όmmol) and cyanodithioiminocarbonate (0.18 g, 1.3 mmol) were placed in pyridine (2.5 mL) and refluxed for 4 h under an argon atmosphere. The mixture was evaporated, was partitioned between 10% aqueous HCl and CH2C12- The organic layer was separated and was dried (Na2SO4) and was evaporated. The residue was purified by flash chromatography (silica gel, 50% hexanes/EtOAc) to provide the title compound as a white solid, 0.18 g (69%). mp 122-123oC.
2(b) (+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]- N'-(t-butoxycarbonyl)-S-methylisothiourea
A 60% NaH/mineral oil suspension (0.03 g, 0.6 mmol) was washed with hexanes under an argon atmosphere and was suspended in THF (1 mL). A solution of the compound from Example 4(a) (0.18 g, 0.4 mmol) in THF (3 mL) was added dropwise. The mixture was stirred at RT for 1 h and di-t-butyl dicarbonate (0.18 g, 0.8 mmol) was added to the mixture. After 18 h at room temperature, the mixture was diluted with water and was extracted with CH2CI2. The organic extract was dried (Na2SO4) and was evaporated. The residue was purified by flash chromatography (silica gel, 20% EtOAc/hexanes) to give the title compound as a white solid, 0.2 g (95%). mp 49-5 loC.
2(c) (+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]- N '-(t-butoxycarbonyl)guanidine
To the compound from Example 2(b) (0.2 g, 0.38 mmol) at -40oC was condensed ammonia (5 mL). The solution was stirred for 8 h and the ammonia was evaporated at room temperature. The residue was diluted with ether and filtered to provide the title compound as a white solid, 0.14 g (71%). mp 150-151oC. 2(d) (+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3- ynyljguanidine To a solution of the compound from Example from 2(c) (0.13 g, 0.26 mmol) in CH2CI2 (2 ml) at OoC under an argon atmosphere was added TFA (2 mL). The mixture was stirred for 0.4 h and neutralized with solid NaHCO3. The mixture was diluted with CH2CI2 and was washed with 10% aqueous NaOH. The organic extract was dried (Na2SO4) and was evaporated. The residue was purified by flash chromatography (silica gel, 3% MeOH/CH2Cl2) to provide the title compound as a white solid, 0.06 g (57%). mp 87-89oC. Example 3
(+/-)-N-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]thiourea 3(a) (+/-)-N-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]-N'- benzoylthiourea To a suspension of the compound from Example 1(d) (0.5 g, 1.3 mmol) in
CHCI3 (10 mL) at OoC was added triethylamine (0.14 g, 1.4 mmol) and benzoylisothiocyanate (0.2 g, 1.3 mmol). The mixture was stirred at room temperature for 0.5 h, was diluted with water and was extracted with CHCI3. The organic extract was dried (MgSO4) and was evaporated. The residue was purified by flash chromatography (silica gel, 20% EtOAc/hexanes) and triturated
(EtOAc/hexanes) to provide 0.5 g (75%) of the title compound as a white solid: mp 118-119 °C.
3(b) (+/-)-N-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]thiourea To a solution of the compound from Example 3(a) (0.25 g, 0.5 mmol) in 4: 1 MeOH/H2θ (5 mL) was added K2CO3 (0.19 g, 1.5 mmol) and the mixture was stirred for 5 h. The mixture was partitioned between water and 10% MeOH/CH2Cl2- The organic extract was dried (Na2SO4) and was evaporated. The residue was purified by flash chromatography (silica gel, 50% EtOAc/hexanes) to provide the title compound as yellow solid, (0.14 g, 68%). mp 69-7 loC. Example 4
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]-N"-
(benzyl)guanidine
4(a) (+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]-
N'-(t-butoxycarbonyl)-N"-(benzyl)guanidine A mixture of the compound from Example 2(b) (0.05 g, 0.09 mmol) and benzyl amine (0.01 g, 0.09 mmol) was stirred in DMF (0.2 mL) for 4 days. The mixture diluted with water and extracted with CH2CI2. The organic extract was dried (MgSO4) and was evaporated. The residue was purified by flash chromatography (silica gel, 20% EtOAc/hexanes) to provide the title compound as a white gum, (0.034 g, 64%). MS(ES) m e 593 [M+H]+. 4(b) (+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]- N"-(benzyl)guanidine
To a solution of the compound from Example 4(a) (0.03 g, 0.05 mmol) in CH2CI2 (1 mL) was added TFA (0.5 mL). The mixture was stirred for 0.4 h and neutralized with solid NaHCO3. The mixture was diluted with CH2CI2 and was washed with 10% aqueous NaOH. The organic extract was dried (MgSO4) and was evaporated. The residue was purified by flash chromatography (silica gel, 2% MeOH/CH2Cl2) to provide the title compound as a yellow foam, 0.019 g (74%). MS(ES) m/e 493 [M+H]+. Example 5
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]-N"- (4-methoxyphenyl)guanidine
Following the procedures of Example 4 except substituting 4-methoxyaniline for benzylamine, the titled compound was prepared (70%). MS(ES) m/e 509 [M+H]+.
Example 6
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]-N"- (3-pyridylmethyl)guanidine
Following the procedures of Example 4 except substituting 3- aminomethylpyridine for benzylamine, the titled compound was prepared (34%). MS(ES) m/e 494 [M+H]+.
Example 7
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]- N"[2-(indol-3-yl)ethyl]guanidine Following the procedures of Example 4 except substituting tryptamine for benzylamine, the titled compound was prepared (64%). MS(ES) m/e 546 [M+H]+.
Example 8
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]-N"- (morpholin-4-yl)guanidine Following the procedures of Example 4 except substituting 4- aminomorpholine for benzylamine, the titled compound was prepared (72%). MS(ES) m/e 488 [M+H]+.
Example 9 (+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]-N"- ( 1 -benzylpiperidin-4-yl)guanidine
Following the procedures of Example 4 except substituting 1 -benzyl-4- aminopiperidine for benzylamine, the titled compound was prepared (71%). MS(ES) m e 576 [M+H]+. Example 10
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyI)-4-phenylbut-3-ynyl]- N",N"-(ethylether)guanidine
Following the procedures of Example 4 except substituting morpholine for benzylamine, the titled compound was prepared (35%). MS(ES) m/e 473 [M+HJ+. Example 11
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]-N"- (4-pyridylmethyl)guanidine
Following the procedures of Example 4 except substituting 4- aminomethylpyridine for benzylamine, the titled compound was prepared (56%). MS(ES) m/e 494 [M+H]+.
Example 12 (+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]-N"- (imidazol- 1 -ylpropyl)guanidine
Following the procedures of Example 6 except substituting 1- aminopropylimidazole for benzylamine, the titled compound was prepared (74%). MS(ES) m/e 511 [M+H]+.
Example 13
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]-N"- (thiophen-2-ylethyl)guanidine Following the procedures of Example 6 except substituting 2- aminoethylthiophene for benzylamine, the titled compound was prepared (61%). MS(ES) m/e 513 [M+H]+.
Example 14 (+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]-N"- (cyclohexyl)guanidine
Following the procedures of Example 6 except substituting cyclohexylamine for benzylamine, the titled compound was prepared (48%). MS(ES) m/e 485 [M+H]+. Example 15
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]-N"- (2-methoxyethyl)guanidine
Following the procedures of Example 6 except substituting 2- methoxyethylamine for benzylamine, the titled compound was prepared (32%). MS(ES) m/e 461 [M+HJ+.
Example 16
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]-N"- (2-pyridylmethyl)guanidine
Following the procedures of Example 6 except substituting 2- aminomethylpyridine for benzylamine, the titled compound was prepared (70%). MS(ES) m/e 494 [M+H]+.
Example 17
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]-N"- (4-methoxyphenylmethyl)guanidine Following the procedures of Example 6 except substituting 4- methoxybenzylamine for benzylamine, the titled compound was prepared (68%). MS(ES) m/e 523 [M+H]+.
Example 18
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]-N"- (morpholin-4-ylethyl)guanidine Following the procedures of Example 6 except substituting 4- aminoethylmorpholine for benzylamine, the titled compound was prepared (86%). MS(ES) m/e 516 [M+H]+.
Example 19 (+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]-N"- (4-t-butylphenyl)guanidine
Following the procedures of Example 6 except substituting 4-t-butylaniline for benzylamine, the titled compound was prepared (54%). MS(ES) m/e 535 [M+H]+. Example 20
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]-N"- (N,N-dimethylaminopropyl)guanidine
Following the procedures of Example 6 except substituting N,N- dimethylpropylenediamine for benzylamine, the titled compound was prepared (68%). MS(ES) m/e 488 [M+H]+.
Example 21
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]-N"- (phenethyl)guanidine
Following the procedures of Example 6 except substituting phenethylamine for benzylamine, the titled compound was prepared (80%). MS(ES) m/e 507 [M+H]+.
Example 22
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]-N"- (acetophenon-2-yl)guanidine Following the procedures of Example 6 except substituting 2- aminoacetophenone for benzylamine, the titled compound was prepared (26%). MS(ES) m/e 521 [M+H]+.
Example 23
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]-N"- (piperidin- 1 -ylethyl)guanidine Following the procedures of Example 6 except substituting 1- aminoethylpiperidine for benzylamine, the titled compound was prepared (76%). MS(ES) m/e 514 [M+H]+.
Example 24 (+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]-N"- (indan-2-yl)guanidine
Following the procedures of Example 6 except substituting 2-aminoindane for benzylamine, the titled compound was prepared (64%). MS(ES) m/e 519 [M+H]+. Example 25
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]-N"- (2-cyanoethyl)guanidine
Following the procedures of Example 6 except substituting 3- aminopropionitrile for benzylamine, the titled compound was prepared (66%). MS(ES) m e 456 [M+H]+.
Example 26
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]-N"- (3 -hydroxypropyl)guanidine
Following the procedures of Example 6 except substituting 3-amino-l- propanol for benzylamine, the titled compound was prepared (48%). MS(ES) m/e 461 [M+H]+.
Example 27
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]-N"- ( 1 -methylpyrrol-2-ylethyl)guanidine Following the procedures of Example 6 except substituting 2-aminoethyl-l- methylpyrrole for benzylamine, the titled compound was prepared (31%). MS(ES) m/e 510 [M+H]+.
Example 28
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]-N"- (6-hydroxyhexyl)guanidine Following the procedures of Example 6 except substituting 6-amino-l- hexanol for benzylamine, the titled compound was prepared (60%). MS(ES) m e 503 [M+H]+.
Example 29 (+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]-N"- (octyl)guanidine
Following the procedures of Example 6 except substituting 1-octylamine for benzylamine, the titled compound was prepared (78%). MS(ES) m/e 515 [M+H]+.
Example 30 (+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]-N"-
(4-amidosulfonylphenylmethyl)guanidine
Following the procedures of Example 6 except substituting 4- aminomethylbenzenesulfonamide for benzylamine, the titled compound was prepared (31%). MS(ES) m/e 572 [M+H]+. Example 31
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]-N"- (2-ethoxycarbonylethyl)guanidine
Following the procedures of Example 6 except substituting β-alanine ethyl ester for benzylamine, the titled compound was prepared (60%). MS(ES) m/e 503 [M+H]+.
Example 32
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]-N"- (4-methylsulfonylphenylmethyl)guanidine
Following the procedures of Example 6 except substituting methyl-p- toluenesulfonate for benzylamine, the titled compound was prepared (46%). MS(ES) m/e 571 [M+H]+.
Example 33
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]-N"- (2,4-dimethoxyphenylmethyl)guanidine Following the procedures of Example 6 except substituting 2.4- dimethoxybenzylamine for benzylamine, the titled compound was prepared (64%). MS(ES) m e 553 [M+H]+.
Example 34 (+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]-N"- [3-(2-pyrrolidinon- 1 -yl)propyl]guanidine
Following the procedures of Example 6 except substituting l-(3- aminopropyl)-2-pyrrolidinone for benzylamine, the titled compound was prepared (55%). MS(ES) m/e 528 [M+H]+. Example 35
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]-N"- (2,2,2-trifluoroethyl)guanidine
Following the procedures of Example 6 except substituting 2,2,2- trifluoroethylamine for benzylamine, the titled compound was prepared (58%). MS(ES) m/e 485 [M+H]+.
Example 36
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]-N"- (cyclopropylmethyl)guanidine
Following the procedures of Example 6 except substituting cyclopropylmethylamine for benzylamine, the titled compound was prepared (50%). MS(ES) m/e 457 [M+H]+.
Example 37
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]-N"- (2-hydroxyethyl)guanidine Following the procedures of Example 4 except substituting ethanolamine for benzylamine, the titled compound was prepared (71%). MS(ES) m/e 447 [M+H]+.
Example 38
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]-N"- (benzimidazol-2-ylmethyl)guanidine Following the procedures of Example 4 except substituting 2- aminomethylbenzimidazole for benzylamine, the titled compound was prepared (79%). MS(ES) m/e 533 [M+H]+.
Example 39 (+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]-N"- (2-aminoethyl)guanidine
Following the procedures of Example 4 except substituting N-boc- ethylenediamine for benzylamine, the titled compound was prepared (36%). MS(ES) m e 446 [M-f-H]+. Example 40
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]-N"- (3-aminopropyl)guanidine
Following the procedures of Example 4 except substituting N-boc- propylenediamine for benzylamine, the titled compound was prepared (32%). MS(ES) m/e 460 [M+H]+.
Example 41
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]-N"- (4-aminobutyl)guanidine
Following the procedures of Example 4 except substituting N-boc- butylenediamine for benzylamine, the titled compound was prepared (36%). MS(ES) m/e 474 [M+H]+.
Example 42
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]-N"- (2-carboxyethyl)guanidine A solution of the compound from Example 31 (0.025 g, 0.05 mmol) in 5:5:2
THF/MeOH/H2O (2 ml) was treated with KOH (0.01 g, 0.15 mmol) and stirred 5 h. The mixture was acidified with 3 N aqueous HCl and extracted with CH2CI2. The organic extract was dried (MgSO4) and was evaporated. The residue was purified by flash chromatography (silica gel, 10% MeOH/CHCl3) to provide the titled compound as a tan foam, 0.007g (30%). MS(ES) m/e 475 [M+H]+. Example 43
(+/-)-N-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]urea
A mixture of the compound from Example 1(d) (0.05 g, 0.13 mmol) and potassium cyanate (0.022 g, O.lόmmol) in 2:1 H2O/ACOH (1 mL) was stirred for 8 days. The mixture was diluted with water and was extracted with CH2CI2. The organic extract was dried (MgSO4) and was evaporated. The residue was purified by flash chromatography (silica gel, 66% EtOAc/hexanes, then 75% EtOAc/CH2θ2) to provide the titled compound as a pale-yellow solid, 0.02 g (40%). mp 68-70 °C.
Example 44 (+/-)-3-(3-cyclopentyloxy-4-methoxyphenyl)-3-ethynylpropionic acid
44(a) (+/-)-2,2-dimethyl-5-( [ l-(3-cyclopentyloxy-4-methoxyphenyl)-3- trimethylsilyl]prop-2-yne)- 1 ,3-dioxane-4,6-dione
Following the procedure of Example 1(b), except substituting trimethylsilylacetylene for phenylacetylene, the titled compound was prepared (63%). mp 105-107°C.
44(b) (+/-)-3-(3-Cyclopentyloxy-4-methoxyphenyl)-3- trimethylsilylethynylpropionic acid
Following the procedure of Example 1 (c), except substituting (+/-)-2,2- dimethyl-5-([l-(3-cyclopentyloxy-4-methoxyphenyl)-3-trimethylsilyl]prop-2-yne)- l,3-dioxane-4,6-dione for (+/-)-2,2-dimethyl-5-([ l-(3-cyclopentyloxy-4- methoxyphenyl)-3-phenyl]prop-2-yne)-l,3-dioxane-4,6-dione the titled compound was prepared (78%). 1H NMR (400MHz, CDCI3) ? 6.98 (d, 1H), 6.88 (d of d, 1H),
6.80 (d, 1H), 4.80 (m, 1H), 4.12 (t, 1H), 3.82 (s, 3H), 2.86 (d of d, 1H), 2.74 (d of d,
1H), 1.78-2.00 (m, 6H), 1.62 (m, 2H). 44(c) (+/-)-3-(3-Cyclopentyloxy-4-methoxyphenyl)-3-ethynylpropionic acid
The compound from Example 44(b) (12.5 g, 37.6 mmol) was dissolved in a mixture of MeOH (75 mL) and H2O (40 mL) and treated with 10% aqueous NaOH (90 mL). The reaction was stirred 1 h at room temperature, was diluted with H2O (200 mL) and was treated with activated carbon. The mixture was filtered and the filtrate was acidified, and extracted with ether. The extracts were washed with H2O, dried (MgSO4), and the solvent evaporated. The residue was crystallized from 1 : 1 he anes/CH2Cl2 (200 ml) providing the titled compound (6.5 g, 60%). mp 128- 131°C.
Example 45 (+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(3-chlorophenyl)but-3- ynyl]-guanidine
45(a) (+/-)-4-amino-3-(3-cyclopentyloxy-4-methoxyphenyl)- 1 -butyne
A solution of the compound from Example 44(c) (8.5 g, 29 mmol) in
Me2CO (300 mL) was cooled to 0°C and treated with Et3N (4.5 mL, 32 mmol) and then isobutyl chloroformate (4.2 mL, 32 mmol) dropwise. A solution of NaN3 (4.2 g, 64 mmol) in H2O (25 mL) was added dropwise to the cold solution, and stirring continued for 0.25 h. The reaction was diluted with H2O, and extracted with Et2θ.
The organic phase was washed with water, was dried (Na2SO4), and was filtered.
The ether extract was slowly added to refluxing toluene (500 mL), and the solution was heated at 110°C for 0.5 h, and was evaporated. The residue was dissolved in a mixture of dioxane (50 mL), water (30 mL), and cone. HCl (30 mL), was refluxed for 0.2 h and was cooled and was evaporated. The residue was treated with 10% aqueous NaOH to pH 9 and was extracted with CH2CI2. The organic extract was washed with brine, was dried (K2CO3) and was evaporated to provide the titled compound as a brown oil, 7.5 g (87%). MS(ES) m/e 260 [M+H]+.
45(b) (+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-but-3-ynyl]-O-
(phenyl)isourea
To a solution of the compound from Example 45(a) (7.6 g, 29 mmol) in isopropanol (200 mL) was added diphenyl cyanocarbonimidate (8.1 g, 34 mmol). The mixture was stirred 18 h and was filtered to provide the titled compound as a white solid, 10.7 g (95%). mp 170-172°C.
45(c) (+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-but-3-ynyl]- guanidine
To a suspension of the compound from Example 45(b) (1.5 g, 3.7 mmol) in isopropanol (50 mL) in a pressure vessel at -78°C was condensed ammonia (15 mL). The vessel was sealed and was warmed to room temperature. After 36 h, the reaction mixture was cooled to -78°C, the reaction vessel was opened and the mixture was warmed to RT and was evaporated. The residue was dissolved in EtOAc, was washed with 10% aqueous NaOH, was dried (MgSO4) and was evaporated to provide the titled compound as a white foam, 1.2 g (100%). MS(ES) m/e 327 [M+H]+.
45(d) (+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(3- chlorophenyl)but-3-ynyl]guanidine
A mixture of the compound from Example 45(c) (0.06 g, 0.18 mmol), 3- chloro-1 -iodobenzene (0.05 g, 0.2 mmol), Cul (0.004 g, 9 μmol) and tertrakis(triphenylphosphine)palladium(0) (0.01 g, 9 μmol) in triethylamine (5 mL) was refluxed under an argon atmosphere for 3 h. The mixture was cooled and was evaporated. The residue was purified by flash chromatography (silica gel, 3% MeOH/CH2θ2) to provide the titled compound as a tan solid, 0.05 g (61%). MS(ES) m/e 437 [M+H]+.
Example 46
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(4-chlorophenyl)but-3- ynyljguanidine
Following the procedure of Example 45(d), except substituting 4-chloro-l- iodobenzene for 3-chloro-l-iodobenzene, the titled compound was prepared (40%). MS(ES) m/e 437 [M+H]+.
Example 47
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-t-butylphenyl)but-3- ynyl]guanidine Following the procedure of Example 45(d), except substituting 4-iodo-l-t- butylbenzene for 3-chloro-l-iodobenzene, the titled compound was prepared (14%). MS(ES) m e 459 [M+H]+.
Example 48
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(3- carboxymethylphenyl)but-3-ynyl]guanidine Following the procedure of Example 45(d), except substituting methyl 3- iodobenzoate for 3-chloro-l-iodobenzene, the titled compound was prepared (34%). MS(ES) m/e 461 [M+H]+.
Example 49 (+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2- carboxymethylphenyl)but-3-ynyl]guanidine
Following the procedure of Example 45(d), except substituting methyl 2- iodobenzoate for 3-chloro-l-iodobenzene, the titled compound was prepared (15%). MS(ES) m/e 461 [M+H]+. Example 50
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(4- methoxycarbonylmethoxyphenyl)but-3-ynyl]guanidine
Following the procedure of Example 45(d), except substituting methyl 4- iodophenoxyacetate for 3-chloro-l-iodobenzene, the titled compound was prepared (44%). MS(ES) m/e 491 [M+H]+.
Example 51
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-carboxyphenyl)but- 3-ynyl]guanidine
A solution of the compound from Example 49 (0.035 g, 0.08 mmol) in 5:5:2 THF/MeOH/H2O (2 mL) was treated with NaOH (0.01 g, 0.24 mmol) and stirred 5 h. The mixture was acidified with 3 N aqueous HCl and filtered to provide the titled compound as a tan solid, 0.016g (50%). mp 173-177 °C.
Example 52
(+/-)-N-cy ano-N '- [2-(3-cyclopenty loxy-4-methoxyphenyl)-4- [3-(5 -methyl- [ 1 ,3 ,4]thiadiazol-2-yl)phenyl]but-3-ynyl]guanidine
Following the procedure of Example 45(d), except substituting 3-(5-methyl- [l,3,4]thiadiazol-2-yl)-l -iodobenzene) for 3-chloro-l-iodobenzene, the titled compound was prepared (18%). MS(ES) m/e 501 [M+H]+. Example 53
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(4- carboxymethoxyphenyl)but-3-ynyl]-guanidine A solution of the compound from Example 50 (0.05 g, 0.1 mmol) in 5:5:2
THF/MeOH/H2θ (2 mL) was treated with NaOH (0.012 g, 0.3 mmol) and stirred 5 h. The mixture was acidified with 3 N aqueous HCl, was extracted with CH2CI2 was dried (MgSO4) to provide the titled compound as a tan foam, 0.033g (67%). MS(ES) m/e 477 [M+H]+. Example 54
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(4-fluoro-3- chlorophenyl)but-3-ynyl]guanidine
Following the procedure of Example 45(d), except substituting 3-chloro-4- fluoroiodobenzene for 3-chloro-l-iodobenzene, the titled compound was prepared (17%). MS(ES) m/e 455 [M+H]+.
Example 55
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(4-chloro-3- fluorophenyl)but-3-ynyl]guanidine
Following the procedure of Example 45(d), except substituting 4-chloro-3- fluoroiodobenzene for 3-chloro-l-iodobenzene, the titled compound was prepared (3%). MS(ES) m/e 455 [M+H]+.
Example 56
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(3,4- difluorophenyl)but-3-ynyl]guanidine Following the procedure of Example 45(d), except substituting 3,4- difluoroiodobenzene for 3-chloro-l-iodobenzene, the titled compound was prepared (1%). MS(ES) m e 439 [M+HJ+.
Example 57
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(3-methoxyphenyl)but- 3-ynyl]guanidine Following the procedure of Example 45(d), except substituting 3- methoxyiodobenzene for 3-chloro-l-iodobenzene, the titled compound was prepared (23%). MS(ES) m/e 433 [M+H]+.
Example 58 (+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(4- trifluoromethoxyphenyl)but-3-ynyl]guanidine
Following the procedure of Example 45(d), except substituting 4- (trifluoromethoxy)iodobenzene for 3-chloro-l-iodobenzene, the titled compound was prepared (26%). MS(ES) m/e 487 [M+H]+. Example 59
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-[3-(5-methyl- [ 1 ,3,4]oxadiazol-2-yl)phenyl]but-3-ynyl]guanidine
Following the procedure of Example 45(d), except substituting 3-(5-methyl- [l,3,4]oxadiazol-2-yl)-l-iodobenzene for 3-chloro-l-iodobenzene, the titled compound was prepared (9%). MS(ES) m e 485 [M+H]+.
Example 60
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(3- trifluoromethylphenyl)but-3-ynyl]guanidine
Following the procedure of Example 45(d), except substituting 3- (trifluoromethyl)iodobenzene for 3-chloro-l-iodobenzene, the titled compound was prepared (14%). MS(ES) m/e 471 [M+H]+.
Example 61
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(4-N- pyrrolylphenyl)but-3-ynyl]guanidine Following the procedure of Example 45(d), except substituting l-(4- iodophenyl)pyrrole for 3-chloro- 1 -iodobenzene, the titled compound was prepared (21%). MS(ES) m/e 468 [M+H]+.
Example 62
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(naphthalen-2-yl)but-3- ynyl]guanidine Following the procedure of Example 45(d), except substituting 2- iodonaphthalene for 3-chloro-l-iodobenzene, the titled compound was prepared (7%). MS(ES) m/e 453 [M+H]+.
Example 63 (+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(4-methoxyphenyl)but- 3-ynyl]guanidine
Following the procedure of Example 45(d), except substituting 4- methoxyiodobenzene for 3-chloro-l-iodobenzene, the titled compound was prepared (8%). MS(ES) m/e 433 [M+H]+. Example 64
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(3-acetylphenyl)but-3- ynyljguanidine
Following the procedure of Example 45(d), except substituting 3'- iodoacetophenone for 3-chloro-l-iodobenzene, the titled compound was prepared (9%). MS(ES) m/e 445 [M+H]+.
Example 65
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(4-methoxyphenyl)but- 3-ynyl]guanidine
Following the procedure of Example 45(d), except substituting 3- fluoroiodobenzene for 3-chloro-l-iodobenzene, the titled compound was prepared (8%). MS(ES) m e 421 [M+H]+.
Example 66
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(3-carboxyphenyl)but- 3-ynyl]guanidine A solution of the compound from Example 48 (0.045 g, 0.1 mmol) in 5:5:2
THF/MeOH/H2O (2 mL was treated with NaOH (0.013 g, 0.3 mmol) and stirred 5 h. The mixture was acidified with 3 N aqueous HCl, was extracted with CH2CI2 was dried (MgSO4) to provide the titled compound as a yellow foam, 0.036g (83%). MS(ES) m/e 477 [M+H]+. Example 67
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl] -O-(phenyl)isourea
(+/-)-4-Amino-3-(3-cyclopentyloxy-4-methoxyphenyl)- 1 -phenyl- 1 -butyne hydrochloride (10.0 g, 26.9 mmol), isopropanol (600 mL), triethylamine (4.0 g, 40.3 mmol) and diphenylcyanocarbonimidate (8.0 g, 33.6 mmol) were combined and stirred at 25 °C for 1 hour. The precipitate material was filtered and washed with isopropanol to afford 6.2 g (48%) of white crystalline: mp 159 -161°C.
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl] guanidine
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl] -O-(phenyl)isourea (6.2 g 12.93 mmol), isopropanol (400 mL) and anhydrous ammonia were combined in a sealed tube and stirred overnight at 25°C. Most of the isopropanol was evaporated in vacuo, water was added, the mixture was extracted with ethyl acetate (3 x 100 mL) and the combined extracts was concentrated to afford 5.0 g (96.0%) of white solid: mp 68-69°C; MS ES+ m/z 403.4 (MH+).
Example 68
(+/-)-N-cyano-N'-[2-(3-hydroxy-4-methoxyphenyl)-4-phenylbut-3-ynyl] guanidine To a solution of (+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)- 4-phenylbut-3-ynyl]guanidine (3.6 g 8.94 mmol) in methylene chloride (160 mL) was cooled to -78 °C and borontribromide (4.5 g 17.9 mmol) was added slowlly and the resulting mixture was stirred for 15 min. The reaction was quenched with sodium methoxide solution in methanol, and the mixture was poured into water and extracted with ethyl acetate. The organic phase was separated, washed with brine, dried (Na2SO4) and concentrated to afford 1.0 g white solid: mp 90 -92 °C; MS ES+ m/z 335.4 (MH+). Example 69
(+/-)-N-cyano-N'-[2-(3-decyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]guanidine
To a solution of (+/-)-N-cyano-N'-[2-(3-hydroxy-4-methoxyphenyl)-4- phenylbut-3-ynyl]guanidine (70 mg 0.21 mmol) in dimethylformamide (50 mL) was added 1-iododecane (62 mg 0.23 mmol) and potassium carbonate (32 mg 0.23 mmol). respectively, and the resulting mixture was stirred at 25 °C for 18 h. The mixture was poured into water and extracted with ethyl acetate. The organic phase was separated, washed with brine and dried (Na2SO4). The residue was concentrated and chromatographed over silica gel (100% ethyl acetate) to afford the title compound (30 mg) as an off-white solid: mp 56 -58°C; MS ES+ m/z 475.5 (MH+).
Following compounds were prepared according to the procedure for Example 69 using the appropriate halide reagents.
Example 70 (+/-)-N-cyano-N'-[2-(3-ethyloxy-4-metoxyphenyl)-4-phenylbut-3-ynyl]guanidine: MS ES+ m/z 363 (MH+).
Example 71
(+/-)-N-cyano-N'-[2-(3-butyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]guanidine: MS ES+ m/z 391 (MH+). Example 72
(+/-)-N-cyano-N'-[2-(3-(4-(ethylcarbonylmethyl) thiazolyl-2-aminocarbonyl- methyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl] guanidine: MS ES+ m/z 561 (MH+).
Example 73 (+/-)-N-cyano-N'-[2-[4-(6,7-dimethoxycumoarin)-3-methoxy-4-methoxy phenyl]-4- phenylbut-3-ynyl]guanidine: MS ES+ m/z 553 (MH+).
Example 74
(+/-)-N-cyano-N'-[2-(3-cyclobutylmethoxy-4-methoxyphenyl)-4-phenylbut-3- ynyljguanidine: MS ES+ m/z 403 (MH+). Example 75
(+/-)-N-cyano-N'-[2-(3-(4-ethyoxycarbonylbutyloxy)-4-methoxyphenyl)-4- phenylbut-3-ynyl]guanidine: MS ES+ m/z 463 (MH+).
Example 76 (+/-)-N-cyano-N'-[2-(3-(4-chlorophenylthiazolylmethoxy-3-methyloxy)-4- methoxyphenyl)-4-phenylbut-3-ynyl]guanidine: MS ES+ m z 543 (MH+).
Example 77
(+/-)-N-cyano-N'-[2-(3-cyclohexylcarbonylmethyloxy)-4-methoxyphenyl-4- phenylbut-3-ynyl]guanidine: MS ES+ m/z 475 (MH+). Example 78
(+/-)-N-cyano-N'-[2-(3-(2-methylthiazole-4-ylmethoxy-4-methoxyphenyl)] -4- phenylbut-3-ynyl]guanidine: MS ES+ m/z 446 (MH+).
Example 79
(+/-)-N-cyano-N'-[2-(3-(cyclohexylethoxy)-4-methoxyphenyl)-4-phenylbut-3-ynyl] guanidine: MS ES+ m/z 445 (MH+).
Example 80
(+/-)-N-cyano-N'-[2-(3-diethyldicarbonylpropoxy)-4-methoxyphenyl)-4-phenylbut- 3-ynyl]guanidine: MS ES+ m/z 535 (MH+).
Example 81 (+/-)-N-cyano-N'-[2-(3-geranyloxy-4-methoxyphenyl)-4-phenylbut-3- ynyljguanidine: MS ES+ m/z 471 (MH+).
Example 82
(+/-)-N-cyano-N'-[2-(3-tetrahydrofuryl-2-methoxy-4-methoxyphenyl)-4-phenylbut- 3-ynyl]guanidine: MS ES+ m/z 419 (MH+). Example 83
(+/-)-N-cyano-N'-[2-(3-(2-ethylhexyloxy)-4-methoxyphenyl)-4-phenylbut-3- ynyljguanidine: MS ES+ m/z 447 (MH+). Example 84
(+/-)-N-cyano-N'-[2-(3-(4-(2,6-dichlorobenzylsulphonylbenzyloxy)-4- methoxyphenyl)-4-phenylbut-3-ynyl]guanidine: MS ES+ m/z 648 (MH+).
Example 85 (R)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(3-methoxyphenyl)but- 3-ynyl]guanidine
Following the procedure of Example 45(d) using enantiomer pure acetylene derived from an acid of Formula (24), except substituting 3-methoxyiodobenzene for 3-chloro-l-iodobenzene, the titled compound was prepared (81%). MS(ES) m/e 433 [M+H]+.
Formulations for pharmaceutical use incorporating compounds of the present invention can be prepared in various forms and with numerous excipients. Examples of such formulations are given below:
Example 86 Inhalant Formulation
A compound of Formula (I), (1 mg to 100 mg) is aerosolized from a metered dose inhaler to deliver the desired amount of drug per use.
Example 87 Tablet Formulation Tablets/Ingredients Per Tablet
1. Active ingredient 40 mg
(Cpd of Form. (I)
2. Corn Starch 20 mg
3. Alginic acid 20 mg 4. Sodium Alginate 20 mg
5. Mg stearate 1.3 mg
Procedure for tablet formulation:
Ingredients 1, 2, 3 and 4 are blended in a suitable mixer/blender. Sufficient water is added portion-wise to the blend with careful mixing after each addition until the mass is of a consistency to permit its conversion to wet granules. The wet mass is converted to granules by passing it through an oscillating granulator using a No. 8 mesh (2.38 mm) screen. The wet granules are then dried in an oven at 140°F (60°C) until dry. The dry granules are lubricated with ingredient No. 5, and the lubricated granules are compressed on a suitable tablet press.
Example 88 Parenteral Formulation
A pharmaceutical composition for parenteral administration is prepared by dissolving an appropriate amount of a compound of formula I in polyethylene glycol with heating. This solution is then diluted with water for injections (to 100 mL). The solution is then rendered sterile by filtration through a 0.22 micron membrane filter and sealed in sterile containers.
All publications, including but not limited to patents and patent applications cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference as though fully set forth.

Claims

What is claimed is:
1. A compound according to Formula (I):
Figure imgf000050_0001
Formula (I) wherein:
R is selected from the group consisting of C2-C12 alkyl, heteroalkyl and arylalkyl;
R1 is selected from the group consisting of hydrogen, OH, halogen, CN, NO2, CF3,
CF2H, Cj-Cio alkoxy and NR4R5;
R2 is aryl, unsubstituted or substituted by a substituent selected from the group consisting of C j -C alkyl, CF3 , CF H, halogen, CO R6, COR6, O(CH2)nCO2R6>
Cj-Cg alkoxy, CN, NO2, OH, NR4R5, pyrrolyl, thiazolyl, and oxadiazolyl, unsubstituted or substituted by Rg;
R3 is selected from the group consisting of hydrogen, C2-C6 aminoalkyl and
C2-Cg hydroxy alkyl; R4 and R5 are independently selected form the group consisting of hydrogen,
C2-C12 alkyl, heteroalkyl and arylalkyl;
R6 is selected from the group consisting of hydrogen, and C^-Cg alkyl;
X is selected from the group consisting of NCN, O, S and NH; and m is an integer from 1 to 4; and n is an integer from 1 to 5.
2. A compound according to claim 1 selected from the group consisting of:
(+/-)-N-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]guanidine,
(+/) -N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3- ynyl]guanidine, (+/-)-N-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]thiourea,
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]-N"-
(benzyl)guanidine,
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]-N"- (N,N-dimethylaminopropyl)guanidine
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]-N"- (piperidin- 1 -ylethyl)guanidine,
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]-N"- (3-hydroxypropyl)guanidine, (+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]-N"- (2-hydroxyethyl)guanidine,
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]-N"- (2-aminoethyl)guanidine,
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]-N"- (3-aminopropyl)guanidine,
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]-N"- (4-aminobutyl)guanidine,
(+/-)-N-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]urea, (+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(3-chlorophenyl)but-3- ynyl]guanidine,
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(4-chlorophenyl)but-3- ynyljguanidine,
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-t-butylphenyl)but-3- ynyljguanidine, (+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(3- carboxymethylphenyl)but-3-ynyl]guanidine,
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(4- methoxycarbonylmethoxyphenyl)but-3-ynyl]guanidine,
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-[3-(5-methyl- [1,3 ,4]thiadiazol-2-yl)phenyl]but-3-ynyl]guanidine, (+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(4- carboxymethoxyphenyl)but-3-ynyl]guanidine,
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(4-fluoro-3- chlorophenyl)but-3-ynyl]guanidine, (+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(4-chloro-3- fluorophenyl)but-3-ynyl]guanidine,
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(3,4- difluorophenyl)but-3-ynyl]guanidine,
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(3-methoxyphenyl)but- 3-ynyl]guanidine,
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(4- trifluoromethoxyphenyl)but-3-ynyl]guanidine,
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-[3-(5-methyl-
[l,3,4]oxadiazol-2-yl)phenyl]but-3-ynyl]guanidine, (+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(3- trifluoromethylphenyl)but-3-ynyl]guanidine,
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(4-N- pyrrolylphenyl)but-3-ynyl]guanidine,
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(naphthalen-2-yl)but-3- ynyljguanidine,
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(4-methoxyphenyl)but-
3-ynyl]guanidine,
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyρhenyl)-4-(3-acetylphenyl)but-3- ynyl]guanidine, (+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(4-methoxyphenyl)but-
3-ynyl]guanidine,
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(3-carboxyphenyl)but-
3-ynyl]guanidine,
(+/-)-N-cyano-N'-[2-(3-hydroxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]guanidine, (+/-)-N-cyano-N'-[2-(3-decyloxy-4-methoxyρhenyl)-4-phenylbut-3-ynyl]guanidine, (+/-)-N-cyano-N'-[2-(3-ethyloxy-4-metoxyphenyl)-4-phenylbut-3-ynyl]guanidine, (+/-)-N-cyano-N'-[2-(3-butyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]guanidine, (+/-)-N-cyano-N'-[2-(3-(4-(ethylcarbonylmethyl) thiazolyl-2-aminocarbonyl- methyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]guanidine, (+/-)-N-cyano-N'-[2-(3-cyclobutylmethoxy-4-methoxyphenyl)-4-phenylbut-3- ynyl]guanidine,
(+/-)-N-cyano-N'-[2-(3-(4-ethyoxycarbonylbutyloxy)-4-methoxyphenyl)-4- phenylbut-3-ynyl]guanidine,
(+/-)-N-cyano-N'-[2-(3-cyclohexylcarbonylmethyloxy)-4-methoxyphenyl-4- phenylbut-3-ynyl]guanidine,
(+/-)-N-cyano-N'-[2-(3-(cyclohexylethoxy)-4-methoxyphenyl)-4-phenylbut-3- ynyljguanidine, and
(+/-)-N-cyano-N'-[2-(3-(2-ethylhexyloxy)-4-methoxyphenyl)-4-phenylbut-3- ynyl]guanidine. 3. A compound according to claim 2, selected from the group consisting of:
(+/-)-N-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]guanidine,
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3- ynyl]guanidine,
(+/-)-N-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]thiourea, (+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]-N"-
(2-hydroxyethyl)guanidine,
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]-N"-
(2-aminoethyl)guanidine,
(+/-)-N-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]urea, (+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(3-chlorophenyl)but-3- ynyljguanidine,
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(4-chlorophenyl)but-3- ynyljguanidine,
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(4- methoxycarbonylmethoxyphenyl)but-3-ynyl]guanidine, (+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(4-fluoro-3- chlorophenyl)but-3-ynyl]guanidine,
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(4-chloro-3- fluorophenyl)but-3-ynyl]guanidine, (+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(3,4- difluorophenyl)but-3-ynyl]guanidine,
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(3-methoxyphenyl)but- 3-ynyl]guanidine,
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(4- trifluoromethoxyphenyl)but-3-ynyl]guanidine,
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(3- trifluoromethylphenyl)but-3-ynyl]guanidine,
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(4-methoxyphenyl)but- 3-ynyl]guanidine, (+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(3-acetylphenyl)but-3- ynyljguanidine,
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(4-methoxyphenyl)but- 3-ynyl]guanidine,
(+/-)-N-cyano-N'-[2-(3-hydroxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]guanidine, (+/-)-N-cyano-N'-[2-(3-decyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]guanidine,
(+/-)-N-cyano-N'-[2-(3-ethyloxy-4-metoxyphenyl)-4-phenylbut-3-ynyl]guanidine,
(+/-)-N-cyano-N'-[2-(3-butyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]guanidine,
(+/-)-N-cyano-N'-[2-(3-(4-(ethylcarbonylmethyl)-thiazolyl-2-aminocarbonyl- methyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]guanidine, (+/-)-N-cyano-N'-[2-(3-cyclobutylmethoxy-4-methoxyphenyl)-4-phenylbut-3- ynyljguanidine,
(+/-)-N-cyano-N'-[2-(3-cyclohexylcarbonylmethyloxy)-4-methoxyphenyl-4- phenylbut-3-ynyl]guanidine,
(+/-)-N-cyano-N'-[2-(3-(cyclohexylethoxy)-4-methoxyphenyl)-4-phenylbut-3- ynyl]guanidine, and (+/-)-N-cyano-N'-[2-(3-(2-ethylhexyloxy)-4-methoxyphenyl)-4-phenylbut-3- ynyljguanidine.
4. A compound according to claim 3 selected from the group consisting of: (+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(3-chlorophenyl)but-3- ynyl]guanidine,
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(4-chlorophenyl)but-3- ynyl]guanidine,
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(4-fluoro-3- chlorophenyl)but-3-ynyl]guanidine, (+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(4-chloro-3- fluorophenyl)but-3-ynyl]guanidine,
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(3,4- difluorophenyl)but-3-ynyl]guanidine,
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(3-methoxyphenyl)but- 3-ynyl]guanidine,
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(4- trifluoromethoxyphenyl)but-3-ynyl]guanidine,
(+/-)-N-cyano-N'-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-(3- trifluoromethylphenyl)but-3-ynyl]guanidine, and (+/-)-N-cyano-N'-[2-(3-decyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]guanidine,
5. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
6. A method of antagonizing a GRP receptor which comprises administering to a subject in need thereof, an effective amount of a compound according to claim 1.
7. A method of treating a disease or disorder selected from the group consisting of chronic renal failure, prostate cancer, small-cell and non-small-cell lung carcinomas, breast cancer, gastric-carcinoma, glioblastoma, colon cancer, thyroid cancer, and pituitary tumor which comprises administering to a subject in need thereof an effective amount of a compound according to claim 1.
8. A method according to claim 7 wherein the disease or disorder treated is chronic renal failure.
9. A method according to claim 8 wherein the disease or disorder treated is prostate cancer.
10. A method of synthesizing a compound according to claim 1 comprising the steps of:
(a) treatment of a compound of Formula (9):
Figure imgf000056_0001
with a base and di-t-butyl dicarbonate to afford a compound of Formula (14):
Figure imgf000056_0002
b) reaction of the compound of Formula (14) with ammonia followed by acidic deprotection to obtain a compound of Formula (16):
Figure imgf000056_0003
11. A method according to claim 10 further comprising the steps of: a) reacting an amine of Formula (8):
Figure imgf000057_0001
with diphenyl cyanocarbonimidate to form a compound of Formula (17):
Figure imgf000057_0002
b) treatment of the compound of Formula (17) with ammonia to provide a compound of Formula (16) wherein R2 represents hydrogen; and c) palladium-catalyzed coupling of the compound of Formula (16), with aryl iodide in the presence of copper iodide to afford a compound of Formula (I), wherein R represents cyclopentyl, R2 represents aryl, and X represents NCN.
12. A method of synthesizing a compound according to claim 1 comprising the steps of: a) treatment of a compound of Formula ( 16) with a Lewis acid to afford a phenol of Formula (18):
Figure imgf000058_0001
b) alkylation of the phenol of Formula (18) with a halide of Formula (19):
RΓÇö X (19)
in presence of a base to provide a compound of Formula (I) wherein R3 represents H.
13. A compound selected from the group consisting of Formula (II), Formula (III) and Formula (IV) hereinbelow:
Figure imgf000058_0002
Formula (IV).
PCT/US1999/018008 1998-08-14 1999-08-13 Grp receptor ligands WO2000009115A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU56716/99A AU5671699A (en) 1998-08-14 1999-08-13 Grp receptor ligands

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US9659698P 1998-08-14 1998-08-14
US60/096,596 1998-08-14
US11792999P 1999-01-29 1999-01-29
US60/117,929 1999-01-29

Publications (1)

Publication Number Publication Date
WO2000009115A1 true WO2000009115A1 (en) 2000-02-24

Family

ID=26791867

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1999/018008 WO2000009115A1 (en) 1998-08-14 1999-08-13 Grp receptor ligands

Country Status (2)

Country Link
AU (1) AU5671699A (en)
WO (1) WO2000009115A1 (en)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8101580B2 (en) 2005-04-21 2012-01-24 Astellas Pharma Inc. Therapeutic agent for irritable bowel syndrome
WO2011143360A3 (en) * 2010-05-11 2012-02-16 Lantheus Medical Imaging, Inc. Compositions, methods and systems for the synthesis and use of imaging agents
US8309609B2 (en) 2000-08-07 2012-11-13 Anamar Ab Use of benzylideneaminoguanidines and hydroxyguanidines as melanocortin receptor ligands
WO2013036869A3 (en) * 2011-09-09 2013-05-02 Lantheus Medical Imaging, Inc. Compositions, methods, and systems for the synthesis and use of imaging agents
US8491868B2 (en) 2006-12-26 2013-07-23 Lantheus Medical Imaging, Inc. Ligands for imaging cardiac innervation
US9388126B2 (en) 2012-07-19 2016-07-12 Drexel University Sigma receptor ligands and methods of modulating cellular protein homeostasis using same
US10842892B2 (en) 2010-02-08 2020-11-24 Lantheus Medical Imaging, Inc. Methods and apparatus for synthesizing imaging agents, and intermediates thereof
US11117870B2 (en) 2017-11-01 2021-09-14 Drexel University Compounds, compositions, and methods for treating diseases
US11744906B2 (en) 2012-08-10 2023-09-05 Lantheus Medical Imaging, Inc. Compositions, methods, and systems for the synthesis and use of imaging agents

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0250264A1 (en) * 1986-06-19 1987-12-23 Smithkline Beecham Corporation Irreversible dopamine-Beta-hydroxylase inhibitors

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0250264A1 (en) * 1986-06-19 1987-12-23 Smithkline Beecham Corporation Irreversible dopamine-Beta-hydroxylase inhibitors

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8309609B2 (en) 2000-08-07 2012-11-13 Anamar Ab Use of benzylideneaminoguanidines and hydroxyguanidines as melanocortin receptor ligands
US8410174B2 (en) 2000-08-07 2013-04-02 Anamar Ab Method for treating arthritis
US9227927B2 (en) 2000-08-07 2016-01-05 Anamar Ab Method of treating inflammation
US8101580B2 (en) 2005-04-21 2012-01-24 Astellas Pharma Inc. Therapeutic agent for irritable bowel syndrome
US10010631B2 (en) 2006-12-26 2018-07-03 Lantheus Medical Imaging, Inc. Ligands for imaging cardiac innervation
US11241509B2 (en) 2006-12-26 2022-02-08 Lantheus Medical Imaging, Inc. Ligands for imaging cardiac innervation
US8491868B2 (en) 2006-12-26 2013-07-23 Lantheus Medical Imaging, Inc. Ligands for imaging cardiac innervation
US10842892B2 (en) 2010-02-08 2020-11-24 Lantheus Medical Imaging, Inc. Methods and apparatus for synthesizing imaging agents, and intermediates thereof
RU2710736C2 (en) * 2010-05-11 2020-01-10 Лантеус Медикал Имэджинг, Инк. Compositions, methods and systems for synthesis and use of imaging agents
US9388125B2 (en) 2010-05-11 2016-07-12 Lantheus Medical Imaging, Inc. Compositions, methods, and systems for the synthesis and use of imaging agents
US9682927B2 (en) 2010-05-11 2017-06-20 Lantheus Medical Imaging, Inc. Compositions, methods, and systems for the synthesis and use of imaging agents
US11174223B2 (en) 2010-05-11 2021-11-16 Lantheus Medical Imaging, Inc. Compositions, methods, and systems for the synthesis and use of imaging agents
WO2011143360A3 (en) * 2010-05-11 2012-02-16 Lantheus Medical Imaging, Inc. Compositions, methods and systems for the synthesis and use of imaging agents
US9550000B2 (en) 2011-09-09 2017-01-24 Lantheus Medical Imaging, Inc. Compositions, methods, and systems for the synthesis and use of imaging agents
CN104159890A (en) * 2011-09-09 2014-11-19 蓝瑟斯医学影像公司 Compositions, methods, and systems for the synthesis and use of imaging agents
WO2013036869A3 (en) * 2011-09-09 2013-05-02 Lantheus Medical Imaging, Inc. Compositions, methods, and systems for the synthesis and use of imaging agents
US9889102B2 (en) 2012-07-19 2018-02-13 Drexel University Sigma receptor ligands and methods of modulating cellular protein homeostasis using same
US9388126B2 (en) 2012-07-19 2016-07-12 Drexel University Sigma receptor ligands and methods of modulating cellular protein homeostasis using same
US10314795B2 (en) 2012-07-19 2019-06-11 Drexel University Sigma receptor ligands and methods of modulating cellular protein homeostasis using same
US11744906B2 (en) 2012-08-10 2023-09-05 Lantheus Medical Imaging, Inc. Compositions, methods, and systems for the synthesis and use of imaging agents
US11117870B2 (en) 2017-11-01 2021-09-14 Drexel University Compounds, compositions, and methods for treating diseases

Also Published As

Publication number Publication date
AU5671699A (en) 2000-03-06

Similar Documents

Publication Publication Date Title
SU1380614A3 (en) Method of producing derivatives of aryltriazoles or hydrochloride or hydrobromic salts thereof
TW200808734A (en) Methods and compositions for modulating sphingosine-1-phosphate (SIP) receptor activity
JPH0220639B2 (en)
EP1689713B1 (en) Benzylether and benzylamino beta-secretase inhibitors for the treatment of alzheimer s disease
CA2548849A1 (en) Phenylamide and pyridylamide beta-secretase inhibitors for the treatment of alzheimer's disease
OA11665A (en) Substituted phenyl derivatives, their preparation and use.
KR20070058455A (en) Methods and compositions for modulating sphingosine-1-phosphate(s1p) receptor activity
JP2008515998A (en) Compound
IL132107A (en) Substituted phenyl derivatives, their preparation and use
JP2004506713A (en) Novel thiourea derivative and pharmaceutical composition containing the same
JPH09188677A (en) Substituted imidazolidine-2,4-dione compound as effective substance of medicine
US6713473B1 (en) Tricyclic compounds
WO2008053913A1 (en) Sulfonylurea derivative capable of selectively inhibiting mmp-13
US11236055B2 (en) Non-systemic TGR5 agonists
CA3143334A1 (en) Glycolate oxidase inhibitors for the treatment of disease
RU2107062C1 (en) N-substituted imidazole derivatives and their salts, method of preparation thereof, intermediate compounds and pharmaceutical composition with angiotensine ii antagonist activity
WO1999062892A1 (en) Aminoazole compounds
WO2001032610A1 (en) Urea derivative, process for producing the same, and medicine containing the urea derivative
CA2054648A1 (en) 1-(2-arylethyl)-pyrrolidines
WO2000009115A1 (en) Grp receptor ligands
JPS62226971A (en) Novel substituted thiazole and oxazole compound
MXPA02001207A (en) Potassium channel openers.
WO2000009116A1 (en) Grp receptor ligands
CN109890826A (en) A kind of efficient IDO/TDO double inhibitors containing azacyclo- helical structure
CA2177960A1 (en) Novel benzodiazepine derivative

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AL AU BA BB BG BR CA CN CR CZ DM EE GE GH GM HR HU ID IL IN IS JP KP KR LC LK LR LT LV MG MK MN MX NO NZ PL RO SG SI SK SL TR TT UA US UZ VN YU ZA

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW SD SL SZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

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