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WO1997023455A1 - Procedes de preparation d'antagonistes de recepteur de tachykinine non peptidyle - Google Patents

Procedes de preparation d'antagonistes de recepteur de tachykinine non peptidyle Download PDF

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Publication number
WO1997023455A1
WO1997023455A1 PCT/US1996/020199 US9620199W WO9723455A1 WO 1997023455 A1 WO1997023455 A1 WO 1997023455A1 US 9620199 W US9620199 W US 9620199W WO 9723455 A1 WO9723455 A1 WO 9723455A1
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WO
WIPO (PCT)
Prior art keywords
compound
formula
added
piperidin
pain
Prior art date
Application number
PCT/US1996/020199
Other languages
English (en)
Inventor
Erik C. Chelius
Douglas P. Kjell
Kurt T. Lorenz
Original Assignee
Eli Lilly And Company
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 Eli Lilly And Company filed Critical Eli Lilly And Company
Priority to AU14645/97A priority Critical patent/AU1464597A/en
Publication of WO1997023455A1 publication Critical patent/WO1997023455A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C07D209/16—Tryptamines

Definitions

  • Tachykinins are a family of peptides which share a common amidated carboxy terminal sequence.
  • Substance P was the first peptide of this family to be isolated, although its purification and the determination of its primary sequence did not occur until the early 1970's.
  • neurokinin A also known as substance K, neuromedin L, and neurokinin ⁇
  • neurokinin B also known as neuromedin K and neurokinin ⁇
  • Tachykinins are widely distributed in both the central and peripheral nervous systems, are released from nerves, and exert a variety of biological actions, which, in most cases, depend upon activation of specific receptors expressed on the membrane of target cells. Tachykinins are also produced by a number of non-neural tissues.
  • tachykinins substance P act through three major receptor subtypes, denoted as NK-1, NK-2, and NK-3, respectively. These receptors are present in a variety of organs.
  • Substance P is believed inter alia to be involved in the neuro transmission of pain sensations, including the pain associated with migraine headaches and with arthritis.
  • These peptides have also been implicated in gastrointestinal disorders and diseases of the gastrointestinal tract such as inflammatory bowel disease.
  • Tachykinins have also been implicated as playing a role in numerous other maladies, as discussed infra.
  • tachykinin receptor antagonists In view of the wide number of clinical maladies associated with an excess of tachykinins, the development of tachykinin receptor antagonists will serve to control these clinical conditions.
  • the earliest tachykinin receptor antagonists were peptide derivatives. These antagonists proved to be of limited pharmaceutical utility because of their metabolic instability.
  • Recent publications have described novel classes of non- peptidyl tachykinin receptor antagonists which generally have greater oral bioavailability and metabolic stability than the earlier classes of tachykinin receptor antagonists.
  • this invention provides processes for preparing a class of potent non-peptidyl tachykinin receptor antagonists similar to those of United States Patent 5,530,009.
  • the compounds prepared by the processes of the present invention do not suffer from the shortcomings, in terms of metabolic instability, of known peptide-based tachykinin receptor antagonists.
  • This invention provides processes for preparing a compound of the formula
  • This invention also provides processes for preparing a compound of the formula
  • this invention provides novel processes for preparing a compound of the formula
  • Ci-C ⁇ alkyl refers to straight or branched, monovalent, saturated aliphatic chains of 1 to 6 carbon atoms and includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, and hexyl.
  • Cj-C ⁇ alkyl includes within its definition the term "C 1 -C 3 alkyl”.
  • Halo represents chloro, fluoro, bromo or iodo.
  • haloformate refers to an ester of a haloformic acid, this compound having the formula
  • X is halo
  • R d is Ci-C ⁇ alkyl.
  • Preferred haloformates are bromoformates and chloroformates. Especially preferred are chloroformates. Those haloformates wherein R d is C 3 -C 6 alkyl are especially preferred. Most preferred is isobutylchloroformate.
  • the compounds prepared in the processes of the present invention have an asymmetric center.
  • the compounds produced in the present invention may occur as racemates, mixtures of enantiomers and as individual enantiomers, as well as diastereomers and mixtures of diastereomers. Processes for preparing such asymmetric forms, individual isomers and combinations thereof, are within the scope of the present invention.
  • R and S are used herein as commonly used in organic chemistry to denote specific configuration of a chiral center.
  • the term “R” (rectus) refers to that configuration of a chiral center with a clockwise relationship of group priorities (highest to second lowest) when viewed along the bond toward the lowest priority group.
  • the term “S” (sinister) refers to that configuration of a chiral center with a counterclockwise relationship of group priorities (highest to second lowest) when viewed along the bond toward the lowest priority group.
  • the priority of groups is based upon their atomic number (in order of decreasing atomic number).
  • the older D-L system is also used in this document to denote absolute configuration, especially with reference to amino acids.
  • a Fischer projection formula is oriented so that the number 1 carbon of the main chain is at the top.
  • the prefix "D” is used to represent the absolute configuration of the isomer in which the functional (determining) group is on the right side of the carbon atom at the chiral center and "L", that of the isomer in which it is on the left.
  • Patent Cooperation Treaty Publication WO 95/14017 published May 26, 1995, teaches, inter alia, a series of tachykinin receptor antagonists of the formula
  • n are independently 0-6;
  • Z is -(CHR ) p -(CHR 6 ) q -, where,
  • p is 0 or 1;
  • R 4 and R 6 are independently selected from the group consisting of hydrogen and C1-C3 alkyl;
  • N-R a or CH-NRbRc
  • R a , R b , and R c are independently selected from the group consisting of hydrogen and Ci-C ⁇ alkyl;
  • R 1 and R 2 are independently hydrogen, halo, Ci-C ⁇ alkoxy, Ci-C ⁇ alkylthio, nitro, trifluoromethyl, or Ci- C 6 alkyl;
  • Particularly preferred compounds are those of Formula I in which m and n are both 1; R 1 and R 2 are independently hydrogen, methoxy, ethoxy, chloro, fluoro, trifluoromethyl, methyl, and ethyl; Z is methylene; and Y, when combined with the heterocyclic group to which it is attached, forms 4-(piperidin-l-yl)piperidin-l-yl, 4- (cyclohexyl)piperazin-l-yl, 4-(phenyl)piperazin-l-yl, or 4- (phenyl )piperidin-l-yl.
  • the present invention describes novel processes for preparing the compounds depicted in Step (g), supra.
  • the advantages of the present process (through an oxalate intermediate, which is then converted to the desired product) over those taught in the art include greater reproducibility, a resulting solid that is easy to handle in subsequent steps, and a greater yield.
  • the prior art process for this acylation reaction directly yielded the dihydrochloride, trihydrate depicted in Step (g). The reproducibility of this reaction is not as great as that of the present invention and, therefore, did not lend itself to a commercial scale.
  • the intermediate amides are reduced to amines using procedures well known in the art. These reductions can be performed using lithium aluminum hydride as well as by use of many other different aluminum-based hydrides.
  • An especially preferred reagent employed in this reduction is RED-AL®, which is the tradename of a 3.4 M solution of sodium bis(2-methoxyethoxy)aluminum hydride in toluene.
  • the amides can be reduced by catalytic hydrogenation, though high temperatures and pressures are usually required for this.
  • Sodium borohydride in combination with other reagents may be used to reduce the amide. Borane complexes, such as a borane dimethylsulfide complex, are especially useful in this reduction reaction.
  • the acylation of the secondary amine can be done using any of a large number of techniques regularly employed by those skilled in organic chemistry.
  • One such reaction scheme is a substitution using an anhydride such as acetic anhydride.
  • Another reaction scheme often employed to acylate a secondary amine employs a carboxylic acid preferably with an activating agent.
  • An amino-de-alkoxylation type of reaction uses esters as a means of acylating the amine.
  • Activated esters which are attenuated to provide enhanced selectivity are very efficient acylating agents.
  • One preferred such activated ester is p-nitrophenyl ester, such as p-nitrophenyl acetate.
  • D-tryptophan 40.0 g, 0.196 mol
  • acetonitrile 240 ml
  • 1,1,1,3,3,3-hexamethyldisilazane 39.5 g, 0.245 mol
  • the resulting mixture was heated to 50-60°C and stirred until homogeneous.
  • trityl chloride 60.06 g, 0.215 mol
  • acetonitrile 120 ml
  • N-trityl-D-tryptophan N-methylmopholine salt 108.0 g, 0.196 mol
  • acetonitrile 800 ml
  • 2-chloro-4,6-dimethoxy-l,3,5-triazine 38.63 g, 0.22 mol
  • N-methylmorpholine 29.1 ml
  • the resulting mixture was stirred at ambient temperature until homogeneous (about ten minutes). After about one hour, 2-methoxybenzylamine (29 ml) was added. The resulting mixture was heated to 35°C and maintained at that temperature overnight.
  • RED-A ® [a 3.4 M, solution of sodium bis(2- methoxyethoxy)aluminum hydride in toluene] (535 ml, 1.819 mol), dissolved in anhydrous tetrahydrofuran (400 ml) was slowly added using an addition funnel to a refluxing solution of the acylation product, (R)-3- (lH-indol-3-yl)-N-(2-methoxybenzyl)-2-(N- triphenylmethylamino)propanamide (228.6 g, 0.404 mols) produced supra, in anhydrous tetrahydrofuran (1.0 L) under a nitrogen atmosphere. The reaction mixture became a purple solution.
  • the reaction was quenched after at least 20 hours by the slow addition of excess saturated Rochelle's salt solution (potassium sodium tartrate tetrahydrate).
  • the organic layer was isolated, washed with brine (2X), dried over anhydrous sodium sulfate, filtered, and concentrated to an oil on a rotary evaporator. No further purification was done and the product was used directly in the next step.
  • Cyclohexylpiperazine (10.0 g, 0.059 mol) was added to ten volumes of methylene chloride at room temperature. To this mixture was added sodium hydroxide (36 ml of a 2N solution, 0.072 mol) and tetrabutylammonium bromide (1.3 g, 0.004 mol). After the addition of the sodium hydroxide and tetrabutylammonium bromide, methyl bromoacetate (7.0 ml, 0.073 mol) was added and the reaction mixture was stirred for four to six hours. The progress of the reaction was monitored by gas chromatography. The organic fraction was separated and the aqueous phase was back-extracted with methylene chloride.
  • the title compound was prepared by dissolving the methyl 2-((4-cyclohexyl)piperazin-l-yl)acetate (10.0 g, 0.042 mol) in ten volumes of diethyl ether. This solution was cooled to 15°C and then potassium trimethylsilanoate (5.9 g, 0.044) was added. This mixture was then stirred for four to six hours. The reaction product was removed by filtration, washed twice with five volumes of diethyl ether, then washed twice with five volumes of hexanes, and then dried in a vacuum oven for 12-24 hours at 50°C. Analysis for C 12 H2 1 KN2O 2 • 1.5 H 2 0: Theory: C, 49.63; H, 7.98; N, 9.65.
  • the title compound was prepared by first cooling 2-((4- cyclohexyl)piperazin-l-yl)acetic acid potassium salt to a temperature between -8°C and -15°C in 5 volumes of anhydrous methylene chloride. To this mixture was added isobutylchloroformate at a rate such that the temperature did not exceed -8°C. The resulting reaction mixture was stirred for about 1 hour, the temperature being maintained between -8°C and -15°C.
  • the reaction was quenched by the addition of 5 volumes of water.
  • the organic layer was washed once with a saturated sodium bicarbonate solution.
  • the organic phase was then dried over anhydrous potassium carbonate and filtered to remove the drying agent.
  • To the filtrate was then added 2 equivalents of concentrated hydrochloric acid, followed by 1 volume of isopropyl alcohol.
  • the methylene chloride was then exchanged with isopropyl alcohol under vacuum by distillation.
  • reaction mixture (10.5 L) under a nitrogen atmosphere.
  • the reaction mixture was heated to 45-50°C for a minimum of 16 hours.
  • the organic fraction was dried over anhydrous magnesium sulfate, filtered, and solvent exchanged from methylene chloride to acetone (3.75 L) on a rotary evaporator.
  • An aqueous solution of hydrochloric acid (0.48 L of 6 N solution, 2.88 mol) and seed crystals (2 g) were added and mixture was stirred for 30-90 minutes.
  • Acetone (13.2 L) was then added and the slurry stirred for one hour.
  • the resulting mixture is then cooled to 0°C, stirred for about ten minutes, and then permitted to warm to room temperature.
  • the progress of the reaction was monitored by chromatography. High performance liquid chromatography showed 99% conversion of the reactants after ninety minutes.
  • the reaction mixture was partitioned between ethyl acetate (375 ml) and a saturated sodium bicarbonate solution (375 ml).
  • the aqueous layer was back extracted with 375 ml of ethyl acetate.
  • the organic fractions were combined, washed with water (3 x 375 ml), and then dried over magnesium sulfate.
  • Potassium hydroxide is then added to the aqueous fraction from above and this resulting basified solution is extracted with ethyl acetate. This organic fraction is then dried over magnesium sulfate.
  • the mixed anhydride process will work in a number of organic solvents, in addition to the anhydrous N,N-dimethylformamide depicted above.
  • solvents which may be employed include acetonitrile, tetrahydrofuran, dichloromethane.
  • the mixed anhydride process can be performed at temperatures below 0°C.
  • the oxalate can be isolated from ethyl acetate as well as from other solvents, probably including acetone, acetonitrile, and t -butyl methyl ether.
  • the use of oxalic acid is, however, very important for the precipitation as a large number of acids do not give a precipitate.
  • acids attempted, but found not satisfactory for the processes of the present invention are citric, anhydrous hydrochloric, tartaric, mandelic, trifluoroacetic, p-nitrobenzoic, phenoxyacetic, maleic, fumaric, glutaric, adipic, methanesulfonic, p-toluenesulfonic, pamoic, trans-l,2-cyclohexane dicarboxylic, succinic, phthalic, trans- l,2-diaminocyclohexane-N,N,N',N'-naphthalenedisulfonic, and 5- sulfosalicylic acids. Only oxalic acid and 1,5 -naphthalene disulfonic acid reproducibly produced a solid.
  • the phases were separated and the aqueous phase was extracted with methylene chloride (20 ml) and separated. The combined organic fractions were back extracted with water (30 ml) and dried over magnesium sulfate. The methylene was removed on an evaporator, leaving a residue. This residue was transferred to a jacketed flask and dissolved into acetone (24 g, 10.25 volumes). Enough water was added to bring the water concentration to eleven percent (by weight) and the resulting mixture was heated to 55°C. Enough concentrated hydrochloric acid was added to lower the pH to 2.0 and the reaction mixture was then permitted to cool to 37°C over 45 minutes. The product solution was seeded and permitted to stir for
  • the compounds prepared by the processes of the present invention are useful as tachykinin receptor-binding compounds. As such, they may be employed as antagonists or agonists of the various tachykinins. These compounds are, therefore, useful in the treatment or prevention of conditions associated with an excess or deficiency of tachykinins.
  • physiological disorder associated with an excess or deficiency of tachykinins encompasses those disorders associated with an inappropriate stimulation of tachykinin receptors, regardless of the actual amount of tachykinin present in the locale.
  • physiological disorders may include disorders of the central nervous system such as anxiety, depression, psychosis, and schizophrenia; neurodegenerative disorders such as dementia, including senile dementia of the Alzheimer's type, Alzheimer's disease, AIDS-associated dementia, and Down's syndrome; demyelinating diseases such as multiple sclerosis and amyotrophic lateral sclerosis and other neuropathological disorders such as peripheral neuropathy, such as diabetic and chemotherapy-induced neuropathy, and post- herpetic and other neuralgias; acute and chronic obstructive airway diseases such as adult respiratory distress syndrome, bronchopneumonia, bronchospasm, chronic bronchitis, drivercough, and asthma; inflammatory diseases such as inflammatory bowel disease, psoriasis, fibrositis, osteoarthritis, and rheumatoid arthritis; disorders of the musculo-skeletal system, such as osteoporosis; allergies such as eczema and rhinitis; hypersensitivity disorders such as poison ivy
  • the compounds of Formula I may suitably be used in the treatment of disorders of the central nervous system such as anxiety, psychosis, and schizophrenia; neurodegenerative disorders such as Alzheimer's disease and Down's syndrome; respiratory diseases such as bronchospasm and asthma; inflammatory diseases such as inflammatory bowel disease, osteoarthritis and rheumatoid arthritis; adverse immunological disorders such as rejection of transplanted tissues; gastrointestinal disorders and diseases such as disorders associated with the neuronal control of viscera such as ulcerative colitis, Crohn's disease and irritable bowel syndrome; incontinence; disorders of blood flow caused by vasodilation; and pain or nociception, for example, that attributable to or associated with any of the foregoing conditions or the transmission of pain in migraine.
  • disorders of the central nervous system such as anxiety, psychosis, and schizophrenia
  • neurodegenerative disorders such as Alzheimer's disease and Down's syndrome
  • respiratory diseases such as bronchospasm and asthma
  • inflammatory diseases such as inflammatory bowel disease, osteoarth
  • NK-1 antagonists are most especially preferred in the treatment of pain, especially chronic pain, such as neuropathic pain, post-operative pain, and migraines, pain associated with arthritis, cancer-associated pain, chronic lower back pain, cluster headaches, herpes neuralgia, phantom limb pain, central pain, dental pain, sunburn pain, neuropathic pain, opioid-resistant pain, visceral pain, surgical pain, bone injury pain, pain during labor and delivery, pain resulting from burns, post partum pain, angina pain, and genitourinary tract-related pain including cystitis.
  • chronic pain such as neuropathic pain, post-operative pain, and migraines, pain associated with arthritis, cancer-associated pain, chronic lower back pain, cluster headaches, herpes neuralgia, phantom limb pain, central pain, dental pain, sunburn pain, neuropathic pain, opioid-resistant pain, visceral pain, surgical pain, bone injury pain, pain during labor and delivery, pain resulting from burns, post partum pain, angina pain, and
  • NK-1 antagonists are especially preferred in the treatment and prevention of urinary incontinence; irritative symptoms of benign prostatic hypertrophy; motility disorders of the gastrointestinal tract, such as irritable bowel syndrome; acute and chronic obstructive airway diseases, such as bronchospasm, bronchopneumonia, asthma, and adult respiratory distress syndrome; atherosclerosis; inflammatory conditions, such as inflammatory bowel disease, ulcerative colitis, Crohn's disease, rheumatoid arthritis, osteoarthritis, neurogenic inflammation, allergies, rhinitis, cough, dermatitis, urticaria, psoriasis, conjunctivitis, irritation-induced miosis; tissue transplant rejection; plasma extravasation resulting from cytokine chemotherapy and the like; spinal cord trauma; stroke; cerebral stroke (ischemia); Alzheimer's disease; Parkinson's disease; multiple sclerosis; amyotrophic lateral sclerosis; schizophrenia; anxiety; and depression.
  • inflammatory conditions such as inflammatory
  • NK-2 antagonists are especially preferred in the treatment of urinary incontinence, bronchospasm, asthma, adult respiratory distress syndrome, motility disorders of the gastrointestinal tract, such as irritable bowel syndrome, and pain.
  • many of the compounds prepared by the processes of the present invention have also been tested in in vivo model systems for conditions associated with an excess of tachykinins. Of those compounds tested in vivo many have shown efficacy against said conditions.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Cette invention concerne de nouveaux procédés de préparation d'un composé correspondant à la formule (I), lesquels consistent à faire réagir un composé correspondant à la formule (II) avec de l'eau et de l'acide chlorhydrique. Cette invention concerne également des procédés de préparation du produit intermédiaire illustré ci-dessus, ainsi qu'un nouveau produit intermédiaire obtenu lors de cette synthèse.
PCT/US1996/020199 1995-12-21 1996-12-20 Procedes de preparation d'antagonistes de recepteur de tachykinine non peptidyle WO1997023455A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU14645/97A AU1464597A (en) 1995-12-21 1996-12-20 Processes for preparing non-peptidyl tachykinin receptor antagonists

Applications Claiming Priority (10)

Application Number Priority Date Filing Date Title
US900395P 1995-12-21 1995-12-21
US900495P 1995-12-21 1995-12-21
US904795P 1995-12-21 1995-12-21
US900595P 1995-12-21 1995-12-21
US60/009,003 1995-12-21
US60/009,005 1995-12-21
US60/009,047 1995-12-21
US60/009,004 1995-12-21
US1013596P 1996-01-17 1996-01-17
US60/010,135 1996-01-17

Publications (1)

Publication Number Publication Date
WO1997023455A1 true WO1997023455A1 (fr) 1997-07-03

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PCT/US1996/020199 WO1997023455A1 (fr) 1995-12-21 1996-12-20 Procedes de preparation d'antagonistes de recepteur de tachykinine non peptidyle

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AU (1) AU1464597A (fr)
WO (1) WO1997023455A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008090117A1 (fr) 2007-01-24 2008-07-31 Glaxo Group Limited Nouvelles compositions pharmaceutiques

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5530009A (en) * 1994-07-12 1996-06-25 Eli Lilly And Company Bis-piperidinyl non-peptidyl neurokinin receptor antagonists
WO1996024353A1 (fr) * 1995-02-10 1996-08-15 Eli Lilly And Company Procede de traitement ou de prevention de troubles psychiatriques

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5530009A (en) * 1994-07-12 1996-06-25 Eli Lilly And Company Bis-piperidinyl non-peptidyl neurokinin receptor antagonists
WO1996024353A1 (fr) * 1995-02-10 1996-08-15 Eli Lilly And Company Procede de traitement ou de prevention de troubles psychiatriques

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE WPIDS ON STN, Week 9638, Columbus, Ohio, USA, Derwent Information Ltd., AN 96-384206; & WO,A,96 24353 (LILLY & CO ELI), September 1996. *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008090117A1 (fr) 2007-01-24 2008-07-31 Glaxo Group Limited Nouvelles compositions pharmaceutiques

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