WO2001068621A1 - Novel cyclohexene derivatives useful as antagonists of the motilin receptor - Google Patents
Novel cyclohexene derivatives useful as antagonists of the motilin receptor Download PDFInfo
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- WO2001068621A1 WO2001068621A1 PCT/US2001/007701 US0107701W WO0168621A1 WO 2001068621 A1 WO2001068621 A1 WO 2001068621A1 US 0107701 W US0107701 W US 0107701W WO 0168621 A1 WO0168621 A1 WO 0168621A1
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- ODPNAOXXFGTSPM-UHFFFAOYSA-N O=C(C(C1)C=CC(F)=C1F)N(CC(CCC1)=CC1(Cc1ccccc1)N[IH](C(Cl)(Cl)Cl)=O)c1cccc(OCCN2CCOCC2)c1 Chemical compound O=C(C(C1)C=CC(F)=C1F)N(CC(CCC1)=CC1(Cc1ccccc1)N[IH](C(Cl)(Cl)Cl)=O)c1cccc(OCCN2CCOCC2)c1 ODPNAOXXFGTSPM-UHFFFAOYSA-N 0.000 description 1
- UBSRNFRTANYCNA-UHFFFAOYSA-N O=C(C(Cl)(Cl)Cl)NC1(Cc2ccccc2)C=C(CN(C(NC2=CCCC=C2)=O)c2cc(OCCN3CCOCC3)ccc2)CCC1 Chemical compound O=C(C(Cl)(Cl)Cl)NC1(Cc2ccccc2)C=C(CN(C(NC2=CCCC=C2)=O)c2cc(OCCN3CCOCC3)ccc2)CCC1 UBSRNFRTANYCNA-UHFFFAOYSA-N 0.000 description 1
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- 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
- C07D295/08—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 bound oxygen or sulfur atoms
- C07D295/084—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 bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/088—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 bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/06—Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
Definitions
- This invention relates to a series of novel cyclohexene derivatives, pharmaceutical compositions containing them and intermediates used in their manufacture
- the compounds of the invention are useful as non-peptidyl antagonists of the moti n receptor
- Motilin is a peptide of 22 ammo acids which is produced in the gastrointestinal system of a number of species Although the sequence of the peptide vanes from species to species, there are a great deal of similarities
- motilin and porcine motilin are identical, while motihn isolated from the dog and the rabbit differ by five and four ammo acids, respectively Motilin induces smooth muscle contractions in the stomach tissue of dogs, rabbits, and humans as well as in the colon of rabbits Apart from local gastrointestinal intestinal tissues, motilin and its receptors have been found in other tissues For example, motilin has been found in circulating plasma, where a rise in the concentration of motilin has been associated with gastric effects which occur during fasting in dogs and humans (Itoh, Z. et al., 1976, Scand. J. Gastroenterol. 11 :93-110; Vantrappen, G. et al., 1979, Dig. Dis Sci 24, 497-500). In addition, when motilin was intravenously administered to humans it was found to increase gastric emptying and gut hormone release
- motilin Aside from motilin itself, there are other substances which are agonists of the motilin receptor and which elicit gastrointestinal emptying.
- One of those agents is the antibiotic erythromycin. Even though erythromycin is a useful drug, a great number of patients are affected by the drug's gastrointestinal side effects. Studies have shown that erythromycin elicits biological responses that are comparable to motilin itself and therefore may be useful in the treatment of diseases such as chronic idiopathic intestinal pseudo-obstruction and gastroparesis (Weber, F. et al., 1993, The American Journal of
- motilin and erythromycin are agonists of the motilin receptor, there is a need for antagonists of this receptor as well.
- the nausea, abdominal cramping, and diarrhea which are associated with motilin agonsits are not always welcome physiological events.
- the increased gut motility induced by motilin has been implicated in diseases such as Irritable Bowel Syndrome and esophageal reflux. Therefore researchers have been searching for motilin antagonists.
- OHM-11526 is a peptide derived from porcine motilin which competes with both motilin and erythromycin for the motilin receptor in a number of species, including rabbits and humans.
- this peptide is an antagonist of the contractile smooth muscle response to both erythromycin and motilin in an in vitro rabbit model
- the present invention is directed to compounds of Formula
- Ri is selected from hydrogen, d.salkyl optionally substituted with halogen, aminoC ⁇ - 5 alkyl, Ci-salkylaminoCi-salkyl, di-Ci-salkylaminoCi-salkyl, C ⁇ -5alkylcarbonyl, C 1 . 5 alkoxycarbonyl, aminocarbonyl, Ci-galkylaminocarbonyl, cycloC 3 .
- Rb are independently selected from hydrogen and Ci-salkyl, or taken together to form a morpholine, piperazine, piperidine, or N-substituted piperidine wherein the N-substitutent is Ci-salkyl or phenylCi-salkyl;
- R 2 is selected from hydrogen, d-salkyl, Ci-salkoxy, phenyl optionally substituted with one or more substituents selected from the group consisting of halogen and Ci-salkyl, and phenylCi-salkyl optionally substituted with one or more substituents selected from the group consisting of halogen, Ci-salkyl, Ci-salkoxy, halo and di-Ci-salkylamino;
- R 3 is selected from hydrogen, Ci-salkylcarbonyl optionally substituted with halogen, and phenylcarbonyl optionally substituted with one or more substituents selected from the group consisting of halogen, Ci-salkyl, Ci-salkoxy, amino, Ci-salkylamino, and di-Ci-salkylamino;
- R 4 is selected from hydrogen, Ci-salkyl, Ci-salkylcarbonyl optionally substituted with halogen, and phenylcarbonyl optionally substituted with one or more substituents selected from the group consisting of halogen, Ci-salkyl, Ci-salkoxy, amino, Ci-salkylamino, and di-Ci-salkylamino;
- n 0-3;
- n 1-5;
- X is oxygen, CH 2 , sulfur, hydroxy, thiol, or NR C wherein R c is selected from hydrogen, Ci-salkyl, morpholinoCi-salkyl, pipehdinylC ⁇ -5alkyl, N-phenylmethylpiperidinyl, and piperazinylC ⁇ -5alkyl, with the proviso that if q and t are 0, X is hydroxy, thiol, or amino, A is C ⁇ - 5 alkoxycarbonyl, phenylcarbonyl, or R R 8 N- wherein R 7 and Re are independently selected from hydrogen,
- Ci-salkyl, and cycloCi-.alkyl, or R 7 and Rs form a 5- or 6-membered heterocyclic ring with one or more heteroatoms selected from the group consisting of oxygen, nitrogen, sulfur, and sulfoxides and N-oxides thereof; and
- R 6 is selected from hydrogen, halogen, Ci-salkoxy, Ci-salkylamino, and di-Ci-salkylamino ;
- the compounds of Formula I are useful in treating gastrointestinal disorders associated with the motilin receptor.
- the compounds compete with erythromycin and motilin for the motilin receptor.
- the compounds are antagonists of the contractile smooth muscle response to those ligands.
- the present invention also comprises pharmaceutical compositions containing one or more of the compounds of Formula I as well as methods for the treatment of disorders related to the gastrointestinal system which are associated with the motilin receptor.
- diseases include Irritable Bowel Syndrome, esophageal reflux, and the gastrointestinal side effects of erythromycin.
- alkyl refers to straight, cyclic and branched-chain alkyl groups and "alkoxy” refers O-alkyl where alkyl is as defined supra.
- Halogen or “halo” means F, Cl, Br, and I.
- Ph refers to phenyl.
- fused bicydic aromatic includes fused aromatic rings such as naphthyl and the like.
- fused bicydic heterocycle includes benzodioxoles and the like.
- heteroaryl as used herein represents a stable five or six membered monocyclic aromatic ring system which consists of carbon atoms and from one to three heteroatoms selected from N, O, or S. The heteroaryl group may be attached at any heteroatom or carbon atom which results in the creation of a stable structure.
- heteroaryl groups include, but are not limited to, triazole, thiazole, thiadiazole, oxazole, imidazole, pyrazole, pyrimidine, isothiazole, isoindole, isoxazole and the like.
- the heteroaryl group may be further substituted with one or more groups such as alkyl, substituted alkyl, and halogen. More particularly, the heteroaryl group may be substituted with methyl.
- subject refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.
- the compounds of the invention may be prepared as a single stereoisomer or in racemic form as a mixture of some possible stereoisomers.
- the non-racemic forms may be obtained by either synthesis or resolution.
- the compounds may, for example, be resolved into their components enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation.
- the compounds may also be resolved by covalent linkage to a chiral auxiliary, followed by chromatographic separation and/or crystallographic separation, and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using chiral chromatography.
- acid addition salts may be prepared and may be chosen from hydrochloric, hydrobromic, hydroiodic, perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, benzoic, cinnamic, mandelic, methanesulfonic, p-toluenesulfonic, cyclohexanesulfamic, salicylic, 2-phenoxybenzoic, 2-acetoxybenzoic, saccharin, and the like.
- Such salts can be made by reacting the free base of compounds of formula I with the acid and isolating the salt.
- Scheme 1 assembles two halves of the molecule and couples them.
- 3-ethoxy-2-cylclohepten-1-one, 1_a (a known compound), may be the starting material, a may be treated with a Grignard reagent, l b, such as 4-fluorobenzyl magnesium bromide (a known compound) preferably at room temperature (rt) under an inert atmosphere, using ether as a solvent to give the ⁇ , ⁇ -unsaturated ketone derivative 1_c.
- a reducing agent such as lithium aluminum hydride (LAH) preferably at 0 °C to room temperature
- LAH lithium aluminum hydride
- This alcohol may be treated with a strong base such as NaH and trichloroacetonitrile preferably from 0 °C to room temperature to give the amide e.
- This seven-membered ring amide may be sequentially treated on dry ice with ozone, dimethylsulfide, and a catalytic amount of acid such as toluene sulfonic acid. Once addition is complete, the mixture can be warmed to room temperature over to give the six membered ring aldehyde, If, as a racemic mixture.
- an aromatic alcohol lg such as 3- hydroxyaniline may be treated with a mild base, such as K 2 CO 3 , in a suitable solvent such as ethanol (EtOH) at reflux.
- a suitable solvent such as ethanol (EtOH) at reflux.
- This mixture may be subsequently treated with a halide derivative 1 h, such as 3-chloropropylmorpholine preferably at room temperature to give the amine 1j.
- This amine may be treated with the aldehyde If and NaCNBH 3 in methanol (MeOH) preferably at room temperature to give a compound of the invention ]c, as a racemic mixture.
- enantiomers may be obtained in any of three stages of the synthesis.
- c may all be separated via HPLC using chiral columns or methods well known in the art. With respect to all three compounds, they may be further manipulated to give other compounds of the invention without sacrificing their enantiomeric purity.
- Scheme 1 may be used to produce other compounds of the invention.
- reagent 1 h simply replace reagent 1 h with an aromatic thiol, such as 3-aminothiophe ⁇ ol and carry out the remaining steps of the Scheme.
- the products of Scheme 1 may be used to produce other compounds of the invention as shown in Scheme 3.
- compound lc may be treated with a phenyl isocyanate preferably at room temperature.
- ]c may be treated preferably at room temperature with acid chloride derivatives such as benzoyl chloride.
- acid chloride derivatives such as benzoyl chloride.
- thiols Ig compounds of type ]c may be treated with isothiocyanates, such as phenylisothiocyanate preferably at room temperature.
- isothiocyanates such as phenylisothiocyanate preferably at room temperature.
- pure enantiomers are desired, they may be obtained by chromatography of the reactant lc or the products.
- Scheme 4 makes use of the intermediate of Scheme 1.
- Treatment of the aldehyde, Tf, with a nitroaniline derivative 4a (a known compound), and NaCNBH 3 preferably at room temperature gives the coupled intermediate 4b.
- This intermediate may be acylated with benzoyl chloride and a mild base such as triethylamine to give the N-acyl intermediate 4c.
- 4c may be treated with a reducing agent such as Pd/C to give the aniline compound Jh.
- This compound may be coupled with a halogen derivative 4d, such as 3-chloropropylpiperidine, using 1 ,8.
- Diazabieyclo (5,4,0) undec-7-ene (DBU) and an alcoholic solvent at reflux to give a mixture of mono- and di-amine products (li and Ij).
- Radiolabeled Motilin The compounds of the invention were tested for their ability to compete with radiolabeled motilin (porcine) for the motilin receptors located on the colon of mature rabbits.
- the colon from mature New Zealand rabbits was removed, dissected free from the mucosa and serosa layers, and diced into small pieces.
- the muscle tissues were homogenized in 10 volumes of buffer (50 mM Tris-CI,
- the binding assay contained the following components added sequentially: buffer (50 mM Tris-CI, 10 mM MgCI 2 , 1 mM EDTA, 15 mg/mL BSA, 5 ⁇ g/mL leupeptin, aprotinin, and pepstatin, and 0.1 mg/mL, bactracin), I 125 motilin (Amersham, ca 50,000-70,000 cpm, 25-40 pM), the test compound (the initial concentration was 2 mM/100% DMSO, which was diluted with H 2 O to a final concentration of 10 ⁇ M) and membrane protein (100-300 ⁇ g).
- buffer 50 mM Tris-CI, 10 mM MgCI 2 , 1 mM EDTA, 15 mg/mL BSA, 5 ⁇ g/mL leupeptin, aprotinin, and pepstatin, and 0.1 mg/mL, bactracin
- I 125 motilin Amersham, ca 50,000-70,000
- the material was cooled on ice and centrifuged at 13,000 x g for 1 minute.
- the pellet was washed with 1 mL 0.9% saline and centrifuged at 13,000 x g for 15 seconds.
- the pellet was washed again with cold saline and the supernatant was removed.
- the pellet was counted in the gamma counter to determine the percentage of unbound motilin and thereby the percent inhibition of the test compound.
- Compounds of the invention may be evaluated for their ability to inhibit motilin and erythromycin induced contractions in the rabbit duodenum smooth muscle. Rabbits may be fasted 24-48 h and euthanized. The venral midline incision may be made approximately 7.5 cm above the umbilicus up to the xyphoid process, exposing the upper peritoneal cavity.
- the first 8 cm of the duodenum starting at the pyloric valve may be quickly removed and placed in Krebs solution containing NaCI (120 mM), KCI (4.7 mM), MgSO 4 * 7 H 2 O (1.2 mM), CaCI 2 * 2 H 2 O (2.4 mM), KH 2 PO 4 (1 mM), D-glucose (10 mM), and NaHCO 3 (24 mM).
- the lumen may be flushed with Krebs solution and excess tissue removed.
- the tissue may be cut lengthwise, splayed open with the longitudinal muscle layer facing up, and the longitudinal muscle layer released away from the circular muscle and cut into 3x30 mm strips.
- a pre-tied 4-0 silk ligature with a loop may be placed at the middle of the strip and the strip folded over the loop so the strip is half its original length.
- the tissues may be mounted in a 10 mL tissue bath (Radnotti Glass Technology, Inc., Monrovia, CA.) containing Krebs solution gassed with 95% O 2 + 5% CO 2 at 37 °C.
- the tissues may be attached to a force displacement transducer (FT03, Grass Instruments, Quincy, MA.) and resting tension slowly increased to 1 g.
- the tissues may be allowed to equilibrate for 60-90 min with 2-3 wash cycles.
- the tissues may be equilibrated with two initial contractions induced by a concentration of acetylcholine (1 x 10 "4 M) that produces a maximal contraction (0.1 mM), with the highest taken as 100% maximal contraction of that tissue.
- Base line and response levels may be expressed as grams tension developed and as a percent of the response to acetylcholine.
- the test compounds may be dissolved in DMSO (2 mM/100% DMSO) and applied to the prepared strips 5- 15 minutes prior to the addition of porcine motihn After addition, the tension is constantly monitored over 5 mm and the maximum tension is recorded The percent contraction may be measured at four ascending concentrations and where appropriate ICso's may be determined
- the preferred compounds are those wherein Ri is selected from phenylaminocarbonyl, substituted phenylaminocarbonyl, phenylcarbonyl, and substituted phenylcarbonyl, R 2 is phenylCi-salkyl, substituted phenylC ⁇ . 5 alkyl or phenyl,
- R 3 is phenylcarbonyl, substituted phenylcarbonyl, or substituted Ci-salkylcarbonyl, R is hydrogen or Ci-salkyl, q is 2 or 3, A is C ⁇ - 5 alkoxycarbonyl or R 7 RsN- wherein R 7 and Re are as described above, n is 0, and m is 1
- Ri is phenylaminocarbonyl or substituted phenylcarbonyl
- R 2 is benzyl, 3-CI benzyl, or 4-methoxy benzyl,
- R 3 is substituted Ci-salkylcarbonyl
- R 4 is hydrogen
- A is R R 8 N- wherein R 7 and Rs taken together form a 5 or 6 membered heterocychc ring with one or more heteroatoms selected from the group consisting of oxygen, nitrogen, sulfur, and N-oxides thereof, and X is oxygen.
- Ri is phenylaminocarbonyl or halo substituted benzoyl
- R 3 is halo substituted Ci-salkylcarbonyl; and A is morpolinyl.
- compositions of this invention one or more compounds or salts thereof, as the active ingredient, is intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral.
- a pharmaceutical carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral.
- any of the usual pharmaceutical media may be employed.
- suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like;
- suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage form, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be sugar coated or enteric coated by standard techniques.
- the carrier will usually comprise sterile water, though other ingredients, for example, for purposes such as aiding solubility or for preservation, may be included.
- injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed.
- the pharmaceutical compositions herein will preferably contain per dosage unit, e.g., tablet, capsule, powder, injection, teaspoonful and the like, from about 5 to about 500 mg of the active ingredient, although other unit dosages may be employed.
- the compounds of this invention may be administered in an amount of from about 0.5 to 100 mg/kg 1 -2 times per day orally.
- the compounds may be administered via injection at 0.1-10 mg/kg per day. Determination of optimum dosages for a particular situation is within the capabilities of formulators.
- 3,4-Difluorobenzoyl chloride (31 mg, 0.18 mM) was added to a solution of 3-benzyl-3-trichloroacetamido-1 -N[(3-(2- morpholinoethoxy)phenyl)amino]methylcyclohexene (26 mg, 0.05 mM) and triethylamine (0.2 mL) in methylene chloride (3 mL) at room temperature under N 2 and stirred for 2 hours. Most of solvent was removed in vacuo and the oily residue was purified by preparative TLC to give the title compound as a thick oil
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Abstract
The compounds of formula (I) are useful in treating gastrointestinal disorders associated with antagonizing the motilin receptor. The compounds compete with erythromycin and motilin for the motilin receptor. In addition the compounds are antagonists of the contractile smooth muscle response to those ligands.
Description
NOVEL CYCLOHEXENE DERIVATIVES USEFUL AS ANTAGONISTS OF
THE MOTILIN RECEPTOR
FIELD OF THE INVENTION
This invention relates to a series of novel cyclohexene derivatives, pharmaceutical compositions containing them and intermediates used in their manufacture The compounds of the invention are useful as non-peptidyl antagonists of the moti n receptor
BACKGROUND
In mammals, the digestion of nutrients and the elimination of waste is controlled by the gastrointestinal system This system is, to say the least, complicated There are a number of natural peptides, gands, enzymes, and receptors which play a vital role in this system and are potential targets for drug discovery Modifying the production of, or responses to these endogenous substances can have an effect upon the physiological responses such as diarrhea, nausea, and abdominal cramping One example of an endogenous substance which affects the gastrointestinal system is motilin
Motilin is a peptide of 22 ammo acids which is produced in the gastrointestinal system of a number of species Although the sequence of the peptide vanes from species to species, there are a great deal of similarities
For example, human motilin and porcine motilin are identical, while motihn isolated from the dog and the rabbit differ by five and four ammo acids, respectively Motilin induces smooth muscle contractions in the stomach tissue of dogs, rabbits, and humans as well as in the colon of rabbits Apart from local gastrointestinal intestinal tissues, motilin and its receptors have been found in other tissues For example, motilin has been found in circulating plasma,
where a rise in the concentration of motilin has been associated with gastric effects which occur during fasting in dogs and humans (Itoh, Z. et al., 1976, Scand. J. Gastroenterol. 11 :93-110; Vantrappen, G. et al., 1979, Dig. Dis Sci 24, 497-500). In addition, when motilin was intravenously administered to humans it was found to increase gastric emptying and gut hormone release
(Christofides, N.D. et al., 1979, Gastroenterology 76:903-907).
Aside from motilin itself, there are other substances which are agonists of the motilin receptor and which elicit gastrointestinal emptying. One of those agents is the antibiotic erythromycin. Even though erythromycin is a useful drug, a great number of patients are affected by the drug's gastrointestinal side effects. Studies have shown that erythromycin elicits biological responses that are comparable to motilin itself and therefore may be useful in the treatment of diseases such as chronic idiopathic intestinal pseudo-obstruction and gastroparesis (Weber, F. et al., 1993, The American Journal of
Gastroenterology, 88:4, 485-90).
Although motilin and erythromycin are agonists of the motilin receptor, there is a need for antagonists of this receptor as well. The nausea, abdominal cramping, and diarrhea which are associated with motilin agonsits are not always welcome physiological events. The increased gut motility induced by motilin has been implicated in diseases such as Irritable Bowel Syndrome and esophageal reflux. Therefore researchers have been searching for motilin antagonists.
One such antagonist is OHM-11526. This is a peptide derived from porcine motilin which competes with both motilin and erythromycin for the motilin receptor in a number of species, including rabbits and humans. In addition, this peptide is an antagonist of the contractile smooth muscle response to both erythromycin and motilin in an in vitro rabbit model
(Depoortere, I. et al., 1995, European Journal of Pharmacology, 286, 241-47).
Although this substance is potent in that model, it is a peptide and as such it is susceptible to the enzymes of the digestive tract (Zen Itoh, Motilin, xvi, 1990). Therefore it is desirable to find other agents which are not peptides as potential motilin antagonists. The compounds of this invention are such agents.
U.S. Pat. No. 5,972,939 to Chen et al. describes cyclopentene derivatives which are useful in treating gastrointestinal disorders associated with antagonizing the motilin receptor.
SUMMARY OF THE INVENTION
The present invention is directed to compounds of Formula
wherein
Ri is selected from hydrogen, d.salkyl optionally substituted with halogen, aminoCι-5alkyl, Ci-salkylaminoCi-salkyl, di-Ci-salkylaminoCi-salkyl, Cι-5alkylcarbonyl, C1.5alkoxycarbonyl, aminocarbonyl, Ci-galkylaminocarbonyl, cycloC3.9alkylaminocarbonyl, heteroarylaminocarbonyl optionally substituted with one or more Ci-salkyl, pyridinylcarbonyl optionally substituted with one or more
substituents selected from the group consisting of halogen and Ci.salkyl, thiophenecarbonyl optionally substituted with one or more substituents selected from the group consisting of halogen and Ci.salkyl, phenyl, phenylCi-salkyl, phenoxycarbonyl, phenylcarbonyl, diphenylmethylcarbonyl, phenylaminocarbonyl, phenylthiocarbonyl, phenylaminothiocarbonyl, said phenyl, phenylCi-salkyl, phenoxycarbonyl, phenylcarbonyl, diphenylmethylcarbonyl, phenylaminocarbonyl, phenylthiocarbonyl, phenylaminothiocarbonyl being optionally substituted with one or more substituents selected from the group consisting of halogen, Ci-salkyl, trihalomethyl, Ci-salkoxy, amino, nitrile, nitro, Ci-salkylamino, and di-Ci-salkylamino, which substituents may be taken together to form a fused bicydic aromatic ring or taken together with the phenyl ring to form a fused bicydic 7-10 membered heterocyclic ring having one or two heteroatoms selected from oxygen, sulfur and nitrogen, and RaRbN-Cι-salkyl wherein Ra and
Rb are independently selected from hydrogen and Ci-salkyl, or taken together to form a morpholine, piperazine, piperidine, or N-substituted piperidine wherein the N-substitutent is Ci-salkyl or phenylCi-salkyl;
R2 is selected from hydrogen, d-salkyl, Ci-salkoxy, phenyl optionally substituted with one or more substituents selected from the group consisting of halogen and Ci-salkyl, and phenylCi-salkyl optionally substituted with one or more substituents selected from the group consisting of halogen, Ci-salkyl, Ci-salkoxy, halo and di-Ci-salkylamino;
R3 is selected from hydrogen, Ci-salkylcarbonyl optionally substituted with halogen, and phenylcarbonyl optionally substituted with one or more substituents selected from the group consisting of halogen, Ci-salkyl, Ci-salkoxy, amino, Ci-salkylamino, and di-Ci-salkylamino;
R4 is selected from hydrogen, Ci-salkyl, Ci-salkylcarbonyl optionally substituted with halogen, and phenylcarbonyl optionally substituted with one or more substituents selected from the group consisting of halogen, Ci-salkyl, Ci-salkoxy, amino, Ci-salkylamino, and di-Ci-salkylamino;
n is 0-3;
m is 1-5;
(CH2)q — (A)t R5 is X' wherein: q is 0-3; t is 0-1 ;
X is oxygen, CH2, sulfur, hydroxy, thiol, or NRC wherein Rc is selected from hydrogen, Ci-salkyl, morpholinoCi-salkyl, pipehdinylCι-5alkyl, N-phenylmethylpiperidinyl, and piperazinylCι-5alkyl, with the proviso that if q and t are 0, X is hydroxy, thiol, or amino, A is Cι-5alkoxycarbonyl, phenylcarbonyl, or R R8N- wherein R7 and Re are independently selected from hydrogen,
Ci-salkyl, and cycloCi-.alkyl, or R7 and Rs form a 5- or 6-membered heterocyclic ring with one or more heteroatoms selected from the group consisting of oxygen, nitrogen, sulfur, and sulfoxides and N-oxides thereof; and
R6 is selected from hydrogen, halogen, Ci-salkoxy, Ci-salkylamino, and di-Ci-salkylamino ;
or a pharmaceutically acceptable salt thereof.
The compounds of Formula I are useful in treating gastrointestinal disorders associated with the motilin receptor. The compounds compete with erythromycin and motilin for the motilin receptor. In addition, the compounds are antagonists of the contractile smooth muscle response to those ligands.
The present invention also comprises pharmaceutical compositions containing one or more of the compounds of Formula I as well as methods for the treatment of disorders related to the gastrointestinal system which are associated with the motilin receptor. Such diseases include Irritable Bowel Syndrome, esophageal reflux, and the gastrointestinal side effects of erythromycin.
DETAILED DESCRIPTION OF THE INVENTION
The terms used in describing the invention are commonly used and known to those skilled in the art. However, the terms that could have other meanings are defined. "Independently" means that when there are more than one substituent, the substituents may be different. The term "alkyl" refers to straight, cyclic and branched-chain alkyl groups and "alkoxy" refers O-alkyl where alkyl is as defined supra. "Halogen" or "halo" means F, Cl, Br, and I.
The symbol "Ph" refers to phenyl. The term "fused bicydic aromatic" includes fused aromatic rings such as naphthyl and the like. The term "fused bicydic heterocycle" includes benzodioxoles and the like. The term "heteroaryl" as used herein represents a stable five or six membered monocyclic aromatic ring system which consists of carbon atoms and from one to three heteroatoms selected from N, O, or S. The heteroaryl group may be attached at any heteroatom or carbon atom which results in the creation of a stable structure. Examples of heteroaryl groups include, but are not limited to, triazole, thiazole, thiadiazole, oxazole, imidazole, pyrazole, pyrimidine, isothiazole, isoindole, isoxazole and the like. The heteroaryl group may be further substituted with
one or more groups such as alkyl, substituted alkyl, and halogen. More particularly, the heteroaryl group may be substituted with methyl.
The term "subject" as used herein, refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.
Since the compounds of the invention have a chiral center, they may be prepared as a single stereoisomer or in racemic form as a mixture of some possible stereoisomers. The non-racemic forms may be obtained by either synthesis or resolution. The compounds may, for example, be resolved into their components enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation. The compounds may also be resolved by covalent linkage to a chiral auxiliary, followed by chromatographic separation and/or crystallographic separation, and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using chiral chromatography.
When compounds contain a basic moiety, acid addition salts may be prepared and may be chosen from hydrochloric, hydrobromic, hydroiodic, perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, benzoic, cinnamic, mandelic, methanesulfonic, p-toluenesulfonic, cyclohexanesulfamic, salicylic, 2-phenoxybenzoic, 2-acetoxybenzoic, saccharin, and the like. Such salts can be made by reacting the free base of compounds of formula I with the acid and isolating the salt.
Compounds of the present invention may be prepared by known methods such as those disclosed in U.S. Pat. No. 5,972,939 to Chen et al., which is hereby incorporated by reference in its entirety.
The compounds of the invention may be prepared by the following procedures, where some schemes produce more than one embodiment of the invention. In those cases, the choice of scheme is a matter of discretion which is within the capabilities of those skilled in the art.
Essentially, Scheme 1 assembles two halves of the molecule and couples them. For one half, 3-ethoxy-2-cylclohepten-1-one, 1_a (a known compound), may be the starting material, a may be treated with a Grignard reagent, l b, such as 4-fluorobenzyl magnesium bromide (a known compound) preferably at room temperature (rt) under an inert atmosphere, using ether as a solvent to give the α,β-unsaturated ketone derivative 1_c. Treatment of 1_c with a reducing agent such as lithium aluminum hydride (LAH) preferably at 0 °C to room temperature will give the alcohol, Id This alcohol may be treated with a strong base such as NaH and trichloroacetonitrile preferably from 0 °C to room temperature to give the amide e. This seven-membered ring amide may be sequentially treated on dry ice with ozone, dimethylsulfide, and a catalytic amount of acid such as toluene sulfonic acid. Once addition is complete, the mixture can be warmed to room temperature over to give the six membered ring aldehyde, If, as a racemic mixture.
To assemble the other half, an aromatic alcohol lg, such as 3- hydroxyaniline may be treated with a mild base, such as K2CO3, in a suitable solvent such as ethanol (EtOH) at reflux. This mixture may be subsequently treated with a halide derivative 1 h, such as 3-chloropropylmorpholine preferably at room temperature to give the amine 1j. This amine may be treated with the aldehyde If and NaCNBH3 in methanol (MeOH) preferably at room temperature to give a compound of the invention ]c, as a racemic mixture.
If pure enantiomers are desired, they may be obtained in any of three stages of the synthesis. The alcohol Id, the aldehyde If, and the product |c may all be separated via HPLC using chiral columns or methods well known in
the art. With respect to all three compounds, they may be further manipulated to give other compounds of the invention without sacrificing their enantiomeric purity.
Scheme 1 may be used to produce other compounds of the invention. For example, to produce compounds where X is sulfur, simply replace reagent 1 h with an aromatic thiol, such as 3-aminothiopheπol and carry out the remaining steps of the Scheme.
Scheme 1
To produce other substitutions at R3 or R , some of the products of Scheme 1 may be used as shown in Scheme 2. For example, to produce a compound where R3 is hydrogen and R is CH3C(O)-, the seven-membered ring intermediate 1 e may be treated with a base, such as barium hydroxide, at reflux in ethanol (EtOH) to give the free amine 2a. The amine may be subsequently treated with an acid anhydride, such as trifluoroacetic anhydride to give 2b. This intermediate may be carried through the remaining steps of Scheme 1 to produce the desired compound ]d.
Scheme 2
The products of Scheme 1 may be used to produce other compounds of the invention as shown in Scheme 3. For example, to produce compounds of type le, compound lc may be treated with a phenyl isocyanate preferably at room temperature. To produce compounds of type Jf, ]c may be treated preferably at room temperature with acid chloride derivatives such as benzoyl chloride. In order to produce thiols Ig, compounds of type ]c may be treated with isothiocyanates, such as phenylisothiocyanate preferably at room temperature. As discussed earlier, if pure enantiomers are desired, they may be obtained by chromatography of the reactant lc or the products.
Scheme 3
Scheme 4 makes use of the intermediate of Scheme 1. Treatment of the aldehyde, Tf, with a nitroaniline derivative 4a (a known compound), and NaCNBH3 preferably at room temperature gives the coupled intermediate 4b. This intermediate may be acylated with benzoyl chloride and a mild base such as triethylamine to give the N-acyl intermediate 4c. 4c may be treated with a reducing agent such as Pd/C to give the aniline compound Jh. This compound may be coupled with a halogen derivative 4d, such as 3-chloropropylpiperidine, using 1 ,8. Diazabieyclo (5,4,0) undec-7-ene (DBU) and an alcoholic solvent at reflux to give a mixture of mono- and di-amine products (li and Ij).
Scheme 4
To prepare compounds of the invention where n is 1-3, products of Scheme 1 may be used as shown in Scheme 5. Intermediate If may be treated with 3-(m-hydroxyphenyl)propylamine, an aromatic amino alcohol derivative 5a known in the art, and NaCNBH3 preferably at room temperature to
give the amine ]k. Treatment of ]k with a thiocyanate derivative 5b, and a mild base preferably at room temperature gives the substituted thioamide jrn. This compound may be treated with a halide reagent, 5c, and a base such as DBU in an alcoholic solvent at reflux to give the O-substituted compound of the invention In.
Scheme 5
To produce compounds of the invention wherein R and Rs form sulfoxide or N-oxide, the procedure of Scheme 6 may be followed (MCPBA refers to 3-chloroperoxybenzoic acid).
Scheme 6
6a
MCPBA
CH2CI2
6b
Radiolabeled Motilin
The compounds of the invention were tested for their ability to compete with radiolabeled motilin (porcine) for the motilin receptors located on the colon of mature rabbits. The colon from mature New Zealand rabbits was removed, dissected free from the mucosa and serosa layers, and diced into small pieces. The muscle tissues were homogenized in 10 volumes of buffer (50 mM Tris-CI,
10 mM MgCI2ι 0.1 mg/mL bactracin, and 0.25 mM Peflabloc, pH 7.5) in a Polytron (29,000 rpm, 4 x 15 seconds). The homogenate was centrifuged at 1000 x g for 15 min. and the supernatant discarded. The pellet was washed twice before being suspended in homogenizing buffer. This crude homogenate was then passed first through a 19 gauge needle then a 23 gauge needle to further suspend the material and stored at -80 °C. In a total volume of 0.50 mL, the binding assay contained the following components added sequentially: buffer (50 mM Tris-CI, 10 mM MgCI2, 1 mM EDTA, 15 mg/mL BSA, 5 μg/mL leupeptin, aprotinin, and pepstatin, and 0.1 mg/mL, bactracin), I125 motilin (Amersham, ca 50,000-70,000 cpm, 25-40 pM), the test compound (the initial concentration was 2 mM/100% DMSO, which was diluted with H2O to a final concentration of 10 μM) and membrane protein (100-300 μg). After 30 min at 30 °C, the material was cooled on ice and centrifuged at 13,000 x g for 1 minute. The pellet was washed with 1 mL 0.9% saline and centrifuged at 13,000 x g for 15 seconds. The pellet was washed again with cold saline and the supernatant was removed. The pellet was counted in the gamma counter to determine the percentage of unbound motilin and thereby the percent inhibition of the test compound.
% inhibition was determined for some compounds by standard techniques:
3-Benzyl-3-trichloroacetamido-1-(N-phenylaminocarbonyl)-N-[(3-(2- morpholinoethoxy)phenyl)amino]methylcyclohexene (Example 6): 62% @ 50nM;
3-Benzyl-3-thchloroacetamido-1-N[(3-(2- morpholinoethoxy)phenyl)amino]methylcyclohexene (Example 7): 59% @ 50nM.
Rabbit duo denum smooth muscle
Compounds of the invention may be evaluated for their ability to inhibit motilin and erythromycin induced contractions in the rabbit duodenum smooth muscle. Rabbits may be fasted 24-48 h and euthanized. The venral midline incision may be made approximately 7.5 cm above the umbilicus up to the xyphoid process, exposing the upper peritoneal cavity. The first 8 cm of the duodenum starting at the pyloric valve may be quickly removed and placed in Krebs solution containing NaCI (120 mM), KCI (4.7 mM), MgSO4 *7 H2O (1.2 mM), CaCI2 *2 H2O (2.4 mM), KH2PO4 (1 mM), D-glucose (10 mM), and NaHCO3 (24 mM). The lumen may be flushed with Krebs solution and excess tissue removed. The tissue may be cut lengthwise, splayed open with the longitudinal muscle layer facing up, and the longitudinal muscle layer released away from the circular muscle and cut into 3x30 mm strips. A pre-tied 4-0 silk ligature with a loop may be placed at the middle of the strip and the strip folded over the loop so the strip is half its original length. The tissues may be mounted in a 10 mL tissue bath (Radnotti Glass Technology, Inc., Monrovia, CA.) containing Krebs solution gassed with 95% O2 + 5% CO2 at 37 °C. The tissues may be attached to a force displacement transducer (FT03, Grass Instruments, Quincy, MA.) and resting tension slowly increased to 1 g. The tissues may be allowed to equilibrate for 60-90 min with 2-3 wash cycles. The tissues may be equilibrated with two initial contractions induced by a concentration of acetylcholine (1 x 10"4 M) that produces a maximal contraction (0.1 mM), with the highest taken as 100% maximal contraction of that tissue. Base line and response levels may be expressed as grams tension developed and as a percent of the response to acetylcholine. The test compounds may be dissolved in DMSO (2 mM/100% DMSO) and applied to the prepared strips 5-
15 minutes prior to the addition of porcine motihn After addition, the tension is constantly monitored over 5 mm and the maximum tension is recorded The percent contraction may be measured at four ascending concentrations and where appropriate ICso's may be determined
The preferred compounds are those wherein Ri is selected from phenylaminocarbonyl, substituted phenylaminocarbonyl, phenylcarbonyl, and substituted phenylcarbonyl, R2 is phenylCi-salkyl, substituted phenylCι.5alkyl or phenyl,
R3 is phenylcarbonyl, substituted phenylcarbonyl, or substituted Ci-salkylcarbonyl, R is hydrogen or Ci-salkyl, q is 2 or 3, A is Cι-5alkoxycarbonyl or R7RsN- wherein R7 and Re are as described above,
n is 0, and m is 1
In another preferred embodiment of the invention
Ri is phenylaminocarbonyl or substituted phenylcarbonyl
R2 is benzyl, 3-CI benzyl, or 4-methoxy benzyl,
R3 is substituted Ci-salkylcarbonyl, R4 is hydrogen,
A is R R8N- wherein R7 and Rs taken together form a 5 or 6 membered heterocychc ring with one or more heteroatoms selected from the group consisting of oxygen, nitrogen, sulfur, and N-oxides thereof, and
X is oxygen.
Also illustrative of the present invention is the compound of Formula I wherein: Ri is phenylaminocarbonyl or halo substituted benzoyl;
R3 is halo substituted Ci-salkylcarbonyl; and A is morpolinyl.
To prepare the pharmaceutical compositions of this invention, one or more compounds or salts thereof, as the active ingredient, is intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral. In preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed. Thus for liquid oral preparations, such as for example, suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like; for solid oral preparations such as, for example, powders, capsules and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage form, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be sugar coated or enteric coated by standard techniques. For parenterals, the carrier will usually comprise sterile water, though other ingredients, for example, for purposes such as aiding solubility or for preservation, may be included. Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed. The pharmaceutical compositions herein will preferably contain per dosage unit, e.g., tablet, capsule, powder, injection, teaspoonful and the
like, from about 5 to about 500 mg of the active ingredient, although other unit dosages may be employed.
In therapeutic use for treating disorders of the gastrointestinal system in mammals, the compounds of this invention may be administered in an amount of from about 0.5 to 100 mg/kg 1 -2 times per day orally. In addition, the compounds may be administered via injection at 0.1-10 mg/kg per day. Determination of optimum dosages for a particular situation is within the capabilities of formulators.
In order to illustrate the invention, the following examples are included. These examples do not limit the invention. They are meant to illustrate and suggest a method of practicing the invention. Although there are other methods of practicing this invention, those methods are deemed to be within the scope of this invention.
EXAMPLES
Example 1 3-Benzyl-2-cyclohepten-1 -one
A solution of 3-ethoxy-2-cylcohepten-1 -one(5g, 0.89mol) in THF (70mL) was added at room temperature to a solution of 2M benzyl magnesium chloride (800ml) under N2 and stirred for 6h. The resulting mixture was poured into a solution of 30% H SO4 and stirred for 5h. The resulting organic layer was separated, and the aqueous layer was extracted with several portions of ether. The combined organic layer was dried (MgSO4), and concentrated in vacuo to give 3-benzyl-2-cyclohepten-1-one (3.1 g, 65%) as a colorless oil. NMR (CDCI3); 3.45(s,2Hιbenzylic protons), 5.97 (bs, 1 H, olefinic proton), 7.22 (m, 5H, aromatic protons).
Example 2 3-Benzyl-2-cyclohepten-1 -ol
A solution of 3-benzyl-2-cyclohepten-1 -one (3.1g, 18 mmol) in either 100 mL) was slowly added to a suspension of lithium aluminum hydride (LAH) (684 mg, 0.87 mol) and ether (100 mL) at 0° C under N2. The resulting mixture was stirred overnight at ambient temperature and cooled to 0° C. Saturated K2CO3 solution was added to quench the excess LAH, the mixture was filtered through Celite and washed with several portions of ether. The combined organic layers were dried (MgSO ) and concentrated in vacuo to give the title compound (3g, 93%) as a colorless oil. NMR (CDCI3):3.32(ABq,J = 6 Hz,2H, benzylic protons), 4.42 (bs, 1 H, CHOH), 5.58 (bs, 1 H, olefinic proton), 7.22 (m, 5H, aromatic protons).
EXAMPLE 3
3-Benzyl-3-tπchloroacetamιdocyclopheptene
A solution of 3-benzyl-2-cycloheptene-1 -ol (1 1 g, 5 45 mmol) in ether (50 mL) was added to a suspension of hexane washed 60% NaH (230 mg, 5 75 mol) in ether (5 mL) at 0° C under N2 and stirred for 1 h Trichloroacetonitπle (0 8g, 5 54 mmol) was slowly added and the resulting mixture was allowed to warm to ambient temperature and stirred overnight The solvent was removed in vacuo, hexane (25 mL) was added and the mixture was cooled to 0° C
Methanol (1 mL) was added and the resulting solid was filtered through Celite The organic solvent was removed in vacuo to give a crude intermediate This intermediate was dissolved in xylene (75 mL) and heated to reflux for 3h under N The solvent was removed in vacuo, and the residue was purified by column on silica gel (100g, ethylacetate (EtOAc)/hexane (1 9)) to give the title compound (207 mg, 11 %) as a white crystal MS (MH+ = 346)
EXAMPLE 4
3-Benzyl-3-tπchloroacetamιdo-2-cyclohexenecarboxaldehyde
A solution of 3-benzyl-3-trιchloroacetamιdocycloheptene (207 mg, 0 60 mmol) in methylene chloride (80 mL) was treated with ozone at -78° C until the solution turned blue The excess of ozone was removed with a stream of N2, dimethyl sulfide (0 2 mL) was added and the mixture was allowed to warm to room temperature paratoluene sulfonic acid-monohydrate (TsOH-H2O) (20 mg) was added and the resulting mixture was stirred for three days The resulting mixture was treated with 1 N NaOH (20 mL) The organic layer was separated and the aqueous layer was extracted with methylene chloride (2 x 15 mL) The combined organic layer was dried and the solvent was removed in vacuo The residue was purified by column on silica gel gel (EtOAc/hexane (1 9~2 9) to
give the aldehyde (63 mg, 30%) as a thick brown oil (crude product), which was carried to Example 5 as its starting material.
EXAMPLE 5 3-Benzyl-3-trichloroacetamido-1 -N-[(3-(2- morpholinoethoxy)phenyl)amino]methylcyclohexene
NaCNBH (23 mg, 0.61 mM.) was added to a solution of 3-benzyl-3- trichloroacetamido-2-cyclohexenecarboxaldehyde (63 mg, 0.17 mmol), 3-(2- morpholinoethoxy) aniline (130 mg, 0.59 mmol) acetic acid (0.05 mL) in methanol (10 mL) at room temperature under N2 and stirred for 30 min. Most of methanol was removed in vacuo and the residue was diluted with methylene chloride, washed with 1 N. NaOH and dried. The solvent was removed in vacuo and residue was purified by column chromatography on silica gel using hexane: ethyl acetate (1 :9) to give the title compound (58 mg, 60%) a a light brown oil.
MS (MH+ = 566).
EXAMPLE 6 3-Benzyl-3-trichloroacetamido-1-(N-phenylaminocarbonyl)-N-[(3-(2- morpholinoethoxy)phenyl)amino]methylcyclohexene
A solution of 3-benzyl-3-trichloroacetamido-1-N[(3-(2- morpholinoethoxy)phenyl)amino]methylcyclohexene (28 mg, 0.05 mM), phenyl isocyanate (59 mg, 0.49 mM) and triethyl amine (100 mg) in methylene chloride (5 mL) was stirred at room temperature for 16 hours. Most of solvent was removed in vacuo and the residue was purified by preparative TLC to give 3- Benzyl-3-trichloroacetylamino-1-(N-phenylcarbonyl)-N-[(3-(2- morpholinoethyl)phenyl)amino]methylcyclohexene as a thick oil (21 mg). MS (MH+ = 685). This was converted to the mono-hydrochlo de salt mp 103-105 (dec).
EXAMPLE 7
3-Benzyl-3-trichloroacetamido-1-N[(3-(2- morpholinoethoxy)phenyl)amino]methylcyclohexene
3,4-Difluorobenzoyl chloride (31 mg, 0.18 mM) was added to a solution of 3-benzyl-3-trichloroacetamido-1 -N[(3-(2- morpholinoethoxy)phenyl)amino]methylcyclohexene (26 mg, 0.05 mM) and triethylamine (0.2 mL) in methylene chloride (3 mL) at room temperature under N2 and stirred for 2 hours. Most of solvent was removed in vacuo and the oily residue was purified by preparative TLC to give the title compound as a thick oil
(22 mg, 58%) . MS (MH+ = 706). This was converted to the moπo- hydrochloride salt mp 103-105 (dec).
Claims
What is claimed is:
A compound of Formula (I):
Ri is selected from hydrogen, Ci-salkyl optionally substituted with halogen, aminoCι-5alkyl, Ci-salkylaminoCi-salkyl, di-Ci-salkylaminoCi-salkyl,
Cι.5alkylcarbonyl, Ci-salkoxycarbonyl, aminocarbonyl, Ci-galkylaminocarbonyl, cycloC3-9alkylaminocarbonyl, heteroarylaminocarbonyl optionally substituted with one or more Ci.salkyl, pyridinylcarbonyl optionally substituted with one or more substituents selected from the group consisting of halogen and Ci-salkyl, thiophenecarbonyl optionally substituted with one or more substituents selected from the group consisting of halogen and Ci-salkyl, phenyl, phenylCi-salkyl, phenoxycarbonyl, phenylcarbonyl, diphenylmethylcarbonyl, phenylaminocarbonyl, phenylthiocarbonyl, phenylaminothiocarbonyl, said phenyl, phenylCi-salkyl, phenoxycarbonyl, phenylcarbonyl, diphenylmethylcarbonyl, phenylaminocarbonyl, phenylthiocarbonyl, phenylaminothiocarbonyl being optionally substituted with one or more substituents selected from the group consisting of halogen, Ci-salkyl, trihalomethyl, Ci-salkoxy, amino, nitrile, nitro, Ci-salkylamino, and di-Ci-salkylamino, which substituents may be taken together to form a fused bicydic aromatic ring or taken together with the phenyl ring to form a fused bicydic 7-10 membered heterocyc c ring having one or two heteroatoms selected from oxygen, sulfur and nitrogen, and RaRbN-Cι-salkyl wherein Ra and Rb are independently selected from hydrogen and Cι.5alkyl, or taken together to form a morpho ne, piperaziπe, piperidine or N-substituted piperidine wherein the N-substitutent is Ci salkyl or phenylCi-salkyl,
R2 is selected from hydrogen, Ci-salkyl, Ci-salkoxy, phenyl optionally substituted with one or more substituents selected from the group consisting of halogen and Ci-salkyl, and phenylCi-salkyl optionally substituted with one or more substituents selected from the group consisting of halogen, Ci-salkyl, Ci-salkoxy, halo and di-Ci-salkylamino,
R3 is selected from hydrogen, Ci-salkylcarbonyl optionally substituted with halogen, and phenylcarbonyl optionally substituted with one or more substituents selected from the group consisting of halogen, Ci-salkyl, Ci-salkoxy, ammo, Ci-salkylamino, and di-Ci_salkylamino,
R4 is selected from hydrogen, Ci-salkyl, Ci-salkylcarbonyl optionally substituted with halogen, and phenylcarbonyl optionally substituted with one or more substituents selected from the group consisting of halogen, Ci-salkyl, Ci-salkoxy, ammo, Ci-salkylamino, and di-Ci-salkylamino,
(CH2)q- -(A)t
X is oxygen, CH2, sulfur, hydroxy, thiol, or NRC wherein
Rc is selected from hydrogen, Ci-salkyl, morpholinoCi-salkyl, piperidinylCι-5alkyl, N-phenylmethylpiperidinyl, and piperaziπylCι-5alkyl, with the proviso that if q and t are 0, X is hydroxy, thiol, or amino, A is Ci-salkoxycarbonyl, phenylcarbonyl, or R R8N- wherein R and R8 are independently selected from hydrogen, Ci-salkyl, and cycloCi-.alkyl, or R7 and R8 form a 5- or 6-membered heterocyclic ring with one or more heteroatoms selected from the group consisting of oxygen, nitrogen, sulfur, and sulfoxides and N-oxides thereof; and
R6 is selected from hydrogen, halogen, Ci-salkoxy, Ci-salkylamino, and di-Ci-salkylamino ;
or a pharmaceutically acceptable salt thereof.
2. A compound of Claim 1 wherein
Ri is selected from phenylaminocarbonyl, substituted phenylaminocarbonyl, phenylcarbonyl, and substituted phenylcarbonyl; R2 is phenylCi-salkyl, substituted phenylCi-salkyl or phenyl; R3 is phenylcarbonyl, substituted phenylcarbonyl, or substituted Ci-salkylcarbonyl; R is hydrogen or Ci-salkyl; q is 2 or 3;
A is Cι.5alkoxycarbonyl or R7R8N- wherein R and R8 are as claimed in Claim 1 ; t is 1 : n is 0; and m is 1.
A compound of Claim 1 , wherein
Ri is phenylaminocarbonyl or substituted phenylcarbonyl;
R2 is benzyl,
3-CI benzyl, or 4-methoxybenzyl;
R3 is substituted Ci-salkylcarbonyl;
R4 is hydrogen;
Re is hydrogen; q is 2;
A is R R8N- wherein R and R8 taken together form a 5 or 6 membered heterocydic ring with one or more heteroatoms selected from the group consisting of oxygen, nitrogen, sulfur, and N-oxides thereof; and
X is oxygen.
4. A compound according to Claim 1 , wherein
Ri is phenylaminocarbonyl or halo substituted benzoyl; R3 is halo substituted Ci-salkylcarbonyl; and A is morpolinyl.
5. A compound of Claim 1 represented by Formula (la).
A compound of Claim 1 represented by Formula (lb)
7. A pharmaceutical composition comprising an effective amount of a compound of Claim 1 and a pharmaceutically acceptable carrier.
8. A pharmaceutical composition comprising an effective amount of a compound of Claim 2 and a pharmaceutically acceptable carrier.
9. A pharmaceutical composition comprising an effective amount of a compound of Formula (la) or (lb), and a pharmaceutically acceptable carrier.
10. A method of treating a condition associated with motilin receptor activity comprising administering to a subject an effective amount of a compound of Claim 1.
11. A method of Claim 10, wherein the condition is irritable bowel syndrome or esophageal reflux.
12. A method of Claim 10, wherein the compound is a compound of Formula (I)
3\
Ri is selected from phenylaminocarbonyl, substituted phenylaminocarbonyl, phenylcarbonyl, and substituted phenylcarbonyl; R2 is phenylCi-salkyl, substituted phenylCi-salkyl or phenyl; R3 is phenylcarbonyl, substituted phenylcarbonyl, or substituted Ci-salkylcarbonyl; R4 is hydrogen or Ci-salkyl; q is 2 or 3; A is Cι-5alkoxycarbonyl or R7R8N- wherein R and R8are as claimed in claim 1 ; t is 1 ; n is 0; and m is 1.
13. A method of Claim 10, wherein the compound is a compound of Formula (I)
Ri is phenylaminocarbonyl or substituted phenylcarbonyl;
R2 is benzyl, 3-CI benzyl, or 4-methoxybenzyl;
R3 is substituted Ci-salkylcarbonyl;
R is hydrogen;
Re is hydrogen; q is 2;
A is R R8N- wherein R7 and R8 taken together form a 5 or 6 membered heterocydic ring with one or more heteroatoms selected from the group consisting of oxygen, nitrogen, sulfur, and N-oxides thereof; and
X is oxygen.
14. A method of Claim 10, wherein the compound is a compound of Formula (la) or (lb).
15. A method of treating a gastrointestinal side effect resulting from administration of erythromycin, which comprises administering to a subject an effective amount of a compound of Claim 1.
16. A method of Claim 15, wherein the condition is irritable bowel syndrome or esophageal reflux.
17. A method of Claim 15, wherein the compound is a compound of
Formula (I)
wherein Ri is selected from phenylaminocarbonyl, substituted phenylaminocarbonyl, phenylcarbonyl, and substituted phenylcarbonyl;
R2 is phenylCi-salkyl, substituted phenylCi-salkyl or phenyl; R3 is phenylcarbonyl, substituted phenylcarbonyl, or substituted Ci-salkylcarbonyl;
R is hydrogen or Ci-salkyl; q is 2 or 3;
A is Ci-salkoxycarbonyl or R R8N- wherein R7 and R8 are as claimed in claim 1 ; t is 1 ; n is 0; and m is 1.
18. A method of Claim 15, wherein the compound is a compound of
Formula (I) 3
\
I wherein
Ri is phenylaminocarbonyl or substituted phenylcarbonyl; R2 is benzyl, 3-CI benzyl, or 4-methoxybenzyl;
R3 is substituted Ci-salkylcarbonyl; R is hydrogen; Re is hydrogen; q is 2; A is R7R8N- wherein R and R8 taken together form a 5 or 6 membered heterocydic ring with one or more heteroatoms selected from the group consisting of oxygen, nitrogen, sulfur, and N-oxides thereof, and
X is oxygen
19 A method of Claim 15, wherein the compound is a compound of Formula (la) or (lb)
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WO2007007018A1 (en) | 2005-07-12 | 2007-01-18 | Glaxo Group Limited | Piperazine heteroaryl derivates as gpr38 agonists |
WO2007144400A1 (en) * | 2006-06-15 | 2007-12-21 | Glaxo Group Limited | Benzylpiperazine derivatives as motilin receptor antagonists |
WO2010098145A1 (en) | 2009-02-27 | 2010-09-02 | Raqualia Pharma Inc. | Oxyindole derivatives with motilin receptor agonistic activity |
EP2431380A2 (en) | 2006-09-11 | 2012-03-21 | Tranzyme Pharma, Inc. | Macrocyclic antagonist of the motilin receptor for treatment of gastrointestinal dysmotility disorders |
EP2441763A1 (en) | 2005-07-26 | 2012-04-18 | Glaxo Group Limited | Benzylpiperazine derivatives useful for the treatment of gastrointestinal disorders |
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WO2004111077A1 (en) | 2003-06-18 | 2004-12-23 | Tranzyme Pharma Inc. | Macrocyclic antagonists of the motilin receptor |
US20050172438A1 (en) * | 2004-01-29 | 2005-08-11 | Applied Materials, Inc. | Methods and apparatus for installing a scrubber brush on a mandrel |
US7596395B2 (en) * | 2004-10-21 | 2009-09-29 | Nokia Corporation | Depressible hinge and mobile stations using same |
NZ560269A (en) * | 2005-03-08 | 2010-12-24 | Nycomed Gmbh | Roflumilast for the treatment of diabetes mellitus |
WO2007103399A2 (en) * | 2006-03-07 | 2007-09-13 | Applied Materials, Inc. | Scrubber brush with sleeve and brush mandrel |
MX2009000110A (en) * | 2006-06-28 | 2009-01-23 | Glaxo Group Ltd | Piperazinyl derivatives useful in the treatment of gpr38 receptor mediated diseases. |
US20080287371A1 (en) * | 2007-05-17 | 2008-11-20 | Tranzyme Pharma Inc. | Macrocyclic antagonists of the motilin receptor for modulation of the migrating motor complex |
Citations (1)
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US5972939A (en) * | 1997-10-28 | 1999-10-26 | Ortho-Mcneil Pharmaceutical, Inc. | Cyclopentene derivatives useful as antagonists of the motilin receptor |
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HU202195B (en) * | 1987-12-31 | 1991-02-28 | Egyt Gyogyszervegyeszeti Gyar | Process for producing new substituted styrene derivatives and medical compositions comprising such compounds |
FR2636628B1 (en) | 1988-08-25 | 1990-12-28 | Sanofi Sa | THIADIAZOLE-1,3,4 DERIVATIVES, PROCESS FOR OBTAINING SAME AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME |
DK0777659T3 (en) | 1994-08-15 | 2001-09-03 | Merck Sharp & Dohme | Morpholine derivatives and their use as therapeutic agents |
-
2001
- 2001-03-09 US US09/803,572 patent/US6423714B2/en not_active Expired - Lifetime
- 2001-03-09 WO PCT/US2001/007701 patent/WO2001068621A1/en active Application Filing
- 2001-03-09 AU AU2001250820A patent/AU2001250820A1/en not_active Abandoned
- 2001-03-13 AR ARP010101167A patent/AR029896A1/en unknown
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5972939A (en) * | 1997-10-28 | 1999-10-26 | Ortho-Mcneil Pharmaceutical, Inc. | Cyclopentene derivatives useful as antagonists of the motilin receptor |
Cited By (8)
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US8236953B2 (en) | 2004-12-29 | 2012-08-07 | Glaxo Group Limited | Process for preparing piper azine derivatives |
WO2007007018A1 (en) | 2005-07-12 | 2007-01-18 | Glaxo Group Limited | Piperazine heteroaryl derivates as gpr38 agonists |
EP2441763A1 (en) | 2005-07-26 | 2012-04-18 | Glaxo Group Limited | Benzylpiperazine derivatives useful for the treatment of gastrointestinal disorders |
WO2007144400A1 (en) * | 2006-06-15 | 2007-12-21 | Glaxo Group Limited | Benzylpiperazine derivatives as motilin receptor antagonists |
JP2009539938A (en) * | 2006-06-15 | 2009-11-19 | グラクソ グループ リミテッド | Benzylpiperazine derivatives as motilin receptor antagonists |
US8012981B2 (en) | 2006-06-15 | 2011-09-06 | Glaxo Group Limited | Benzylpiperazine derivatives as motilin receptor agonists |
EP2431380A2 (en) | 2006-09-11 | 2012-03-21 | Tranzyme Pharma, Inc. | Macrocyclic antagonist of the motilin receptor for treatment of gastrointestinal dysmotility disorders |
WO2010098145A1 (en) | 2009-02-27 | 2010-09-02 | Raqualia Pharma Inc. | Oxyindole derivatives with motilin receptor agonistic activity |
Also Published As
Publication number | Publication date |
---|---|
US20020002192A1 (en) | 2002-01-03 |
AR029896A1 (en) | 2003-07-23 |
AU2001250820A1 (en) | 2001-09-24 |
US6423714B2 (en) | 2002-07-23 |
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