WO1992004025A1 - Amino acid analogs as cck antagonists - Google Patents

Amino acid analogs as cck antagonists Download PDF

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Publication number
WO1992004025A1
WO1992004025A1 PCT/US1991/006181 US9106181W WO9204025A1 WO 1992004025 A1 WO1992004025 A1 WO 1992004025A1 US 9106181 W US9106181 W US 9106181W WO 9204025 A1 WO9204025 A1 WO 9204025A1
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Prior art keywords
methyl
amino
dec
tricyclo
phenylethyl
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PCT/US1991/006181
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French (fr)
Inventor
David Christopher Horwell
Julian Aranda
Corinne Elizabeth Augelli-Szafran
Hans-Jurgen Betche
Ann Holmes
Michael David Mullican
Martyn Clive Pritchard
Reginald Stewart Richardson
Bruce David Roth
Edward Roberts
Bradley Dean Tait
Bharat Kalidas Trivedi
Uwe Trostmann
Paul Charles Unangst
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Warner-Lambert Company
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Priority claimed from US07/726,656 external-priority patent/US5331006A/en
Application filed by Warner-Lambert Company filed Critical Warner-Lambert Company
Publication of WO1992004025A1 publication Critical patent/WO1992004025A1/en

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    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
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    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
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    • C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
    • C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
    • C07D243/18—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals substituted in position 2 by nitrogen, oxygen or sulfur atoms
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    • C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • 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
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    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
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    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
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    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
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    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans 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 carbon atoms of the hetero ring
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    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Definitions

  • cholecystokinin (CCK) receptors may induce satiety (Schick, Yaksh, and Go, Regulatory Peptides
  • CCK-peptides have been found in the brains of schizophrenic patients compared with controls (Roberts, Ferrier, Lee, Crow, Johnston, Owens, Bacarese-Hamilton, McGregor, O'Shaughnessey, Polak, and Bloom, Brain Research 288:199-211, 1983). It has been proposed that changes in the activity of CCK neurones projecting to the nucleus accumbens may play a role in schizophrenic processes by influencing dopaminergic function (Totterdell and Smith,
  • agents modifying CCK receptor activity may have therapeutic value in conditions associated with disturbed function of central dopaminergic function such as schizophrenia and Parkinson's
  • CCK and gastrin peptides share a common carboxy terminal pentapeptide sequence and CCK peptides can bind to the gastrin receptor of the stomach mucosa and elicit acid secretion in many species including human (Konturek, Gastrointestinal Hormones, ed.
  • Antagonists of the CCK-B receptor would also be expected to be antagonists at the stomach gastrin receptor and this would also be of value for
  • gastrin-secreting cells are associated with certain gastrointestinal tumors as in the Zollinger-Ellison syndrome (Stadil, ibid., pp. 729-739), and some colorectal tumors may also be gastrin/CCK dependent (Singh, Walker, Townsend, and Thompson, Cancer Research 46:1612, 1986; Smith,
  • the CCK peptides are widely distributed in various organs of the body, including the
  • CCK peptides The high concentrations of CCK peptides in many brain areas also indicate major brain functions for these peptides (Dockray, Br. Med. Bull. 38(3):253-258, 1982). The most abundant form of brain CCK found is CCK26-33, although small quantities of CCK30-33 exist (Rehfeld and Gotterman, J. Neurochem. 32:1139-1341, 1979). The role of central nervous system CCK is not known with certainty, but it has been implicated in the control of feeding (Della-Fera and Baile, Science 206:471-473, 1979).
  • appetite suppressant drugs either act peripherally, by increasing energy
  • Centrally acting appetite suppressants either potentiate central catecholamine pathways and tend to be stimulants (for example, amphetamine), or influence serotonergic pathways (for example, fenfluramine).
  • Other forms of drug therapy include bulking agents which act by filling the stomach, thereby inducing a "feeling" of satiety.
  • CCK is known to be present in some cortical interneurones which also contain gamma-aminobutyric acid (GABA) (DeMeulemeester, et al, J. Neuroscience
  • Agents that modify GABA action may have utility as anxiolytic or hypnotic agents
  • the invention relates to novel compounds of the formula
  • R 1 , R 2 , R 3 , R 4 , R 9 , R 12 , R 13 , A, Ar, and Ar 2 are as defined hereinbelow.
  • the present invention also relates to a pharmaceutical composition containing an effective amount of a compound according to formula I in combination with a pharmaceutically acceptable carrier in unit dosage form effective for appetite suppression.
  • the compounds are also useful as anxiolytics, antipsychotics, especially for treating schizophrenic behavior, as agents in treating disorders of the extrapyramidal motor system, as agents for blocking the trophic and growth stimulating actions of CCK and gastrin, and as agents for treating gastrointestinal motility.
  • Compounds of the invention are also useful as analgesics and potentiate the effect of morphine.
  • morphine and other opioids can be used as an adjunct to morphine and other opioids in the treatment of severe pain such as cancer pain and reduce the dose of morphine in treatment of pain where morphine is contraindicated.
  • a suitably radiolabeled derivative such as iodine-131 or iodine-127 isotope gives an agent suitable for treatment of
  • gastrin-dependent tumors such as those found in colonic cancers.
  • radiolabeled compounds can also be used as a diagnostic agent by localization of gastrin and CCK-B receptors in both peripheral and central tissue.
  • the invention further relates to a method of appetite suppression in mammals which comprises administering an amount effective to suppress appetite of the composition described above to a mammal in need of such treatment.
  • the invention also relates to a pharmaceutical composition for reducing gastric acid secretion
  • formula K in combination with a pharmaceutically acceptable carrier in unit dosage form effective for reducing gastric acid secretion.
  • the invention also relates to a method for
  • the invention also relates to a method for reducing anxiety in mammals which comprises
  • the invention further relates to a method for treating gastrointestinal ulcers in mammals which comprises administering an amount effective for gastrointestinal ulcer treatment of the composition as described above to a mammal in need of such treatment.
  • the invention also relates to a pharmaceutical composition containing an effective amount of a compound of formula I in combination with a pharmaceutical composition containing an effective amount of a compound of formula I in combination with a pharmaceutical composition containing an effective amount of a compound of formula I in combination with a pharmaceutical composition containing an effective amount of a compound of formula I in combination with a pharmaceutical composition containing an effective amount of a compound of formula I in combination with a pharmaceutical composition containing an effective amount of a compound of formula I in combination with a
  • the invention further relates to a method for treating psychosis in mammals which comprises
  • the invention also relates to pharmaceutical compositions effective for stimulating or blocking CCK or gastrin receptors, for altering the activity of brain neurons, for schizophrenia, for treating disorders of the extrapyramidal motor system, for blocking the trophic and growth stimulating actions of CCK and gastrin, and for treating gastrointestinal motility.
  • the invention also relates to a pharmaceutical composition for preventing the withdrawal response produced by chronic treatment or abuse of drugs or alcohol.
  • the invention further relates to a method for treating the withdrawal response produced by
  • drugs include benzodiazepines, especially diazepam, cocaine, caffeine, opioids, alcohol, and nicotine. Withdrawal symptoms are treated by administration of an effective withdrawal treating amount of a compound of the instant invention.
  • the invention also relates to a method for
  • treating and/or preventing panic in mammals which comprises administering an amount effective for panic treatment and/or prevention of the composition
  • the invention further relates to the use of the compounds of formula I to prepare pharmaceutical and diagnostic compositions for the treatment and
  • the invention further provides processes for the preparation of compounds of formula I.
  • the invention further provides novel
  • the compounds of the present invention are formed by the condensation of two modified amino acids and are therefore not peptides. Rather, they are
  • dipeptoids synthetic peptide-related compounds differing from natural dipeptides in that the
  • substituent group R 2 is not hydrogen.
  • R 1 is a cycloalkyl or polycycloalkyl hydrocarbon of from three to twelve carbon atoms with from zero to four substituents each independently selected from the group consisting of a straight or branched alkyl of from one to about six carbon atoms, halogen, CN, OR* , SR* , CO 2 R* , CF 3 , NR 5 R 6 , and -(CH 2 ) n OR 5 wherein R* is hydrogen or a straight or branched alkyl of from one to six carbon atoms, R 5 and R 6 are each independently hydrogen or alkyl of from one to about six carbon atoms and n is an integer from zero to six;
  • n is an integer from zero to six;
  • n, R*, R 5 , and R 6 are as defined above and Ar is as defined below;
  • R 3 and R 4 are each independently selected from hydrogen, R 2 and -(CH 2 ) n ,-B-D wherein:
  • n' is an integer of from zero to three;
  • R 7 or R 8 are independently selected from hydrogen and R 2 or together form a ring (CH 2 ) m wherein m is an integer of from 1 to 5 and n is as defined above;
  • n is an integer of from 0 to 2
  • R*, R 2 , R 5 , and R 6 are as defined above;
  • R 9 is hydrogen or a straight or branched alkyl of from one to about six carbon atoms, - (CH 2 ) n CO 2 R*, -(CH 2 ) n OAr', -(CH 2 ) n NR 5 R 6 , wherein n, R*, R 5 , and R 6 are as defined above or taken from R 3 and Ar' is taken from Ar as defined below; R 12 and R 13 are each independently hydrogen or are each independently taken with R 3 and R 4 , respectively, to form a moiety doubly bonded to the carbon atom;
  • Ar is a mono- or polycyclic unsubstituted or substituted carbo- or heterocyclic aromatic or carbo- or heteroaromatic moiety
  • Ar 2 can be selected from Ar as defined above or the CH 2 Ar 2 moiety of formula I is the sidechain of a biologically significant amino acid, with the proviso that Ar 2 cannot be
  • Preferred compounds of the instant invention are those wherein
  • R 1 is a cycloalkyl or a polycycloalkyl of
  • CN F, Cl, Br, OR*, SR*, wherein R*, R 5 , and R 6 are as defined in Claim 1 and n is an integer of from 1 to 3;
  • R 2 is -CH 3 , -CH 2 CO 2 H, or -CH 2 C ⁇ CH;
  • R 3 is -(CH 2 ) n ,-B-D or H;
  • R 4 is -(CH 2 ) n ,-B-D or H;
  • R 9 is hydrogen or methyl
  • Ar is a monocyclic 5- or 6-member ring
  • each ring having from 0 to 4 heteroatoms each independently nitrogen, oxygen, or sulfur, a bicyclic ring system wherein each ring is independently a 5- or 6-member ring containing from 0 to 3 heteroatoms each independently selected from nitrogen, oxygen, and sulfur,
  • each ring is independently a 5- or 6-member ring containing from 0 to 5 heteroatoms selected from nitrogen, oxygen, sulfur, or
  • Ar 2 is a monocyclic 5- or 6-member ring
  • each ring is independently a 5- or 6-member ring containing from 0 to 3 heteroatoms, each independently selected from nitrogen, oxygen, and sulfur,
  • each ring independently is a 5- or 6-member ring containing from 0 to 5 heteroatoms selected from nitrogen, oxygen, and sulfur,
  • More preferred compounds of the instant invention are those wherein R 1 is an unsubstituted or substituted
  • R*, R 5 , and R 6 are as defined in Claim 1 and n is an integer of from 1 to 3;
  • R 2 is -CH 3 , -CH 2 CO 2 H, or -CH 2 C ⁇ CH;
  • R 3 is H, CH 2 OH, CH 2 OCOCH 2 CH 2 CO 2 H,
  • R 12 is hydrogen
  • R 13 is hydrogen
  • Ar and Ar 2 are as above.
  • Still more preferred compounds of the instant invention are those wherein
  • R 1 is 2-adamantyl, 1-(S)-2-endobornyl, or
  • R 2 is CH 3 ;
  • R 3 is H, CH 2 OH, CH 2 OCOCH 2 CH 2 CO 2 H,
  • R 12 is hydrogen
  • R 13 is hydrogen
  • Ar 2 is as defined above for Ar or the CH 2 Ar 2 moiety of formula I is the sidechain of a biologically significant amino acid.
  • Preferred compounds are those of formula 1 wherein Ar 2 is:
  • Each of the above moieties for Ar or Ar 2 can be independently unsubstituted, mono- or polysubstituted wherein the substituent is independently selected from NR 5 R 6 , halogen, alkyl, or alkoxy.
  • Especially preferred compounds of the instant invention are those wherein Ar 2 is
  • Butanoic acid 4-[[2-(4-quinolinylmethyl)-1-oxo- 2-[[(tricyclo[3.3.1.1 3 ' 7 ]dec-2-yloxy)carbonyl]amino]- propyl]amino-1-phenylethyl]amino]-4-oxo-,
  • Butanoic acid 4-[[2-[2-(1,2,3,4-tetrahydro)- quinolinylmethyl]-1-oxo-2-[[(tricyclo[3.3.1.1 3 ' 7 ]dec-2- yloxy)carbonyl]amino]propyl]amino]-1- phenylethyl]amino]-4-oxo-,
  • Butanoic acid 4-[[2-[2-(1,2-dihydro)- quinolinylmethyl]-1-oxo-2-[[(tricyclo[3.3.1.1 3 ' 7 ]dec-2- yloxy)carbonyl]amino]propyl]amino]-1-phenylethyl]- amino]-4-oxo-,
  • naphthalenylmethyl center is RS, other center is S
  • Tricyclo[3.3.1.1 3 ' 7 ]dec-2-yl [2-[[1-hydroxymethyl)- 2-phenylethyl]amino]-1-methyl-1-(2- naphthalenylmethyl)-2-oxoethyl]carbamate (naphthalene center is RS, hydroxymethyl center is S),
  • Tricyclo[3.3.1.1 3 ' 7 ]dec-2-yl [2-[[2-hydroxy-1- (hydroxymethyl)-2-phenylethyl]amino]-1-[(4-hydroxyphenyl)methyl]-1-methyl-2-oxoethyl]carbamate (mixture of [1S-[1R*(R*),2R*]] and [1S-[1R*(S*),2R*]] isomers), Tricyclo[3.3.1.1 3 ' 7 ]dec-2-yl [2-[[2-hydroxy-1- (hydroxymethyl)-2-phenylethyl]amino]-1-[(4-methoxy- phenyl)methyl]-1-methyl-2-oxoethyl]carbamate (mixture of [1S-[1R*(R*),2R*]] and [1S- [1R* (S*), 2R*]] isomers), Tricyclo[3.3.1.1 3 ' 7 ]dec-1-y
  • the compounds include solvates and hydrates and pharmaceutically acceptable salts of the compounds of formula I.
  • the compounds of the present invention can have multiple chiral centers including those designated in the above formula I by a depending on their structures. For example, when R 3 taken with R 12 and R 4 taken with R 13 form double bonds to these carbon atoms they are no longer chiral. In addition, centers of asymmetry may exist on substituents R 1 , R 9 , R 3 , R 4 , Ar, and/or Ar 2 . In particular, the compounds of the present invention may exist as diastereomers, mixtures of diastereomers, or as the mixed or the individual optical enantiomers.
  • the present invention
  • benzathine chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc.
  • the compounds of the present invention can be formed by coupling individual substituted ⁇ -amino acids by methods well known in the art. (See, for example, standard synthetic methods discussed in the multi-volume treatise "The Peptides, Analysis,
  • X is Br or Cl
  • Y is hydrogen or 4-Cl; i; LDA or LHMDSA-THF :H 3 O + :OH- ii; 2-AdocCl-THF-Et 3 N:OH- iii; DCCI or WSDCCI; PfpOH or HOBt; PhCh 2 CH (R) NH 2 -EtOAc iv; HCO 2 NH 4 -10% Pd/C-MeOH-cC 6 H 8 when Ar is e) above.
  • benzylbromide, NaOH, and tetrabutyl ammonium bromide affording the ether 14, the aldehyde of which is reduced to the primary alcohol 15 using NaBH 4 .
  • the bromomethylene compound 16 is prepared from the primary alcohol by treatment of 15 with Ph 3 P, Br 2 , and Et 3 N. This is then reacted with lithiomethyl- N-benzalalaninate, and the imine hydrolyzed with aqueous acid to the amine 17 , which is coupled with 2-adamantyl chloroformate to give the urethane 18. Ester hydrolysis of 18 with LiOH to 19 followed by condensation with 2-phenethylamine gave 20 upon which gave the product 21 (Example 14) upon hydrogenation of the ether over Pd/C.
  • Scheme IV shows how aniline derivatives are synthesized in an exactly analogous way to that described in Scheme III, the primary alcohol 22 was converted to the methyl bromide 23 from which the amine-ester 24 was prepared.
  • Methyl N-benzalalaninate was treated with sodium dimesyl in dimethyl sulphoxide solution.
  • Scheme VI illustrates preparative steps in the process for making compounds of the instant invention as exemplified by Examples 17-29.
  • Scheme VII shows a typical sequence similar to that illustrated in Scheme V. Reaction of
  • heteroarylmethyl halides II with the carbanion derived from methyl N-benzalalaninate III gives, upon acidic hydrolysis of the imine, the amine IV, this when treated with an appropriate chloroformate V yields the urethane - ester VI.
  • Hydrolysis of the ester with lithium hydroxide gave the carboxylic acid VII, which may be converted to give an appropriate amide I by reaction of an active ester derivative (such as pentafluoro phenyl ester) with the corresponding amine.
  • Hydrogenation of compound X gave a mixture of amines XI, XI, and VIII, which were acylated to various R 2 groups.
  • Scheme IX shows another route to compound 6.
  • a mixture of methyl-3-indazole carboxylate 1 and sodium hydride in THF was treated with p-toluenesulphonyl chloride to give the N-tosyl protected indazole 8 .
  • Reduction of the ester 8 with Red-Al (sodium dihydro- bis (2-methoxyethoxy) aluminate) gave the primary alcohol 9 , which on treatment with thionyl chloride gave the methyl chloride 10.
  • the chloromethyl derivative 10 was treated with the carbanion derived from treating methyl N-benzalalanate with sodium hydride in DMSO and the imine hydrolyzed with dilute hydrochloric acid.
  • Scheme X shows the synthesis of several amides 13a-c derived from 6 via the active ester of the carboxylic acid group in 6 and the appropriate amine.
  • the benzyl ester 13c was converted to the acid 14 by hydrogenation using Pearlman's catalyst in ethanol (Scheme XI).
  • the present invention is also concerned with compounds of the formula I and processes for the preparation thereof (see Scheme XIV)
  • R 1 is a group of the formula
  • the present invention is also concerned with compounds of the formula I and processes for the preparation thereof (see Scheme XVI)
  • R 1 is a group of the formula and R 2 is
  • This acid (intermediate II) is condensed with the amines 9 as illustrated in Scheme XVII to produce the final products 10.
  • the present invention is concerned with compounds of the general formula I and processes for the
  • R 1 is a group of the formula
  • R 3 is a hydrogen atom
  • Scheme VIII (Route A) and Scheme IX (Route B) illustrate processes for the preparation of a compound of the above formula for the intermediate.
  • Scheme VIII involves reacting the quaternary salt 1 with the aldimine 3 in the presence of sodium hydride in dimethylsulfoxide (cf., for example, EP A 0037271).
  • the Schiff base thus formed is not isolated and is subjected to hydrolysis with 1N hydrochloric acid to give the free amine 3.
  • This is condensed with 2-adamantyl chloroformate (4) to give the methyl ester 5 which is hydrolyzed with lithium hydroxide in dioxane/water followed by further acid work up to give the free acid 6 .
  • the acid 6 is condensed with amines such as illustrated in Scheme X to produce final products, for example, condensation of 6 with phenylethylamine gives compound 13a with (S)-(-)-2-amino-3-phenyl-1-propanol gives compound 13b and with (R)-4-[[(2-amino-1- phenyl)ethyl]amino]-4-oxobutanoic acid benzyl ester to give 13c and 13d.
  • amines such as illustrated in Scheme X to produce final products, for example, condensation of 6 with phenylethylamine gives compound 13a with (S)-(-)-2-amino-3-phenyl-1-propanol gives compound 13b and with (R)-4-[[(2-amino-1- phenyl)ethyl]amino]-4-oxobutanoic acid benzyl ester to give 13c and 13d.
  • the benzyl ester 13c is reduced to the free carboxylic acid 14 using hydrogen and 20% Pd(OH) 2 on carbon catalyst (Scheme XI). BIOLOGICAL ACTIVITY
  • the final pellet was resuspended in 20 volumes of 10 nM Hepes buffer (pH 7.2 at 23°C) containing 130 mM NaCl, 4.7 nM KCl, 5 nM MgCl 2 , 1 nM EDTA, 5 mg/mL bovine albumin, and bacitracin
  • nonspecific binding was defined as that persisting in the presence of the unlabeled octapeptide CCK 26-33 (10- 6 M).
  • the specific binding to CCK receptor sites was defined as the total bound tritiated pentagastrin minus the amount of tritiated pentagastrin bound in the presence of 10 -6 octapeptide, CCK 26-33 .
  • TC 50 values were defined as the concentration of test compound required to produce 50% inhibition of specific binding).
  • K i The inhibition constant (K i ) of the test compound was then calculated according to the Cheng-Prusoff equation: where [L] is the concentration of radiolabel and K a is the equilibrium dissociation constant.
  • Each rat was presented with 20 to 30 g of the palatable diet for 30 minutes per day during the light phase of the light-dark cycle over a training period of 5 days.
  • the intake of palatable diet was measured by weighing the food container before and after the 30-minute access period (limits of accuracy 0.1 g). Care was taken to collect and correct for any spillage of the diet. Rats had free access to pellet food and water except during the 30-minute test period.
  • the compounds of the instant invention are administered to the patient at dosage levels of from about 200 to about 2800 mg per day.
  • the cavity of the stomach is perfused at a rate of 3 mL/min with 5.4% w/v glucose solution through both the esophageal and body cannula.
  • the fluid is propelled by a roller pump (Gilson, Minipuls 2), through heating coils to bring its temperature to 37 ⁇ 1°C.
  • the perfusion fluid is collected by the fundic collecting funnel and passed to a pH electrode connected to a Jenway pH meter (PHM6). An output is taken from the pH meter to a Rikadenki chart recorder for the on-line recording of the pH of the gastric perfusate.
  • Pentagastrin is stored as a frozen aliquot and diluted to the required concentrations with sterile 0.9% w/v NaCl. Novel compounds are dissolved in sterile 0 . 9% w/v NaCl on the day of the experiment .
  • Drugs are administered IV through a cannulated jugular vein as a bolus in a dose volume of 1 mL/kg washed in with 0.15 mL 0.9% w/v NaCl. Basal pH is allowed to stabilize before administration of compounds is begun. Typically, 30 minutes elapses between surgery and the first compound administration.
  • the compounds of the instant invention are also expected to be useful as antiulcer agents as discussed hereinbelow.
  • Aspirin-induced gastric damage is assessed in groups of 10 rats each.
  • CMC carboxymethylcellulose
  • the animals are sacrificed 5 hours after aspirin administration and the stomachs removed and opened for examination.
  • the compounds of the instant invention are also expected to be useful as anxiolytic agents as
  • the apparatus is an open-topped box, 45 cm long, 27 cm wide, and 27 cm high, divided into a small (2/5) area and a large (3/5) area by a partition that extended 20 cm above the walls. There is a 7.5 x 7.5 cm opening in the partition at floor level.
  • the small compartment is painted black and the large compartment white.
  • the floor of each compartment is illuminated by a 100-watt tungsten bulb 17 cm above the box and the black compartment by a similarly placed 60-watt red bulb.
  • the laboratory is
  • mice 0 minutes and 18 hundred hours, 0 minutes.
  • Each mouse is tested by placing it in the center of the white area and allowing it to explore the novel environment for 5 minutes. Its behavior is recorded on videotape and the behavioral analysis is performed subsequently from the recording. Five parameters are measured: the latency to entry into the dark compartment, the time spent in each area, the number of transitions between compartments, the number of lines crossed in each compartment, and the number of rears in each compartment.
  • the compounds of the instant invention are expected to be useful as antipsychotic agents.
  • mice Male Sprague Dawley (CD) Bradford strain rats are used. The rats are housed in groups of five at a temperature of 21 ⁇ 2°C on a 12-hour light-dark cycle of lights-on between 07 hours, 00 minutes and
  • Rats 20 hours, 00 minutes. Rats are fed CRM diet (Labsure) and allowed water ad libitum.
  • Rats are anesthetized with chloral hydrate
  • Rats are manually restrained and the stylets removed.
  • Intracerebral injection cannulae 0.3 mm diameter, are inserted and drugs delivered in a volume of 0.5 ⁇ L over 5 seconds (a further 55 seconds was allowed for deposition) from Hamilton syringes
  • locomotor activity e . g . , sedation, prostration, stereotyped movements, that could interfere with the recording of locomotor activity.
  • the abilities of the compounds to inhibit the hyperactivity caused by the injection of amphetamine into the nucleus accumbens of the rat is measured.
  • locomotor activity follows the bilateral injection of amphetamine (20 ⁇ g) into the nucleus accumbens; peak hyperactivity (50 to 60 counts 5 minutes -1 ) occurs 20 to 40 minutes after injection. Intraperitoneal injection of the rats with a compound at 10, 20, or 30 mg/kg reduces the
  • the compounds of the instant invention are expected to prevent and treat the withdrawal response produced when chronic treatment by a drug is stopped or when alcohol abuse is stopped. These compounds are therefore useful as therapeutic agents in the
  • Animals are given nicotine, 0.1 mg/kg i.p. b.d. for 14 days. After a 24-hour withdrawal period, a compound is typically given at 0.1 to 100 mg/kg i.p. b.d.
  • the increased time spent in the light area is a sensitive measure of the effect of the compound as an agent to treat withdrawal effects from nicotine.
  • mice The effect of long-term treatment and withdrawal from diazepam with intervention with a compound can be shown.
  • Five mice are given diazepam at 10 mg/kg i.p. b.d. for 7 days. Withdrawal is for a 24-hour period; a compound of the invention is typically given at 0.01 to 100 mg/kg i.p. b.d.
  • the increased time spent in the light section shows the effect of the compound.
  • mice Five mice are given diazepam at 10 mg/kg i.p. b.d. for 7 days.
  • the amount of time spent in the light section after the compound is administered demonstrates the effectiveness of the compound.
  • the effect of a compound of the invention on the long-term treatment and withdrawal from alcohol can be shown.
  • Five mice are given alcohol in drinking water 8% w/v for 14 days. After a withdrawal period of 24 hours, a compound is typically given at 1.0 mg/kg i.p. b.d.
  • mice Five mice were given alcohol in drinking water, 8% w/v for 14 days. After a withdrawal period of 24 hours, the compound was given at 10 mg/kg i.p. b.d. The increased time spent in the light section shows the effect of the compound on the mice.
  • mice Five mice are given cocaine as 1.0 mg/kg i.p. b.d. for 14 days.
  • the increased time in the light section illustrates the effectiveness of the compound in the treatment.
  • mice Five mice are given cocaine at 1.0 mg/kg i.p. b.d. for 14 days after a withdrawal period of 24 hours, the compound is given at 1.0 mg/kg i.p. b.d.
  • the effect of intervention with the compound is shown by the increase in time spent in the light section.
  • the anxiolytic effect of the compound is indicated by the increase in time spent in social interaction compared with the control value C.
  • Compounds of the invention depress the flexor response in a stimulated spinalized decerebrated rat preparation similar to morphine.
  • the effect of giving a compound with morphine greatly potentiates the effect which lasts for about 3 hours.
  • inert, pharmaceutically acceptable carriers can be either solid or liquid.
  • Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, and
  • a solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, or tablet disintegrating agents; it can also be an encapsulating material.
  • the carrier is a finely divided solid which is in a mixture with the finely divided active component.
  • the active component is mixed with the carrier having the necessary binding
  • low-melting wax such as a mixture of fatty acid glycerides and cocoa butter
  • the active ingredient is dispersed therein by, for example, stirring.
  • the molten homogeneous mixture is then poured into convenient sized molds and allowed to cool and solidify.
  • the powders and tablets preferably contain 5 to about 70% of the active component.
  • Suitable carriers are magnesium carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low-melting wax, cocoa butter, and the like.
  • a preferred pharmaceutically acceptable salt is the N-methyl glucamine salt.
  • preparation is intended to include the formulation of the active component with encapsulating material as a carrier providing a capsule in which the active component (with or without other carriers) is surrounded by a carrier which is thus in association with it. Similarly, cachets are included.
  • Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral
  • Liquid form preparations include solutions, suspensions, and emulsions. Sterile water or
  • liquid preparations suitable for parenteral administration may be mentioned as an example of liquid preparations suitable for parenteral administration.
  • Liquid preparations can also be formulated in solution in aqueous polyethylene glycol solution.
  • dicyclohexylurea formed was filtered off before the addition of the amino component (phenethylamine or L-phenylalaninol; 0.7 mmol) wherein the mixture was stirred overnight with a brief period at reflux if TLC indicated that activated ester was still present.
  • the ethyl acetate solution was cooled, washed with dilute aqueous citric acid solution, dilute aqueous sodium bicarbonate solution, and finally saline solution before being dried (MgSO 4 ) and evaporated. The residual material was purified as indicated.
  • the carboxylic acid 6 is esterified by treatment of a methanolic solution of the acid with thionyl chloride.
  • the two free amines are then protected as the tert-butyl urethanes by treatment with di-tert-butvldicarbonate yielding 3.
  • Treatment of this with benzylchloromethylether in dichloromethane gave the N-BOM-protected imidazole ring 9 .
  • the ester group was then hydrolyzed with lithium hydroxide in aqueous methanol to 10 and the pentafluorophenyl ester made using N,N'-dicyclohexyl carbodiimide.
  • This active ester was then treated with 2-phenethylamine to give the amide 11 and the ring deprotected by hydrogenation using Pearlman's catalyst in ethanol yielding 12 (Example 13).
  • the ⁇ -Bom group was removed from the imidazole ring of the intermediate from Step 5 (0.58 mmol) by hydrogenolysis in ethanol (50 mL) containing palladium hydroxide (70 mg) at a pressure of 50 psi at 50°C for 6 hours. After removal of the catalyst and solvent, the residue was chromatographed (silica gel,
  • n-BuLi (4.9 mL) of a 16M solution in n-hexane, 7.84 mmol) was added via syringe to a stirred solution of diisopropylamine (1.1 mL, 7.89 mmol) in anhydrous THF (20 mL) at -78°C under dry N 2 . The cold solution was stirred for 30 minutes and then the Schiff base
  • Triethylamine (0.642 mL, 4.60 mmol) was added to a stirred solution of the amino ester (1.25 g,
  • N,N'-dicyclohexylcarbodiimide (0.122 g, 0.59 mmol) and the mixture stirred for 1 hour. This was followed by 4-dimethylaminopyridine (0.017 g, 0.14 mmol) and then a solution of 2-phenethylamine (0.098 g, 0.81 mmol) in EtOAc (1 mL) and the mixture stirred at room temperature
  • Triethylamine (0.524 mL, 3.76 mmol) was added to a stirred solution of the amino ester (0.814 g,
  • Lithium hydroxide monohydrate (0.67 g,
  • N,N'-dicyclohexylurea was filtered off and the EtOAc washed with aqueous 5% citric acid solution
  • reaction mixture was diluted with 250 mL water and extracted with ether.
  • the ethereal phase was washed with water, dried over magnesium sulfate, and concentrated in vacuo.
  • the oily residue (10 g) was purified by column chromatography on silica gel with a mixture of methylene chloride/methanol (98:2) as eluant.
  • the first fraction was educt (1.28 g), followed by 2,3-dihydro-2-hydroxymethyl-1-methyl-5-phenyl-1H- 1,4-benzodiazepine (0.62 g) and the desired product (3.36 g, 37% yield) as a dark red oil.
  • N,N-dicyclohexylcarbodiimide (0.23 g, 1.1 mmol) in 5 mL dry ethyl acetate at 4°C.
  • the reaction mixture was kept at this temperature for 16 hours.
  • the precipitate was filtered off and 2-phenylethylamine (0.133 g, 1.1 mmol) was added. After stirring
  • a second crystalline fraction was obtained as a yellow foam (0.16), m.p. 60-70°C. It was a mixture of nine parts diastereomer 2 and four parts
  • N-[(2-adamantyloxy)- carbonyl)- ⁇ -methyl- ⁇ -(2-pyridyl-1-oxide)-D,L-alanine (2.43 g, 6.5 mmol) in 150 mL dry tetrahydrofuran at - 20°C was added N-methylmorpholine (0.76 g, 7.5 mmol) and isobutyl chloroformate (1.02 g, 7.5 mmol). The mixture was stirred for 20 minutes at this temperature followed by addition of 2-phenethylamine (1.21 g, 10 mmol), stirred for 3 hours at -25°C, and then warmed to room temperature.
  • N-[(2-adamantyloxy)- carbonyl)- ⁇ -methyl- ⁇ -(4-pyridyl-1-oxide)-D,L-alanine (0.37 g, 1 mmol) in 20 mL dry tetrahydrofuran at room temperature was added N,N-carbonyldiimidazole (0.16 g, 1 mmol). The mixture was stirred for 3 hours followed by addition of 2-phenylethylamine (0.12 g, 1 mmol). After stirring overnight the intermediate imidazolide could still be detected by TLC (methylenechloride:
  • N,N'-dicyclohexylcarbodiimide (0.45 g, 2.2 mmol) in 8 mL dry ethyl acetate at 4°C. The reaction mixture was stirred 48 hours at this temperature.
  • Diastereomer 1 was obtained as a foam (0.42 g, 41% yield). Diastereomer 2 was obtained as a foam (0.50 g, 49% yield).
  • Diastereomer 1 was obtained in 7% yield as a colorless foam softens at 94-980C.
  • Diastereomer 2 was obtained in 2% yield as a colorless foam softens at 98-102oC.
  • Example 17 The method is as described in Example 17, except diastereomer 2 of Example 19A was used.
  • the product was obtained in 37% yield as a colorless foam softens at 61-64°C.
  • Rf 0.35 (ethyl acetate).
  • Example 17 The method is as described in Example 17, except diastereomer 1 of Example 20 was used.
  • the product was obtained in 77% yield as a colorless solid, m.p. 163-1640C.
  • Example 17 The method is as described in Example 17, except diastereomer 2 of Example 17, Step D, Method C was used.
  • N-(2- adamantyloxy-carbonyl)-2-[9-(methylsulfonyl)- ⁇ - carbolin-3-yl]-alanine was isolated as a yellow foam (0.68 g, 95.5%).
  • N-(2-adamantyloxycarbonyl)-2-(quinolinyl)-alanine methyl ester (3.6 g, 38.0%) as a light tan solid.
  • N,N'-carbonyldiimidazole (23.4 g, 0.14 mmol) in portions and the reaction mixture was stirred at room temperature for 2 hours.
  • the organic solvent was evaporated in vacuum and the residue was dissolved in dry ethanol (200 mL).
  • Sodium (0.1 g) was added and the reaction mixture was refluxed for 2 hours.
  • Example 30 Method was as described for Example 30 but using N-(2-adamantyloxy-carbonyl)-4-(quinolin-yl)-alanine from Example 37, Step 6.
  • the crude product mixture was extracted with 7.5% citric acid solution, dried over Na 2 SO 4 and evaporated in vacuum.
  • the residue was chromatographed on silica gel using ethyl acetate as eluant to obtain the title compound which was
  • Butanoic acid 4-[[2-(4-quinolinylmethyl)-1-oxo-2- [[(tricyclo[3.3.1.13,7]dec-2-yloxy)carbonyl]amino]- propyl]-amino]-1-phenylethyl]amino]-4-oxo-,
  • Butanoic acid 4-[[2-[2-(1,2,3,4-tetrahvdro)- quinolinylmethyl]-1-oxo-2-[[(tricyclo[3.3.1.1 3,7 ]dec-2- yloxy)carbonyl]amino]propyl]amino]-1-phenylethyl]- amino]-4-oxo- STEP 1
  • Example 40 Method was as described for Example 40, Step 1, but using N-(2-adamantyloxy-carbonyl)-2-methy1-3- (quinolin-2-yl)alanine (1.42 g, 3.5 mmol) prepared in Example 34, Step 4.
  • the crude residue was flash chromatographed on silica gel using toluene/ethanol (0.8% to 1.5%) as eluant to yield carbamic acid,
  • Example 39 Method was as described for Example 39, Step 3, but using carbamic acid, [2-[[2-amino-2-phenyl]amino]- 1-methyl-2-oxo-1-(2-(1,2-dihydro)quinolinylmethyl)- ethyl]-, tricyclo[3.3.1.1 3 ' 7 ]dec-2-yl ester (95 mg, 0.18 mmol) from Example 40A, Step 2.
  • the reaction mixture was heated to reflux for 6 hours and worked up in the usual manner to isolate the title compound (62 mg), m.p. 102-112°C (D-(-)-N-methylglucamate salt).
  • 1,3-dihydro-3-hydroymethyl-1-methyl-5-phenyl-2H- 1,4-benzodiazepin-2-one 980 mg, 3.5 mmol was dissolved in methylene chloride and thionylchloride (1.65 g, 14 mol) was added in portions. The reaction mixture was heated to reflux for 3 hours and then allowed to cool to room temperature overnight. The reaction mixture was evaporated in vacuum, dissolved in methylene chloride and the organic solution was basified with aqueous NaHCO 3 in water.
  • Step 2 (12.0 g, 40 mmol) in dry toluene (100 mL) was added dropwise SOCl 2 (15 mL) and the mixture was heated at 75-80°C for 30 minutes. Excess SOCl 2 and the solvent were removed in vacuo and the residue triturated with ethyl ether (50 mL) to give the desired product (9.5 g, 74%) as a beige crystalline solid, m.p. 150-153°C.
  • N-(phenylmethylene)-DL-alanine methyl ester (3.82 g, 20 mmol) in dry DMSO (20 mL) under nitrogen and stirred for 1 hour.
  • the reaction mixture was then cooled to 10°C and a solution of the compound from Step 3 (5 . 78 g, 18 mmol) in dry DMSO (100 mL) was added in one portion and the resultant mixture left stirring for 24 hours at room temperature. After removing the solvent in vacuo the residue was

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Abstract

Novel unnatural dipeptoids useful as agents in the treatment of obesity, hypersecretion of gastric acid in the gut, gastrin-dependent tumors, or as antipsychotics are disclosed. Further, the compounds are antianxiety agents and antiulcer agents. The compounds are agents useful for preventing the response to withdrawal from chronic treatment or use of nicotine, diazepam, alcohol, cocaine, caffeine, and opioids. The compounds are also useful in treating and/or preventing panic attacks. Also disclosed are pharmaceutical compositions and methods of treatment using the dipeptoids as well as processes for preparing them and novel intermediates useful in their preparation. An additional feature of the invention is the use of the subject compounds to prepare diagnostic compositions.

Description

AMINO ACID ANALOGS AS CCK ANTAGONISTS
CROSS-REFERENCE TO RELATED APPLICATION
This application is a continuation-in-part application of United States Serial Number 07/576,308, filed August 31, 1990.
BACKGROUND OF THE INVENTION
Agents acting as agonists at central
cholecystokinin (CCK) receptors may induce satiety (Schick, Yaksh, and Go, Regulatory Peptides
14:277-291, 1986). They are also expected to act as analgesics (Hill, Hughes, and Pittaway,
Neuropharmacology 26:289-300, 1987), and as
anticonvulsants (MacVicar, Kerrin, and Davison, Brain Research 406:130-135, 1987).
Reduced levels of CCK-peptides have been found in the brains of schizophrenic patients compared with controls (Roberts, Ferrier, Lee, Crow, Johnston, Owens, Bacarese-Hamilton, McGregor, O'Shaughnessey, Polak, and Bloom, Brain Research 288:199-211, 1983). It has been proposed that changes in the activity of CCK neurones projecting to the nucleus accumbens may play a role in schizophrenic processes by influencing dopaminergic function (Totterdell and Smith,
Neuroscience 19:181-192, 1986). This is consistent with numerous reports that CCK peptides modulate dopaminergic function in the basal ganglia and
particularly the nucleus accumbens (Weiss, Tanzer, and Ettenberg, Pharmacology, Biochemistry and Behaviour 30:309-317, 1988; Schneider, Allpert, and Iversen, Peptides 4:749-753, 1983). It may therefore be expected that agents modifying CCK receptor activity may have therapeutic value in conditions associated with disturbed function of central dopaminergic function such as schizophrenia and Parkinson's
disease.
CCK and gastrin peptides share a common carboxy terminal pentapeptide sequence and CCK peptides can bind to the gastrin receptor of the stomach mucosa and elicit acid secretion in many species including human (Konturek, Gastrointestinal Hormones, ed.
G. B. J. Glass, Raven Press, NY, Ch. 23, pp. 529-564, 1980). Antagonists of the CCK-B receptor would also be expected to be antagonists at the stomach gastrin receptor and this would also be of value for
conditions involving excessive acid secretion.
CCK and gastrin peptides have trophic effects on the pancreas and various tissues of the
gastrointestinal tract (Johnson, ibid., pp. 507-527), actions which are associated with increased DNA and RNA synthesis. Moreover, gastrin-secreting cells are associated with certain gastrointestinal tumors as in the Zollinger-Ellison syndrome (Stadil, ibid., pp. 729-739), and some colorectal tumors may also be gastrin/CCK dependent (Singh, Walker, Townsend, and Thompson, Cancer Research 46:1612, 1986; Smith,
Gastroenterology 95:1541, 1988). Antagonists of CCK/gastrin receptors could, therefore, be of
therapeutic value as antitumor agents.
The CCK peptides are widely distributed in various organs of the body, including the
gastrointestinal tract, endocrine glands, and the nerves of the peripheral and central nervous systems. Various biologically active forms have been
identified, including a 33-amino acid hormone and various carboxyl-terminus fragments of this peptide (e.g., the octapeptide CCK26-33 and the tetrapeptide CCK30-33) (Dockray, Br. Med. Bull. 38(3):253-258, 1982).
The various CCK peptides are thought to be involved in the control of smooth muscle
contractility, exocrine and endocrine gland secretion, sensory nerve transmission, and numerous brain
functions. Administration of the native peptides cause gall bladder contraction, amylase secretion, excitation of central neurons, inhibition of feeding, anticonvulsive actions, and other behavioral effects (Cholecystokinin: Isolation, Structure and Functions, G. B. J. Glass, ed., Raven Press, New York, pp.
169-221, 1980; Morley, Life Sciences 27:355-368, 1980; Cholecystokinin in the Nervous System,
J. de Belleroche and G. J. Dockray, eds., Ellis
Horwood, Chichester, England, pp. 110-127, 1984).
The high concentrations of CCK peptides in many brain areas also indicate major brain functions for these peptides (Dockray, Br. Med. Bull. 38(3):253-258, 1982). The most abundant form of brain CCK found is CCK26-33, although small quantities of CCK30-33 exist (Rehfeld and Gotterman, J. Neurochem. 32:1139-1341, 1979). The role of central nervous system CCK is not known with certainty, but it has been implicated in the control of feeding (Della-Fera and Baile, Science 206:471-473, 1979).
Currently available appetite suppressant drugs either act peripherally, by increasing energy
expenditure (such as thyroxine), or in some other manner (such as the biguanides), or act by exerting a central effect on appetite or satiety.
Centrally acting appetite suppressants either potentiate central catecholamine pathways and tend to be stimulants (for example, amphetamine), or influence serotonergic pathways (for example, fenfluramine).
Other forms of drug therapy include bulking agents which act by filling the stomach, thereby inducing a "feeling" of satiety.
CCK is known to be present in some cortical interneurones which also contain gamma-aminobutyric acid (GABA) (DeMeulemeester, et al, J. Neuroscience
8:988-1000, 1988). Agents that modify GABA action may have utility as anxiolytic or hypnotic agents
(S. C. Harvey, The Pharmacological Basis of
Therapeutics (7th ed.), pp. 339-371, 1985, MacMillan). Thus, agents which modify CCK action may have parallel anxiolytic or hypnotic activities. TIPS 11:271, 1990 discloses the role of CCK antagonists. SUMMARY OF THE INVENTION
The invention relates to novel compounds of the formula
I
Figure imgf000006_0001
and the pharmaceutically acceptable salts thereof wherein R1, R2, R3, R4, R9, R12, R13, A, Ar, and Ar2 are as defined hereinbelow.
In commonly owned copending applications
07/576,628, 07/576,296, 07/576,315, 07/576,024, and 07/576,297, filed on August 31, 1990 by Horwell, et al, the disclosures of which are incorporated herein by reference, CCK antagonists are disclosed.
In the continuation-in-part applications of the above applications also commonly owned and copending ____________, ____________, _____________, _____________, and __________, filed on even date herewith by Horwell, et al, the disclosures of which are incorporated herein by reference, CCK antagonists are disclosed.
In like manner, the present invention also relates to a pharmaceutical composition containing an effective amount of a compound according to formula I in combination with a pharmaceutically acceptable carrier in unit dosage form effective for appetite suppression.
The compounds are also useful as anxiolytics, antipsychotics, especially for treating schizophrenic behavior, as agents in treating disorders of the extrapyramidal motor system, as agents for blocking the trophic and growth stimulating actions of CCK and gastrin, and as agents for treating gastrointestinal motility.
Compounds of the invention are also useful as analgesics and potentiate the effect of morphine.
They can be used as an adjunct to morphine and other opioids in the treatment of severe pain such as cancer pain and reduce the dose of morphine in treatment of pain where morphine is contraindicated.
An additional use for suitably radiolabeled iodinated compounds is that a suitably radiolabeled derivative such as iodine-131 or iodine-127 isotope gives an agent suitable for treatment of
gastrin-dependent tumors such as those found in colonic cancers. Such radiolabeled compounds can also be used as a diagnostic agent by localization of gastrin and CCK-B receptors in both peripheral and central tissue.
The invention further relates to a method of appetite suppression in mammals which comprises administering an amount effective to suppress appetite of the composition described above to a mammal in need of such treatment.
The invention also relates to a pharmaceutical composition for reducing gastric acid secretion
containing an effective amount of a compound of
formula K in combination with a pharmaceutically acceptable carrier in unit dosage form effective for reducing gastric acid secretion.
The invention also relates to a method for
reducing gastric acid secretion in mammals which comprises administering an amount effective for
gastric acid secretion reduction of the composition described above to a mammal in need of such treatment.
The invention also relates to a pharmaceutical composition containing an effective amount of a compound of formula I in combination with a
pharmaceutically acceptable carrier in unit dosage form effective for reducing anxiety.
The invention also relates to a method for reducing anxiety in mammals which comprises
administering an amount effective for anxiety
reduction of the composition described above to a mammal in need of such treatment.
The invention also relates to a pharmaceutical composition containing an effective amount of a compound of formula I in combination with a
pharmaceutically acceptable carrier in unit dosage form effective for treating gastrointestinal ulcers.
The invention further relates to a method for treating gastrointestinal ulcers in mammals which comprises administering an amount effective for gastrointestinal ulcer treatment of the composition as described above to a mammal in need of such treatment.
The invention also relates to a pharmaceutical composition containing an effective amount of a compound of formula I in combination with a
pharmaceutically acceptable carrier in unit dosage form effective for treating psychosis, i.e.,
schizophrenia.
The invention further relates to a method for treating psychosis in mammals which comprises
administering an amount effective for treating psychoses of a composition as described above to a mammal in need of such treatment.
The invention also relates to pharmaceutical compositions effective for stimulating or blocking CCK or gastrin receptors, for altering the activity of brain neurons, for schizophrenia, for treating disorders of the extrapyramidal motor system, for blocking the trophic and growth stimulating actions of CCK and gastrin, and for treating gastrointestinal motility.
The invention also relates to a pharmaceutical composition for preventing the withdrawal response produced by chronic treatment or abuse of drugs or alcohol.
The invention further relates to a method for treating the withdrawal response produced by
withdrawal from chronic treatment or withdrawal from abuse of drugs or alcohol. Such drugs include benzodiazepines, especially diazepam, cocaine, caffeine, opioids, alcohol, and nicotine. Withdrawal symptoms are treated by administration of an effective withdrawal treating amount of a compound of the instant invention.
The invention also relates to a pharmaceutical composition containing an effective amount of a compound of formula I in combination with a
pharmaceutically acceptable carrier in unit dosage form effective for treating and/or preventing panic. The invention also relates to a method for
treating and/or preventing panic in mammals which comprises administering an amount effective for panic treatment and/or prevention of the composition
described above to a mammal in need of such treatment.
The invention further relates to the use of the compounds of formula I to prepare pharmaceutical and diagnostic compositions for the treatment and
diagnosis of the conditions described above.
The invention further provides processes for the preparation of compounds of formula I.
The invention further provides novel
intermediates useful in the preparation of compounds of formula I and also provides processes for the preparation of the intermediates.
DETAILED DESCRIPTION OF THE INVENTION
The compounds of the present invention are formed by the condensation of two modified amino acids and are therefore not peptides. Rather, they are
"dipeptoids", synthetic peptide-related compounds differing from natural dipeptides in that the
substituent group R2 is not hydrogen.
The compounds of the present invention are represented by the formula
I
Figure imgf000010_0001
or a pharmaceutically acceptable salt thereof wherein:
R1 is a cycloalkyl or polycycloalkyl hydrocarbon of from three to twelve carbon atoms with from zero to four substituents each independently selected from the group consisting of a straight or branched alkyl of from one to about six carbon atoms, halogen, CN, OR* , SR* , CO2R* , CF3, NR5R6, and -(CH2)nOR5 wherein R* is hydrogen or a straight or branched alkyl of from one to six carbon atoms, R5 and R6 are each independently hydrogen or alkyl of from one to about six carbon atoms and n is an integer from zero to six;
A is -(CH2)nCO-, -SO2-, -S(=O)-, -NHCO-,
Figure imgf000011_0001
-(CH2)n-OC-, -SC-, -O-(CH2)nCO-, or -HC=CHCO- wherein n is an integer from zero to six;
R2 is a straight or branched alkyl of from one to about six carbon atoms, -HC=CH2, -C≡CH, - (CH2)n-CH=CH2, -(CH2)nC≡CH, -(CH2)nAr, -(CH2)nOR*, -(CH2)nOAr,
-(CH2)nCO2R*, or -(CH2)nNR5R6 wherein n, R*, R5, and R6 are as defined above and Ar is as defined below;
R3 and R4 are each independently selected from hydrogen, R2 and -(CH2)n,-B-D wherein:
n' is an integer of from zero to three;
B is a bond,
-OCO(CH2)n-,
-O(CH2)n-,
-NHCO(CH2)n-,
-CONH(CH2)n-,
-NHCOCH=CH-,
-COO(CH2)n-,
-CO(CH2)n-,
-S-(CH2)n- -S(=O)-(CH2)n-,
-SO2-(CH2)n-,
-NHSO2(CH2)n-,
-SO2NH(CH2)n-,
Figure imgf000012_0001
wherein R7 or R8 are independently selected from hydrogen and R2 or together form a ring (CH2)m wherein m is an integer of from 1 to 5 and n is as defined above;
D is -COOR*,
-CH2OR*,
-CHR2OR*,
-CH2SR*,
-CHR2SR* ,
-CONR5R6,
-CN,
-NR5R6,
-OH,
-H and acid replacements such as tetrazole
Figure imgf000012_0002
Figure imgf000013_0001
wherein m is an integer of from 0 to 2,
wherein R*, R2, R5, and R6 are as defined above;
R9 is hydrogen or a straight or branched alkyl of from one to about six carbon atoms, - (CH2)nCO2R*, -(CH2)nOAr', -(CH2)nNR5R6, wherein n, R*, R5, and R6 are as defined above or taken from R3 and Ar' is taken from Ar as defined below; R12 and R13 are each independently hydrogen or are each independently taken with R3 and R4, respectively, to form a moiety doubly bonded to the carbon atom;
Ar is a mono- or polycyclic unsubstituted or substituted carbo- or heterocyclic aromatic or carbo- or heteroaromatic moiety; and
Ar2 can be selected from Ar as defined above or the CH2Ar2 moiety of formula I is the sidechain of a biologically significant amino acid, with the proviso that Ar2 cannot be
Figure imgf000014_0001
Ar2 is also - (CH2) 2NHC (=NH)NHNO2, -(CH2)2NMe2, or —CH2CO2CH3.
Preferred compounds of the instant invention are those wherein
R1 is a cycloalkyl or a polycycloalkyl of
from about six to about ten carbon atoms with from zero to four substituents each independently selected from hydrogen, straight or branched alkyl of from one to six carbon atoms, CF3, NR5R6, - (CH2)nCO2R*,
CN, F, Cl, Br, OR*, SR*, wherein R*, R5, and R6 are as defined in Claim 1 and n is an integer of from 1 to 3;
A is -NHCO-, OC(=O)-, -S(=O), -SO2-, -SCO- or -CH2CO-;
R2 is -CH3, -CH2CO2H, or -CH2C≡CH;
R3 is -(CH2)n,-B-D or H;
R4 is -(CH2)n,-B-D or H;
R9 is hydrogen or methyl;
R12 is hydrogen; R13 is hydrogen;
Ar is a monocyclic 5- or 6-member ring
having from 0 to 4 heteroatoms each independently nitrogen, oxygen, or sulfur, a bicyclic ring system wherein each ring is independently a 5- or 6-member ring containing from 0 to 3 heteroatoms each independently selected from nitrogen, oxygen, and sulfur,
a tricyclic ring system wherein each ring is independently a 5- or 6-member ring containing from 0 to 5 heteroatoms selected from nitrogen, oxygen, sulfur, or
a hydroaromatic ring;
Ar2 is a monocyclic 5- or 6-member ring
having from 0 to 4 heteroatoms each independently nitrogen, oxygen, or sulfur, a bicyclic ring system wherein each ring is independently a 5- or 6-member ring containing from 0 to 3 heteroatoms, each independently selected from nitrogen, oxygen, and sulfur,
a tricyclic ring system wherein each ring independently is a 5- or 6-member ring containing from 0 to 5 heteroatoms selected from nitrogen, oxygen, and sulfur,
a hydroaromatic ring,
an alkyl carboxylic acid, or
an alkyl amine with the proviso that Ar2 cannot be 2- or 3-indole.
More preferred compounds of the instant invention are those wherein R1 is an unsubstituted or substituted
cycloalkyl or polycycloalkyl
Figure imgf000016_0001
wherein W, X, Y, and Z are each
independently hydrogen, a straight or branched alkyl of from one to six carbon atoms, CF3, NR5N6, - (CH2) nCO2R*, CN, F, Cl, Br, OR*, SR*, wherein R*, R5, and R6 are as defined in Claim 1 and n is an integer of from 1 to 3;
A is -NHCO-, OCO-, -SO2-, -S (=O) - or
-CH2CO-;
R2 is -CH3, -CH2CO2H, or -CH2C≡CH;
R3 is H, CH2OH, CH2OCOCH2CH2CO2H,
CH2OCOCH=CHCO2H, CH2NHCOCH2CH2CO2H, CH2NHCOCH=CHCO2H, CH2SCH2CO2H, or
R4 is H, -NHCOCH2CH2CO2H or NHCOCH=CHCO2H, R9 is H or methyl,
R12 is hydrogen,
R13 is hydrogen,
Ar and Ar2 are as above.
Still more preferred compounds of the instant invention are those wherein
R1 is 2-adamantyl, 1-(S)-2-endobornyl, or
2-methylcyclohexyl; A is -OC(=O);
R2 is CH3;
R3 is H, CH2OH, CH2OCOCH2CH2CO2H,
CH2OCOCH=CHCO2H, CH2NHCOCH2CH2CO2H, CH2NHCOCH=CHCO2H, CH2SCH2CO2H, or
R4 is H, -NHCOCH2CH2CO2H ([D] configuration) or NHCOCH=CHCO2H ([D] configuration); R9 is hydrogen or methyl;
R12 is hydrogen;
R13 is hydrogen;
Figure imgf000018_0001
Ar2 is as defined above for Ar or the CH2Ar2 moiety of formula I is the sidechain of a biologically significant amino acid.
Preferred compounds are those of formula 1 wherein Ar2 is:
Figure imgf000020_0001
Each of the above moieties for Ar or Ar2 can be independently unsubstituted, mono- or polysubstituted wherein the substituent is independently selected from NR5R6, halogen, alkyl, or alkoxy.
Especially preferred compounds of the instant invention are those wherein Ar2 is
1-naphthyl,
2-naphthyl,
3-benzo[b]thbenyl,
2-(1-BOC-benzimidazolyl),
3-(2-bromobenz[b]furanyl),
2-benzimidazolyl,
3-benzo[b]furanyl,
2-quinolinyl,
3-quinolinyl,
4-quinolinyl,
2-pyridyl,
3-pyridyl,
4-pyridyl,
1H-pyrrolo[2,3-b]pyridin-3-yl,
1H-pyrrolo[3,2-c]pyridin-3-yl,
2-dihydroquinolinyl,
2-tetrahydroquinolinyl,
3-imidazo[1,5-a]pyridinyl,
2-2,3-dihydro-1-methyl-5-phenyl-4H-1,4- benzodiazepine, or
3-indazolyl.
Most especially preferred compounds of the instant invention are:
Tricyclo[3.3.1.13'7]dec-2-yl [2-[[1-
(hydroxymethyl)-2-phenylethyl]amino]-1-methyl-2-oxo-1- (9H-pyrido[3,4-b]indol-3-ylmethyl)ethyl]-carbamate (alanine center is RS, other center is S), Tricyclo[3.3.1.13'7]dec-2-yl [1-methyl-1-[[9- (methylsulfonyl)-9H-pyrido[3,4-b]indol-3-yl]methyl]-2- oxo-2-[(2-phenylethyl)amino]ethyl]-carbamate,
Tricyclo[3.3.1.13'7]dec-2-yl [2-[[1- (hydroxymethyl)-2-phenylethyl]amino]-1-methyl-1-[[9-
(methylsulfonyl)-9H-pyrido[3,4-b]indol-3-yl]methyl]-2- oxoethyl [carbamate (phenylmethyl center S, other center RS),
4-[[2-[[2-methyl-1-oxo-2-(2-quinolinyl)-2- [[tricyclo[3.3.1.13'7]dec-2-yloxy)carbonyl]amino]- propyl]amino]-1-phenylethyl]amino]-4-oxobutanoic acid (mixture of [R-(R*,R*)] and [R-(R*,S*)] isomers),
Butanoic acid, 4-[[2-(4-quinolinylmethyl)-1-oxo- 2-[[(tricyclo[3.3.1.13'7]dec-2-yloxy)carbonyl]amino]- propyl]amino-1-phenylethyl]amino]-4-oxo-,
[R-(R*,R*)]-,
Butanoic acid, 4-[[2-[2-(1,2,3,4-tetrahydro)- quinolinylmethyl]-1-oxo-2-[[(tricyclo[3.3.1.13'7]dec-2- yloxy)carbonyl]amino]propyl]amino]-1- phenylethyl]amino]-4-oxo-,
Butanoic acid, 4-[[2-[2-(1,2-dihydro)- quinolinylmethyl]-1-oxo-2-[[(tricyclo[3.3.1.13'7]dec-2- yloxy)carbonyl]amino]propyl]amino]-1-phenylethyl]- amino]-4-oxo-,
Tricyclo[3.3.1.13'7]dec-2-yl [2-[[1-
(hydroxymethyl)-2-phenylethyl]amino]-1-methyl-1-(1- naphthalenylmethyl)-2-oxoethyl[carbamate
(naphthalenylmethyl center is RS, other center is S), Tricyclo[3.3.1.13'7]dec-2-yl [2-[[1-hydroxymethyl)- 2-phenylethyl]amino]-1-methyl-1-(2- naphthalenylmethyl)-2-oxoethyl]carbamate (naphthalene center is RS, hydroxymethyl center is S),
Tricyclo[3.3.1.13'7]dec-2-yl (±)-[1-methyl-1-(1- naphthalenylmethyl)-2-oxo-2-[(2-phenylethyl)- amino]ethyl]carbamate, Tricyclo[3.3.1.13'7]dec-2-yl (±)-[1-methyl-1-(2- naphthalenylmethyl)-2-oxo-2-[(2-phenylethyl)- amino]ethyl]carbamate,
Tricyclo[3.3.1.13'7]dec-2-yl [2-[[1- (hydroxymethyl)-2-phenylethyl]amino]-1-methyl-1-(2- naphthalenylmethyl)-2-oxoethyl]carbamate (hydroxy center is S, other center is R or S) (Isomer I),
Tricyclo[3.3.1.13'7]dec-2-yl (±)[1-(3- benzofuranylmethyl)-1-methyl-2-oxo-2-[(2- phenylethyl)amino]ethyl]carbamate,
Tricyclo[3.3.1.13'7]dec-2-yl [1-(3- benzofuranylmethyl)-2-[[1-(hydroxymethyl)-2- phenylethyl]amino]-1-methyl-2-oxoethyl[carbamate
(benzofuranylmethyl center is RS, other center is S), Tricyclo[3.3.1.13'7]dec-2-yl [1-[(2-bromo-3- benzofuranyl)methyl]-2-[[1-(hydroxymethyl)-2- phenylethyl]amino]-1-methyl-2-oxoethyl[carbamate
(benzofuran center is RS, hydroxymethyl center is S), Tricyclo[3.3.1.13'7]dec-2-yl (±)-[1-[(2-bromo-3- benzofuranyl)methyl]-1-methyl-2-oxo-2-[(2- phenylethyl)amino]ethyl]carbamate,
2-MethyIpropyl 2-[[2-methyl-1-oxo-3-(3- pyridinyl)-2-[[(tricyclo[3.3.1.13'7]dec-2- yloxy)carbonyl]amino]propyl]amino]-3-phenylpropyl- carbonate (pyridine center is RS, other center is S),
Tricyclo[3.3.1.13'7]dec-2-yl [2-[[1-hydroxymethyl)- 2-phenylethyl]amino]-1-methyl-2-oxo-1-(3-pyridinyl- methyl) ethyl] carbamate (hydroxymethyl center is S, other is (±)) (Diastereomer I),
Tricyclo[3.3.1.13'7]dec-2-yl (±)-[1-methyl-2-oxo-2-
[(2-phenylethyl)amino]-1-(4-pyridinylmethyl)ethyl]- carbamate,
4-[[2-[[2-methyl-1-oxo-3-(4-pyridinyl)-2- [[(tricyclo[3.3.1.13'7]dec-2-yloxy)carboncl]amino]- propyl]amino]-1-phenylethyl]amino]-4-oxobutanoic acid, Tricyclo[3.3.1.13'7]dec-2-yl [2-[[1- (hydroxymethyl)-2-phenylethyl]amino]-1-methyl-2-oxo-1- (2-pyridinylmethyl)ethyl]carbamate (hydroxymethyl center is S, other center is R or S) (Diastereomer I), Tricyclo[3.3.1.13'7]dec-2-yl (±)-[1-methyl-2-oxo-2-
[(2-phenylethyl)amino]-1-[(2-pyridinyl)- methyl]ethyl]carbamate,
Tricyclo[3.3.1.13'7]dec-2-yl (±)-[1-[(2- aminophenyl)methyl]-1-methyl-2-oxo-2-[(2- phenylethyl)amino]ethyl]carbamate,
Tricyclo[3.3.1.13'7]dec-2-yl (±)-[1-[(2- hydroxyphenyl)methyl]-1-methyl-2-oxo-2-[(2- phenylethyl)amino]ethyl]carbamate,
Tricyclo[3.3.1.13'7]dec-2-yl (±)-[1-methyl-2-oxo-2- [(2-phenylethyl)amino]-1-[(2-quinolinyl)- methyl]ethyl]carbamate,
Tricyclo[3.3.1.13'7]dec-2-yl [2-[[1- (hydroxymethyl)-2-phenylethyl]amino]-1-methyl-2-oxo-1- (4-quinolinylmethyl)ethyl]carbamate (hydroxymethyl center is S, other center is RS),
Tricyclo[3.3.1.13'7]dec-2-yl (±)-[1-methyl-2-oxo-2- [(2-phenylethyl)-amino]-1-(4-quinolinylmethyl)ethyl)- carbamic acid,
Tricyclo[3.3.1.13'7]dec-2-yl (±)-[1-methyl-2-oxo-2- [(2-phenylmethyl)amino]-1-(3-quinolinyl-methyl)ethyl]- carbamate,
Tricyclo[3.3.1.13'7]dec-2-yl [2-[[1- (hydroxymethyl)-2-phenylethyl]amino]-1-methyl-2-oxy-1- (4-pyridinylmethyl)ethyl]carbamate (hydroxymethyl center is S, other center is R or S) (Diastereomer I), Tricyclo[3.3.1.13'7]dec-2-yl [2-[[1-(hydroxymethyl)-2-phenylethyl]amino]-1-methyl-2-oxo-1-(2- quinolinylmethyl)ethyl[carbamate (alanine center is RS, other center is S), Tricyclo[3.3.1.13'7]dec-2-yl (±)-[1-(1H-indazol-3- ylmethyl)-1-methyl-2-oxo-2-[(2-phenylethyl)amino]ethyl]carbamate,
Tricyclo[3.3.1.13'7]dec-2-yl [2-[[1-(hydroxy- methyl)-2-phenylethyl]amino]-1-(1H-indazol-3- ylmethyl)-1-methyl-2-oxoethyl]carbamate (hydroxymethyl center is S, other center is RS),
Tricyclo[3.3.1.13'7]dec-2-yl (±)-1-[1-(1H- benzimidazol-2-ylmethyl)-1-methyl-2-oxo-2-[(2- phenylethyl]amino]ethyl]carbamate,
Tricyclo[3.3.1.13'7]dec-2-yl [1-(1H-benzimidazol-2- ylmethyl)-2-[[1-(hydroxymethyl)-2-phenylethyl]amino]- 1-methyl-2-oxoethyl]carbamate (hydroxy center is S, other center is RS),
Tricyclo[3.3.1.13'7]dec-2-yl [1-(benzo[b]thien-3- ylmethyl)-2-[[1-(hydroxymethyl)-2-phenylethyl]amino]- 1-methyl-2-oxoethyl]-carbamate (benzothiophene center is RS, hydroxymethyl center is S),
Tricyclo[3.3.1.13'7]dec-2-yl (±)-[1-(benzo[b]thien- 3-ylmethyl)-1-methyl-2-oxo-2-[(2-phenylethyl)amino]- ethyl]carbamate,
Tricyclo[3.3.1.13'7]dec-2-yl [2-[(2-amino-2- phenylethyl)amino]-1-(1H-indazol-3-ylmethyl)-1-methyl- 2-oxoethyl]carbamate,
4-[[2-[[2-methyl-1-oxo-3-(1,2,3,4-tetrahydro-2- quinolinyl)-2-[[(tricyclo[3.3.1.13'7]dec-2-yloxy)- carbonyl]amino]propyl]amino]-1-phenylethyl]amino]-4- oxobutanoic acid compd. with 1-deoxy-1-(methylamino)- D-glucitol,
4-[[2-[[3-(1,2-dihydro-2-quinolinyl)-2-methyl-1- oxo-2-[[(tricyclo[3.3.1.13'7]dec-2-yloxy)carbonyl]- amino]propyl]amino]-1-phenylethyl]amino]-4-oxobutanoic acid compd. with 1-deoxy-1-(methylamino)-D-glucitol, 4-[[2-[[2-methyl-1-oxo-3-(4-quinolinyl)-2- [[(tricyclo[3.3.1.13'7]dec-2-yloxy)carbonyl]amino]- propyl]amino]-1-phenylethyl]amino]-4-oxobutanoic acid compd. with 1-deoxy-1-(methylamino)-D-glucitol,
Tricyclo[3.3.1.13'7]dec-2-yl [S-[R*(R or S),R]]-
[2-[[2-hydroxy-1-(hydroxymethyl)-2-phenylethyl]amino]- 1-methyl-2-oxo-1-(1H-pyrrolo[2,3-b]pyridin-3- ylmethyl)ethyl[carbamate and
Tricyclo[3.3.1.13'7]dec-2-yl-[S-[R*(S or R),R*]]- [2-[[2-hydroxy-1-(hydroxymethyl)-2-phenylethyl]amino]- 1-methyl-2-oxo-1-(1H-pyrrolo[2,3-b]pyridin-3- ylmethyl)ethyl]carbamate, and
Tricyclo[3.3.1.13'7]dec-2-yl-[1S-[1R*(S or
R),2R*]]-[2-[[2-hydroxy-1-(hydroxymethyl)-2- phenylethyl]amino]-1-methyl-2-oxo-1-(1H- pyrrolo[3,2-c]pyridin-3-ylmethyl)ethyl] carbamate.
Other compounds are:
Tricyclo[3.3.1.13'7]dec-2-yl-[1S-[1R*(R or
S),2R*]]-[2-[[2-hydroxy-1-(hydroxymethyl)-2- phenylethyl]amino]-1-methyl-2-oxo-1-(1H-pyrrolo- [3,2-c]pyridin-3-ylmethyl)ethyl]carbamate,
Tricyclo[3.3.1.13'7]dec-2-yl (±)-[1-methyl-2-oxo- [(2-phenylethyl)amino]-1-(3-pyridmylmethyl)ethyl]- carbamate,
2-MethyIpropyl 2-[[2-methyl-1-oxo-3-(3- pyridinyl)-2-[[(tricyclo[3.3.1.13'7]dec-2-yloxy)- carbonyl]amino]propyl]amino]-3-phenyIpropylcarbonate, N-oxide (phenylmethyl center is S, other center is RS),
Tricyclo[3.3.1.13'7]dec-2-yl [2-[[1-hydroxy- methyl)-2-phenylethyl]amino]-1-methyl-2-oxo-1-(2- pyridinylmethyl)ethyl]carbamate (hydroxymethyl center is S, other center is S or R) (Diastereomer II),
Tricyclo[3.3.1.13'7]dec-2-yl [2-[[1- (hydroxymethyl-2-phenylethyl]amino]-1-methyl-2-oxo-1- (2-pyridinylmethyl)ethyl]carbamate, N-oxide, Tricyclo[3.3.1.13'7]dec-2-yl [2-[[1-(hydroxymethyl)-2-phenylethyl]amino]-1-methyl-2-oxo-1-(3- pyridinylmethyl)ethyl]carbamate (hydroxymethyl center is S, other is (±)) (Diastereomer II),
Tricyclo[3.3.1.13'7]dec-2-yl [2-[[1-
(hydroxymethyl)-2-phenylethyl]amino]-1-methyl-2-oxo-1- (2-pyridinylmethyl)ethyl]carbamate, N-oxide
(hydroxymethyl center is S, other center is S or R) (Diastereomer II),
Tricyclo[3.3.1.13'7]dec-2-yl (±)-[1-methyl-2-oxo-2-
[(2-phenylethyl)amino]-1-(2-pyridinylmethyl)ethyl]- carbamate, N-oxide,
Tricyclo[3.3.1.13'7]dec-2-yl (±)-[1-methyl-2-oxo-2- [(2-phenylethyl)amino]-1-(3-pyridinylmethyl)ethyl]- carbamate, N-oxide,
Tricyclo[3.3.1.13'7]dec-2-yl [2-[[1- (hydroxymethyl)-2-phenylethyl[amino]-1-methyl-2-oxo-1- (3-pyridinylmethyl)ethyl]carbamate, N-oxide
(hydroxymethyl center is S, other center is S or R) (Diastereomer I),
Tricyclo[3.3.1.13'7]dec-2-yl [2-[[1- (hydroxymethyl)-2-phenylethyl]amino]-1-methyl-2-oxo-1- (3-pyridmylmethyl)ethyl]carbamate, N-oxide
(hydroxymethyl center is S, other center is R or S) (Diastereomer II),
Tricyclo[3.3.1.13'7]dec-2-yl [2-[[2-hydroxy-1- (hydroxymethyl)-2-phenylethyl]amino]-1-methyl-2-oxo-1- [[4-(phenylmethoxy)phenyl]methyl]ethyl]carbamate
(mixture of [1S- [1R* (R*), 2R*] ] and [1S- [1R* (S*), 2R*]] isomers),
Tricyclo[3.3.1.13'7]dec-2-yl [2-[[2-hydroxy-1- (hydroxymethyl)-2-phenylethyl]amino]-1-[(4-hydroxyphenyl)methyl]-1-methyl-2-oxoethyl]carbamate (mixture of [1S-[1R*(R*),2R*]] and [1S-[1R*(S*),2R*]] isomers), Tricyclo[3.3.1.13'7]dec-2-yl [2-[[2-hydroxy-1- (hydroxymethyl)-2-phenylethyl]amino]-1-[(4-methoxy- phenyl)methyl]-1-methyl-2-oxoethyl]carbamate (mixture of [1S-[1R*(R*),2R*]] and [1S- [1R* (S*), 2R*]] isomers), Tricyclo[3.3.1.13'7]dec-1-yl [2-[[2-hydroxy-1-
(hydroxymethyl)-2-phenylethyl]amino]-1-methyl-2-oxo-1- [[4-(phenylmethoxy)phenyl]methyl]ethyl]carbamate
(mixture of [1S-[1R*(R*),2R*]] and [1S-[1R* (S*), 2R*]] isomers,
Tricyclo[3.3.1.13,7]dec-2-yl (±)-[1-methyl-2-oxo-
2-[(2-phenylethyl)amino]-1-[(5,6,7,8-tetrahydro- 5,5,8,8-tetramethyl-2-naphthalenyl)methyl]ethyl]- carbamate,
α-Methyl-β-(3-1H-pyrrolo[3,1-c]pyridinyl)-D,L- alanine methyl ester dihydrochloride,
Carbamic acid, [-[(2,3-dimethyl)-1H-pyrrol-4- ylmethyl]-1-methyl-2-oxo-2-[(2-phenylethyl)amino]- ethyl-, tricyclo[3.3.1.13'7]dec-2-yl ester,
N-[(2-Adamantyloxy)carbonyl]-3-[(2,3-dimethyl)- 1H-pyrrol-4-yl)]-2-methyl-alanine,
3-[[2,3-Dimethyl-1-(4-methylphenyl)sulfonyl]-1H- pyrrol-4-yl]-2-methyl-alanine methyl ester,
Carbamic acid, [1-[(2,3-dimethyl)-1H-pyrrol-4- ylmethyl]-2-[[1-(hydroxymethyl)-2-hydroxy-2-phenyl- ethyl]amino]-1-methylethyl]-, tricyclo[3.3.1.13'7]dec- 2-yl ester (mixture of isomers),
Carbamic acid [1-(imidazo[1,5-a]pyridin-3- ylmethyl)-2-oxo-2-[(2-phenylethyl)amino]ethyl]-, tricyclo[3.3.1.13'7]dec-2-yl ester,
Carbamic acid, [2-[[1-(hydroxymethyl)-2-hydroxy-
2-phenylethyl]amino]-1-(imidazo[1,5-a]pyridin-3- ylmethyl)-1-methylethyl]-, tricyclo[3.3.1.13'7]dec-2-yl ester (mixture of isomers),
N-[(2-Adamantyloxy)carbonyl]-3-[(2,3-dimethyl)- 1H-pyrrol-4-yl)]-2-methyl-alanine, Carbamic acid, [1-[(2,3-dimethyl)-1H-pyrrol-4- ylmethyl]-2-[[1-(hydroxymethyl)-2-hydroxy-2-phenyl- ethyl]amino]-1-methylethyl]-, tricyclo[3.3.1.l3'7]dec- 2-yl ester (mixture of isomers),
N-[(2-Adamantyloxy)carbonyl]-3-(imidazo[1,5-a]- pyridin-3-yl)-2-methyl-alanine,
Tricyclo[3.3.1.1.3'7]dec-2-yl [1-[(2,3-dihydro-1- methyl-5-phenyl-1H-1,4-benzodiazepin-2-yl)methyl]-1- methyl-2-[(2-phenylethyl)amino]-2-oxoethyl]carbamate, 4-[[2-[[3-(2,3-dihydro-1-methyl-5-phenyl-1H-1,4- benzodiazepin-2-yl)-2-methyl-1-oxo-2-[[(tricyclo- [3.3.1.13'7]dec-2-yloxy)carbonyl]amino]propyl]amino]-1- phenylethyl]amino]-4-oxobutanoic acid compd. with 1-deoxy-1-(methylamino)-D-glucitol,
Tricyclo[3.3.1.13'7]dec-2-yl [2-[[1-
(hydroxymethyl)-2-phenylethyl]amino]-1-methyl-2-oxo-1- [4-pyridinylmethyl)ethyl]carbamate (hydroxymethyl center is S, other center is R or S (Diastereomer II), 4-[[2-[3-(1H-indazol-3-yl)-2-methyl-1-oxo-2- [[tricyclo[3.3.1.13'7]dec-2-yloxy)carbonyl]amino]- propyl]amino]-1-phenylethyl]amino]-4-oxobutanoic acid (mixture of isomers),
Carbamic acid [1-(imidazo[1,5-a]pyridin-3- ylmethyl)-2-oxo-2-[(2-phenylethyl)amino]ethyl]-, tricyclo[3.3.1.13,7]dec-2-yl ester, and
Carbamic acid, [2-[[1-(hydroxymethyl)-2-hydroxy- 2-phenylethyl]amino]-1-(imidazo[1,5-a]pyridin-3- ylmethyl)-1-methylethyl]-, tricyclo[3.3.1.13'7]dec-2-yl ester (mixture of isomers).
Table I below lists representative biologically significant amino acids. This includes the primary or genetically coded amino acids as well as some
secondary amino acids.
Figure imgf000030_0001
Table II below illustrates representative compounds of the invention. Stereochemistry is not shown in Table II.
Figure imgf000032_0001
Figure imgf000033_0001
Figure imgf000034_0001
Figure imgf000035_0001
Figure imgf000036_0001
Figure imgf000037_0001
Figure imgf000038_0001
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000045_0001
The compounds include solvates and hydrates and pharmaceutically acceptable salts of the compounds of formula I.
The compounds of the present invention can have multiple chiral centers including those designated in the above formula I by a
Figure imgf000046_0001
depending on their structures. For example, when R3 taken with R12 and R4 taken with R13 form double bonds to these carbon atoms they are no longer chiral. In addition, centers of asymmetry may exist on substituents R1, R9, R3, R4, Ar, and/or Ar2. In particular, the compounds of the present invention may exist as diastereomers, mixtures of diastereomers, or as the mixed or the individual optical enantiomers. The present invention
contemplates all such forms of the compounds. The mixtures of diastereomers are typically obtained as a result of the reactions described more fully below. Individual diastereomers may be separated from
mixtures of the diastereomers by conventional
techniques such as column chromatography or repetitive recrystallizations. Individual enantiomers may be separated by conventional method well known in the art such as conversion to a salt with an optically active compound, followed by separation by chromatography or recrystallization and reconversion to the nonsalt form.
Pharmaceutically acceptable salts are:
benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc.
The compounds of the present invention can be formed by coupling individual substituted α-amino acids by methods well known in the art. (See, for example, standard synthetic methods discussed in the multi-volume treatise "The Peptides, Analysis,
Synthesis, Biology," by Gross and Meienhofer, Academic Press, New York). The individual substituted alpha amino acid starting materials are generally known or, if not known, may be synthesized and, if desired, resolved by methods within the skill of the art.
(Synthesis of racemic [DL]-α-methyl tryptophan
methylester - see M. F. Brana, et al, J. Heterocyclic Chem. 17:829, 1980).
The following schemes illustrate methods for preparing compounds of the invention.
Scheme I below illustrates preparative steps in the process for making compounds of the instant invention. As shown, the Schiff's base (1) prepared by standard literature procedures is deprotonated using lithium diisopropyl amide and this carbanion is reacted with the aryl methyl halide 2. Following this substitution, the Schiff's base is hydrolyzed with aqueous acid to the free amine 3. This amine 3 is reacted with 2-adamantyl chloroformate in the presence of triethylamine to yield the urethane. The ester moiety was then saponified using hydroxide to the carboxylic acid 4. An active ester of this acid was prepared by treatment with N,N'-dicyclohexyl- carbodiimide and pentafluorophenol (or
1-hydroxybenzotriazole) which underwent further reaction with the appropriate amine to give the amides 5a-h, Examples 1-12.
Figure imgf000048_0001
Ar is
a) 1-Naphthyl,
b) 2-Naphthyl,
c) 3-Benzothienyl,
d) 2-(1-Boc-benzimidazolyl),
e) 3(2-Bromobenzofuranyl),
f) 2-Benzimidazolyl,
g) 3-Benzofuranyl, or
h) imidazolyl;
X is Br or Cl;
Y is hydrogen or 4-Cl; i; LDA or LHMDSA-THF :H3O+:OH- ii; 2-AdocCl-THF-Et3N:OH- iii; DCCI or WSDCCI; PfpOH or HOBt; PhCh2CH (R) NH2-EtOAc iv; HCO2NH4-10% Pd/C-MeOH-cC6H8 when Ar is e) above. Preparative Examples (Scheme I)
Alkylation Procedure
A solution of Y-PhCH=N-CH(CH3)CO2CH3 (50 mmol) in THF (150 mL) was added to a stirred solution of LDA (55 mmol) in THF at -78°C. The resulting yellow anion was further treated with a solution of the aralkyl halide (ArCH2) (50 mmol) and the resulting mixture allowed to stir overnight. Following removal of volatile materials the viscous residue was treated with 1N HCI solution (100 mmol) and stirred rapidly for 1 to 2 hours. Benzaldehyde was removed by
extraction with ether and the aqueous phase made alkaline using 10% aqueous sodium bicarbonate
solution. The amino ester
Figure imgf000049_0001
was extracted into ether, the organic phase dried (MgSO4) and evaporated, leaving the crude product which was purified as indicated. α-Methyl-DL-3(1-naphthyl)alanine methyl ester (3a)
Using 1-bromomethylnaphthalene, the product was isolated in 60% yield as a pale yellow, crystalline solid from ether. NMR (CDCl3) δ 1.47 (3H, s), 1.6 (2H, s), 3.46 (2H, dd), 3.58 (3H, s), 7.31-7.52 (4H, m), 7.75 (2H, dd), 8.13 (1H, d). α-Methyl-DL-3(2-naphthyl)alanine methyl ester) (3b) Starting from 2-bromomethylnaphthalene as alkyl halide, the product was isolated in 90% yield as a pale yellow solid from ether. NMR (CDCl3) δ 1.41 (3H, s) , 1 . 6 (2H, s) , 3. 1 (2H, dd) , 3 . 7 (3H, s) , 7 . 24-7 . 88 (7H, m) . α-Methyl-DL-3(3-benzothienyl)alanine methyl ester (3c) Using 3-chloromethylbenzothiophene as alkylating agent, the product was isolated in 78% crude yield as a light yellow oil. Chromatography (silica gel, 4% MeOH-CH2Cl2) gave 67% overall yield of a colorless oil. NMR (CDCl3) δ 1.45 (3H, s), 1.65 (2H, s), 3.24 (2H, dd), 3.63 (3H, s), 7.2 (1H, s), 7.29-7.4 (2H, m), 7.81-7.85 (2H, m). α-Methyl-DL-3(2-bromo-3-benzofuranyl)alanine methyl ester (3e)
Starting from 2-bromo-3-bromomethylbenzofuran, the product was isolated in 43% crude yield and 23% overall yield of a pale yellow oil following
chromatography as above. NMR (CDCl3 δ 1.46 (3H, s), 1.81 (2H, s), 3.02 (2H, dd), 3.67 (3H, s), 7.18-7.27 (2H, m), 7.39 (1H, m), 7.53 (1H, m). α-Methyl-DL-(2-benzimidazolyl)alanine methyl ester
(3f)
1-Boc-2-chloromethylbenzimidazole was used as alkylating agent and provided an 83% crude yield of a viscous oil, used without further purification. IR (film); 1733 cm-1; NMR (CDCl3) δ 1.41 (3H, s), 3.28 (2H, s), 3.77 (3H, s), 7.26-7.34 (3H, m), 7.54-7.57 (2H, m).
Acylation-saponification procedure
A solution of the desired amino ester (2 mmol) in dry THF (20 mL) was treated with 2-AdocCl (2.2 mmol) followed by the dropwise addition of triethylamine (2.2 mmol). The mixture was stirred for 4 hours at room temperature. Volatile material was removed under vacuum and the residue partitioned between ethyl acetate and water. The organic layer was washed with dilute aqueous citric acid solution followed by dilute sodium bicarbonate solution then saline solution.
After drying the solution (MgSO4), the solvent was removed, leaving the crude protected ester. This was dissolved in dioxan or methanol (15 mL) and a 1N
solution of lithium hydroxide added (10 mmol). When TLC revealed completion of the reaction, the solvent was removed and the residue suspended between ethyl acetate and dilute aqueous citric acid solution. The organic layer was removed, washed once with water, dried, and evaporated to give the product. 2-Adoc-α-methyl-DL-3(1-naphthyl) alanine (4a)
79% crude overall yield from α-methyl-DL-3(1- naphthyl) alanine methyl ester, of a viscous resin.
Not purified further before use. NMR (CDCl3) δ
1.52-2.1 (17H, m), 3.81 (2H, s), 4.88 (1H, s), 5.19 (1H, s), 7.25-7.46 (5H, m), 7.75-7.85 (2H, m), 8.12
(1H, m).
2-Adoc-α-methyl-DL-3(2-naphthyl)alanine (4b)
Starting from α-methyl-DL-3(2-naphthyl alanine methyl ester, this was isolated as a white powder from ether, 86%. NMR (CDCl3) δ 1.53-2.13 (17H, m), 3.48 (2H, dd), 4.84 (1H, s), 6.58 (1H, s), 7.24-7.79 (7H, m).
2-Adoc-α-methyl-DL-3(benzothienyl)alanine (4c)
Starting from α-methyl-DL-3(3-benzothionyl)- alanine methyl ester, this was isolated as a white powder, 77%. NMR (CDCl3) δ 1.44-2.0 (17H, m), 3.51 (2H, dd), 4.74 (1H, s), 6.63 (1H, s), 7.23-7.36 (3H, m), 7.77-7.86 (2H, m).
2-Adoc-α-methyl-DL-3(2-bromo-3-benzofuranyl)alanine
(4e)
This was isolated as a pale pink foam, of uncertain stability, in 74% yield. Used without purification. NMR (CDCl3) δ 1.49-2.08 (17H, m), 3.41
(2H, dd), 4.91 (1H, s), 5.24 (1H, s), 7.15-7.36 (2H, m), 7.4-7.48 (2H, m). 2-Adoc-α-methyl-DL-3(2-benzimidazo,lyl)alanine (4d) Isolated in 35% yield as a white powder, mp 222-232°C, from α-methyl-DL-(2-benzimidazolyl)-alanine methyl ester. NMR (DMSO-d6) δ 1.46 (3H, s), 1.67-1.97 (14H, m), 3.28 (1H, d, J=14Hz), 3.42-3.51 (1H, m), 4.64 (1H, s), 7.01-7.1 (3H, m), 7.45 (2H, s).
Figure imgf000053_0001
Scheme III below illustrates synthetic steps towards some phenolic derivatives of the instant invention. The phenol 13 is treated with
benzylbromide, NaOH, and tetrabutyl ammonium bromide, affording the ether 14, the aldehyde of which is reduced to the primary alcohol 15 using NaBH4. The bromomethylene compound 16 is prepared from the primary alcohol by treatment of 15 with Ph3P, Br2, and Et3N. This is then reacted with lithiomethyl- N-benzalalaninate, and the imine hydrolyzed with aqueous acid to the amine 17 , which is coupled with 2-adamantyl chloroformate to give the urethane 18. Ester hydrolysis of 18 with LiOH to 19 followed by condensation with 2-phenethylamine gave 20 upon which gave the product 21 (Example 14) upon hydrogenation of the ether over Pd/C.
Figure imgf000055_0001
Scheme IV shows how aniline derivatives are synthesized in an exactly analogous way to that described in Scheme III, the primary alcohol 22 was converted to the methyl bromide 23 from which the amine-ester 24 was prepared. Reaction with
2-adamantyl chloroformate gave 25, hydrolysis of the ester to 26 and condensation with 2-phenethylamine gave 27 . Reduction of the nitro group was effected using 10% palladium on carbon under an atmosphere of hydrogen to give the product 28 (Example 15).
Figure imgf000057_0001
Scheme V illustrates the synthesis of compound exemplified by Example 16.
Methyl N-benzalalaninate was treated with sodium dimesyl in dimethyl sulphoxide solution. To this, a solution of 2-chloromethyl-2,3-dihydro-1-methyl-5- phenyl-1H-1,4-benzodiazepine 29 in a dimethyl
sulphoxide-THF mixture was added. This gave after work-up and purification the β-(2,3-dihydro-1-methyl- 5-phenyl-1H-1,4-benzodiazepin-2-yl)-α-methyl alanine methyl ester 30 in 37% yield as a mixture of
2 diastereoisomers. Treatment of the free amine 30 with 2-adamantyl chloroformate gave the urethane 31 and the carboxylic acid ester was saponified with lithium hydroxide and the appropriate amide prepared via the active pentafluorophenyl ester and the corresponding amine, as seen in earlier schemes, yielding 33, exemplified by Example 16. The resultant 2 diastereoisomers were separable by flash
chromatography.
SCHEME V
Scheme V below illustrates a process for preparing compounds of the instant invention as exemplified by Example 16.
Figure imgf000059_0001
Scheme VI below shows chloromethylpyridine-1- oxide 34 as a solution in dimethylsulphoxide was treated with the carbanion formed by treating methyl N-benzalalaninate with potassium tert-butoxide in tetrahydrofuran to give the corresponding imine
Schiff's base, this imine was hydrolyzed to the amine hydrochloride salt with methanolic HCI, 35. This α-methvl-β-(pvridvl-1-oxide) DL alanine methyl ester dihydrochloride 35 was then treated with 2-adamantyl chloroformate in the presence of base to give the urethane 36. The ester group was hydrolyzed as before, using lithium hydroxide to the end 37. The appropriate amides 38 were prepared by treatment of the active esters such as the pentafluoro phenyl ester or that from N,N-carbonyldiimidazole, or via the mixed anhydride formed by treatment of the acid with
isobutyl chloroformate and N-methyl morpholine, with the corresponding amines. The pyridyl-1-oxide moiety was reduced using 10% palladium on carbon and an atmosphere of hydrogen at 30 bar pressure to give, for example, the N-[(2-adamantyloxy)carbonyl]-α-methyl-β- (2-pyridyl)-DL-alanine-2-phenethylamide, Example 18.
SCHEME VI
Scheme VI below illustrates preparative steps in the process for making compounds of the instant invention as exemplified by Examples 17-29.
Figure imgf000061_0001
Scheme VII shows a typical sequence similar to that illustrated in Scheme V. Reaction of
heteroarylmethyl halides II with the carbanion derived from methyl N-benzalalaninate III gives, upon acidic hydrolysis of the imine, the amine IV, this when treated with an appropriate chloroformate V yields the urethane - ester VI. Hydrolysis of the ester with lithium hydroxide gave the carboxylic acid VII, which may be converted to give an appropriate amide I by reaction of an active ester derivative (such as pentafluoro phenyl ester) with the corresponding amine. Hydrogenation of compound X gave a mixture of amines XI, XI, and VIII, which were acylated to various R2 groups.
Figure imgf000063_0001
Figure imgf000064_0001
Scheme VIII shows one route to racemic
N-[[(2-adamantyloxy)carbonyl]-3-(1H-indazole-3-yl)-2- methylalanine. Here a suspension of sodium hydride and methyl N-benzalalaninate 2 in DMSO was treated with a solution of 3-dimethylaminomethyl- indazolomethiodide 1 in DMSO. This gave the Schiff's base which was hydrolyzed using aqueous hydrochloric acid, the hydrochloride salt yielded the free amine 3 on treatment with potassium carbonate. This free amine 3 yielded the di-urethane 5 on treatment with 2-adamantyl chloroformate in 4 in the presence of triethylamine. Treatment of 5 with lithium hydroxide in aqueous 1,4-dioxan gave 6 as an amorphous solid.
Figure imgf000066_0001
Scheme IX shows another route to compound 6. A mixture of methyl-3-indazole carboxylate 1 and sodium hydride in THF was treated with p-toluenesulphonyl chloride to give the N-tosyl protected indazole 8 . Reduction of the ester 8 with Red-Al (sodium dihydro- bis (2-methoxyethoxy) aluminate) gave the primary alcohol 9 , which on treatment with thionyl chloride gave the methyl chloride 10. The chloromethyl derivative 10 was treated with the carbanion derived from treating methyl N-benzalalanate with sodium hydride in DMSO and the imine hydrolyzed with dilute hydrochloric acid. Treatment of the resultant HCI salt with potassium carbonate yielded the free amine 11. Reaction of 11 with 2-adamantyl chloroformate 4 in the presence of triethylamine gave the expected urethane 12. Treatment of 12 with potassium hydroxide in aqueous dioxan gave the required intermediate 6.
Figure imgf000068_0001
Scheme X shows the synthesis of several amides 13a-c derived from 6 via the active ester of the carboxylic acid group in 6 and the appropriate amine. The benzyl ester 13c was converted to the acid 14 by hydrogenation using Pearlman's catalyst in ethanol (Scheme XI).
Figure imgf000070_0001
O
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
The present invention is also concerned with compounds of the formula I and processes for the preparation thereof (see Scheme XIV)
Figure imgf000074_0001
wherein R1 is a group of the formula
Figure imgf000074_0002
and R2 is
i) ii)
Figure imgf000074_0004
A key intermediate in the preparation of compounds of formula I of Scheme XIV is a compound of formula II
Figure imgf000074_0003
Schemes XIV and XV below illustrate the preparative steps in the process for making compounds of the instant invention. As shown, the pyrrolecarboxylic acid methyl ester 1 is protected on the pyrrole nitrogen by tosylation to give 3 which is reduced by Red-Al to the corresponding 4-hydroxymethyl compound 4. The alcohol 4 is converted to the corresponding chloride 5 using thionyl chloride in toluene. The chloromethyl derivate 5 is reacted with the carbanion derived from treating methyl N-benzalanate with sodium hydride in DMSO and the imine hydrolyzed with dilute hydrochloric acid to the HCI salt of aminoester 7. Treatment with potassium carbonate yielded the free aminoester 7 . This aminoester reacted with
2-adamantyl chloroformate (8) to the methyl ester 9 which is hydrolyzed with potassium hydroxide in ethanol, followed by further acidic work up to give the carboxylic acid 10. This acid is condensed with the amines 11 as illustrated in Scheme XV to produce the final products 12.
The present invention is also concerned with compounds of the formula I and processes for the preparation thereof (see Scheme XVI)
Figure imgf000075_0001
wherein R1 is a group of the formula
Figure imgf000075_0002
and R2 is
i) -CH2-CH2-C6H5 OH
Figure imgf000076_0002
ii) -CH-CH-C6H5
Figure imgf000076_0003
CH2-OH .
A key intermediate in the preparation of
compounds of formula I of Scheme XVI is a compound of formula II
Figure imgf000076_0001
Schemes XVI and XVII below illustrate the preparative steps in the process for making compounds of the instant invention. As shown, the reaction of
imidazo [1,5-a]pyridine (1) with formaldehyde and dimethylamine in acetic acid gives the Mannich base 2 , which is converted to the corresponding methiodide 3 by reaction with ICH3 in ethanol. The methiodide 3 is reacted with the carbanion derived from treating
N-benzalanate (4) with potassium t-butoxide in THF and the imine is hydrolyzed with dilute hydrochloric acid to the HCI salt of aminoester 5. Treatment with potassium carbonate gives the free aminoester 5 which is reacted with 2-adamantyl chloroformate (6) to the methyl ester 7 , which is hydrolyzed with lithium hydroxide in dioxane/water, followed by further acidic work up to give the carboxylic acid 8 . This acid (intermediate II) is condensed with the amines 9 as illustrated in Scheme XVII to produce the final products 10.
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000080_0001
The present invention is concerned with compounds of the general formula I and processes for the
preparation thereof
(I)
Figure imgf000081_0001
wherein R1 is a group of the formula
a)
Figure imgf000081_0002
wherein R3 is a hydrogen atom
and R2 is
Figure imgf000081_0003
A key intermediate in the preparation of
compounds of formula I is a compound of formula below:
Figure imgf000082_0001
Compounds of formula I can be synthesized as shown in Scheme X and Scheme XI.
Scheme VIII (Route A) and Scheme IX (Route B) illustrate processes for the preparation of a compound of the above formula for the intermediate.
One process (Scheme VIII) involves reacting the quaternary salt 1 with the aldimine 3 in the presence of sodium hydride in dimethylsulfoxide (cf., for example, EP A 0037271). The Schiff base thus formed is not isolated and is subjected to hydrolysis with 1N hydrochloric acid to give the free amine 3. This is condensed with 2-adamantyl chloroformate (4) to give the methyl ester 5 which is hydrolyzed with lithium hydroxide in dioxane/water followed by further acid work up to give the free acid 6 .
In another process (Scheme IX), the indazole methyl-3-carboxylate (7) is protected on the indazole 1-nitrogen by tosylation to give 8 which is reduced by Red-Al to the corresponding 3-hydroxymethyl compound 9 . The alcohol 9 is converted into the corresponding chloride 10 using thionyl chloride in toluene. The chloride 10 is used to alkylate the anion of the aldimine 2 (cf. for example J. Heterocyclic Chem.
16:333, 1979). The above intermediate is not isolated and is subjected to hydrolysis with 1N hydrochloric acid to give the free amine 1 1. This amine is condensed with 2-adamantyl chloroformate (4) to give the methyl ester 12 which is hydrolyzed with potassium hydroxide in dioxane/water followed by further acid work-up to give the free carboxylic acid 6.
The acid 6 is condensed with amines such as illustrated in Scheme X to produce final products, for example, condensation of 6 with phenylethylamine gives compound 13a with (S)-(-)-2-amino-3-phenyl-1-propanol gives compound 13b and with (R)-4-[[(2-amino-1- phenyl)ethyl]amino]-4-oxobutanoic acid benzyl ester to give 13c and 13d.
The benzyl ester 13c is reduced to the free carboxylic acid 14 using hydrogen and 20% Pd(OH)2 on carbon catalyst (Scheme XI). BIOLOGICAL ACTIVITY
The biological activity of compounds of the present invention was evaluated employing an initial screening test which rapidly and accurately measured the binding of the tested compound to known CCK receptor sites. Specific CCK receptors have been shown to exist in the central nervous system. (See Hays, et al, Neuropeptides 1:53-62, 1980; and Satuer, et al, Science 208:1155-1156, 1980.)
In this screening test the cerebral cortices taken from male CFLP mice weighing between 30 to 40 g were dissected on ice, weighed, and homogenized in 10 volumes of 50 mM Tris-HCl buffer (pH 7.4 at 0° to 4°C). The resulting suspension was centrifuged, the supernate was discarded, and the pellet was washed by resuspension in Tris-HCl buffer followed by
recentrifugation. The final pellet was resuspended in 20 volumes of 10 nM Hepes buffer (pH 7.2 at 23°C) containing 130 mM NaCl, 4.7 nM KCl, 5 nM MgCl2, 1 nM EDTA, 5 mg/mL bovine albumin, and bacitracin
(0.25 mg/mL).
In saturation studies, cerebral cortical
membranes were incubated at 23°C for 120 minutes in a final volume of 500 μL of Hepes incubation buffer (pH 7.2) together with 0.2-20 nM
tritiated-pentagastrin (Amersham International,
England).
In the displacement experiments, membranes were incubated with a single concentration (2 nM) of ligand, together with increasing concentrations of competitive test compound. In each case, the
nonspecific binding was defined as that persisting in the presence of the unlabeled octapeptide CCK26-33 (10- 6M).
Following incubation, radioactivity bound to membranes was separated from that free in solution by rapid filtration through Whatman GF/B filters and washed three times with 4 mL of ice cold Tris-HCl buffer. Filters from samples incubated with tritiated pentagastrin were placed in polyethylene vials with 4 mL of scintillation cocktail, and the radioactivity was estimated by liquid scintillation spectrometry (efficiency 47% to 52%).
The specific binding to CCK receptor sites was defined as the total bound tritiated pentagastrin minus the amount of tritiated pentagastrin bound in the presence of 10-6 octapeptide, CCK26-33.
Saturation curves for specific tritiated
pentagastrin binding to mouse cortical membranes were analyzed by the methods of Scatchard (Ann. New York Acad. Sci. 51:660-672, 1949; Hill, J. Physiol.
40:IV-VIII, 1910) to provide estimates for the maximum number of binding sites (Bmax) and the equilibrium dissociation constant (Ka). In displacement experiments, inhibition curves were analyzed by either logit-log plots or the iterative curve fitting computer program ALLFIT
(DeLean, Munson, and Redbard, 1978) to provide estimates of the IC50 and nH (apparent Hill
coefficient) values). TC50 values were defined as the concentration of test compound required to produce 50% inhibition of specific binding).
The inhibition constant (Ki) of the test compound was then calculated according to the Cheng-Prusoff equation:
Figure imgf000085_0001
where [L] is the concentration of radiolabel and Ka is the equilibrium dissociation constant.
The Ki values for several representative
compounds of the present invention are present in Table II.
Compounds of the present invention are expected to be useful as appetite suppressants as based on the tests described hereinbelow.
In the Palatable Diet Feeding assay, adult male hooded Lister rats weighing between 200 to 400 g were housed individually and trained to eat a palatable diet. This diet consisted of Nestles sweetened condensed milk, powdered rat food, and rat water which, when blended together, set to a firm
consistency. Each rat was presented with 20 to 30 g of the palatable diet for 30 minutes per day during the light phase of the light-dark cycle over a training period of 5 days. The intake of palatable diet was measured by weighing the food container before and after the 30-minute access period (limits of accuracy 0.1 g). Care was taken to collect and correct for any spillage of the diet. Rats had free access to pellet food and water except during the 30-minute test period.
After the training period, dose-response curves were constructed for CCK8 and several representative compounds of the present invention (n = 8 to 10 rats per dose level). MPE50 values (±95% confidence limits) were obtained for the anorectic effects of these compounds.
In therapeutic use as appetite suppression agents, the compounds of the instant invention are administered to the patient at dosage levels of from about 200 to about 2800 mg per day.
Table II above shows the binding data for
representative compounds of the invention.
Male hooded Lister rats (175-250 g) are housed individually and fasted overnight (free access to water). They are anesthetized with urethane (1.5 g/kg IP) and the trachea cannulated to aid spontaneous respiration. The stomach is perfused continuously using a modification of the original method of Ghosh & Schild in "Continuous recording of the acid secretion in the rat", Brit. J. Pharmac. 13:54-61, 1956, as described by Parsons in "Quantitative Studies of Drug-Induced Gastric Acid Secretion" (Ph.D. Thesis, University of London, 1969). The cavity of the stomach is perfused at a rate of 3 mL/min with 5.4% w/v glucose solution through both the esophageal and body cannula. The fluid is propelled by a roller pump (Gilson, Minipuls 2), through heating coils to bring its temperature to 37 ± 1°C. The perfusion fluid is collected by the fundic collecting funnel and passed to a pH electrode connected to a Jenway pH meter (PHM6). An output is taken from the pH meter to a Rikadenki chart recorder for the on-line recording of the pH of the gastric perfusate.
Pentagastrin is stored as a frozen aliquot and diluted to the required concentrations with sterile 0.9% w/v NaCl. Novel compounds are dissolved in sterile 0 . 9% w/v NaCl on the day of the experiment . Drugs are administered IV through a cannulated jugular vein as a bolus in a dose volume of 1 mL/kg washed in with 0.15 mL 0.9% w/v NaCl. Basal pH is allowed to stabilize before administration of compounds is begun. Typically, 30 minutes elapses between surgery and the first compound administration.
The compounds of the instant invention are also expected to be useful as antiulcer agents as discussed hereinbelow.
Aspirin-induced gastric damage is assessed in groups of 10 rats each.
All animals are fasted for 24 hours before and throughout the experiment. Drug or vehicle is given 10 minutes before an oral dose of 1 mL of a 45-mg/mL suspension of aspirin in 0.5% carboxymethylcellulose (CMC).
The animals are sacrificed 5 hours after aspirin administration and the stomachs removed and opened for examination.
Gastric damage is scored as follows:
Score
1 Small hemorrhage
2 Large hemorrhage
3 Small ulcer
4 Large ulcer
5 Perforated ulcer
The specific dosages employed, however, may be varied depending upon the patient, the severity of the condition being treated, and the activity of the compound employed. Determination of optimum dosages is within the skill of the art.
The compounds of the instant invention are also expected to be useful as anxiolytic agents as
described and discussed below.
Anxiolytic activity is assessed in the light/dark exploration test in the mouse (B. J. Jones, et al,
Brit. J. Pharmac. 93:985-993, 1988). The compound is given PO in 0.1-, 1-, and 10-mg/kg doses.
The apparatus is an open-topped box, 45 cm long, 27 cm wide, and 27 cm high, divided into a small (2/5) area and a large (3/5) area by a partition that extended 20 cm above the walls. There is a 7.5 x 7.5 cm opening in the partition at floor level. The small compartment is painted black and the large compartment white. The floor of each compartment is illuminated by a 100-watt tungsten bulb 17 cm above the box and the black compartment by a similarly placed 60-watt red bulb. The laboratory is
illuminated with red light.
All tests are performed between 13 hundred hours,
0 minutes and 18 hundred hours, 0 minutes. Each mouse is tested by placing it in the center of the white area and allowing it to explore the novel environment for 5 minutes. Its behavior is recorded on videotape and the behavioral analysis is performed subsequently from the recording. Five parameters are measured: the latency to entry into the dark compartment, the time spent in each area, the number of transitions between compartments, the number of lines crossed in each compartment, and the number of rears in each compartment.
In this test an increase in the time spent in the light area is a sensitive measure of, that is directly related to, the anxiolytic effects of several standard anxiolytic drugs. Drugs are dissolved in water or saline and administered either subcutaneously,
intraperitoneally, or by mouth (PO) via a stomach needle.
The compounds of the instant invention are expected to be useful as antipsychotic agents.
Compounds are tested for their ability to reduce the effects of intra-accumbens amphetamine in the rat as described hereinafter.
Male Sprague Dawley (CD) Bradford strain rats are used. The rats are housed in groups of five at a temperature of 21 ± 2°C on a 12-hour light-dark cycle of lights-on between 07 hours, 00 minutes and
20 hours, 00 minutes. Rats are fed CRM diet (Labsure) and allowed water ad libitum.
Rats are anesthetized with chloral hydrate
(400 mg/kg SC) and placed in a Kopf stereotaxic frame. Chronically indwelling guide cannulae (constructed of stainless steel tubing 0.65 mm diameter held
bilaterally in Parspex holders) are implanted using standard stereotaxic techniques to terminate 3.5 mm above the center of the nucleus accumbens (Ant. 9.4, Vert. 0.0, Lat. 1.6) or 5.0 mm above the central nucleus of the amygdala (Ant. 5.8, Vert. -1.8, Lat. ±4.5) (atlas of De Groot, 1959). The guides are kept patent during a 14-day recovery period using stainless steel stylets, 0.3 mm diameter, which
extended 0.5 mm beyond the guide tips.
Rats are manually restrained and the stylets removed. Intracerebral injection cannulae, 0.3 mm diameter, are inserted and drugs delivered in a volume of 0.5 μL over 5 seconds (a further 55 seconds was allowed for deposition) from Hamilton syringes
attached via polythene tubing to the injection units. Animals are used on a single occasion only.
Behavioral experiments are conducted between 07 hours, 30 minutes and 21 hours, 30 minutes in a quiet room maintained at 22 ± 2°C. Rats are taken from the holding room and allowed 1 hour to adapt to the new environment. Locomotor activity is assessed in individual screened Perspex cages (25 x 15 x 15 cm (high)) (banked in groups of 30), each fitted with one photocell unit along the longer axis 3.5 cm from the side; this position has been found to minimize
spurious activity counts due to, for example, preening and head movements when the animal is stationary.
Interruptions of the light beam are recorded every 5 minutes. At this time, animals are also observed for the presence of any nonspecific change in
locomotor activity, e . g . , sedation, prostration, stereotyped movements, that could interfere with the recording of locomotor activity.
The abilities of the compounds to inhibit the hyperactivity caused by the injection of amphetamine into the nucleus accumbens of the rat is measured.
An increase in locomotor activity follows the bilateral injection of amphetamine (20 μg) into the nucleus accumbens; peak hyperactivity (50 to 60 counts 5 minutes-1) occurs 20 to 40 minutes after injection. Intraperitoneal injection of the rats with a compound at 10, 20, or 30 mg/kg reduces the
hyperactivity caused by the intra-accumbens injection of amphetamine. This test is known to be predictive of antipsychotic activity (Costall, Domeney & Naylor & tyers, Brit. J. Pharmac. 92:881-894).
The compounds of the instant invention are expected to prevent and treat the withdrawal response produced when chronic treatment by a drug is stopped or when alcohol abuse is stopped. These compounds are therefore useful as therapeutic agents in the
treatment of drug or alcohol abuse as discussed and described below.
The effect of the compounds of the instant invention is illustrated, for example, in the mouse "light/dark box" test.
Animals are given nicotine, 0.1 mg/kg i.p. b.d. for 14 days. After a 24-hour withdrawal period, a compound is typically given at 0.1 to 100 mg/kg i.p. b.d. The increased time spent in the light area is a sensitive measure of the effect of the compound as an agent to treat withdrawal effects from nicotine.
The effect of long-term treatment and withdrawal from diazepam with intervention with a compound can be shown. Five mice are given diazepam at 10 mg/kg i.p. b.d. for 7 days. Withdrawal is for a 24-hour period; a compound of the invention is typically given at 0.01 to 100 mg/kg i.p. b.d. The increased time spent in the light section shows the effect of the compound.
The effect of a compound of the invention on the long-term treatment and withdrawal from diazepam.
Five mice are given diazepam at 10 mg/kg i.p. b.d. for 7 days. The amount of time spent in the light section after the compound is administered demonstrates the effectiveness of the compound. The effect of a compound of the invention on the long-term treatment and withdrawal from alcohol can be shown. Five mice are given alcohol in drinking water 8% w/v for 14 days. After a withdrawal period of 24 hours, a compound is typically given at 1.0 mg/kg i.p. b.d. The amount of time spent in the light section after the compound is administered
demonstrates the effectiveness of the compound.
The effect of a compound of the invention on long-term treatment and withdrawal from alcohol can be shown. Five mice were given alcohol in drinking water, 8% w/v for 14 days. After a withdrawal period of 24 hours, the compound was given at 10 mg/kg i.p. b.d. The increased time spent in the light section shows the effect of the compound on the mice.
The effectiveness in the long-term treatment and withdrawal from cocaine can be shown. Five mice are given cocaine as 1.0 mg/kg i.p. b.d. for 14 days. The increased time in the light section illustrates the effectiveness of the compound in the treatment.
The effect of long-term treatment and withdrawal from cocaine with the intervention of a compound of the invention can be shown. Five mice are given cocaine at 1.0 mg/kg i.p. b.d. for 14 days after a withdrawal period of 24 hours, the compound is given at 1.0 mg/kg i.p. b.d. The effect of intervention with the compound is shown by the increase in time spent in the light section.
The anxiolytic effects of a compound of the invention in the Rat Social Interaction Test on a dose range of 0.001 to 1.0 mg/kg when paired rats are dosed s.c. The anxiolytic effect of the compound is indicated by the increase in time spent in social interaction compared with the control value C.
(Costall, B., University of Bradford.) The anxiolytic effects of a compound of the invention in the Rat Elevated X-Maze Test on a dose range of 0.01 to 1.0 mg/kg s.c. The anxiolytic effect is indicated by the time spent in the open arm end section compared with control C.
Compounds of the invention depress the flexor response in a stimulated spinalized decerebrated rat preparation similar to morphine. The effect of giving a compound with morphine greatly potentiates the effect which lasts for about 3 hours.
For preparing pharmaceutical compositions from the compounds of this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, and
suppositories.
A solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, or tablet disintegrating agents; it can also be an encapsulating material.
In powders, the carrier is a finely divided solid which is in a mixture with the finely divided active component. In tablets, the active component is mixed with the carrier having the necessary binding
properties in suitable proportions and compacted in the shape and size desired.
For preparing suppository preparations, a
low-melting wax such as a mixture of fatty acid glycerides and cocoa butter is first melted and the active ingredient is dispersed therein by, for example, stirring. The molten homogeneous mixture is then poured into convenient sized molds and allowed to cool and solidify. The powders and tablets preferably contain 5 to about 70% of the active component. Suitable carriers are magnesium carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low-melting wax, cocoa butter, and the like.
A preferred pharmaceutically acceptable salt is the N-methyl glucamine salt.
The term "preparation" is intended to include the formulation of the active component with encapsulating material as a carrier providing a capsule in which the active component (with or without other carriers) is surrounded by a carrier which is thus in association with it. Similarly, cachets are included.
Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral
administration.
Liquid form preparations include solutions, suspensions, and emulsions. Sterile water or
water-propylene glycol solutions of the active compounds may be mentioned as an example of liquid preparations suitable for parenteral administration. Liquid preparations can also be formulated in solution in aqueous polyethylene glycol solution.
The following Examples 1-52 are illustrative of methods for preparing compounds of the instant invention. They are not intended to limit the scope of the invention.
Coupling Procedure
To a stirred solution of the urethane protected acid (0.5 mmol) in ethyl acetate (10 mL) was added pentafluorophenol or N-hydroxybenzotriazole
(0.55 mmol) followed by DCC (0.6 mmol). The
dicyclohexylurea formed was filtered off before the addition of the amino component (phenethylamine or L-phenylalaninol; 0.7 mmol) wherein the mixture was stirred overnight with a brief period at reflux if TLC indicated that activated ester was still present. The ethyl acetate solution was cooled, washed with dilute aqueous citric acid solution, dilute aqueous sodium bicarbonate solution, and finally saline solution before being dried (MgSO4) and evaporated. The residual material was purified as indicated.
Scheme II above illustrates the preparation of compounds wherein Ar2 is the sidechain for a
genetically coded amino acid. The carboxylic acid 6 is esterified by treatment of a methanolic solution of the acid with thionyl chloride. The two free amines are then protected as the tert-butyl urethanes by treatment with di-tert-butvldicarbonate yielding 3. Treatment of this with benzylchloromethylether in dichloromethane gave the N-BOM-protected imidazole ring 9 . The ester group was then hydrolyzed with lithium hydroxide in aqueous methanol to 10 and the pentafluorophenyl ester made using N,N'-dicyclohexyl carbodiimide. This active ester was then treated with 2-phenethylamine to give the amide 11 and the ring deprotected by hydrogenation using Pearlman's catalyst in ethanol yielding 12 (Example 13).
EXAMPLE 1
2-Adoc-α-methyl-DL-3(1-naphthyl)alanyl phenethylamide
A white powder was isolated in 39% yield from 2-Adoc-α-methyl-DL-3(1-naphthyl)alanine following chromatography as described above, m.p. 184-6°C. NMR (CDCl3) δ 1.43 (3H, s), 1.51-2.01 (14H, m), 2.57 (2H, t, J=7Hz), 3.37 (2H, m, J=7Hz), 3.73 (2H, dd), 4.82 (1H, s), 5.16 (1H, s), 5.94 (1H, br.s), 7.01-8.11 (13H, m). IR (film); 1663, 1703 cm-1. FAB-MS M+l:511. EXAMPLE 2
2-Adoc-α-methyl-DL-3(1-naphthyl)alanyl-L- (1'-hydroxymethyl)phenethylamide
This was prepared in 47% yield from 2-Adoc- α-methyl-DL-3 (2-naphthyl) alanine using a water soluble carbodiimide in place of DCC. Purification was by chromatography as described above and gave a
noncrystalline solid. NMR (CDCl3 δ 1.56 (3H, s), 1.61-2.07 (14H, m), 2.60-2.81 (2H, m), 3.37-3.57 (2H, m), 3.7-3.86 (2H, m), 3.98 & 4.17 (total 1H, 2br.s), 4.78 & 4.86 (total 1H, 2br.m), 4.92 & 5.15 (total 1H, 2s), 6.05 (1H, m), 7.03-8.11 (13H, m). IR (film);
1665, 1700 cm-1.
EXAMPLE 3
2-Adoc-α-methyl-DL-3(2-naphthyl)alanyl phenethylamide Starting from 2-Adoc-α-methyl-DL-3(2-naphthyl) alanine this was isolated as a colorless solid
following column chromatography as described above in 66% yield, m.p. 121-128°C. NMR (CDCl3) δ 1.45 (3H, s), 1.51-2.08 (14H, m), 2.79 (2H, m), 3.4 (2H, dd), 3.49-3.56 (2H, m), 2.91 (2H, br.d), 6.27 (1H, br.s), 7.12-7.28 (6H, m), 7.45 (2H, m), 7.55 (1H, s),
7.72-7.82 (3H, m). IR (film); 1664 cm-1. FAB-MS M++l:511. EXAMPLE 4
2-Adoc-α-methyl-DL-3(2-naphthyl)alanyl- L-(1'-hydroxymethyl)phenethylamide
Starting from 2-Adoc-α-methyl-DL-3(2-naphthyl) alanine and following column chromatography (silica gel; 5% MeOH-CH2Cl2 + 1% AcOH) a white, noncrystalline solid was isolated in 36% yield. NMR (CDCl3) δ 1.28 & 1.43 (3H, 2s), 1.54-2.15 (14H, m), 2.85 (2H, m), 3.23-3.52 (2.5H, m), 3.67 (1H, qd), 3.84 (0.5H, dd), 4.08 & 4.24 (1H, 2m, 4.83 (1H, s), 4.89 & 5.01 (1H, s), 6.22 & 6.31 (1H, 2d), 7.13-7.27 (6H, m), 7.42-7.55 (3H, m), 7.71-7.82 (3H, m). IR (film); 1665,
1695 cm-1. FAB-MS M++1:541. EXAMPLE 5
2-Adoc-α-methyl-3(3-benzothienyl)alanyl phenethylamide
Starting with 2-Adoc-α-methyl-DL-3 (benzothienyl) alanine, column chromatography (silica gel; 4%
MeOH-CH2Cl2) of the crude product gave a white solid in 80% yield, m.p. 129-137°C. NMR (CDCl3 δ 1.46 (3H, s), 1.5-1.98 (14H, m), 2.65 2H, t), 3.45 (2H, m), 3.53 (2H, dd), 4.81 (1H, s), 5.16 (1H, s), 6.15 (1H, br.t), 7.07 (3H, m), 7.15-7.27 (3H, m), 7.3-7.39 (2H, m), 7.77-7.85 (2H, m). IR (film) 1644, 1677, 1704 cm-1. FAB-MS M++1:517.
EXAMPLE 6
2-Adoc-α-methyl-DL-3(3-benzothienyl)alanyl- L-(1'-hydroxymethyl)phenethylamide
From 2-Adoc-α-methyl-DL-3 (benzothienyl) alanine and purification, as described above, yielded 67% of product as a white powder, m.p. 86-91°C. NMR (CDCl3) δ 1.29 & 1.47 (3H, 2s), 1.53-1.98 (14H, m), 2.64-2.81 (3H, m), 3.32-3.61 (3.5H, m), 3.78 (0.5H, m), 4.03 & 4.22 (1H, 2m), 4.82 (1H, 2s), 4.99 & 5.17 (1H, 2s), 6.16 & 6.23 (1H, d), 7.02-7.4 (10H, m), 7.75-7.86 (2H, m). IR (film) 1683 cm-1. FAB-MS M++1:547.
EXAMPLE 7
2-Adoc-α-methyl-DL-3(2-bromo-3-benzofuranyl)alanyl- phenylethylamide
This was prepared from 2-Adoc-α-methyl-DL-3 (2- bromo-3-benzofuranyl) alanine using a water soluble carbodiimide in place of DCC. Crude product was purified by column chromatography (silica gel;
hexane-EtOAc:6-4) yielding 91% of a tan-colored noncrystalline solid. NMR (CDCl3) δ 1.54 (3H, s), 1.55-2.03 (14H, m), 2.62 (2H, t), 3.29 (2H, dd), 3.41 (2H, m), 4.83 (1H, S), 5.27 (1H, br.s), 6.07 (1H, br.t), 7.05 (2H, d), 7.16-7.27 (5H, m), 7.41 (1H, d), 7.49 (1H, d). IR (film) 1665, 1704 cm-1.
EXAMPLE 8
2-Adoc-α-methyl-DL-3(2-bromo-3-benzofuranyl)alanyl- L-(1'-hydroxymethyl)phenethylamide
Standard reaction of 2-Adoc-α-methyl-DL-3(2- bromo-3-benzofuranyl)alanine yielded a pale pink, noncrystalline solid in 89% yield which needed no further purification. NMR (CDCl3) δ 1.34 & 1.55 (3H, 2s), 1.42-2.04 (14H, m), 2.54 & 2.69 (2H, 2m),
3.06-4.11 (4H, mm), 4.83 (1H, br.d), 5.05 & 5.25 (1H, 2s), 6.04 & 6.12 91H, 2d), 7.01-7.51 (9H, m). IR (film) 1668, 1698 cm-1.
EXAMPLE 9
2-Adoc-α-methyl-DL-3(2-benzimidazolyl)alanyl
phenethylamide
This was prepared in 24% overall yield from 2-Adoc-α-methyl-DL-3(2-benzimidazolyl)alanine via the pentafluorophenyl ester as a white solid,
m.p. 209-211°C. IR (film) 1703, 1642 cm-1. NMR (CDCl3) δ 1.47-1.96 (17H, m), 2.68-2.82 (2H, m), 3.36-3.60 (4H, m), 4.73 (1H, s), 6.47 (1H, s),
7.06-7.25 (7H, m), 7.4-7.54 (3H, m). FAB-MS M+:501 (100). EXAMPLE 10
2-Adoc-α-methyl-DL-3(2-benzimidazolyl)alanyl-L-(1'- hydroxymethyl)phenethylamide
Prepared via the pentafluorophenyl ester of
2-Adoc-α-methyl-DL-3(2-benzimidazolyl)alanine as described above. Chromatography yielded the
diastereomeric mixture as a white solid,
m.p. 96-103°C, in 13% overall yield. IR (film) 1696, 1658 cm-1. NMR (CDCl3) δ 1.48-2.03 (17H, m), 2.79-2.99 (2H, m), 3.46 (1H, dd, J=7.1Hz), 3.51-3.93 (3H, m), 4.13-4.28 (1H, m), 4.73 & 4.8 (1H, 2s), 6.26 & 6.64 (1H, 2s), 6.87-7.52 (11H, m). FAB-MS M+:531.
EXAMPLE 11
2-Adoc-α-methyl-DL-3(benzofuranyl)alanyl
phenethylamide
A solution of the 2-bromo compound
2-Adoc-α-methyl-DL-3(2-bromo-3-benzofuranyl)- alanylphenethylamide (0.33 mmol) in methanol (15 mL) was treated with DIPEA (0.42 mmol), 1,4-cyclohexadiene (4 mL) and 10% Pd/C. After a short induction period heat was evolved. Stirring was continued overnight, after which the catalyst was removed and all volatiles evaporated. The residue was taken up in ethyl acetate and this washed with water followed by dilute aqueous citric acid solution and finally dried. Evaporation of the solvent followed by chromatography of the residue as described above yielded a white foam containing no bromine atoms. NMR (CDCl3) δ 1.36 (3H, s), 1.51-2.04 (14H, m), 2.73 (2H, t), 3.35 (4H, m), 4.74 (1H, s), 6.9 (1H, s), 7.22-7.34 (6H, m), 7.57 (3H,m ), 7.91 (1H, m). IR (film) 1779 cm-1.
The same product was isolated following
debromination of the intermediate acid 2-Adoc-α- methyl-DL-3(2-bromo-3-benzofuranyl)alanine followed by coupling of the crude, unpurified intermediate to phenethylamine.
EXAMPLE 12
2-Adoc-α-methyl-DL-3(3-benzofuranyl)alanyl-L-(1'- hydroxymethyl)phenethylamide
Debromination, as described above, starting from 2-Adoc-α-methyl-DL-3(2-bromo-3-benzofuranyl)alanyl-L- (1'-hydroxymethyl)phenethylamihe and phenylalaninol), noncrystalline. NMR (DMSO-d6) δ 1.25 & 1.32 (3H, 2s), 1.48 (2H, m), 1.7-1.94 (12H, m), 2.67-2.91 (2H, m),
3.11-3.42 (4H, m), 3.97 (1H, m), 4.69 (1H, s), 6.75 & 6.92 (1H, 2s), 7.19-7.31 (7H, m), 7.54 (3H, m). IR (film) 1660, 1695 cm-1.
EXAMPLE 13
Boc-α-methyl-DL-histidyl phenethylamide
STEP 1
α-Methyl histidine (4.1 mmol) was esterified using thionyl chloride (30 mmol)/methanol (25 mL), giving the methyl ester dihydrochloride in 81% yield. NMR (D2O) δ 1.64 (3H, s), 3.24 (1H, d, J=15.4Hz) 3.38 (1H, d, J=15.8Hz), 3.85 (3H, s), 7.25 (1H, s), 8.2 (1H, s).
STEP 2
The methyl ester dihydrochloride (3.36 mmol) in methanol (10 mL) was treated with triethylamine
(7.1 mmol) followed by di-tert butyl dicarbonate
(7.4 mmol) and the mixture stirred at room temperature overnight. Removal of the solvent was followed by extraction of the residue with chloroform and this washed with 5% aqueous citric acid solution and water. The extracts were dried and evaporated to an oil, Nα,Nτ-bis-BOC histidine methyl ester, in 74% yield. NMR (CDCl3) δ 1.44 (9H, s), 1.52 (3H, s), 1.61 (9H, s), 3.15-3.25 (2H, m), 3.76 (3H, s), 5.8 (1H, s), 7.12 (1H, s), 7.98 (1H, s).
STEP 3
The methyl ester from Step 2 (2.5 mmol) was dissolved in dry dichloromethane (10 mL) and
benzylchloromethyl ether (5.03 mmol) added. The mixture was stirred overnight. Removal of the solvent left a residue which was precipitated from methanol, giving the Nα-BOC, NπBom-histidine methyl ester hydrochloride, 100% yield. NMR (CDCl3) δ 1.42 (9H, s), 1.49 (3H, s), 3.41 (2H, s), 3.46 (3H, s),
4.64-4.71 (4H, m), 5.7-5.8 (1H, m), 7.1 (1H, s), 7.27-7.36 (5H, m), 9.63 (1H, s).
STEP 4
The ester from Step 3 (1.54 mmol) was treated with lithium hydroxide hydrate (7.7 mmol) in methanol (15 mL) at reflux for 2.5 hours. Removal of the solvent was followed by extraction of the residue with ether and this washed with water. Combined aqueous phases were acidified to pH 4.5 with aqueous 1N HCI solution and extracted with chloroform. After drying the extracts they were filtered and evaporated to a solid foam, the free acid, in 40% yield. NMR (CDCl3) δ 1.44 (9H, s), 1.71 (3H, s), 3.19 (1H, d, J=15.2Hz), 3.74 (1H, d, J=15.7Hz), 4.45 (2H, s), 5.41 (1H, d, J=10.8Hz), 5.46 (1H, d, J=10.8Hz), 6.15 (1H, s), 6.92 (1H, s), 7.23-7.34 (5H, m) , 7.77 (1H, br.s), 7.98 (1H, s).
STEP 5
The free acid (0.62 mmol) was coupled to
phenethylamine as described above for Examples 26-37. The crude product was isolated as an oil which could not be crystallized. 94%, IR (film) 1709, 1657 cm-1. NMR (CDCl3) l 1.39 (12H, s), 2.75-2.82 (2H, m), 3.23 (1H, d, J=15.8Hz), 3.38 (1H, d, J=15.8Hz), 3.4-3.51 (2H, m), 4.48 (2H, s), 5.24-5.33 (2H, m), 5.74 (1H, s), 6.68-6.7 (1H, m), 6.9 (1H, s), 7.13-7.36 (10H, m), 7.71 (1H, s).
STEP 6
The π-Bom group was removed from the imidazole ring of the intermediate from Step 5 (0.58 mmol) by hydrogenolysis in ethanol (50 mL) containing palladium hydroxide (70 mg) at a pressure of 50 psi at 50°C for 6 hours. After removal of the catalyst and solvent, the residue was chromatographed (silica gel,
MeOH-CH2Cl2 gradient 4-10% MeOH) giving the pure product as a white foam, 60%. IR (film) 1701,
1651 cm-1. NMR (CDCl3) δ 1.41 (9H, s), 1.49 (3H, s), 2.76-2.81 (2H, m), 2.94 (1H, d, J=14.7Hz), 3.18 (1H, d, J=14.7Hz), 3.45-3.58 (2H, m), 5.8 (1H, br.s), 6.86 (1H, s), 7.15-7.32 (5H, m), 7.54 (1H, s). FAB-MS M+:373.
This BOC-α-methyl-DL-histidyl phenethylamide is then converted to a compound of the invention by ... EXAMPLE 14
(±)-[1-[(2-Hydroxyphenyl)methyl]-1-methyl-2-oxo-2-[(2- phenylethyl)amino]ethyl]carbamic acid
tricyclo[3.3.1.13'7]dec-2-ylester (21)
STEP 1 (14)
To a stored suspension of aqueous NaOH (33 g in
H2O, 33 mL, 0.83 mol) in CH2Cl2 (250 mL) was added in one portion 2-hydroxybenzaldehyde (10 g, 81-87 mmol). After 30 minutes at room temperature, tetra-n-butyl ammonium bromide (2.64 g, 8.2 mmol) was added followed by dropwise addition of benzylbromide (9.8 mL,
82-39 mmol) over 10 minutes. The mixture was stirred at room temperature for 24 hours and the CH2Cl2 layer separated. This was washed with water (2 x 100 mL), dried over MgSO4, filtered and the solvent removed in vacuo. Purification by chromatography over silica using 50% n-hexane/50% CH2Cl2 as eluant gave the prpduct (15.31 g, 95%) as an oil; IR (film) 1688 and 1599 cm-1. NMR (CDCl3) δ 5.15 (2H, s), 6.97-.03 (2H, m), 7.29-7.52 (6H, m), 7.83 (1H, dd, J 8.6, 2.6Hz), 1.55
STEP 2 (15)
NaBH4 (2.0 g, 52-87 mmol) was added in portions to MeOH (20 mL) and stirred at 0°C. The aldehyde (5.0 g, 25.48 mmol) in MeOH (15 mL) was then added dropwise over 10 minutes and the cold mixture stirred for 30 minutes and then for 2 hours at room
temperature. This was followed by dropwise addition of IN NaOH (51 mL, 51.0 mmol) and stirring continued for 15 minutes. The mixture was extracted with Et2O (2 x 50 mL), Et2O dried over MgSO4, filtered, and the solvent removed in vacuo to give the product as a syrup (4.45 g, 88%). IR (film) 3398, 3064, 3034, 1603, and 1590 cm-1. NMR (CDCl3) δ 2.37 (1H, bs), 4.71 (2H, s), b.09 (2H, s), 6.91-6.97 (2H, m), 7.21-7.42 (7H, m).
STEP 3 (16)
Bromine (0.3 mL, 5.86 mmol) in CCl4 (5 mL) was added dropwise to a stirred solution of
triphenylphosphine (1.53 g, 5.83 mmol) in CCl4
(25 mL), causing a yellow solid to precipitate. The mixture was stirred for 10 minutes at room temperature and then the alcohol (1.16 g, 5.83 mmol) and
triethylamine (0.81 mL, 5.83 mmol) in CCl4 (10 mL) was added dropwise over 10 minutes. The mixture was stirred for 5 hours at room temperature and the triphenylphosphine oxide which had precipitated was filtered off and the solvents removed in vacuo.
n-Hexane (25 mL) was added to the residue, causing more triphenylphosphine oxide to precipitate. This was filtered off and the n-hexane removed in vacuo to give the product (1.30 g, 86%) as a syrup. IR (film) 3032 and 1601 cm-1. NMR (CDCl3) δ 4.60 (2H, s), 5.14 (2H, s), 6.89-6.94 (2H, m).
STEP 4
To a stirred solution of alanine methyl ester hydrochloride (10 g, 71.64 mmol) and excess MgSO4 in CH2Cl2 (100 mL) at room temperature was added
f-chlorobenzaldehyde (10.06 g, 71.64 mmol) and then dropwise addition of triethylamine (10 mL,
71.64 mmol). After stirring at room temperature for 20 hours, the mixture was filtered and the solvent removed in vacuo. The residue was stirred in Et2O and triethylamine hydrochloride filtered off and the Et2O extract removed in vacuo, giving the product as an oil (15.69 g, 97%). IR (film) 1746 and 1645 cm-1. NMR (CDCl3) δ 1.52 (3H, d, J=6.7 Hz), 3.73 (3H, s), 4.16 (1H, q, J=6.7Hz), 7.37 (2H, d, J=8.27Hz), 7.70 (2H, d, J=8.4Hz), 8.26 (1H, s).
STEP 5 (17)
n-BuLi (4.9 mL) of a 16M solution in n-hexane, 7.84 mmol) was added via syringe to a stirred solution of diisopropylamine (1.1 mL, 7.89 mmol) in anhydrous THF (20 mL) at -78°C under dry N2. The cold solution was stirred for 30 minutes and then the Schiff base
(1.58 g, 7.01 mmol) in anhydrous THF (10 mL) was added dropwise over 2 minutes. The mixture was stirred for 30 minutes at -78°C and then 2-benzyloxybenzyl bromide (1.83 g, 7.01 mmol) in anhydrous THF (10 mL) was added and the mixture stirred overnight at room temperature. The solvents were removed in vacuo and the syrup stirred for 1 hour in 1N HCI (15 mL, 15 mmol). The acidic solution was extracted once with Et2O (20 mL), made pH 10 with 1N Na and extracted with Et2O
(2 x 25 mL). The Et2O was dried to give the product (1.25 g, 60%) as a syrup. IR (film) 3370, 1732, and 1601 cm-1. NMR (CDCl3) δ 1.40 (3H, s), 2.53 (2H, b), 3.05 (1H, d, J=13.4Hz), 3.16 (1H, d, J=13.3Hz), 3.58 (3H, s), 5.06 (2H, s), 6.87-6.92 (2H, m), 7.12-7.44 (7H, m).
STEP 6 (18)
Triethylamine (0.642 mL, 4.60 mmol) was added to a stirred solution of the amino ester (1.25 g,
4.18 mmol) in anhydrous THF (10 mL) . This was followed by dropwise addition of
2-adamantylchloroformate (1.00 g, 4.60 mmol) in anhydrous THF (10 mL) over 10 minutes. After 3 hours at room temperature, the triethylamine hydrochloride was filtered off and the THF removed in vacuo. The residue was dissolved in Et2O (25 mL) and washed with water (2 x 25 mL), Et2O dried over MgSO4, filtered, and the solvent removed in vacuo to give the product (1.80 g, 90%) as a foam. NMR (CDCl3) δ 1.43-1.96 (17H, m), 3.13-3.23 (2H, m), 3.60 (3H, s), 4.74 (1H, s) , 5.13 (2H, s), 6.10 (1H, b), 6.88-6.96 (2H, m), 7.05-7.08 (1H, m), 7.19-7.48 (6H, m).
STEP 7 (19)
LiOH·H2O (0.79 g, 18.85 mmol) was added in one portion to a stirred solution of the methyl ester (1.80 g, 3.77 mmol) in MeOH (20 mL) and the mixture heated at reflux for 6 hours. The MeOH was removed in vacuo and the residue partitioned between EtOAc
(25 mL) and 1N HCI (25 mL). EtOAc dried over MgSO4, filtered, and the solvent removed in vacuo to give the product (997 mg, 57%) as a foam. NMR (DMSO-d6) δ 1.20 (3H, s), 1.24-2.04 (14H, m), 3.15 (1H, d, J=13.3Hz), 3.22 (1H, d, J=13.4Hz), 4.60 (1H, s), 5.11 (2H, s), 6.83-6.88 (1H, m), 6.99-7.07 (2H, m), 7.17-7.23 (1H, m), 7.30-7.48 (5H, m). STEP 8 (20)
1-Hydroxybenzotriazole monohydrate (0.092 g, 0.60 mmol) was added to a stirred solution of the acid (0.25 g, 0.54 mmol) in EtOAc (25 mL) and the mixture cooled to 0°C. To this stirred solution was added
N,N'-dicyclohexylcarbodiimide (0.122 g, 0.59 mmol) and the mixture stirred for 1 hour. This was followed by 4-dimethylaminopyridine (0.017 g, 0.14 mmol) and then a solution of 2-phenethylamine (0.098 g, 0.81 mmol) in EtOAc (1 mL) and the mixture stirred at room
temperature for 24 hours. The N,N'-dicyclohexylurea was filtered off and the EtOAc washed with aqueous 5% citric acid solution (2 x 25 mL), saturated NHCO3 (2 x 25 mL), aqueous 5% citric acid solution (25 mL), and brine (25 mL). The EtOAc solution was dried over MgSO4, filtered, and the solvent removed in vacuo.
The residue was purified by chromatography over silica using 2% MeOH/98% CH2Cl2 as eluant, which gave the product as a foam (0.232 g, 76%). IR (film) 3369, 1713, and 1658 cm-1. NMR (CDCl3) δ 1.42-1.88 (17H, m), 2.62-2.69 (2H, m), 3.14-3.19 (2H, m), 3.38-3.50 (2H, m) , 4.70 (1H, s), 5.13 (1H, d, J=12.12Hz), 5.17 (1H, d, J=12.1Hz), 6.23 (1H, b), 6.35 (1H, b), 6.90-7.48 (14H, m).
STEP 9
A solution of the benzyl ester (0.232 g,
0.41 mmol) in absolute EtOH (30 mL) was hydrogenated over 20% Pd (OH)2-H2O/C (0.1 g) at 30°C under an H2 atmosphere at 45 psi for 5 hours. The catalyst was filtered off and the solvents removed in vacuo and the residue purified by chromatography over silica using 2% MeOH/98% CH2Cl2 as eluant, giving the product
(0.156 g, 80%) as a foam, m.p. 75-84°C. IR (film) 3325, 1701, and 1651 cm-1. NMR (CDCl3 δ 1.51-1.93 (17H, m), 2.65-2.75 (2H, m), 3.06 (1H, d, J=14.2Hz), 3.21 (1H, d, J=14.3Hz), 3.40-3.51 (2H, m), 4.77 (1H, s), 5.97 (1H, b), 6.52 (1H, b), 6.80-7.27 (9H, m) , 8.63 (1H, bs) . Anal. (C29H36N2O4 0.25 n-hexane) ; C, H, N. EXAMPLE 15
(±)-tricyclo[3.3.1.13'7]dec-2-ylester-[1-[2-amino- phenyl)methyl]-1-methyl-2-oxo-2-](2-phenylethyl)- amino]ethyl]carbamic acid
STEP 1
To a stirred solution of triphenylphosphine
(2.76 g, 10.51 mmol) in CCl4 (50 mL) was added a solution of bromine (0.54 mL, 10.54 mmol) in CCl4 (5 mL) dropwise over 5 minutes. After 15 minutes, a solution of O-nitrobenzylalcohol (1.61 g, 10.51 mmol) and triethylamine (1.5 mL, 10.51 mmol) in CCH4 (50 mL) was added dropwise over 15 minutes and the mixture stirred at room temperature for 4 hours. Triphenylphosphine oxide was filtered off and the solvent removed in vacuo to give a syrup. Addition of
n-hexane (50 mL) caused more triphenylphosphine oxide to precipitate, which was removed by filtration and the solvent removed in vacuo to give the product
(1.93 g, 85%) as a yellow crystalline solid.
STEP 2
To a stirred solution of alanine methyl ester hydrochloride (10 g, 71.64 mmol) and excess MgSO4 in CH2Cl2 (100 mL) at room temperature was added
p-chlorobenzaldehyde (10.06 g, 71.64 mmol) and then dropwise addition of triethylamine (10 mL,
71.64 mmol). After stirring at room temperature for 20 hours, the mixture was filtered and the solvent removed in vacuo. The residue was stirred in Et2O and triethylamine hydrochloride filtered off and the Et2O extract removed in vacuo, giving the product as an oil (15.69 g, 97%). IR (film) 1746 and 1645 cm-1. NMR (CDCl3) δ 1.52 (3H, d, J=6.7Hz), 3.73 (3H, s), 4.16 (1H, q, J=6.7Hz), 7.37 (2H, d, J=8.2Hz), 7.70 (2H, d, J=8.4Hz), 8.26 (1H, s).
STEP 3
To a stirred solution of diisopropylamine
(1.1 mL, 7.63 mmol) in anhydrous THF (25 mL) at -78°C was added n-BuLi (4.8 mL of a 1.6M solution in
n-hexane, 7.68 mmol) via syringe. After 30 minutes at -78°C the Schiff base (1.57 g, 6.94 mmol) in anhydrous THF (5 mL) was added dropwise over 5 minutes and stirring at -78°C continued for a further 30 minutes. This was followed by a solution of o-nitrobenzyl bromide (1.5 g, 6.94 mmol) in anhydrous THF (5 mL) added over 5 minutes and the resulting mixture stirred overnight at room temperature. The solvents were removed in vacuo and the orange syrup stirred for 1 hour in 1N HCI (15 mL, 15 mmol). The aqueous solution was extracted once with Et2O (25 mL), the aqueous solution made pH 10 with 1N NaOH, and over MgSO4, filtered and the solvent removed in vacuo to give the product (0.814 g, 49%) as a syrup. NMR (CDCI3) δ 1.32 (3H, s), 1.60 (2H, bs), 3.27 (1H, d, J=13.6Hz), 3.55 91H, d, J=13.6Hz), 3.69 (3H, s), 7.34-7.53 (3H, m), 7.84 (1H, dd, J=8.3, 1.4Hz).
STEP 4
Triethylamine (0.524 mL, 3.76 mmol) was added to a stirred solution of the amino ester (0.814 g,
3.42 mmol) in anhydrous THF (10 mL) at room
temperature. This was followed by a solution of 2-adamantylchloroformate (0.808 g, 3.76 mmol) in anhydrous THF (10 mL) added dropwise over 10 minutes. The mixture was stirred at room temperature for
4 hours and the solvent removed in vacuo to give a syrup which was dissolved in Et2O (25 mL) and washed with 1N HCI (25 mL) and brine (25 mL). The Et2O was dried over MgSO4, filtered, and the solvent removed in vacuo to give the product (1.33 g, 94%) as a foam. IR (film) 1742, 1713, and 1530 cm-1.
STEP 5
Lithium hydroxide monohydrate (0.67 g,
15.97 mmol) was added in one portion to a solution of the methyl ester (1.33 g, 3.19 mmol) in MeOH (25 mL) and the mixture heated at reflux for 6 hours. The solvent was removed in vacuo and the residue dissolved in EtOAc (25 mL) and washed with 1N HCI (25 mL) and brine (25 mL). EtOAc dried over MgSO4, filtered, and the solvent removed in vacuo to give the product
(1.1 g, 86%) as a foam. IR (film) 1714 cm-1. NMR (DMSO-d6) 1.05 (3H, s), 1.48-2.03 (14H, m), 3.46 (1H, d, J=13.9Hz), 3.65 (1H, d, J=13.9Hz), 4.65 (1H, s), 7.14 (1H, bs), 7.28 (1H, d, J=7.5Hz), 7.45-7.61 (2H, m), 7.85 (1H, dd, J=8.0, 1.1Hz), 12.58 (1H, bs).
STEP 6
1-Hydroxybenzotriazole monohydrate (0.126 g,
0.82 mmol) and N,N'-dicyclohexylcarbodiimide (0.170 g, 0.83 mmol) were added to a stirred solution of the acid (0.300 g, 0.75 mmol) in EtOAc (10 mL) at 0°C and the mixture stirred for 1 hour. This was followed by 4-dimethylaminopyridine (0.023 g, 0.19 mmol) and
2-phenethylamine (0.137 g, 1.13 mmol) in EtOAc (2 mL) and the mixture stirred at 0°C for 2 hours and then at room temperature for 48 hours. The
N,N'-dicyclohexylurea was filtered off and the EtOAc washed with aqueous 5% citric acid solution
(2 x 10 mL), saturated NaHCO3 solution (2 x 10 mL), 5% citric acid solution (10 mL), and brine (10 mL). The EtOAc was dried over MgSO4, filtered, and the solvent removed in vacuo. Using 2% MeOH/98% CH2Cl as eluant gave the product (0.243 g, 64%) as a white solid, m.p. 164.5-169°C. IR (film) 1711, 1656, and
1527 cm-1. NMR (CDCl3) δ 1.47-1.96 (17H, m), 2.76 (2H, t, J=7.1Hz), 3.38-3.55 (3H, m), 3.66 (1H, d,
J=14.2Hz), 4.78 (1H, s), 5.67 (1H, bs), 6.17 (1H, m), 7.12-7.46 (8H, m), 7.80 (1H, dd, J=8.0, 1.3Hz). Anal. (C29H35N3O5) C, H, N.
STEP 7
A solution of the product from Step 6 (0.187 g, 0.37 mmol) in absolute EtOH (40 mL) was hydrogenated over 10% Pd/C (40 mg) at 30°C under an H2 atmosphere at 45 psi for 6 hours. The catalyst was filtered and washed with EtOH (40 mL) and the solvent removed in vacuo. Purification of the residue by chromatography over silica using 2% MeOH/98% CH2Cl2 as eluant gave the product (0.157 g, 89%) as a white solid,
m.p. 66-72°C. IR (film) 3346, 1705, and 1659 cm-1. NMR (CDCl3) δ 1.54-1.94 (17H, m), 2.65-2.76 (2H, m), 2.94 (1H, d, J=14.5Hz), 3.17 (1H, d, J=14.5Hz),
3.37-3.51 (2H, m), 3.85 (2H, bs), 4.76 (1H, s),
6.93-7.27 (7H, m). Anal. (C29H37N3O3) C, H, N.
EXAMPLE 16
STEP 1
β- (2 ,3-Dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin- 2-yl)-α-methyl-alanine methyl ester diastereomeric mixture
A suspension of sodium hydride (0.76 g,
25.5 mmol) in 70 mL dimethylsulfoxide was heated for 90 minutes under nitrogen at 70°C. After cooling to room temperature a solution of methyl N-benzalalanate (J. W. Tilley, P. Levitan, R. W. Kirstead, J.
Heterocyclic Chem., 16, 333 (1979) (4.9 g, 25.5 mmol) in 10 mL dimethylsulfoxide was added. After stirring 30 minutes at room temperature, the dark red solution became dark green. A solution of 2-chloromethyl-2,3-dihydro-1- methyl-5-phenyl-1H-1,4-benzodiazepine (United States Patent 4,325,957) (7.23 g, 25.5 mmol) in a mixture of 25 mL dimethylsulfoxide and 15 mL tetrahydrofuran was added. The resulting slurry was stirred 30 minutes at room temperature and 90 minutes at 70°C.
The reaction mixture was diluted with 250 mL water and extracted with ether. The ethereal phase was washed with water, dried over magnesium sulfate, and concentrated in vacuo. The oily residue (10 g) was purified by column chromatography on silica gel with a mixture of methylene chloride/methanol (98:2) as eluant.
The first fraction was educt (1.28 g), followed by 2,3-dihydro-2-hydroxymethyl-1-methyl-5-phenyl-1H- 1,4-benzodiazepine (0.62 g) and the desired product (3.36 g, 37% yield) as a dark red oil.
STEP 2
N-[(2-Adamantyloxy)carbonyl]-β-(2,3-dihydro-1-methyl- 5-phenyl-1H-1,4-benzodiazepin-2-yl)-α-methyl-alanine methyl ester diastereomeric mixture
To a stirred solution of β-(2,3-dihydro-1-methyl- 5-phenyl-1H-1,4-benzodiazepin-2-yl)-α-methyl-alanine methyl ester (diastereomeric mixture, 0.35 g, 1 mmol) in 10 mL tetrahydrofuran at 4°C was added a solution of 2-adamantyl chloroformate (0.25 g, 1.16 mmol) in 3 mL tetrahydrofuran, followed by dropwise addition of N-ethyldiisopropylamine (0.3 g, 2.3 mmol), dissolved in 3 mL tetrahydrofuran.
After 24 hours, the reaction mixture was
filtered, the solvent removed in vacuo, and the oily residue diluted with ethyl acetate. The ethyl acetate solution was washed twice with 5% citric acid and once with saturated brine. The organic layer was dried over magnesium sulfate. The solvent was removed in vacuo to give an oil residue (0.6 g), which was purified by flash chromatography on silica gel to yield the title compound (0.39 g, 65% yield) as a yellow oil.
STEP 3
N-[(2-Adamantyloxy)carbonyl]-&-(2,3-dihydro-1-methyl- 5-phenyl-1H-1,4-benzodiazepin-2-yl)-α-methyl-alanine diastereomeric mixture
To a stirred solution of N-[(2-adamantyloxy)- carbonyl]-β-(2,3-dihydro-1-methyl-5-phenyl-
1H-1,4-benzodiazepin-2-yl)-α-methyl-alanine methyl ester (diastereomeric mixture, 5.3 g, 10 mmol) in a mixture of 150 mL dioxane and 75 mL water was added lithium hydroxide (0.72 g, 30 mmol).
After stirring overnight, dioxane was removed in vacuo. The aqueous phase was extracted with ethyl acetate to remove unreacted ester. The basic phase was acidified with 5% citric acid, pH 3, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated in vacuo to yield the title compound as an orange foam (5.27 g,
quantitative).
STEP 4
N-[(2-Adamantyloxy)carbonyl]-β-(2,3-dihydro-1-methyl- 5-phenyl-1H-1,4-benzodiazepin-2-yl)-α-methyl-alanine- 2-phenylethylamide diastereomeric mixture
To a stirred suspension of N-[(2-adamantyloxy)- carbonyl]-β-(2,3-dihydro-1-methyl-5-phenyl-1H-2,4- benzodiazepin-2-yl)-α-methyl-alanine (diastereomeric mixture, 0.52 g, 1 mmol) in 15 mL dry ethyl acetate at room temperature was added pentafluorophenol (0.2 g, 1.1 mmol) followed by addition of a solution of
N,N-dicyclohexylcarbodiimide (0.23 g, 1.1 mmol) in 5 mL dry ethyl acetate at 4°C. The reaction mixture was kept at this temperature for 16 hours. The precipitate was filtered off and 2-phenylethylamine (0.133 g, 1.1 mmol) was added. After stirring
16 hours at room temperature the solvent was removed in vacuo. The oily residue was separated by flash chromatography using a mixture of methylene chloride and ethyl acetate (9:1 to 3:1).
Diastereomer 1
Diastereomer 1 was obtained as yellow crystals (0.09 g), m.p. 140-145°C. Rf = 0.34 (methylene chloride:ethyl acetate = 3:1).
Diastereomer 2
A second crystalline fraction was obtained as a yellow foam (0.16), m.p. 60-70°C. It was a mixture of nine parts diastereomer 2 and four parts
diastereomer 1. Rf = 0.41 (methylene chloride: ethyl acetate = 3:1).
EXAMPLE 17
STEP A
α-Methyl-β-(2-pyridyl-1-oxide)-D,L-alanine methyl ester
To a suspension of potassium t-butoxide (11.22 g, 100 mmol) in 300 mL tetrahydrofuran at -30°C was added a solution of methyl N-benzalalanate (J. W. Tilley, P. Levitan, R. W. Kierstead, J. Heterocyclic Chem., 16,, 333 (1979) (19.12 g, 100 mmol) in 100 mL dry tetrahydrofuran. The mixture was stirred for
30 minutes at this temperature followed by addition of a solution of 2-chloromethyl-pyridine-1-oxide
(14.36 g, 100 mmol) in 100 mL DMSO. This mixture was stirred for 3 hours at -25°C and then warmed to room temperature. The reaction mixture was diluted with 1.5 L of methylene chloride, washed with water (5x), and dried over magnesium sulfate. Methylene chloride was removed in vacuo to give the Schiff base (25.65 g, 86% yield). To the stirred solution of the Schiff base in 500 mL methanol at 0°C was added gaseous HCI. After 1 hour methanol was removed in vacuo to give the dihydrochloride of α-methyl-β-(2-pyridyl-1-oxide)-D,L- alanine methyl ester (20,6 g, 85% yield) as a white solid after recrystallization from methanol/diethyl ether, m.p. 144-147°C.
STEP B
N-[(2-Adamantyloxy)carbonyl]-α-methyl-β-(2-pyridyl-1- oxide)-D,L-alanine methyl ester
To a stirred suspension of α-methyl-β-(2-pyridyl- 1-oxide)-D,L-alanine methyl ester dihydrochloride (4.25 g, 15 mmol) in 50 mL dry tetrahydrofuran at room temperature was added diisopropylethylamine (4.52 g, 35 mmol). The mixture was stirred for 30 minutes followed by addition of a solution of 2-adamantyl chloroformate (3.22 g, 15 mmol) in 10 mL
tetrahydrofuran and a solution of
diisopropylethylamine (2.33 g, 18 mmol) in 10 mL tetrahydrofuran. After 24 hours, the reaction mixture was filtered, the solvent removed in vacuo, and the oily residue diluted with ethyl acetate. After filtration, the ethyl acetate solution was washed twice with 5% citric acid and once with saturated brine. The organic phase was dried over magnesium sulfate and the solvent removed in vacuo to yield the title compound as a colorless foam (5.68 g, 97% yield).
STEP C
N-[(2-Adamantyloxy)carbonyl]-α-methyl-β-(2-pyridyl-1- oxide)- D,L-alanine
To a stirred solution of N-[(2- adamantyloxy)carbonyl]-α-methyl-β-(2-pyridyl-1-oxide)- D,L-alanine methyl ester (5.83 g, 15 mmol) in a mixture of 150 mL dioxane and 100 mL water was added under nitrogen lithium hydroxide (1.2 g, 50 mmol). After stirring overnight, dioxane was removed in vacuo. The aqueous phase was extracted with ethyl acetate to remove unreacted ester. The basic phase was acidified with 5% citric acid to pH 3 and
extracted with ethyl acetate (and a little bit ethanol). The organic layer was dried over magnesium sulfate and concentrated in vacuo to yield the title compound as a white solid (5.39 g, 96% yield), m.p. 230-242°C.
STEP D, METHOD A
N-[(2-Adamantyloxy)carbonyl]-α-methyl-β-(2-pyridyl-1- oxide)-D,L-alanine-2-phenylethylamide
To a stirred suspension of N-[(2-adamantyloxy)- carbonyl)-α-methyl-β-(2-pyridyl-1-oxide)-D,L-alanine (2.43 g, 6.5 mmol) in 150 mL dry tetrahydrofuran at - 20°C was added N-methylmorpholine (0.76 g, 7.5 mmol) and isobutyl chloroformate (1.02 g, 7.5 mmol). The mixture was stirred for 20 minutes at this temperature followed by addition of 2-phenethylamine (1.21 g, 10 mmol), stirred for 3 hours at -25°C, and then warmed to room temperature. The solvent was removed in vacuo at room temperature, and the residue was diluted with ethyl acetate and water . The solution was washed with 5% citric acid (3x) and water (2x) followed by 5% potassium hydrogen carbonate (3x), water (2x), and brine. The organic phase was dried over magnesium sulfate. The solvent was removed in vacuo to yield an oily residue which crystallized by addition of diethyl ether/n-hexane (2.76 g, 89% yield), m.p. 76-80°C. STEP D, METHOD B
N-[(2-Adamantyloxy)carbonyl]-α-methyl-β-(4-pyridyl-1- oxide)-D,L-alanine-2-phenylethylamide
To a stirred suspension of N-[(2-adamantyloxy)- carbonyl)-α-methyl-β-(4-pyridyl-1-oxide)-D,L-alanine (0.37 g, 1 mmol) in 20 mL dry tetrahydrofuran at room temperature was added N,N-carbonyldiimidazole (0.16 g, 1 mmol). The mixture was stirred for 3 hours followed by addition of 2-phenylethylamine (0.12 g, 1 mmol). After stirring overnight the intermediate imidazolide could still be detected by TLC (methylenechloride:
methanol = 4:1). Additional amount of
2-phenylethylamine (0.12 g, 1 mmol) was added. After stirring 4 hours at room temperature no imidazolide could be detected. The solvent was removed in vacuo at 40°C. The crystalline residue was washed with water and recrystallized from ethyl acetate to yield the title compound (0.28 g, 59% yield), m.p.
120-126°C.
STEP D, METHOD C
N-[(2-Adamantyloxy)carbonyl]-α-methyl-β-(4-pyridyl-1- oxide)- D,L-alanine-(1S-hydroxymethyl-2- phenyl)ethylamide mixture of diastereomers
To a stirred suspension of N-[(2-adamantyloxy)- carbonyl)-α-methyl-β-(4-pyridyl-1-oxide)-D,L-alanine (0.75 g, 2 mmol) in 40 mL dry ethyl acetate at room temperature was added pentafluorophenol (0.41 g,
2.2 mmol) followed by addition of a solution of
N,N'-dicyclohexylcarbodiimide (0.45 g, 2.2 mmol) in 8 mL dry ethyl acetate at 4°C. The reaction mixture was stirred 48 hours at this temperature. The
precipitate was filtered and a solution of (S)-(-)-2- amino-3-phenyl-propanol in 10 mL dry ethyl acetate was added. After stirring 16 hours at room temperature the solvent was removed in vacuo. The residue was separated by flash chromatography using ethyl
acetate:ethanol = 9:1. Diastereomer 1 was obtained as a foam (0.42 g, 41% yield). Diastereomer 2 was obtained as a foam (0.50 g, 49% yield).
STEP E
(±)-Tricyclo[3 . 3 .1.13'7]dec-2-yl [1-methyl-2-oxo-2-[ (2- phenylethyl)amino]-1-[(2-pyridinyl)methyl]ethyl]- carbamate
A solution of N-[(2-adamantyloxy)carbonyl]-α - methyl-β-(2-pyridyl-1-oxide)-D,L-alanine-2- phenethylamide (1.64 g, 3.4 mmol) in 50 mL ethyl acetate was hydrogenated (30 bar hydrogen pressure, room temperature) over 350 mg of 10% palladium on charcoal overnight. The reaction mixture was filtered and evaporated to give an oil, which was purified by flash chromatography with ethyl acetate. The solvent was removed in vacuo to yield the title compound as an oil, which solidified on cooling (0.34 g, 21% yield), softening at 40-43°C. EXAMPLE 18
N-[(2-Adamantyloxy)carbonyl]-α-methyl-β-(3-pyridyl-1- oxide)-D,L-alanine-2-phenylethylamide
STEP A
α-Methyl-β-(3-pyridyl-1-oxide)-D,L-alanine methyl ester
The method is as described in Step A, Example 17, except 3-chloromethyl-pyridine-1-oxide was used. An extremely hygroscopic dihydrochloride was obtained in
99% yield.
STEP B
N-[(2-Adamantyloxy)carbonyl]-α-methyl-β-(3-pyridyl-1- oxide)-D,L-alanine methyl ester
The method is as described in Step B, Example 17, except α-methyl-β-(3-pyridyl-1-oxide)-D,L-alanine methyl ester dihydrochloride was used. The desired product was obtained in 26% yield as colorless
crystals, m.p. 160-163°C. Rf = 0.64
[chloroform:methanol: NH4OH(conc.) = 250:50:8].
STEP C
N-[(2-Adamantyloxy)carbonyl]-α-methyl-β-(3-pyridyl-1- oxide)- D,L-alanine
The method is as described in Step C, Example 17, except N-[(2-adamantyloxy)carbonyl]-α-methyl-β-(3- pyridyl-1-oxide)-D,L-alanine methyl ester was used. The title compound was isolated in 88% yield as a white solid, m.p. 228-231°C.
STEP D
N-[(2-Adamantyloxy)carbonyl]-α-methyl-β-(3-pyridyl-1- oxide)-D,L-alanine-2-phenylethylamide
The method is as described in Step D, Method A, Example 17, except N-[(2-adamantyloxy)carbonyl]-α- methyl-β-(3-pyridyl-1-oxide)-D,L-alanine was used.
The product was obtained in 89% yield as a white solid, m.p. 76-80ºC. Rf = 0.72 [chloroform:methanol: NH4OH (conc.) = 250:50:8.
EXAMPLE 19
STEP A
α-Methyl-β-(4-pyridyl-1-oxide)-D,L-alanine methyl ester
The method is as described in Step A, Example 17, except 4-chloromethyl-pyridine-1-oxide was used. A very hygroscopic dihydrochloride was obtained in 89% yield. Rf (base) = 0.47 (methylene chloride:methanol = 4:1).
STEP B
N- [ (2-Adamantyloxy) carbonyl] -α-methyl-β- (4-pyridyl-1- oxide) - D , L-alanine methyl ester The method is as described in Step B, Example 17, except α-methyl-β-(4-pyridyl-1-oxide)-D,L-alanine methyl ester dihydrochloride was used. The waxy product was obtained in 77% yield. Rf = 0.77
(methylene chloride:methanol = 4:1).
STEP C
N-[(2-Adamantyloxy)carbonyl]-α-methyl-β-(4-pyridyl-1- oxide)-D,L-alanine
The method is as described in Step C, Example 17, except N-[(2—adamantyloxy)carbonyl]-α-methyl-β-(4- pyridyl-1-oxide) -D, L-alanine methyl ester was used. The product was obtained in 45% yield as a white solid, m.p. 224-225°C.
EXAMPLE 19A
N-[(2-Adamantyloxy)carbonyl]-α-methyl-β-(2-pyridyl-1- oxide)-D,L-alanine-(1S-hydroxymethyl-2- phenyl)ethylamide mixture of diastereomers
The method is as described in Step D, Method A, except (S)-(-)-2-amino-3-phenyl-propanol was used. The diastereomeric mixture, obtained in 85% yield, was separated by flash chromatography using methylene chloride at first and afterwards methylene
chloride:methanol = 98:2. Diastereomer 1 was obtained as a foam softens at 74-76°C. Rf = 0.27 (methylene chloride:methanol = 95:5). Diastereomer 2 was
obtained as a foam softens at 59-67°C. Rf = 0.16 (methylene chloride:methanol = 95:5).
EXAMPLE 20
Carbonic acid, 2-[[2-methyl-1-oxo-3-(3-pyridinyl-1- oxide)-2-[[(tricyclo [3.3.1.13,7] dec-2- yloxy)carbonyl]amino]propyl]-amino]-3-phenylpropyl-2- methyIpropylester (Pyridine center RS, other center S) and
Carbamic acid, [2- [[1-(hydroxymethyl)-2- phenylethyl]amino]-1-methyl-2-oxo-1-[(3-pyridinyl N- oxide)methyl]ethyl], tricyclo[3.3.1.13'7]dec-2-yl ester (Hydroxymethyl center S, other center R or S) mixture of diastereomers
The method is as described in Example 17,
Method A, except N-[(2-adamantyloxy)carbonyl]-α- methyl-β-(3-pyridyl-1-oxide)-D,L-alanine and (S)-(-)- 2-amino-3-phenyl-propanol were used. The complex reaction mixture was separated by flash chromatography using ethyl acetate :methanol = 3:1.
Carbonic acid ester
The ester was obtained in 6% yield as a colorless foam softens at 77-80°C. Rf = 0.54 (ethyl
acetate:methanol = 3:1).
Carbamic acid esters
Diastereomer 1 was obtained in 7% yield as a colorless foam softens at 94-980C. Rf = 0.36 (ethyl acetate:methanol = 3:1). Diastereomer 2 was obtained in 2% yield as a colorless foam softens at 98-102ºC.
EXAMPLE 21
Tricyclo[3.3.1.13'7]dec-2-yl [2-[[1-(hydroxymethyl)-2- phenylethyl]amino]-1-methyl-2-oxo-1-(2- pyridinylmethyl)ethyl]-carbamate (Hydroxymethyl center S, other center R or S) (Diastereomer 1)
The method is as described in Example 17, except diastereomer 1 of Example 19A was used. The product was obtained in 26% yield as a colorless foam softens at 62-65°C. Rf = 0.34 (ethyl acetate). EXAMPLE 22
Tricyclo[3.3.1.13'7]dec-2-yl [2-[[1-(hydroxymethyl)-2- phenylethyl]amino]-1-methyl-2-oxo-1-(2- pyridinylmethyl)ethyl]-carbamate Hydroxymethyl center S, other center R or S) (Diastereomer 2)
The method is as described in Example 17, except diastereomer 2 of Example 19A was used. The product was obtained in 37% yield as a colorless foam softens at 61-64°C. Rf = 0.35 (ethyl acetate).
EXAMPLE 23
(±)-Tricyclo[3.3.1.13'7]dec-2-yl [1-methyl-2-oxo-2-[(2- phenylethyl)amino]-1-(3-pyridinylmethyl)ethyl]- carbamate
The method is as described in Example 17, except the phenylethylamide of Example 18 was used. The product was obtained in 54% yield as a colorless solid, m.p. 167-169°C. Rf = 0.24 (ethyl acetate).
EXAMPLE 24
Carbonic acid, 2-[[2-methyl-1-oxo-3-(3-pyridinyl)-2- [[(tricyclo[3.3.1.13,7]dec-2-yloxy)carbonyl]amino]- propyl]amino]-3-phenylpropyl 2-methyIpropyl ester (Pyridine center RS, other center S) The method is as described in Example 17, except carbonic ester of Example 9 was used. The product was obtained in 31% yield as a colorless foam softens at 56-58°C. Rf = 0.43 (ethyl acetate). EXAMPLE 25
Tricyclo[3.3.1.13'7]dec-2-yl [2-[[1-(hydroxymethyl)-2- phenylethyl]amino]-1-methyl-2-oxo-1-(3- pyridinylmethyl) ethyl]-carbamate (hydroxymethyl center S, other center R or S) (Diastereomer 1)
The method is as described in Example 17, except diastereomer 1 of Example 20 was used. The product was obtained in 77% yield as a colorless solid, m.p. 163-1640C. Rf = 0.65 (ethyl acetate:methanol = 3:1).
EXAMPLE 26
Tricyclo[3.3.1.13'7]dec-2-yl [2-[[1-(hydroxymethyl)-2- phenylethyl]amino]-1-methyl-2-oxo-l-(3- pyridinylmethyl)ethyl]-carbamate (hydroxymethyl center S, other center R or S) (Diastereomer 2)
The method is as described in Example 17, except diastereomer 2 of Example 20 was used. The product was obtained in 50% yield as a colorless solid, m.p. 63-670C. Rf = 0.62 (ethyl acetate:methanol = 3:1). EXAMPLE 27
(±)-Tricyclo[3.3.1.13'7]dec-2-yl [1-methyl-2-oxo-[(2- phenylethyl)amino]-1-(4-pyridinylmethyl)ethyl]- carbamate
The method is as described in Example 17, except the phenylethylamide of Example 17/Step D, Method B was used. The product was obtained in 35% yield as a colorless solid, m.p. 176°C. Rf = 0.55 (methylene chloride:methanol = 9:1). EXAMPLE 28
Tricyclo[3.3.1.1.3'7]dec-2-yl [2- [[1-(hydroxymethyl)-2- phenylethyl]amino]-1-methyl-2-oxo-1-(4- pyridinylmethyl)ethyl]-carbamate (hydroxymethyl center S, other center R or S) (Diastereomer 1)
The method is as described in Example 17, except diastereomer 1 of Example 17, Step D, Method C was used. The product was obtained in 34% yield as colorless crystals, m.p. 169-1710C. Rf = 0.46
(methylene chloride:methanol = 9:1).
EXAMPLE 29
Tricvclo[3.3.I.I.3'7]dec-2-yl [2-[[1-(hydroxymethyl)-2- phenylethyl]amino]-1-methyl-2-oxo-1-(4- pyridinylmethyl)ethyl]-carbamate (hydroxymethyl center S, other center R or S) (Diastereomer 2)
The method is as described in Example 17, except diastereomer 2 of Example 17, Step D, Method C was used. The product was obtained in 56% yield as a beige amorphous powder, m.p. 90-100°C. Rf = 0.44 (methylene chloride:methanol = 9:1).
EXAMPLE 30
Tricyclo[3.3.1.13,7]dec-2-yl [1-methyl-2-oxo-2-[(2- phenylethyl)amino]-1-(1-[methylsulfonyl]pyrido[3,4-b]indol-3-yl-methyl)ethyl]carbamate, (±)
STEP 1
To a stirred solution of 1H-β-carboline-3- carboxylic acid methylester (4.44 g, 19.6 mmol) in THF (500 mL) was added LiBH4 (2.56 g, 118 mmol) and the reaction mixture was stirred for 8 hours. The
solution was cooled in an ice/water bath, treated with 65 mL water and stirred on while warming to room temperature. The mixture was evaporated in vacuum, diluted with 400 mL water and extracted with ethyl acetate (400 mL) followed with methylene chloride (400 mL). The combined organic layers were dried over Na2SO4 and evaporated in vacuum. The residue was treated with 2N HCI (100 mL) and the solution was extracted with methylene chloride. The aqueous solution was made basic with 2N NaOH (pH = 9-10) and the precipitate was filtered, washed with water and dried in vacuum (2.25 g, 57.8%).
STEP 2
A solution of 3-(hydroxymethyl)-1H-β-carboline
(1.38 g, 7 mmol) in methylene chloride (30 mL) was cooled to -20°C and diisopropylethylamine was added. To this solution was added mesyl chloride (1.60 g, 14 mmol) dropwise with stirring. After 5 minutes ice water was added, the organic layer was separated, washed with water, dried over Na2SO4 and methylene chloride was evaporated in vacuum at room temperature. 25 mL THF were added and the solution was used for the next step.
STEP 3
The Schiffs' base (1.34 g, 7.0 mmol), derived from alanine methyl ester and benzaldehyde was
dissolved in THF (25 mL), and cooled to -76°C. To this was added a solution of LDA (11.6 mL of 10% in n-hexane) in THF (15 mL). After stirring for
30 minutes this solution was treated with
3-(methylsulfonylmethyl)-9-methylsulfonyl-β-carboline (25 Ml in THF) from Step 2, warmed to room temperature and stirred over night. The brown suspension was evaporated in vacuum, the residue dissolved in ethyl acetate and the solution was washed with water, combined with 100 mL 1N HCI and was stirred for 1 hour at room temperature. The organic layer was separated and the aqueous solution was treated with Na2CO3 to pH 8-9. This was extracted with ethyl acetate (2 x 100 mL), dried over Na2SO4 and the organic solvent was evaporated in vacuum. The residue was flash chromatographed on silica gel using 5%
methanol/methylene chloride to yield 2-[9- (methylsulfonyl)-β-carbolin-3-yl]-alanine methyl ester (0.53 g, 21.2%) as a yellow oil.
STEP 4
To a stirred solution of 2-[9-(methylsulfonyl)-β- carbolin-3-yl]-alanine methylester (0.5 g, 1.4 mmol) in THF (10 mL) was added 2-adamantyloxycarbonyl chloride (345 mg, 1.7 mmol) and the solution was treated with diisopropyl ethylamine (219 mg, 1.7 mmol) in THF (5 mL). The reaction mixture was stirred for 4 hours at room temperature, evaporated in vacuum and partitioned between ethyl acetate (100 mL) and water (50 mL). The organic layer was separated, washed successively with 7.5% citric acid solution (50 mL), 8% NaHCO3 solution (50 mL) and then dried over Na2SO4. The solvent was evaporated in vacuum and N-(2- adamantyloxy-carbonyl)-2-[9-(methylsulfonyl)-β- carbolin-3-yl]-alanine methylester was isolated as a yellow oil which solidified upon drying (0.73 g, 97.7%).
STEP 5
In a mixture of dioxane (10 mL) and water (5 mL) was stirred N-(2-adamantyloxycarbonyl)-2-[9- (methylsulfonyl)-β-carbolin-3-yl]-alanine methylester (0.73 g, 1.4 mmol) and lithium hydroxide (131 mg, 5.5 mmol) over 16 hours at room temperature. Dioxane was evaporated in vacuum, the residue was diluted with water (1C mL), 7.5% citric acid solution was added (ph = 6) and the organic components were extracted with ethyl acetate (50 mL). The organic extract was washed with saturated salt solution and dried over Na2SO4. After removing the solvent in vacuum N-(2- adamantyloxy-carbonyl)-2-[9-(methylsulfonyl)-β- carbolin-3-yl]-alanine was isolated as a yellow foam (0.68 g, 95.5%).
STEP 6
N-(2-adamantyloxy-carbonyl)-2-[9-
(methylsulfonyl)-β-carbolin-3-yl]-alanine (330 mg, 0.63 mmol) was dissolved in DMF (5 mL) and cooled to 0°C. To this was added sequentially with stirring (in 3 minute intervals) hydroxybenzotriazole (85 mg,
0.63 mmol), dicyclohexylcarbodiimide (130 mg,
0.63 mmol) and phenylethylamine (76 mg, 0.63 mmol) in DMF (3 mL). The solution slowly warmed to room temperature and stirred over 16 hours. The reaction mixture was filtered free of precipitate and
evaporated in vacuum. The residue was dissolved in ethyl acetate (50 mL) and washed successively with 7.5% citric acid solution, saturated NaHCO3 solution (50 mL) and saturated salt solution (50 mL). The organic layer was dried over Na2SO4 and evaporated in vacuum to give a foam. The reaction mixture was separated on silica gel with ethyl acetate:methylene chloride=1:1. Carbamic acid, [1-methyl-2-oxo-2-[(2- phenylethyl)amino]-1-[3[9-(methylsulfonyl)]β- carbolinyl]methyl]ethyl]-tricyclo[3.3.1.13'7]dec-2-yl ester (0.215 g, 54.4%) was isolated as a white foam, m.p. 89-920C.
EXAMPLE 31
Tricyclo[3.3.1.3'7]dec-2-yl [2-[[1-(hydroxymethyl)-2- phenylethyl]amino]-1-methyl-2-oxo-1-(1- [methylsulfonyl]-pyrido[3,4-b]-indol-3- ylmethyl)ethyl]carbamate (mixture of diastereomers, phenylethyl center is R)
Synthetic method was as described for Example 30 Step 6 but using (S)-(-)-2-amino-3-phenyl-1-propanol. The crude residue was chromatographed over silica gel using ethyl acetate:methylene chloride 1:1 as eluant to obtain the title compound (0.135 g, 35.9%) as a foam, m.p. 78-83°C EXAMPLE 32
Tricyclo[3.3.1.13'7]dec-2-yl [1-methyl-2-oxo-2-[(2- phenylethyl)-amino]-1-(1H-pyrido[3,4-b]indol-3-yl- methyl)ethyl]carbamate, (±)
STEP 1
To thionylchloride (50 mL) was added
3-(hydroxymethyl)-1H-β-carboline (2.60 g, 13.12 mmol) and the reaction mixture was refluxed for 1 hour.
After cooling down to room temperature the mixture was evaporated in the vacuum and treated with ether
(300 mL). The gray solid was collected by filtration, washed with ether and dried in the vacuum to give 3-(chloromethyl)-1H-β-carboline hydrochloride (3.3 g, 100%).
STEP 2
In THF (85 mL) was dissolved the Schiffs' Base
(2.45 g, 12.8 mmol), derived from alanine methyl ester and benzaldehyde, and cooled to -40°C. To this was added potassium-t-butoxide (2.92 g, 26 mmol) and the orange solution stirred under nitrogen at -40°C for 30 minutes. To this was added 3-(chloromethyl)-1H-β- carboline hydrochloride salt (3.24 g, 12.8 mmol), the reaction mixture stirred for another 30 minutes at -40°C and then slowly warmed to room temperature overnight. The black solution was evaporated in the vacuum and then partitioned between ethyl acetate
(150 mL) and water (50 mL). To the organic layer was added 1N HCI (100 mL) and the mixture was stirred for 2 hours. Then the organic was separated, washed with Na2CO3 solution, dried over Na2SO4 and evaporated in the vacuum to give 2-(9H-β-carboline-3-yl)-alanine methyl ester (2.4 g, 50.5%) as a light tan foam.
STEP 3
Synthetic method was as described for Example 30, Step 4, but using 2-(9H-β-carboline-3-yl)-alanine ester (2.4 g, 8.4 mmol) from Step 2 to give N-(2- adamantyloxy-carbonyl)-2-(9H-β- carboline-3-yl)- alanine methyl ester (1.1 g, 28.2 g).
Step 4
Method was as described for Example 30, step 5, but using N-(2-adamantyloxy-carbonyl)-2-(9H-β- carboline-3-yl)-alanine methyl ester (1.0 g, 2.2 mmol). N-(2-adamantyloxy-carbonyl)-2-(9H-β- carboline-3-yl)-alanine (0.9 g, 93.1 %) was isolated as a yellow solid.
STEP 5
Synthetic method was as described for Example 30 Step 6 but using N-(2-adamantyloxy-carbonyl)-2-(9H-β- carboline-3-yl)-alanine. The crude residue was chromatographed over silica gel using ethyl
acetate:methylene chloride = 5:1 as eluant to obtain the title compound (0.46 g, 83.5%). mp. 94-103°C.
EXAMPLE 33
Tricyclo[3.3.1.3'7]dec-2-yl [2-[[1-(hydroxymethyl)-2- phenyl- ethyl]amino]-1-methyl-2-oxo-1-(1H-pyrido[3,4- b]-indol-3-ylmethyl)ethyl]carbamate (mixture of diastereomers, phenylethyl center is R)
Synthetic method was as described for Example 30,
Step 6, but using (S)-(-)-2-amino-3-phenyl-1-propanol. The crude residue was chromatographed on silica gel using ethyl acetate : methylene chloride = 5:1 as eluant to obtain the title compound (0.21 g, 36.2%). m.p. 76-92°C. EXAMPLE 34
Carbamic acid, [1-methyl-2-oxo-2-[(2-phenylethyl)- amino]-1-[(2-quinolinyl)methyl]ethyl]tricyclo- [3.3.1.13'71dec-2-yl ester, (±)- STEP 1
To a solution of chinaldine (14.3 g, 0.1 mol) and N-bromosuccinimide (17.8 g, 0.1 mol) in CCl4 (150 mL) was added benzoylperoxide (2.6 g, 0.025 mol) and the mixture was heated under reflux for 4 hours. The reaction mixture was cooled to room temperature and evaporated in vacuum. The residue was treated with 5% HBr solution, the precipitate was filtered off and the filtrate was treated with celite and then basified with NaHCO3 solution. The product was extracted with ether and crystallized from petrolether to yield
2-(bromomethyl)-quinoline (2.8 g, 12.6%) as light tan crystals.
STEP 2
Method was as described for Example 30, Step 3 but using 2-(bromo-methyl)-quinoline (7.0 g, 30 mmol) and Schiff's Base (6.03 g, 30 mmol). The product was obtained without chromatography but with
crystallization methods using diethylether (3.4 g, 38.6%).
STEP 3
A solution of 2-quinolinyl-2-methyl-alanine methyl ester (4.1 g, 16.8 mmol) (40 ml) and
2-adamantyloxycarbonyl chloride (4.5 g, 20.8 mmol) in anhydrous THF (40 mL) at room temperature was treated with pyridine (1.6 g, 20.8 mmol). The reaction mixture was stirred for 2 hours at RT, the organic solvent was evaporated in vacuum and the residue was dissolved in ethyl acetate. The precipitate was filtered, the filtrate evaporated in vacuum and the residue dissolved in ether and filtered again. The filtrate evaporated in vacuum to obtain
N-(2-adamantyloxycarbonyl)-2-(quinolinyl)-alanine methyl ester (3.6 g, 38.0%) as a light tan solid.
STEP 4
Method was as described for Example 30, Step 5, but using N-(2-adamantyloxy-carbonyl)-2-(quinolin-yl)- alanine methyl ester (3.5 g, 8.3 mmol) to obtain N-(2- adamantyloxy-carbonyl)-2-(quinolin-yl)-alanine (2.0 g, 59.0%) as a beige solid from n-pentane.
STEP 5
Synthetic method was as described for Example 30, Step 6, but using N-(2-adamantyloxy-carbonyl)-2- (quinolin-yl)-alanine (0.40 g, 1 mmol). The crude residue was chromatographed on silica gel using dichloromethane:methanol = 18:1 as eluant to yield the title compound (0.12 g, 24%) as a solid from
ether/pentane, m.p. 75-76°C.
EXAMPLE 35
Carbamic acid, [2-[[1-(hydroxymethyl)-2-phenylethyl]- amino]-1-methyl-2-oxo-1-(2-quinolinylmethyl)ethyl]-, tricylo[3.3.1.13'7]dec-2-yl ester (hydroxymethyl center is S, other center is R, S)
Method was as described for Example 30, Step 6, but using N-(2-adamantyloxy-carbonyl)-2-(quinolin-yl)- alanine (0.40 g, 1 mmol) prepared in Example 34,
Step 4. The crude residue was chromatographed on silica gel using dichloromethane/methanol (18:1) as eluant to yield the title compound (40 mg, 10%), m.p. 75-86°C. EXAMPLE 36
Carbamic acid, [1-methyl-2-oxo-2-[(2- phenylethyl)amino]-1-[(3-quinolinyl)methyl]ethyl]-, tricyclo[3.3.1.13'7]dec-2-yl ester, (±)- STEP 1
To a solution of quinoline-3-carboxylic acid (25 g, 0.14 mmol) in dry THF (100 mL) was added
N,N'-carbonyldiimidazole (23.4 g, 0.14 mmol) in portions and the reaction mixture was stirred at room temperature for 2 hours. The organic solvent was evaporated in vacuum and the residue was dissolved in dry ethanol (200 mL). Sodium (0.1 g) was added and the reaction mixture was refluxed for 2 hours. The alcohol was evaporated in vacuum and quinoline-3- carboxylic ethyl ester (27.1 g, 93.5%) was isolated from ethanol/water = 1:1 (150 mL) at 5°C as a white crystalline compound.
STEP 2
To a solution of quinoline-3-carboxylic ethyl ester (10.0 g, 50 mmol) in anhydrous diethylether
(250 mL) was added at -15°C LAH (2.5 g, 66 mmol) in portions over 10 minutes. The reaction mixture was stirred for 2 hours at room temperature and 4 mL water was added. The organic layer was separated and the precipitate of the hydroxides was treated with hot ethanol (100 mL). The organic solutions were combined and treated with 47% HBr solution. The oily phase washed with ether, dissolved in ethanol (40 mL) and the product was separated by addition of diethyl ether. The precipitate was separated and treated with ethyl acetate to yield 3-(hydroxymethyl)-quinoline hydrobromide (3.0 g). After evaporating the
ethanol/ether mixture and treating the residue with ethyl acetate another 5.3 g of the product was isolated. Yield: 8.3 g (69.7%). STEP 3
A solution of 3-(hydroxymethyl)-quinoline
hydrobromide (5.3 g, 22 mmol) in thionylchloride
(15 mL) was heated to reflux for 30 minutes. The reaction mixture was evaporated in vacuum, the residue was taken up in ethyl acetate and washed with NaHCO3- solution. The dark brown organic solution was washed with water, decolorized with celite, dried over Na2SO4 and evaporated in vacuum. 3-(Chloromethyl)-quinoline (2.2 g, 37.3%) crystallized from n-pentane in white needles (turning brown standing at room temperature) STEP 4
Synthetic method was as described for Example 32, Step 2, but using 3-(chloromethyl)-quinoline (2.2 g, 12 mmol). The reaction mixture was chromatographed on silica gel using ethyl acetate: ethanol (9:1) to give 3-quinolinyl-2-methyl-alanine methyl ester 0.7 g, 23.1%) as a light brown solid.
STEP 5
Method was as described for Example 30, Step 4, but using 3-quinolinyl-2-methyl-alanine methyl ester (0.7 g, 3 mmol). N-(2-adamantyloxy-carbonyl)-3- (quinolin-yl)-alanine methylester (1.0 g, 83.3%) was obtained as a solid after drying.
STEP 6
Method was as described for Example 30, Step 5, but using N-(2-adamantyloxy-carbonyl)-3-(quinolin-yl)- alanine methylester (1.0 g, 2 mmol) to obtain N-(2- adamantyloxy-carbonyl)-3-(quinolin-yl)-alanine
(0.41 g, 42.4%) as a solid from n-pentane.
STEP 7
Synthetic method was as described for Example 30, Step 6, but using N-(2-adamantyloxy-carbonyl)-3- (quinolin-yl)-alanine (0.40 g, 1 mmol). The residue chromatographed on silica gel using ethyl acetate as eluant to obtain the title compound as a solid from n- pentane, m.p. 130-133°C.
EXAMPLE 37
Carbamic acid, [1-methyl-2-oxo-2-[(2-phenylethyl)- amino]-1-[(4-quinolinyl)methyl]ethyl]-tricyclo- [3.3.1.13'7]dec-2-yl ester, (±)- STEP 1
Method was as described for Example 36, Step 1, but using quinoline-4-carboxylic acid. The crude reaction mixture was chromatographed on silica gel using ethyl acetate as a eluant to obtain quinoline-4- carboxylic acid methylester (28.6 g, 98.6%) as a oil. STEP 2
To a solution of quinoline-4-carboxylic acid methylester (10.0 g, 50 mmol) in anhydrous
diethylether (250 mL) was added LAH (2.5 g, 66 mmol) in portions over a period of 20 minutes at -10°C. The reaction mixture stirred for 1 hour at 0°C and then water (4 mL) was added. The organic layer was
separated and the precipitate of the hydroxides was treated with hot ethanol (50 mL). The combined organic solutions were treated with 47% HBr, the red precipitate was filtered off and treated with
methanol. 4-(Hydroxymethyl)-quinoline hydrobromide (200 mg ) was isolated as a white solid. The
diethylether/ethanol mixture was concentrated in vacuum to yield 4.0 g (33.6%) of the product.
STEP 3
A reaction mixture of 4-(hydroxymethyl)-quinoline hydrobromide (2.0 g, 12.6 mmol) and thionylchloride (20 mL) was heated to reflux for 2 hours. This was allowed to cool and then concentrated in vacuum. The green solid was treated with ethyl ether, filtered, washed with ethyl ether and dried in vacuum to yield 4-(chloromethyl)-quinoline hydrochloride (2.17 g, 80.7%).
STEP 4
Method was as described for Example 32, Step 2, but using 4-(chloromethyl)-quinoline, (derived from 4-(chloromethyl)-quinoline hydrochloride (5.5 g,
(30 mmol) and NaHCO3). The crude reaction mixture was chromatographed on silica gel (flash) using ethyl acetate/cyclohexane = 4:1 as an eluant to separate the impurities and then ethyl acetate/ethanol = 9:1 to obtain 4-quinolinyl-2-methyl-alanine methylester
(1.8 g, 25.7%) as a solid from n-pentane.
STEP 5
Method was as described for Example 30, Step 4, but using 4-quinolinyl-2-methyl-alanine methyl ester to obtain N-(2-adamantyloxy-carbonyl)-3-(quinolin-yl)- alanine methyl-ester (3.2 g, 74.4%) as a light brown solid upon drying.
STEP 6
Method was as described for Example 30, Step 5, but using N-(2-adamantyloxy-carbonyl)-4-(quinolin-yl)- alanine methylester to yield N-(2-adamantyloxycarbonyl)-3-(quinolin-yl)-alanine (2.3 g, 74.2%) as a solid from n-pentane.
STEP 7
Method was as described for Example 30, Step 6, but using N-(2-adamantyloxy-carbonyl)-4-(quinolin-yl)- alanine. The crude product mixture was extracted with 7.5% citric acid solution, dried over Na2SO4 and evaporated in vacuum. The residue was chromatographed on silica gel using ethyl acetate as eluant to obtain the title compound (80 mg, 40.0%) as a light brown solid from ethylether/n-pentane, m.p. 83-85°C. EXAMPLE 38
Carbamic acid, [2-[[1-(hydroxymethyl)-2-phenylethyl]- amino]-1-methyl-2-oxo-1-(4-quinolinylmethyl)ethyl]-, tricylo-[3.3.1.13,7]dec-2-yl ester (hydroxymethyl center is S, other center is R, S)
Method was as described for Example 30 but using N-(2-adamantyloxy-carbonyl)-4-(quinolin-yl)-alanine from Example 37, Step 6. The crude product mixture was extracted with 7.5% citric acid solution, dried over Na2SO4 and evaporated in vacuum. The residue was chromatographed on silica gel using ethyl acetate as eluant to obtain the title compound which was
crystallized from ether/n-pentane to give a solid (40 mg, 8%). m.p. 85-90ºC. EXAMPLE 39
4-[[2-[[2-methyl-1-oxo-2-(2-quinolinyl)-2-[[tricyclo- [3.3.1.13,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-1- phenylethyl]aminol-4-oxobutanoic acid (mixture of [R- (R*,R*)] and [R-(R*,S*)] isomers
STEP 1
A reaction mixture of N- (2-adamantyloxy- carbonyl)-2-methyl-3-(quinolin-2yl)-alanine (1.54 g, 3.8 mmol) from Example 34, Step 4 and
N,N-carbonyldiimidazole (0.68 g, 4.2 mmol) was
dissolved in THF (15 mL) and stirred at room
temperature overnight. The reaction mixture was cooled down with ice and a solution of
2-(N-BOC-amino)-2-phenylamine (1.13 g, 4.2 mmol) in THF (4.0 mL) was added. After reaction overnight the organic solvent was evaporated in vacuo, the residue dissolved in ethyl acetate, washed with 7.5% citric acid and NaHCO3 solution, and dried in vacuo. The organic solution was evaporated in vacuo and the residue flash chromatographed on silica gel using toluene/ethanol (1% to 3%) as eluant to give carbamic acid, [2-[[2-(N-BOc-amino)-2-phenyl]amino-1-methyl-2- oxo-1-(2-quinolinylmethyl)ethyl]-,
tricyclo[3.3.1.13,7]dec-2-yl ester as a solid from ether (400 mg).
Step 2
To a solution of carbamic acid, [2-[[2-(N-BOC- amino)-2-phenyl]amino]-1-methyl-2-oxo-1-(2- quinolinylmethyl)ethyl]-, tricyclo[3.3.1.13'7]dec-2-yl ester (200 mg, 0.32 mmol) in dichloromethane (8 mL) was added p-toluenesulphonic acid monohydrate (76 mg) and the reaction mixture stirred over 24 hours.
Another portion of p-toluenesulphonic acid monohydrate (76 mg) was added, the reaction mixture was stirred overnight, diluted with ethyl acetate, and washed with 1N NaOH. The organic layer was dried over Na2SO4, evaporated in vacuo and carbamic acid, [2-[[2-amino-2- phenyl]amino]-1-methyl-2-oxo-1-(2-quinolinylmethyl)- ethyl]-, tricyclo[3.3.1.13,7]dec-2-yl ester ws isolated as a solid (180 mg).
STEP 3
A solution of [2-[[2-amino-2-phenyl]amino]-1- methyl-2-oxo-1-(2-quinolinylmethyl)ethyl]-,
tricyclo[3.3.1.13'7]dec-2-yl ester (112 mg, 0.21 mmol) in dry ethyl acetate (2 mL) was given to a mixture of succinic anhydride (22 mg, 0.22 mmol) and DMAP (26 mg, 0.22 mmol) in dry ethyl acetate (2 mL) and heated to reflux for 2.5 hours. The reaction mixture was cooled to room temperature and ethyl acetate was added
(50 mL). The solution was washed with 7.5% citric acid solution, dried over N2SO4 and evaporated in vacuo to isolate the title compound (140 mg, 93%), m.p. 93-106°C (D-(-)-N-methylglucamate salt). EXAMPLE 40
Butanoic acid, 4-[[2-(4-quinolinylmethyl)-1-oxo-2- [[(tricyclo[3.3.1.13,7]dec-2-yloxy)carbonyl]amino]- propyl]-amino]-1-phenylethyl]amino]-4-oxo-,
TR-(R*,R*)]- STEP 1
A reaction mixture of N-(2-adamantyloxycarbonyl)-4-(quinolinyl)alanine (610 mg, 1.25 mmol) and N,N'-carbonyldiimiazole (245 mg, 1.6 mmol) was dissolved in dry THF (5 mL) and stirred overnight at room temperature. Then a solution of 1N-(benzyloxy- carbonyl)-1-phenyl-2-amino-ethane (from PD-6352) (385 mg, 1.5 mmol) was added and the reaction mixture was stirred for another 22 hours, then filtered and the filtrate was evaporated in vacuo. The residue was dissolved in ethyl acetate and successively washed with 7.5% citric acid solution, water, NaHCO3 solution and water again. After drying over Na2SO4 and
evaporating of the water again. After drying over Na2SO4 and evaporating of the solvent the residue was chromatographed on silica gel using toluene/ethanol (5%) as a eluant to isolate the product (480 mg, 58%) as a solid from n-pentane.
STEP 2
A solution of carbamic acid, [2-[[2-(N-benzyloxy- carbonylamino)-2-phenyl]amino]-1-methyl-2-oxo-1-(4- quinolinylmethyl)ethyl]-, tricyclo[3.3.1.13'7]dec-2-yl ester (480 mg, 0.73 mmol) in ethanol (25 mL) was treated with 20% palladium on carbon (150 mg, 50% water) and put under an atmosphere of hydrogen of 80 bar at room temperature with agitation. After 15 hours when no more hydrogen was seen to be taken up, the mixture was filtered over celite and
concentrated in vacuo to isolate a mixture of carbamic acid, [2-[[2-amino-2-phenyl]amino]-1-methyl-2-oxc-1- (4-quinolinylmethyl)ethyl]-, tricyclo[3.3.1.13'7]dec-2- yl ester (1) and carbamic acid, [2-[[2-amino-2- phenyl]amino]-1-methyl-2-oxo-1-(4-1,2,3,4-tetrahydro)- quinolinylmethyl)ethyl]-, tricyclo[3.3.1.13'7]dec-2-yl ester (2) and which were separated by chromatography on silica gel using ethyl acetate/methanol (3% to 55) as an eluant.
Yield: Compound 1 (RF = 0.11, EE/MeOH=9:1): 195 mg.
Compound 2 (RF = 0.17, EE/MeOH=9:1): 85 mg. STEP 3
Method was as described for Example 39, Step 3, but using carbamic acid, [2-[[2-amino-2-phenyl]amino]- 1-methyl-2-oxo-1-(4-quinolinyl)ethyl]-,
tricyclo[3.3.1.13'7]dec-2-yl ester (195 mg, 0.37 μmol) from Step 2 to yield the title compound (190 mg, 82%), m.p. 120-132°C (D-(-)-N-methylglucamate salt).
EXAMPLE 40A
Butanoic acid, 4-[[2-[2-(1,2,3,4-tetrahvdro)- quinolinylmethyl]-1-oxo-2-[[(tricyclo[3.3.1.13,7]dec-2- yloxy)carbonyl]amino]propyl]amino]-1-phenylethyl]- amino]-4-oxo- STEP 1
Method was as described for Example 40, Step 1, but using N-(2-adamantyloxy-carbonyl)-2-methy1-3- (quinolin-2-yl)alanine (1.42 g, 3.5 mmol) prepared in Example 34, Step 4. The crude residue was flash chromatographed on silica gel using toluene/ethanol (0.8% to 1.5%) as eluant to yield carbamic acid,
[2-[[2-(N-benzyloxy-carbonyl-amino)-2-phenyl]amino]-1- methyl-2-oxo-1-(2-quinolin-yl-methyl)ethyl]-,
tricyclo[3.3.1.13'7]dec-2-yl ester (1.7 g, 71.3%) as a light brown solid. STEP 2
Method was as described for Example 40, Step 2 , but using carbamic acid, [2-[[2-(N-benzyloxy-carbonyl- amino)-2-phenyl]amino]-1-methyl-2-oxo-1-(2-quinolin- yl-methyl)ethyl]-, tricyclo[3.3.1.13'7]dec-2-yl ester from Step 1. The crude reaction mixture was
chromatographed on silica gel using toluene/ethanol (1 to 2.5%) as eluant to yield carbamic acid,
[2-[[2-amino-2-phenyl]amino]-1-methyl-2-oxo-1-(2- (1,2,3,4-tetrahydrl)quinolinylmethyl)ethyl]-,
tricyclo[3.3.1.13'7]dec-2-yl ester (1) (RF = 0.38) (0.28 g) and carbamic acid, [2-[[2-amino-2-phenyl]- amino]-1-methyl-2-oxo-1-(2-(1,2-dihydro)quinolinyl- methyl)ethyl]-, tricyclo[3.3.1.13'7]dec-2-yl ester (2) (RF = 0.15) (0.50 g) .
STEP 3
Method was as described for Example 39, Step 3, but using carbamic acid, [2-[[2-amino-2-phenyl]amino]- 1-methyl-2-oxo-1-(2-(1,2,3,4-tetrahydro)quinolinyl- methyl)ethyl]-, tricyclo[3.3.1.13'7]dec-2-yl ester
(95 mg, 0.18 mmol) from Step 2. The reaction mixture was heated to reflux for 9 hours and worked up in a usual manner. The crude residue was chromatographed on silica gel using ethyl acetate/methanol (1% to 10%) as eluant to yield the title compound (48 mg), m.p. 165-173°C (D-(-)-N-methylglucamate salt).
EXAMPLE 40B
Butanoic acid, 4-[[2-[2-(1,2-dihydro)guinolinyl- methyl]-1-oxo-2-[[(tricyclo[3.3.1.13'7]dec-2-yloxy)- carbonyl]aminoIpropyl]amino]-1-phenylethyl]amino]- 4-oxo- STEP 1
Method was as described for Example 39, Step 3, but using carbamic acid, [2-[[2-amino-2-phenyl]amino]- 1-methyl-2-oxo-1-(2-(1,2-dihydro)quinolinylmethyl)- ethyl]-, tricyclo[3.3.1.13'7]dec-2-yl ester (95 mg, 0.18 mmol) from Example 40A, Step 2. The reaction mixture was heated to reflux for 6 hours and worked up in the usual manner to isolate the title compound (62 mg), m.p. 102-112°C (D-(-)-N-methylglucamate salt).
EXAMPLE 41
N-[Tricyclo[3.3.1.13'7]dec-2-yloxy]-2-[3-(1,3-dihydro- 1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one-yl)]- methyl-alanine
STEP 1
A reaction mixture of 1,3-dihydro-1-methyl-5- phenyl-2H-1,4-benzodiazepin-2-one (J. Orq. Chem. 52, 3232, (1987)) (12.6 g, 50 mmol), formaline-solution (37% in water, 75 mL) and sodium hydroxide (4.4 g, 110 mmol) was heated to reflux for 4.5 hours. Then additional formaline solution (35 mL) and sodium hydroxide (2.2 g) was added and the reaction mixture was heated for 4 hours. The cooled suspension was diluted with ethyl acetate, the organic layer
separated, washed with water and dried over Na2SO4. The organic solution was evaporated in vacuum and the residue flash-chromatographed on silica gel using toluene/ethanol (3.5%) as eluant to give 1,3-dihydro- 3-hydroxymethyl-1-methyl-5-phenyl-2H-1,4- benzodiazepin-2-one (2.15 g, 15%).
STEP 2
1,3-dihydro-3-hydroymethyl-1-methyl-5-phenyl-2H- 1,4-benzodiazepin-2-one (980 mg, 3.5 mmol) was dissolved in methylene chloride and thionylchloride (1.65 g, 14 mol) was added in portions. The reaction mixture was heated to reflux for 3 hours and then allowed to cool to room temperature overnight. The reaction mixture was evaporated in vacuum, dissolved in methylene chloride and the organic solution was basified with aqueous NaHCO3 in water. The organic layer was separated, dried over Na2SO4 and evaporated in vacuum to give crude 1,3-dihydro-3-chloromethyl-1- methyl-5-phenyl-2H-1,4-benzodiazepin-2-one (1.1 g) which was used for the next step.
STEP 3
Synthetic method was as described for Example 32, Step 2, but using 1,3-dihydro-3-chloromethyl-1-methyl- 5-phenyl-2H-1,4- benzodiazepin-2-one (1.0 g, 3.5 mmol) from Step 2. The crude residue was chromatographed on silica gel (flash) using ethyl acetate:ethanol (3.5%) as eluant to obtain 2-[3-(1,3-dihydro-1-methyl-5- phenyl-2H-1,4-benzodiazepin-2-one-yl)methyl-alanine methylester (460 mg, 36%).
STEP 4
Method was as described for Example 30, Step 4, but using 2-[3-(1,3-dihydro-1-methyl-5-phenyl-2H-1,4- benzodiazepin-2-one-yl)methyl-alanine methylester
(770 mg, 2.1 mmol) to obtain N-(adamantyloxycarbonyl- 2-[3-(1,3-dihydro-1-methy1-5-pheny1-2H-1,4- benzodiazepin-2-one-yl)]methyl-alanine methylester (1.2 g, 100%) as a light yellow foam.
STEP 5
Method was as described for Example 30, Step 5, but using the ester synthesized in Step 4 this
example. After working up in the usual manner N- (adamantyloxycarbonyl-2-[3-(1,3-dihydro-1-methyl-5- phenyl-2H-1,4-benzodiazepin-2-one-yl)]methylalanine (1.2 g, 100%) was isolated as a yellow solid. EXAMPLE 42
Carbamic acid [1-(1H-indazol-3-ylmethyl)-1-methyl-2- oxo-2-(2- phenylethyl)aminoethyl]tricyclo[3.3.1.13,7]dec-2-yl ester, (±)-
To a solution of racemic N-[(2-adamantyloxy)- carbonyl]-3-(1H-indazol-3-yl)-2-methyl-alanine
(0.45 g, 1.1 mmol) in dry THF (20 mL) was added
1,1'-carbonyldiimidazole (0.18 g, 1.1 mmol) and stirred for 1 hour. To this mixture was added
dropwise a solution of 2-phenethylamine (0.24 g, 2.0 mmol) in dry THF (5 mL) and the resultant mixture left stirring for 3 hours. After removing the solvent in vacuo the residue was partitioned between water (20 mL) and CH2Cl2 (30 mL). The organic phase was dried over MgSO4 and the solvent evaporated. The residue was purified by chromatography over silica gel using MeOH:CH2Cl2 2:98 (v/v) as eluant to give the title compound (0.14 g, 25%) as a colorless amorphous solid, m.p. 86-87°C.
Intermediate
Racemic N-[(2-Adamantyloxy)carbonyl]-3-(1H-indazol-3- yl)-2-methyl-alanine
ROUTE A, STEP 1
Racemic 3-(1H-indazol-3-yl)-2-methyl-alanine methyl ester
To a stirred suspension of sodium hydride
(0.60 g, 20 mmol, 80% in paraffin oil) in dry DMSO (20 mL) was added dropwise a solution of
N-(phenylmethylene)-DL-alanine methyl ester (3.82 g, 20 mmol) in dry DMSO (15 mL) under nitrogen and stirred for 1 hour. The reaction mixture was then cooled to 10°C and a solution of methiodide of
3-dimethylaminomethylindazolo (H. R. Snyder, Crayton B. Thompson, and R. L. Hinman, J. Am. Chem. Soc., 74, 2009 (1952)) (6.4 g, 20 mmol) in dry DMSO (40 mL) was added in one portion and the resultant mixture left stirring for 24 hours at room temperature. After removing the solvent in vacuo the residue was
partitioned between water (30 mL) and CH2Cl2 (200 mL). The organic phase was dried over MgSO4 and the solvent evaporated. The residue was stirred with ethyl ether (2 x 250 mL) until forming of a fine precipitate.
This was removed by filtration and the filtrate evaporated. The resulting oil was stirred for 4 hours with 1N hydrochloric acid (20 mL) and ethyl ether (20 mL), the aqueous phase was made basic with
potassium carbonate, extracted with CH2Cl2 and dried over MgSO4. After removing the solvent in vacuo, the residue was chromatographed over silica gel using MeOH/CH2Cl2 2:98, then MeOH:CH2Cl2 5:95 (v/v) as eluants to yield the required compound (0.45 g, 10%) as a yellow oil which solidified upon standing. IR (KBr) 1729 cm-1. NMR (CDCl3), δ 1.50 (3H, s), 2.20 (2H, br.s), 3.25 (1H, d, J=15.0Hz), 3.55 (1H, d,
J=15.Hz), 3.60 (3H, s), 7.10-7.68 (4H, m), 10.5 (1H, br.s).
STEP 2
Racemic
N-[(2-Adamantyloxy)carbonyl]-3-[[1-(2-adamantyloxy)- carbonyl]-1H-indazol-3-yl]-2-methyl-alanine methyl ester
To a stirred solution of 2-adamantyl
chloroformate (0.60 g, 2.8 mmol) in dry THF (10 mL) was added a solution of compound of Step 1 (0.46 g,
2.0 mmol) in dry THF (20 mL) followed by a solution of triethylamine (0.51 g, 5.0 mmol) in dry THF (10 mL) dropwise . After 4 hours , the reaction mixture was filtered, the solvent removed in vacuo and the residue chromatographed over silica gel using MeOH:CH2Cl2 2:98 (v/v) as eluant to provide 0.80 g (73%) of product as a colorless amorphous solid, m.p. 79-82°C. MS (70 ev) : m/z 589 (H+, 7.89), 135 (100).
STEP 3
To a solution of compound of Step 2 (0.80 g,
1.4 mmol) in a mixture of 1.4-dioxan (20 mL) and water (8 mL) was added LiOH (0,30 g, 12.5 mmol) and stirred for 48 hours. After removing the solvent in vacuo the residue was partitioned between water (30 mL) and ethyl ether (30 mL) and stirred. The clear water phase was separated, acidified with 1M citric acid solution to pH 4.5, and extracted with ethyl acetate. The organic phase was dried over MgSO4 and evaporated in vacuo to yield the title compound (0.48 g, 87%) as an amorphous solid, sintering at 140°C, used without further purification.
ROUTE B STEP 1
1-(4-Methylphenyl)sulfonyl-1H-indazole-3-carboxylic acid methyl ester
To a suspension of sodium hydride (4.6 g,
150 mmol, 80% in paraffin oil) in dry THF (100 mL), a solution of 3-indazolecarboxylic acid methyl ester [(J. Am. Chem. soc., 74, 2009 (1952)] (22.0 g,
125 mmol) in dry THF (100 mL) was added dropwise with stirring while the inner temperature was maintained under 30°C. The reaction mixture was stirred for 30 minutes and then a solution of p-toluenesulphonyl chloride (28.0 g, 150 mmol) in dry THF (100 mL) was added dropwise to the stirring reactant. After
4 hours, the solvent was evaporated in vacuo and the residue partitioned between water and CH2Cl2. The organic phase was separated, dried over Na2SO4 and the solvent evaporated to leave a solid which was recrystallized from ethyl acetate (31.0 g, 75%), m.p. 163-165°C.
STEP 2
3-Hydroxymethyl-1-(4-methylphenyl)sulfonyl-1H-indazole To a stirred suspension of ester of Step 1
(31.0 g, 94 mmol) in dry THF (600 mL) cooled at 5°C and under nitrogen was added dropwise and at this temperature a solution of Red-Al (sodium dihydrobis (2-methoxyethoxy)aluminate - 70% in toluene)
(34 mL, 114 mmol) in dry THF (30 mL). After stirring 2 hours at 5°C, and then 1 hour at room temperature the mixture was cooled at 10°C and treated dropwise with 2N NaOH (100 mL) to effect hydrolysis of the intermediate complex. The organic phase was separated and the solvent in vacuo evaporated. The residue was chromatographed over silica gel using MeOH/CH2Cl2 5 : 95 (v/v) as eluant to give the required alcohol (13.5 g, 54%) as a yellow oil which solidified upon standing, m.p. 95-98°C.
STEP 3
3-Chloromethyl-1-(4-methylphenyl)sulfonyl)-1H-indazole
To a stirred suspension of the alcohol from
Step 2 (12.0 g, 40 mmol) in dry toluene (100 mL) was added dropwise SOCl2 (15 mL) and the mixture was heated at 75-80°C for 30 minutes. Excess SOCl2 and the solvent were removed in vacuo and the residue triturated with ethyl ether (50 mL) to give the desired product (9.5 g, 74%) as a beige crystalline solid, m.p. 150-153°C.
STEP 4
Racemic
2-Methyl-3 -[[1-(4-methylphenyl)sulfonyl]-1H-indazol- 3-yl]-alanine methyl ester
To a stirred suspension of sodium hydride
(0.60 g, 20 mmol, 80% in paraffin oil) in dry DMSO (20 mL) was added dropwise a solution of
N-(phenylmethylene)-DL-alanine methyl ester (3.82 g, 20 mmol) in dry DMSO (20 mL) under nitrogen and stirred for 1 hour. The reaction mixture was then cooled to 10°C and a solution of the compound from Step 3 (5 . 78 g, 18 mmol) in dry DMSO (100 mL) was added in one portion and the resultant mixture left stirring for 24 hours at room temperature. After removing the solvent in vacuo the residue was
partitioned between water (30 mL) and CH2Cl2 (200 mL). The organic extract was dried (Na2SO4) and evaporated. The resulting oil was stirred for 4 hours with 1N hydrochloric acid (50 mL) and ethyl ether (50 mL), the aqueous phase was separated, made basic with potassium carbonate, extracted with CH2Cl2 and dried (Na2SO4). After removing the solvent in vacuo, the residue was purified by chromatography over silica using
MeOH/CH2Cl2 2:98 (v/v) as eluant to give the desired compound (5.5 g, 79%) as a yellow oil which solidified upon standing. IR (film) 1736 cm-1.
STEP 5
Racemic
N-[(2-Adamantyloxy)carbonyl]-2-methyl-3-[[ 1-(4-methylphenyl)sulfonyl]-1H-indazol-3-yl]-alanine methyl ester To a stirred solution of 2-adamantyl
chloroformate (6.4 g, 30 mmol) in dry THF (15 mL) was added a solution of compound of Step 4 (8.9 g,
23 mmol) in dry THF (100 mL) followed by a solution of triethylamine (6.1 g, 56 mmol) in dry THF (15 mL) dropwise. After 1 hour, the reaction mixture was filtered, the solvent removed in vacuo, and the residue triturated with ethyl ether to give the desired compound (9.2 g, 71%) as a white solid, m.p. 136-138°C. STEP 6
A stirred mixture of the ester from Step 5
(4.96 g, 8.8 mmol), dioxan (100 mL), KOH (5.0 g), and water (50 mL) was heated at 75-80°C for 8 hours.
After removing the solvents in vacuo the residue was dissolved in water (125 mL), the clear water solution acidified with 1M citric acid solution to pH 4.5 and extracted with CH2Cl2. The organic extract was dried over Na2SO4, evaporated in vacuo, and the residue triturated with petroleum ether to give the title compound (3.2 g, 91%) as a colorless amorphous solid, sintering at 139°C.
EXAMPLE 43
Carbamic acid, [2-[1-(hydroxymethyl)-2- phenylethyl] amino-1-(1H-indazol-3-yl-methyl)-1-methyl- 2-oxo]ethyl-, tricyclo[3.3.1.13,7]dec-2-yl ester
(hydroxymethyl center is S, other center is RS)
To a solution of racemic N-[(2- adamantyloxy)carbonyl]-3-(1H-indazol-3-yl)-2-methyl- alanine (0.36 g, 0.9 mmol) in dry THF (20 mL) was added 1,1'-carbonyldiiimidazole (0.18 g, 1.0 mmol) and stirred for 1 hour. To this mixture was added dropwise a solution of (S)-(-)-2-amino-3-phenyl-1- propanol (0.15 g, 1.0 mmol) in dry THF (10 mL) and the resultant mixture left stirring for 12 hours. After removing the solvent in vacuo, the residue was partitioned between water (20 mL) and CH2Cl2 (40 mL). The organic phase was dried over MgSO4 and the solvent evaporated. The residue was subjected to silica gel chromatography using ethyl acetate as eluant to give the title compound (0.20 g, 42%) as a colorless, amorphous solid and a mixture of two diastereomers, m.p. 80-85°C. EXAMPLE 44
4-[[2-[3-(1H-indazol-3-yl)-2-methyl-1-oxo-2- [[(tricyclo[3.3.1.13,7]dec-2-yloxy)carbonyl]amino]- propyl]amino]-1-phenylethyl]amino]-4-oxobutanoic acid benzyl ester (mixture of isomers)
Method was as described for Example 43 above but instead using 4-[[(2-amino-1-phenyl)ethyl]amino]-4- oxobutanoic acid benzyl ester as amine. The crude residue was chromatographed over silica gel using MeOH:CH2Cl2 0.5-1/99.5-99 (v/v) as eluant to give the title compound (100 mg, 6%) as a colorless gum, the compounds of Example 46 (see Scheme X, compound 13d) and the benzyl ester of the starting carboxylic acid. MS (70 ev) : m/e (DCI:CH4) 708 (M+H)+; Rf = 0.35
(MeOH/CH2Cl2 1:9).
EXAMPLE 45
4-[[2-[3-(1H-indazol-3-yl)-2-methyl-1-oxo-2- [[(tricyclo[3.3.1.l3'7]dec-2-yloxy)carbonyl]amino]- propyl]amino]-1-phenylethyl]amino]-4-oxobutanoic acid (mixture of isomers)
A solution of benzyl ester of Example 44
(0.080 g, 0.12 mmol) in absolute ethanol (10 mL) was treated with 20% Pd(OH)2 on carbon and placed under an atmosphere of hydrogen at 25°C for 15 hours. The reactions mixture was then filtered and the filtrate concentrated in vacuo to give the desired compound (35 mg, 52%) as an amorphous solid and a mixture of two diastereomers, m.p. 108-122°C; IR (KBr) 1698 and 1659 cm-1; MS (70 ev): m/e (DCI-NH2) 614 (M-1)+. EXAMPLES 46A AND 46B
Tricyclo[3.3.1.13'7]dec-2-yl-(R or S,R)-[2-[[2-(2,5- dioxo-1-pyrrolidinyl)-2-phenylethyl]amino]-1-(1H- indazol-3-ylmethyl)-1-methyl-2-oxoethyl]carbamate and Tricyclo[3. 3 .1.13'7]dec-2-yl-(S or R,R)-[2-[ [2-(2,5- dioxo-1-pyrrolidinyl)-2-phenylethyl]amino]-1-(1H- indazol-3-ylmethyl)-1-methyl-2-oxoethyl]carbamate
The compounds were isolated by chromatographic separation of the crude residue of Example 44.
Diastereomer 1 (46A): (160 mg, 10%) white amorphous solid, m.p. 101-108°C. MS (70 ev) : m/z (DCI+NH3) 598 (M+H)+; Rf = 0.45 (MeOH/CH2Cl2 1:9).
Diastereomer 2 (46B) : (65 mg, 6.5%) white amorphous solid, m.p. 128-130°C. MS (70 ev) : m/z (DCI+NH3) 598 (M+H)+; RF = 0.42 (MeOH/CH2Cl2 1:9).
EXAMPLE 47
Tricyclo[3.3.1.13'7]dec-2-yl [2-[[2-hvdroxy-1- (hydroxymethyl)-2-phenylethyl]amino]-1-methyl-2-oxo-1- [[4-(phenylmethoxy)phenyl]methyl]ethyl]carbamate
(Mixture of [1S-[1R*(R*),2R*]] and [1S-[1R*(S*),2R*]] isomers)
STEP A: Preparation of methyl α-methyl-N-[(tricvclo- [3.3.1.13,7]dec-2-yloxy)carbonyl]-DL-tyrosinate
To a solution of tricyclo [3 , 3.1.13'7] dec-2-yl carbonchloridate [5.77 g, 0.026 mol, prepared from 2-adamantanol and bis (trichloromethyl) carbonate
(Horwell, D.C., et al, J. Med. Chem. 1991, 34.,
404-414)] in 60 mL THF, a solution of DL-α-methyl- tyrosine methyl ester (5.0 g, 0.0238 mol, prepared from the DL-α-methyltyrosine methyl ester
hydrochloride using 1M K2CO3 and EtOAc) in 320 mL THF was added dropwise via an addition funnel, keeping the temperature below 25°C. A solution of triethylamine (4.81 g, 0.047 mol) in 120 mL THF was then added dropwise and the heterogeneous reaction mixture was stirred for 16 hours at room temperature under a nitrogen atmosphere. The amine salt was filtered and the filtrate was concentrated in vacuo to give a tan, fluffy solid. Purification by flash chromatography (silica gel, 10% EtOAc/hexane) yielded the title compound. MS: 388 (MH+); 387 (M+) .
STEP B: Preparation of methyl α-methyl-O- (phenylmethyl)-N-[(tricyclo[3.3.1.13'7]dec-2- yloxy)carbonyl]-DL-tyrosinate
To a solution of methyl α-methyl-N-[(tricyclo- [3.3.1.13'7] dec-2-yloxy) carbonyl]-D,L-tyrosinate
(1.0 g, 0.0025 mol) in 12.5 mL acetonitrile, potassium carbonate (0.51 g, 0.0038 mol, 1.5 eq) was added, followed by the addition of benzyl chloride (0.49 g, 0.0038 mol, 1.5 eq). This reaction mixture was then heated to reflux for 6 hours under a nitrogen
atmosphere. After cooling to room temperature, the reaction mixture was concentrated in vacuo to give a tan residue. The residue was diluted with water and ethyl acetate. The layers were separated and the aqueous layer was extracted two times with ethyl acetate. The combined organic layers were washed with brine, dried (Na2SO4), and concentrated in vacuo to yield the desired product in quantitative yield. MS: 478.1 (MH+) .
STEP C: Preparation of α-methyl-O-(phenylmethyl)-N- [(tricyclo[3.3.1.13,7]dec-2-yloxy)carbonyl]-DL-tyrosine To a stirred solution of methyl α-methyl-O- (phenylmethyl)-N-[(tricyclo[3.3.1.13'7]dec-2-yloxy)- carbonyl]-DL-tyrosinate (1.10 g, 0.0023 mol) in 8.8 mL dioxane and 4.4 mL water, lithium hydroxide
monohydrate (0.145 g, 0.003 mol, 1.5 eq) was added. This reaction mixture was then stirred for 48 hours at room temperature. The reaction mixture was then concentrated in vacuo and the resulting white syrup was diluted with 20 mL H2O . This basic solution
(pH 13) was then acidified (pH 2) with 1 mL 10% HCI, upon which white solid precipitated. This acidified aqueous suspension was then extracted three times each with ether. The combined organic layers were dried (Na2SO4) and concentrated in vacuo to give the desired product (0.78 g, 0.0016 mol, 73%). MS: 464.3 (MH+); 463.3 (M+) .
STEP D: Preparation of Tricyclo[3.3.1.13'7]dec-2-yl
[2-[[2-hydroxy-1-(hydroxymethyl)-2-phenylethyl]amino]- 1-methyl-2-oxo-1-[[4-(phenylmethoxy)phenyllmethyl]- ethyl]carbamate (Mixture of [1S-[1R*(R*),2R*]] and
[1S-[1R*(S*),2R*]] isomers)
To a solution of α-methyl-O-(phenylmethyl)-N-
[(tricyclo[3.3.1.13'7]dec-2-yloxy)carbonyl]-DL-tyrosine (300 mg, 0.647 mmol) in 10 mL ethyl acetate,
1-hydroxybenzotriazole (96.2 mg, 0.71 mmol, 1.1 eq) was added followed by the addition of N,N'-dicyclo- hexylcarbodiimide (160 mg, 0.77 mmol, 1.2 eq). This turbid mixture was then stirred for 3 hours at room temperature under a nitrogen atmosphere. The white solid (dicyclohexyl urea) was filtered off and to the clear filtrate was added a warm solution of
(1S,2S)-(+)-2-amino-1-phenyl-1,3-propanediol (150 mg, 0.90 mmol, 1.4 eq) in 10 mL ethyl acetate. Upon addition of this diol, a white solid precipitated out of solution immediately. This white heterogeneous mixture was stirred for 16 hours at room temperature under a nitrogen atmosphere. The white solid was filtered and the mother liquor was concentrated in vacuo to give a crude oil. Purificatior. by flash chromatography (silica gel, 75% EtOAc/hexane) yielded the title compound (151.6 mg, 0.247 mmol, 38.2%).
Analysis for C37H44N2O6·2 mol H2O: Calcd: C, 68.49; H, 7.45; N, 4.31.
Found: C, 68.15; H, 6.94; N, 4.27.
MS: 613.5 (MH+) .
EXAMPLE 48
Tricyclo[3.3.1.13'7]dec-2-yl [2-[[2-hydroxy-l-(hydroxymethyl)-2-phenylethyl]amino]-1-[(4-hydroxyphenyl)- methyl]-1-methyl-2-oxoethyl]carbamate (Mixture of
[1S-[1R* (R*),2R*]] and [1S-[1R*(S*),2R*]] isomers)
STEP A: Preparation of α-methyl-N-[(tricyclo- 3.3.1.13,7]dec-2-yloxy)carbonyl]-DL-tyrosine
The title compound was prepared from methyl α-methyl-N-[(tricyclo[3.3.1.13,7]dec-2-yloxy)carbonyl]- DL-tyrosinate (482 mg, 1.24 mmol, prepared using the procedure described in Example 47, Step A) and lithium hydroxide monohydrate (156.6 mg, 3.72 mmol) using the procedure described in Example 1, Step C.
Analysis for C21H27NO5· 0.75 mol H2O:
Calcd: C, 65.18; H, 7.42; N, 3.61.
Found: C, 65.17; H, 7.63; N, 3.44.
MS: 374 (MH+), 373 (M+).
STEP B: Preparation of Tricyclo[3.3.1.13,7]dec-2-yl [2-[[2-hydroxy-l-(hydroxymethyl)-2-phenylethyl]amino]- 1-[(4-hydroxypheny]l)methy]-1-methyl-2-oxoethyl]- carbamate (Mixture of [1S-[1R*(R*),2R*]] and
[1S-[1R*(S*),2R*]] isomers)
The title compound was prepared from α-methyl-N- [(tricyclo [3.3.1.13'7] dec-2-yloxy)carbonyl]-DL-tyrosine (250 mg, 0.669 mmol), 1-hydroxybenzotriazole
(156.7 mg, 0.937 mmol), N,N'-dicyclohexylcarbodiimide (165.6 mg, 0.802 mmol), and (1S,2S)-(+)-2-amino-1- phenyl-1,3-propanediol (156.7 mg, 0.937 mmol)) using the procedure described in Example 47, Step D.
Purification by flash chromatography (silica gel, 100% EtOAc) yielded the title compound (124.5 mg,
0.238 mmol, 35.5%) .
Analysis for C30H38N2O6- 1.9 mol EtOAc:
Calcd: C, 65.42; H, 7.76; N, 4.08.
Found: C, 65.76; H, 7.77; N, 4.41.
MS: 523.3 (MH+) .
EXAMPLE 49
Tricyclo[3.3.1.13'7]dec-2-yl [2-[[2-hydroxy-1-(hydroxymethyl)-2-phenylethyl]amino]-1-[(4-methoxyphenyl)- methyl]-1-methyl-2-oxoethyl]carbamate (Mixture of
[1S-[1R*(R*),2R*)]] and [1S- [1R* (S*), 2R*]] isomers) STEP A: Preparation of methyl O,α-dimethyl-N- [(tricyclo[3.3.1.13,7]dec-2-yloxy)carbonyl]-DL- tyrosinate
The title compound was prepared from methyl α-methyl-N-[(tricyclo[3.3.1.13,7]dec-2-yloxy)carbonyl]- DL-tyrosinate (0.671 g, 0.0017 mol, prepared using the procedure described in Example 47, Step A), potassium carbonate (0.345 g, 0.0025 mol) and iodomethane
(0.368 g, 0.0025 mol) using the procedure described in Example 47, Step B. MS: 402.4 (MH+) .
STEP B: Preparation of Q,α-dimethyl-N-[(tricyclo- [3,3.1.13'7]dec-2-yloxy)carbonyl]-DL-tyrosine
The title compound was prepared from methyl
O,α-dimethyl-N-[(tricyclo[3.3.1.13'7]dec-2- yloxy)carbonyl]-DL-tyrosinate (0.40 g, 0.001 mol) and lithium hydroxide monohydrate (0.066 g, 0.001 mol, 1.5 eq) using the procedure described in Example 47, Step C. MS: 388.0 (MH+) ; 387.0 (M+) . STEP C: Preparation of Tricyclo[3.3.1.13,7]dec-2-yl [2-[[2-hydroxy-1-(hydroxymethyl)-2-phenylethyl]amino]- 1-[(4-methoxyphenyl)methyl]-1-methyl-2-oxoethyl]- carbamate (Mixture of [1S- [1R* (R*),2R*] and
[1S-[1R* (S*),2R*]] isomers)
The title compound was prepared from
O, α-dimethyl-N-[(tricyclo[3.3.1.13'7]dec-2-yloxy)- carbonyl]-DL-tyrosine (250 mg, 0.645 mmol),
1-hydroxybenzotriazole (95 mg, 0.709 mmol),
N,N'-dicyclohexylcarbodiimide (160 mg, 0.774 mmol) and (1S,2S)-(+)-2-amino-1-phenyl-1,3-propanediol (151 mg, 0.903 mmol) using the procedure described in
Example 47, Step D. Purification by flash
chromatography (silica gel, 75% EtOAc/hexane) yielded the title compound (190 mg, 0.354 mmol, 55%).
Analysis for C31H40N2O6· 0.5 mol H2O:
Calcd: C, 67.51; H, 7.74; N, 5.25.
Found: C, 67.73; H, 7.57; N, 5.12.
MS: 537.2 (MH+) . EXAMPLE 50
Tricyclo[3.3.1.13'7]dec-1-yl [2-[[2-hydroxy-1-(hydroxymethyl)-2-phenylethyl]amino]-1-methyl-2-oxo-1-[[4- (phenylmethoxy)phenyl]methyl]ethyl]carbamate (Mixture of [1S-[1R*(R*),2R*]] and [1S-[1R* (S*), 2R*]] isomers) STEP A: Preparation of methyl α-methyl-N-[(tricyclo- [3.3.1.13,71dec-1-yloxy)carbonyl]-DL-tyrosinate
The title compound was prepared from tricyclo- [3.3.1.13,7]dec-1-ylcarbonofluoridate (1.36 g,
0.0068 mol) and D,L-α-methyltyrosine methyl ester (1.50 g, 0.006 mol) using the procedure described in Example 47, Step A. MS: 388 (MH+); 387 (M+).
STEP B: Preparation of methyl α-methyl-O-(phenyl- methyl)-N-[(tricyclo[3.3.1.13'7]dec-1-yloxy)carbonyl]- DL-tyrosinate The title compound was prepared from methyl α-methyl-N-[(tricyclo[3.3.1.13'7]dec-[-yloxy)carbonyl]- DL-tyrosinate (0.97 g, 0.002 mol), potassium carbonate (0.35 g, 0.0025 mol), and benzyl chloride (0.475 g, 0.003 mol) using the procedure described in Example 1, Step B. MS: 478.3 (MH+) ; 477.2 (M+).
STEP C: Preparation of α-methyl-O-(phenylmethyl)-N- [(tricyclo[3.3.1.13,7]dec-1-yloxy)carbonyl]-DL-tyrosine The title compound was prepared from methyl α-methyl-O-(phenylmethyl)-N-[(tricyclo[3.3.1.13'7] dec- 1-yloxy) carbonyl]-DL-tyrosine (200 mg, 0.418 mmol) and lithium hydroxide monohydrate (26.3 mg, 0.628 mmol, 1.5 eq) using the procedure described in Example 47, Step C.
STEP D: Preparation of Tricyclo[3.3.1.13,7]dec-1-yl
[2-[[2-hydroxy-1-(hydroxymethyl)-2-ρhenylethyl]amino]- 1-methyl-2-oxo-1-[[4-(phenylmethoxy)phenyl]methyl]- ethyl]carbamate (Mixture of [1S- [1R* (R*), 2R*]] and
[1S-[1R*(S*),2R*]] isomers)
The title compound was prepared from α-methyl-O-
(phenylmethyl)-N-[(tricyclo[3.3.1.13'7]dec-1-yloxy)- carbonyl]-DL-tyrosine (92.8 mg, 0.20 mmol),
1-hydroxybenzotriazole (28.6 mg, 0.21 mmol),
N,N[-dicyclohexylcarbodiimide (46.6 mg, 0.22 mmol) and (1S,2S)-(+)-2-amino-1-phenyl-1,3-propanediol (33.4 mg, 0.20 mmol) using the procedure described in
Example 47, Step D.
Analysis for C37H44N2O6.4 mol H2O:
Calcd: C, 64.89; H, 7.65; N, 4.09.
Found: C, 65.25; H, 7.57; N, 4.16.
MS: 613.2 (MH+) .
Alkylation Procedure (See Examples 51-57)
A solution of PhCh=N-CH(CH3)CO2CH3 (50 mmol) in THF (150 mL) was added to a stirred solution of LDA (55 mmol) in THF at -78°C. The resulting yellow anion was further treated with a solution of the alkyl halide (ArCH2) (50 mmol) and the resulting mixture allowed to stir overnight. Following removal of volatile materials the viscous residue was treated with 1N HCI solution (100 mmol) and stirred rapidly for 1 to 2 hours. Benzaldehyde was removed by
extraction with ether and the aqueous phase made alkaline using 10% aqueous sodium bicarbonate
solution. The amino ester
Figure imgf000156_0001
was extracted into ether, the organic phase dried (MgSO4) and evaporated, leaving the crude product which was carried on without purification.
A solution of the desired amino ester (2 mmol) in dry THF (20 mL) was treated with 2-AdocCl (2.2 mmol) followed by the dropwise addition of triethylamine (2.2 mmol). The mixture was stirred for 4 hours at room temperature. Volatile material was removed under vacuum and the residue partitioned between ethyl acetate and water. The organic layer was washed with dilute aqueous citric acid solution followed by dilute sodium bicarbonate solution, then saline solution. After drying the solution (MgSO4), the solvent was removed, leaving the crude protected ester.
Figure imgf000156_0002
Using 4-(chloromethyl)-3,5-dimethyl-isoxazole as the alkylating agent, the product was isolated after chromatography on silica gel using ethyl acetate/ CH2Cl2/hexane 1/1/2 as eluant in 36% yield. NMR
(CDCl3) δ 1.46-2.05 (17H, m), 2.17 (3H, s), 2.29 (3H, s), 3.07 (2H, s), 3.77 (3H, s), 4.8 (1H, a) , 5.25 (1H, s).
Figure imgf000157_0002
Using 2-acetamido-4-(chloromethyl)thiazole as the alkylating agent and 2 equivalents of the imine anion, the methyl ester was isolated in 41% yield after flash chromatography using CH2Cl2/MeOH 95/5 as eluant. NMR (CDCI3) δ 1.45-2.05 (17H, m), 2.31 (3H, s), 3.15 (2H, m), 3.75 (3H, s), 4.75-4.85 (1H, m), 5.70-5.90 (1H, m), 6.63 (1H, s).
Figure imgf000157_0001
Using 1-chloromethylbenzotriazole as the
alkylating agent, the methyl ester was isolated after chromatography on silica gel using CH2Cl2/MeOH 99.5/.5 as eluant in 71% yield. NMR (CDCl3) δ 1.35-2.10 (14H, m), 3,88 (3H, s), 4.75-4.85 (1H, m), 5.25-5.40 (3H, m), 7.25-7.50 (2H, m), 7.55 (1H, d), 8.05 (1H, d).
Figure imgf000158_0001
Using 4-(4-bromomethylphenyl-1,2,3-thiadiazole as alkylating agent, the product was isolated in 27% overall yield after chromatography (silica gel, 10% EtOAc-hexane) as a white foam. NMR (CDCl3) δ 1.5-2.09 (17H, mult), 3.2-3.75 (4H, mult), 3.78 (3H, s), 4.8 (1H, broad singlet), 5.4 (1H, broad singlet), 7.2 (2H, doublet), 7.9 (2H, doublet), 8.6 (1H, singlet).
Figure imgf000158_0002
Using 7-chloromethyl-1,1,4,4-tetramethyl- tetrahydro naphthalene as alkylating agent, the product was isolated in 28% overall yield after chromatography (silica gel, 10% EtOAc/hexane) as a clear glass. NMR (CDCl3) δ 1.24 (6H, s), 1.25 (6H, s), 1.61-2.05 (19H, m), 3.18-3.3 (2H, m), 3.78 (3H, s), 4.86 (1H, broad singlet), 5.41 (1H, broad
singlet), 6.79-7.19 (4H, m).
Saponification - coupling (See Examples ?)
The methyl ester (9 mmol) dissolved in dioxane (15 mL) and a 1N solution of lithium hydroxide was added (10 mmol). When TLC revealed completion of the reaction, the solvent was removed and the residue suspended between ethyl acetate and dilute aqueous citric acid solution. The organic layer was removed, washed once with water, dried, and evaporated to give the crude acid which was carried on without further purification.
Figure imgf000159_0001
To a solution of the acid (0.45 mmol) in CH2Cl2 (10 mL) is added 1-(3-dimethylaminopropyl)-3-ethyl- carbodiimide hydrochloride (0.5 mmol), triethylamine (0.5 mmol), and 1-hydroxybenzotriazole hydrate
(0.6 mmol). The resulting mixture is stirred 2 hours at room temperature before (S)-(-)-2-amino-3-phenyl-1- propanol or (1S,2S)-(+)-2-amino-1-phenyl-1,3- propanediol or phenethyl amine (0.5 mmol) is added in one portion. The resulting mixture is stirred overnight at room temperature.
Workup A: The mixture is concentrated and the residue dissolved in chloroform and placed on a flash silica gel column. Elution with the appropriate solvent gave the pure desired product.
Workup B: The reaction is poured into CH2Cl2/H2O and the aqueous layer extracted 2 x CH2Cl2. The combined organic extracts are washed with saturated NaHCO3, dried over MgSO4 , and concentrated in vacuo EXAMPLE 51
Tricyclo[3.3.1.13'7]dec-2-yl (±)-[1-[(3,5-dimethyl-4- isoxazolyl)methyl]-1-methyl-2-oxo-2-[(2-phenylethyl) amino]ethyl]carbamate
Figure imgf000160_0001
Using phenethylamine and Workup B in the coupling afforded a 71% yield of a solid after flash
chromatography using CH2Cl2/MeOH 98/2 as eluant, m.p. 70-73°C. Mass Spec (Cl) Parent 508. IR (cm-1)
(CHCl3) 3407, 3313, 3004, 2998, 1715, 1674, 1629, 1603, 1491. NMR (CDCl3) δ 1.34 (3H, s), 1.35-2.01
(14H, m), 2.16 (3H, s), 2.27 (3H, s), 2.81 (2H, t), 2.90 (1H, d), 3.11 (1H, D), 3.53 (2H, M), 4.81 (1H, M), 4.85-5.20 (1H, m), 6.11 (1H, t), 7.15-7.31 (5H, m).
EXAMPLE 52
Tricyclo[3.3.1.13,7]dec-2-yl (±)-[1-[[2-(acetylamino)- 4-thiazolyl]methyl]-1-methyl-2-oxo-2-[(2-phenylethyl) amino]ethyl]carbamate
Figure imgf000161_0001
Using phenethylamine and Workup B in the coupling afforded a 35% yield of a white solid after flash chromatography using CH2Cl2/MeOH 98/2 as eluant.
m.p. 93-97°C. Mass spec (El) parent 525. IR (cm-1) (KBr) 3464, 3460, 2998, 1716, 1700, 1695, 1617, 1603, 1575. NMR (CDCl3) δ 1.49 (3H, s), 1.49-2.00 (14H, m), 2.25 (3H, s), 2.50-2.85 (2H, m), 2.85-3.65 (5H, m), 4.77 (1H, s), 6.61 (1H, s), 6.60-7.00 (1H, m),
7.15-7.28 (5H, m).
EXAMPLE 53
Tricyclo[3.3.1.13'7]dec-2-yl (±)-[1-(1H-benzotriazol-1- ylmethyl)-1-methyl-2-oxo-2-[(2-phenylethyl)amino]- ethyl]carbamate
Figure imgf000161_0002
Using phenethylamine and Workup B in the coupling afforded a 10% yield of a solid after flash
chromatography using 99/1 CH2Cl2/MeOH as eluant, m.p. 180-185°C. Mass spec (El) parent 501. IR (cm-1) (CHCI3) 2983, 2968, 1733, 1717, 1700, 1647. NMR (CDCI3) δ 1.51 (3H, s), 1.35-2.05 (14H, m), 2.50-2.85 (2H, m), 3.46 (2H, q), 4.78 (1H, s), 5.00 (1H, d), 5.34 (1H, d), 5.37 (1H, s), 6.40 (1H, m), 7.09-7.62 (8H, m), 8.04 (1H, d).
EXAMPLE 54
Tricyclo[3 .3 .1.13'7]dec-2-yl (RS,S) [2-[[1-(hydroxymethyl)-2-phenylethyl]amino1-1-methyl-2-oxo-1-[[4- (1,2,3-thiadiazol-4-yl)phenyl]methyl]ethyl]carbamate
Figure imgf000162_0001
and (S)-(-)-2-amino-3-phenyl-1-propanol, the product was isolated by Workup A. Recrystallization from EtOAc-hexane gave 24% overall yield. Mixture of diastereomers. White solid, m.p. 97-117°C.
Calcd: C, 66.87; H, 6.66; N, 9.75.
Found: C, 66.83; H, 6.90; N, 9.34. EXAMPLE 55
Tricyclo[3.3.1.13'7]dec-2-yl (S or R, S)-[2-[[2- hydroxy-1-(hydroxymethyl)-2-phenylethyllamino]-1- methyl-2-oxo-1-[[4-(1,2,3-thiadiazol-4-yl)phenyl]- methyl]ethyl]carbamate
Using
Figure imgf000163_0001
and (1S,2S)-(+)-2-amino-1-phenyl-1,3-propanediol the product was isolated by Workup A. The diastereomers were separated. Higher RF isomers. White solid. NMR (CDCl3) δ 1.35 (3H, s), 1.5-2.15 (14H, m), 3.11-3.3 (2H, dd), 3.92-4.02 (4H, m), 4.84-5.16 (4H, m), 6.81 (1H, d), 7.12-7.41 (7H, m), 7.90 (2H, d), 8.63 (1H, s), 80% pure by HPLC, m.p. 120-129°C. Lower RF isomer. White solid, m.p. 118-124°C.
Calcd: C, 65.06; H, 6.48; N, 9.48.
Found: C, 64.68; H, 6.57; N, 9.38.
EXAMPLE 56
Methyl 5-[(2-butyl-4-methyl-1H-benzimidazol-1- yl)methyl]-3-isoxazolecarboxylate
Using
Figure imgf000164_0001
and (S)-(-)-2-amino-3-phenyl-1-propanol the product was isolated by Workup A. Recrystallization from t-butylmethyl ether-hexane gave 27% overall yield. Mixture of diastereomers. White solid. Isolated as 0.28 hydrate, m.p. 96-101°C.
Calcd: C, 75.33; H, 8.74; N, 4.62.
Found: C, 75.33; H, 8.55; N, 4.95.
EXAMPLE 57
Tricyclo[3.3.1.13,7]dec-2-yl (±)-[1-methyl-2-oxo-2-[(2- phenylethyl)amino]-1-[(5,6,7,8-tetrahydro-5,5,8,8- tetramethyl-2-naphthalenyl)methyl]ethyl]carbamate
Using
Figure imgf000165_0001
and phenethyl amine the product was isolated by
Workup A. Crystallization from t-butylmethyl
ether-hexane gave 62% overall yield. White solid.
Isolated as 0.18 hydrate, m.p. 156-159°C.
Calcd: C, 77.42; H, 8.84; N, 4.88.
Found: C, 77.44; H, 8.85; N, 4.78.
INTERMEDIATES FOR EXAMPLES 58 AND 59
Figure imgf000165_0002
To a 100 mL reaction flask oven-dried under N2 was added 3-methylbenzofuran-2-carboxylic acid
(10 mmol), dimethyl amine hydrochloride (10.5 mmol), CH2Cl2 (50 mL), 1-hydroxybenzotriazole (10.5 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (10.5 mmol), and triethylamine
(21 mmol). The reaction was stirred at room
temperature for 3 days and poured into CH2Cl2/.1N HCI
(200 mL/200 mL). The aqueous layer was extracted with 3 x 200 mL of CH2Cl2, dried over MgSO4, and then concentrated via roto evaporation. The crude reaction mixture was flash chromatographed on silica gel using
98/2 CH2Cl2/MeOH as eluant. Yielded 89% of
Figure imgf000166_0001
NMR δ (CDCl3) 2.46 (s, 3H), 3.13 (bs, 3H), 3.20 (bs,
3H) , 7.25-7.60 (m, 4H). Mass Spec. (El) parent ion at 203. IR (CHCl3) cm-1 3009, 1628.
Figure imgf000166_0002
To a 50 mL reaction flask oven-dried under N2 was added (3-methylbenzofuran-2-?) (.98 mmol), CCl4
(10 mL), and N-bromosuccinimide (1.03 mmol), and finally benzoyl peroxide (.049 mmol). The reaction was heated to reflux and refluxed for 30 minutes, cooled to room temperature, and filtered off solid. The mother liquors were concentrated and flash chromatographed on silica gel using hexane/ethyl acetate 75/25 as eluant. The product was isolated in
43% yield.
CHN:
Calc: C, 51.09; H, 4.29; N, 4.96.
Found: C, 51.19; H, 4.32; N, 5.04.
NMR (CDCl3) δ 3.28 (bs, 3H), 3.39 (bs, 3H), 5.06 (s,
2H), 7.46-7.93 (m, 4H) .
d
Figure imgf000167_0001
alkylating agent the product was isolated in 33% yield.
NMR (DMSO) δ 1.20-2.05 (m, 14H), 2.50 (s, 3H), 3.02
(s, 3H), 3.11 (s, 3H) , 3.20-3.65 (m, 2H), 3.53 (s,
3H) , 4.67 (s, 1H), 7.20-7.78 (m, 4H) .
EXAMPLE 58
Figure imgf000168_0001
Utilizing workup B and phenethylamine the product was isolated as a white solid, m.p. 72-83°C in 34% yield after flash chromatography on silica gel using CH2Cl2/MeOH 97.5/2.5 as eluant. Mass Spec. FAB
(thioglycerol) parent ion 572.
EXAMPLE 59
Figure imgf000168_0002
To a 50 mL reaction flask was added (.414 mmol) of A in 5 mL of THF. Cooled to 0°C and added 1M BH3 (THF) (.725 mmol). Heated to reflux and refluxed for 1 hour. Cooled to room temperature and added 5 mL of MeOH. Stirred at room temperature for 3 hours. The reaction mixture was concentrated and flash
chromatographed on silica gel using CH2Cl2/MeOH
100/0 —> 98/2. NMR (CDCI3) δ 1.30-2.15 (m, 17H), 2.61 (s, 3H), 2.69 (s, 3H), 3.40 (q, 2H), 3.72 (s, 3H), 4.10 (s, 2H), 4.95 (s, 1H) , 5.25 (s, 1H), 7.05-7.75 (m, 4H) .
Utilizing workup B and phenethylamine, the product was isolated as a white solid, m.p. 69-78°C in 14% yield after flash chromatography on silica gel using CH2Cl2/MeOH 97/3 as eluant. Mass Spec Cl M+1 558.
EXAMPLE 60
Tricyclo[3.3.1.13'7]dec-2-yl [S-[R*(R or S), R*]]-2-[[2- hvdroxy-1-(hydroxymethyl)-2-phenylethyl]amino]-1- methyl-2-oxo-1-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)- ethyl] carbamate
STEP 1
α-Methyl-β-(3-1H-pyrrolo[2,3-b]pyridinyl]-D,L-alanine methyl ester dihydrochloride
To a suspension of potassium butoxide (560 mg, 5 mmol) in 50 mL dry tetrahydrofuran at -30°C was added a solution of methyl N-benzalalanate
(J. W. Tilley, P. Levitan, R. W. Kirstead, J.
Heterocyclic Chem. 16, 333 (1979)) (960 mg, 5 mmol) in 10 mL dry tetrahydrofuran. The mixture was stirred for 30 minutes at this temperature followed by
addition of a solution of 3-dimethylaminomethyl-1H- pyrrolo [2,3-b]pyridine methiodide (1.58 g, 5 mmol), prepared in two steps by Mannich reaction of
1H-pyrrolo [2,3-b]pyridine with dimethylamine
hydrochloride and paraformaldehyde in n-butanol
(W. R. N. Williamson (J. Chem. Soc. (C) 2833 (1962)) and quaternization with methyl iodide (E. Benghiat, P. A. Crooks, J. Heterocyclic Chem. 20, 677 (1983)), in the minimum amount of DMSO. This mixture was stirred for 3 hours at -25°C and then warmed to room temperature. Tetrahydrofuran was removed in vacuo, the residue was diluted with 500 mL water, followed by extraction with ethyl ether. The organic phase was dried over magnesium sulfate. The solvent was removed in vacuo to yield the Schiff base (1.2 g).
To the stirred solution of the crude Schiff base (1.2 g) in 100 mL methanol at 0°C was added gaseous HCI. After 1 hour methanol was removed in vacuo to give the dihydrochloride of α-methyl-β-(3-1H- pyrrole[2,3-b]pyridinyl]-D,1-alanine methyl ester (1.14 g, 74.5% yield) as a colorless foam.
STEPS 2 and 3
N-[(2-Adamantyloxy)carbonyl]-α-methyl-β-(3-1H- pyrrolo[2,3-blpyridinyl)-D,L-alanine
To a stirred suspension of crude α-methyl-β-(3-
1H-pyrrolo[2,3-b]pyridinyl)-D,L-alanine methyl ester dihydrochloride (18.4 g, 60 mmol) in 400 mL dry tetrahydrofuran at room temperature was added
diisopropylethylamine (19.4 g = 26.1 mL, 150 mmol). The mixture was stirred for 30 minutes followed by addition of a solution of 2-adamantyl chloroformate (12.88 g, 60 mmol) in (12.88 g, 60 mmol) in 50 mL dry tetrahydrofuran and a solution of
diisopropylethylamine (9.7 g = 13.1 mL, 75 mmol) in 20 mL tetrahydrofuran.
After 24 hours, the solvent was removed in vacuo, the residue dissolved in 50 mL water and extracted with ethyl acetate. The ethyl acetate solution was washed twice with 5% citric acid and once with
saturated brine. The organic phase was dried over magnesium sulfate and the solvent was removed in vacuo to yield a mixture of mono- and bis-[(2-adamantyloxy)- carbonyl] adduct (26.19 g crude product).
To a stirred solution of the above crude product (19.41 g) in a mixture of 400 mL water and 200 mL dioxane was added under nitrogen lithium hydroxide (4.8 g, 200 mmol). After stirring overnight, dioxane was removed in vacuo. The aqueous phase was extracted with ethyl acetate to remove unreacted ester. The basic phase was acidified with 5% citric acid to pH 3 and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated in vacuo to yield the title compound as a colorless foam. The foam was dissolved in methanol and the acid precipitated by addition of water to yield a white powder (6.48 g, 36% overall yield), m.p. 145-148°C. STEP 4
N-[(2-Adamantyloxy)carbonyl]-α-methyl-β-(3-1H- pyrrolo[2,3-b]pyridinyl)-D,L-alanine-(2S-hydroxy-1S- hydroxymethyl)-2-phenylethylamide
To a stirred suspension of N-[(2-adamantyloxy)- carbonyl]-α-methyl-β-(3-1H-pyrrolo[2,3-b]pyridinyl)- D,L-alanine (2.79 g, 7 mmol) and pentafluorophenol (1.37 g, 7.4 mmol) in 50 mL dry ethyl acetate at 0°C was added N,N'-dicyclohexylcarbodiimide (1.53 g,
7.4 mmol). The reaction mixture was stirred 24 hours at this temperature. The precipitate was filtered and (1S,2S)-(+)-2-amino-1-phenyl-1,3-propandiol (1.24 g, 7.4 mmol) was added. This mixture was stirred
24 hours at room temperature, the solvent was removed in vacuo, and the resulting oily residue was separated by flash chromatography using ethyl acetate as
solvent.
Diastereomer 1
Diastereomer 1 was obtained as a foam (0.96 g,
25% yield), softening at 85°C. RF = 0.27 (ethyl acetate). Diastereomer 2
Diastereomer 2 was obtained as a foam (0.85 g, 22% yield), softening at 80°C. Rf = 0.16 (ethyl acetate). EXAMPLE 61
Tricyclo[3 . 3 .1.13'7]dec-2-yl [1S-[1R*(R or S), 2R*]]-2- [[2-hydroxy-1-(hydroxymethyl)-2-phenylethyl]amino]-1- methyl-2-oxo-1-(1H—pyrrolo [3,2-c]pyridin-3-ylmethyl)- ethyl]carbamate
STEP 1
α-Methyl-β-(3-1H-pyrrolo[3,1-c]pyridinyl)-D,L-alanine methyl ester dihydrochloride
To a suspension of potassium butoxide (2.8 g, 25 mmol) in 150 mL dry tetrahydrofuran at -30°C was added a solution of methyl N-benzalalanate
(J. W. Tilley, P. Levitan, R. W. Kirstead, J.
Heterocyclic Chem., 16, 333 (1979)) (4.76 g, 25 mmol) in 50 mL dry tetrahydrofuran. The mixture was stirred for 30 minutes at this temperature followed by
addition of a solution of .3-dimethylaminomethyl-1H- pyrrolo [3,2-c]pyridine methiodide (7.95 g, 25 mmol), prepared in two steps by Mannich reaction of
1H-pyrrolo [3,2-c] pyridine with dimethylamine
hydrochloride and paraformaldehyde in n-butanol
(W. R. N. Williamson, J. Chem. Soc. (C) 2833 (1962)) and quaternization with methyl iodide (E. Benghiat, P. A. Crooks, J. Heterocyclic Chem., 20, 677 (1983)), in the minimum amount of DMSO. This mixture was stirred for 3 hours at -25°C and then warmed to room temperature. Tetrahydrofuran was removed in vacuo, the residue was diluted with 500 mL water, followed by extraction with ethyl ether. The organic phase was dried over magnesium sulfate. The solvent was removed in vacuo to yield the Schiff base (4.43 g). To the stirred solution of the crude Schiff base (4.43 g) in 100 mL methanol at 0°C was added gaseous HCI. After 18 hours methanol was removed in vacuo to give the dihydrochloride of α-methyl-β-(3-1H-pyrrolo- [3,2-c] pyridinyl)-D,L-alanine methyl ester (2.1 g, 50% yield) as a colorless powder.
STEPS 2 AND 3
N-[(2-Adamantyloxy)carbonyl]-α-methyl-β-(3-1H- pyrrolo [3,2-c]pyridinyl-D,L-alanine
To a stirred suspension of crude α-methyl-β-
(3-1H-pyrrolo [3,2-c]pyridinyl)-D,L-alanine methyl ester dihydrochloride (2.58 g, 7.5 mmol) in 60 mL dry tetrahydrofuran at room temperature was added
diisopropylethylamine (3.88 g = 5.23 mL, 30 mmol). The mixture was stirred for 60 minutes followed by addition of a solution of 2-adamantyl chloroformate (3.21 g, 15 mmol) in 20 mL dry tetrahydrofuran.
After 24 hours, the solvent was removed in vacuo, the residue dissolved in 500 mL water, and extracted with ethyl acetate. The ethyl acetate solution was washed twice with 5% citric acid and once with
saturated brine. The organic phase was dried over magnesium sulfate and the solvent was removed in vacuo to yield a mixture of mono- and bis-[(2-adamantyloxy)- carbonyl] adduct (4.03 g crude product).
To a stirred solution of the above crude product (4.03 g) in a mixture of 75 mL water and 150 mL dioxane was added under nitrogen lithium hydroxide (0.36 g, 15 mmol). After stirring overnight, dioxane was removed in vacuo. The aqueous phase was extracted with ethyl acetate to remove unreacted ester. The basic phase was acidified with 15 mL 1N HCI to pH 5 to yield the acid as a white precipitate (0.48 g, 16% overall yield), m.p. 245°C. STEP 4
N-[(2-Adamantyloxy)carbonyl]-α-methyl-β-(3-1H- pyrrolo[3,2-c]pyridinyl)-D,L-alanine-(2S-hydroxy-1S- hydroxymethyl)-2-phenylethylamide
To a stirred suspension of N-[(2-adamantyloxy)- carbonyl]-α-methyl-β-(3-1H-pyrrolo[2,3-b]pyridinyl)- D, L-alanine (397 mg, 1 mmol) and pentafluorophenol (190 mg, 1.03 mmol) in 40 mL dry ethyl acetate at 0°C was added N,N[-dicyclohexylcarbodiimide (230 mg,
1.12 mmol). The reaction mixture was stirred 24 hours at this temperature, followed by addition of
N,N'-dicyclohexylcarbodiimide (230 mg, 1.12 mmol) and stirring this mixture at 60°C for 3 hours. The precipitate was filtered and (1S,2S)-(+)-2-amino-1- phenyl-1,3-propandiol (167 mg, 1 mmol) was added.
This mixture was stirred 48 hours at room temperature, the solvent was removed in vacuo, and the resulting foam was separated by column chromatography using methylene chloride/methanol 98/2 as solvent. Diastereomer 1
Diastereomer 1 was obtained as a white powder (0.12 g, 22% yield), m.p. 150-175°C. RF = 0.5
(methylene chloride:methanol 4:1).
Diastereomer 2
Diastereomer 2 was obtained as a white powder
(0.13 g, 22% yield), m.p. 155-175°C. Rf = 0.4
(methylene chloride: methanol 4:1). EXAMPLE 62
Carbamic acid, [1-[(2,3-dimethyl)-1H-pyrrol-4- ylmethyl]-1-methyl-2-oxo-2-[(2-phenylethyl)amino]- ethyl-, tricyclo[3.3.1.13,7]dec-2-yl ester
Intermediate II (compound 10, Scheme XIV)
Racemic
N-[(2-Adamantyloxy)carbonyl]-3-[(2,3-dimethyl)-1H- pyrrol-4-yl)]-2-methyl-alanine
STEP 1
2,3-Dimethyl-1-(4-methylphenyl)sulfonyl-1H-pyrrole-4- carboxylic acid methyl ester
To a stirred solution of 2,3-dimethyl-1H-pyrrole- 4-carboxylic acid methyl ester (Heterocvcles 1977, 7 , 77) (7.95 g, 51.9 mmol) in THF (160 mL) was added dropwise 50% NaOH (80 mL). The reaction mixture was stirred for 5 minutes and then a solution of
p-toluenesulfonyl chloride (11.87 g, 62.3 mmol) in THF (160 mL) was added dropwise to the stirred mixture at room temperature. The mixture was stirred at room temperature for 30 minutes then cooled to 5 to 10°C and treated dropwise with water (200 mL). The THF was evaporated in vacuo and the aqueous residue was thoroughly extracted with CH2Cl2. The organic extract was washed, dried (Na2SO4), and concentrated in vacuo. The residue was chromatographed over silica gel using toluene as eluant to give the required compound
(13.6 g, 85%) as a pale yellow solid, m.p. 108-114°C. STEP 2
2,3-Dimethyl-4-hydroxymethyl-1-(4-methylphenyl)- sulfonyl-1H-pyrrole
To a stirred solution of the ester of Step 1 (11.1 g, 36 mmol) in dry THF (60 mL), cooled to 10 to 15°C and under nitrogen, was added dropwise a solution of Red-Al (18 mL) in dry THF (60 mL). After stirring for 3 hours at room temperature the mixture was cooled to 5 to 10°C and hydrolyzed dropwise with 2N NaOH
(40 mL). The organic phase was separated, dried
(Na2SO4), and concentrated in vacuo. The residue was chromatographed over silica gel using toluene/ethyl acetate 95-90/5-10 (v/v) as eluant to give the desired alcohol (8.0 g, 80%) as a brownish solid,
m.p. 83-86°C.
STEP 3
4-Chloromethyl-2,3-dimethyl-1-(4-methylphenyl)- sulfonyl-1H-pyrrole
To a stirred solution of the alcohol from Step 2 (6.8 g, 24.3 mmol) in dry toluene (70 mL) was added dropwise SOCl2 (9.5 mL) and the mixture was stirred for 3 hours at room temperature. The excess of SOCl2 and the solvent were removed in vacuo and the residue partitioned between water (10 mL) and diethyl ether (100 mL). The organic phase was separated, dried (NaSO4), and concentrated in vacuo to give the
required compound as a brown solid, m.p. 105-109°C, which was used without further purification.
STEP 4
Racemic
3-[[2,3-Dimethyl-1-(4-methylphenyl)sulfonyl]-1H- pyrrol-4-yl]-2-methyl-alanine methyl ester
To a stirred suspension of sodium hydride
(0.66 g, 80 Wt % in paraffin oil, 22 mmol) in dry DMSO (20 mL) at room temperature under a nitrogen
atmosphere was added dropwise a solution of
N-(phenylmethylene)-DL-alanine methyl ester (4.2 g, 22 mmol) in dry DMSO (20 mL). After 1 hour stirring the reaction mixture was cooled to 10 to 15°C and a solution of the compound from Step 3 (5.95 g, 20 mmol) in dry DMSO (30 mL) was added in one portion and the resultant mixture left stirring for 24 hours at room temperature. After removing the solvent in vacuo, the residue was partitioned between water (200 mL) and CH2Cl2 (400 mL). The organic extract was dried
(Na2SO4) and evaporated. The resulting oil was stirred for 3 hours with IN hydrochloric acid (80 mL) and diethyl ether (100 mL), the aqueous phase was separated, made basic with potassium carbonate, extracted with CH2Cl2, and dried (Na2SO4). After removing the solvent in vacuo, the residue was
purified by chromatography over silica using
MeOH/CH2Cl2 1:99 (v/v) as eluant to give the desired compound (4.5 g, 62%) as a yellow oil, which
solidified upon standing; IR (KBr) 1730 cm-1.
STEP 5
Racemic
N-[(2-Adamantyloxy)carbonyl]-3-[[2,3-dimethyl-1-(4- methylphenyl)sulfonyl]-1H-pyrrol-4-yl]-2-methyl- alanine methyl ester
To a stirred solution of the compound of Step 4 (4.3 g, 11.8 mmol) in dry THF (60 mL) was added a solution of 2-adamantyl chloroformate (2.8 g, 13 mmol) in dry THF (10 mL) followed by a solution of
triethylamine (1.3 g, 13 mmol) in dry THF (10 mL) dropwise. After 2 hours stirring, the reaction mixture was filtered, the solvent removed in vacuo, and the residue chromatographed over silica gel using ethanol/toluene 1:20 (v/v) as eluant to provide 6.1 g (95%) of product as a noncrystalline solid; IR (KBr) 1745 and 1720 cm-1.
STEP 6
A mixture of the ester of Step 5 (2.9 g,
5.3 mmol) and KOH (2.0 g, 35.6 mmol) in ethanol
(40 mL) was refluxed for 26 hours. After removing the solvent in vacuo the residue was partitioned between water 9150 μL) and CH2Cl2 (50 mL). The water phase was separated, acidified with IM citric acid solution to pH 4.5, and extracted with diethyl ether. The organic extract was dried (Na2SO4), treated with activated charcoal, and evaporated in vacuo to give the title compound (1.6 g, 80%) as a brownish
amorphous solid, sintering at 120°C, used without further purification; IR (KBr) 1711 cm-1; MS (70 e/v): m/z (DCI+NH3) 375 (M+H)+.
Carbamic acid, [1-[(2,3-dimethyl)-1H-pyrrol-4- ylmethyl]-1-methyl-2-oxo-2-[(2-phenylethyl)amino]- ethyl-, tricyclo[3.3.1.l3'7]dec-2-yl ester
To a solution of racemic N-[(2-adamantyloxy)- carbonyl]-3-[[2,3-dimethyl)-1H-pyrrol-4-yl)]-2-methyl- alanine (0.375 g, 1 mmol) in dry THF (8 mL) was added 1,1'-carbonyldiimidazole (0.172 g, 1.1 mmol) and stirred for 1 hour. To this mixture was added
dropwise a solution of phenylethylamine (0.121 g, 1 mmol) in dry THF (4 mL). After stirring for
20 hours the solvent was removed in vacuo and the residue was partitioned between water (50 mL) and diethyl ether (75 mL). The organic phase was
separated, washed, dried (Na2SO4), and the solvent evaporated. The residue was chromatographed over silica gel using MeOH/CH2Cl2 1:99 (v/v) as eluant to give the title compound (0.10 g, 22%) as a light brown amorphous solid, m.p. 81-88°C.
EXAMPLE 63
Carbamic acid, [1-[(2,3-dimethyl)-1H-pyrrol-4- ylmethyl]-2-[[1-(hydroxymethyl)-2-hydroxy-2-phenyl- ethyl]amino]-1-methylethyl]-, tricyclo[3.3.1.13,7]dec- 2-yl ester (mixture of isomers)
Method was as described for Example 60 above, except the amine used was (1S,2S)-(-)-2-amino-1- phenyl-1,3-propanediol. Yield 0.090 g (13%) as a light brown amorphous solid, m.p. 113-121°C.
EXAMPLE 64
Carbamic acid [1-(imidazo[1,5-a]pyridin-3-ylmethyl)-2- oxo-2-[(2-phenylethyl)amino]ethyl]-, tricyclo- [3.3.1.13'7]dec-2-yl ester
Intermediate II (see Compound 8, Scheme XVI)
Racemic
N-[(2-Adamantyloxy)carbonyl]-3-(imidazo[1,5-alpyridin- 3-yl)-2-methyl-alanine
STEP 1
3-Dimethylaminomethyl-imidazo[1,5-a]pyridine
A mixture of 40% aqueous dimethylamine (10.2 g), formalin (7.4 g), and glacial acetic acid, cooled to 0 to 5°C, was given to imidazo [1,5-a]pyridine [J. Chem. Soc., 1955, 2834] (10.0 g, 84 mmol). The resulting dark mixture was left stirring for 48 hours at room temperature, then was made basic with 2N NaOH and extracted with CH2Cl2. The combined extracts
(2 x 100 mL) were dried (Na2SO4) and evaporated. The residue was purified by chromatography over silica gel using MeOH/CH2Cl2 2:98 as eluant to give the title compound (3.0 g, 20%) as an oil; MS (70 eV): m/z 175 (M+).
STEP 2
3-Dimethylaminomethyl-imidazo[1,5-a]pyridine
methiodide
The compound of Step 1 (3.5 g, 20 mmol) was dissolved in a mixture of absolute ethanol (35 mL) and absolute tetrahydrofuran (28 mL) containing glacial acetic acid (0.18 mL). Methyl iodide (1.17 mL,
18.7 mmol) was added to the solution which was stirred at room temperature for 15 minutes and then kept at 4°C for 3 hours. The resultant precipitate was filtered off and washed with diethyl ether to give the required compound (5.0 g, 80%) as an almost colorless solid, m.p. 251-252°C.
STEP 3
Racemic 3-(Imidazo[1,5-a]pyridin-3-yl)-2-methyl- alanine methyl ester
A solution of N-(phenyImethylene)-DL-alanine methyl ester (2.86 g, 15 mmol) in dry THF (20 mL) was added to a stirred solution of potassium t-butoxide (1.70 g, 15 mmol) in dry THF (90 mL) at -30°C under a nitrogen atmosphere. The resulting bright red
solution was stirred at -30°C for 30 minutes and a solution of the methiodide of Step 2 (4.70 g,
14.8 mmol) in dry DMSO (20 mL) was added dropwise.
The resulting mixture was stirred 2 hours at -20 to -30°C, then 48 hours at room temperature. After removing the solvent in vacuo, the residue was
partitioned between water (100 mL) and CH2Cl2
(200 mL). The organic extract was dried (Na2SO4) and evaporated. The resulting oil was stirred for 3 hours with 1N hydrochloric acid (10 mL) and diethyl ether (10 mL), the aqueous phase was separated, made basic with potassium carbonate, extracted with CH2Cl2m dried (Na2SO4), and the solvent removed in vacuo to give the product (0.83 g, 24%) as a syrup, which was used without further purification; IR (film) 1734 cm-1.
STEP 4
Racemic
N-[(2-Adamantyloxy)carbonyl]-3-(imidazo[1,5-alpyridin- 3-yl)-2-methyl-alanine methyl ester
To a stirred solution of the crude compound of Step 3 (0.83 g, 3.56 mmol) in dry THF (10 mL) was added a solution of 2-adamantyl chloroformate (0.80 g, 3.7 mmol) in dry THF (3 mL) followed by a solution of triethylamine (0.38 g, 3.8 mmol) in dry THF (5 mL) dropwise. After 2 hours stirring, the reaction mixture was filtered, and the solvent removed in vacuo to give the product (1.2 g, 82%) as a colorless amorphous solid, which was used without further purification; IR (KBr) 1737 and 1699 cm-1.
STEP 5
To a solution of the crude ester of Step 4 in a mixture of 1,4-dioxane (40 mL) and water (15 mL) was added LiOH (0.30 g, 12 mmol) and the mixture stirred for 4 hours. After removing the solvent in vacuo, the residue was partitioned between water (80 mL) and diethyl ether (30 mL). The water phase was separated, acidified with 1M citric acid solution to pH 4.5, and extracted with ethyl acetate. The organic extract was dried (Na2SO4) and evaporated in vacuo to give the title compound (0.80 g, 70%) as a pale yellow
amorphous solid, which was used without further purification; IR (KBr) 1704 cm-1.
Carbamic acid, [1-(imidazo[1,5-a]pyridin-3-ylmethyl)- 2-oxo-2-[(2-phenylethyl)amino]ethyl]-, tricyclo- [3.3.1.13'71dec-2-yl ester
To a solution of racemic N-[(2-adamantyloxy)- carbonyl]-3-(imidazo[1,5-a]pyridin-3-yl)-2-methyl- alanine (0.30 g, 0.75 mmol) in dry THF (20 mL) was added 1,1'-carbonyldiimidazole (0.13 g, 0.80 mmol) and stirred for 1 hour. To this mixture was added
dropwise a solution of phenylethylamine (90 mg,
0.75 mmol) in dry THF (3 mL). After stirring for 3 hours the solvent was removed in vacuo and the residue was partitioned between water (50 mL) and CH2Cl2 (100 mL). The organic phase was separated, washed, dried (Na2SO4), and the solvent evaporated. The residue was chromatographed over silica gel using MeOH/CH2Cl2 2:98 (v/v) as eluant to give the title compound which was triturated with dry diethyl ether to obtain a colorless solid, which was removed by filtration (60 mg, 22%), m.p. 171-172°C.
EXAMPLE 65
Carbamic acid, [2-[[1-(hydroxymethyl)-2-hydroxy-2- phenylethyl]aminol-1-(imidazo[1,5-a]pyridin-3- ylmethyl)-1-methylethyl]-, tricyclo[3.3.1.13'7]dec-2-yl ester (mixture of isomers)
Method was as described for Example 64 above, except the amine used was (1S,2S)-(-)-2-amino-1- phenyl-1,3-propanediol. Yield 0.14 g (20%) as a colorless amorphous solid, sintering at 101°C.
The following compounds were made in an analogous manner:
4-[[2-[[2-Methyl-1-oxo-3-(4-pyridinyl)-2-
[[(tricyclo[3.3.1.13'7]dec-2-yloxy)carbonyl]amino]- propyl]amino]-1-phenylethyl]amino]-4-oxobutanoic acid, 4-[[2-[[3-(2,3-dihydro-1-methyl-5-phenyl-1H- benzodiazepin-2-yl)-2-methyl-1-oxo-2-[[(tricyclo- [3.3.1.13'7]dec-2-yloxy)carbonyl]amino]propyl]amino]-1- phenylethyl]amino]-4-oxobutanoic acid compd. with
1-deoxy-1-(methylamino)-D-glucitol,
Tricyclo[3.3.1.13'7]dec-2-yl [2-[[1-
(hydroxymethyl)-2-phenylethyl]amino]-1-methyl-2-oxo-1- (2-pyridinylmethyl}ethyl] carbamate, N-oxide,
Tricyclo[3.3.1.13'7]dec-2-yl [1-[(2,3-dihydro-1- methyl-5-phenyl-1H-1,4-benzodiazepin-2-yl)methyl]-1- methyl-2-[(2-phenylethyl)amino]-2-oxoethyl]carbamate, and
Tricyclo[3.3.1.13'7]dec-2-yl [2-[[1-hydroxy- methyl)-2-phenylethyl]amino]-1-methyl-2-oxo-1-(4- pyridinylmethyl)ethyl]carbamate.

Claims

1 . A compound of formula
Figure imgf000183_0001
or a pharmaceutically acceptable salt thereof wherein:
R1 is a cycloalkyl or polycycloalkyl hydrocarbon of from three to twelve carbon atoms with from zero to four substituents each
independently selected from the group consisting of a straight or branched alkyl of from one to about six carbon atoms, halogen, CN, OR*, SR*,
C02R*, CF3, NR5R6, and -(CH2)nOR5 wherein R* is hydrogen or a straight or branched alkyl of from one to six carbon atoms, R5 and R6 are each independently hydrogen or alkyl of from one to about six carbon atoms and n is an integer from zero to six;
A is -(CH2)nCO-, -SO2-, -S(=O)-, -NHCO-,
Figure imgf000183_0002
-(CH2)n-OC-, -SC-, -O-(CH2)nCO-, or -HC=CHCO- wherein n is an integer from zero to six;
R2 is a straight or branched alkyl of from one to about six carbon atoms, -HC=CH2, -C≡CH, -(CH2)n-CH=CH2, -(CH2)nC≡CH, -(CH2)nAr, -(CH2)nOR*, -(CH2)nOAr, -(CH2) nCO2R*, or -(CH2)nNR5R6 wherein n, R*, R5, and R6 are as defined above and Ar is as defined below; R3 and R4 are each independently selected from hydrogen, R2 and -(CH2)n, -B-D wherein:
n' is an integer of from zero to three;
B is a bond,
-OCO(CH2)n-,
-O(CH2)n-,
-NHCO(CH2)n-,
-CONH(CH2)n-,
-NHCOCH=CH-,
-COO(CH2)n-,
-CO(CH2)n-,
-S-(CH2)n- -S(=O)-(CH2)n-,
-SO2-(CH2)n-,
-NHSO2-(CH2)n-,
-SO2NH(CH2)n-,
NHCO-C=C-,
Figure imgf000184_0001
Λ7Λ 1.
CONH-C=C-,
Figure imgf000184_0002
R7R8
H H
Figure imgf000184_0003
NHCO-C-C-,
Figure imgf000184_0004
R7R8
H H
Figure imgf000184_0005
CONH-C-C-
Figure imgf000184_0006
R7R8
wherein R7 or R8 are independently selected from hydrogen and R2 or together form a ring (CH2)m wherein m is an integer of from 1 to 5 and n is as defined above;
D is -COOR*,
-CH2OR*,
-CHR2OR*, -CH2SR*,
-CHR2SR*,
-CONR5R6,
-CN,
-NR5R6,
-OH,
-H and acid replacements such as tetrazole
Figure imgf000185_0001
Figure imgf000186_0001
wherein m is an integer of from 0 to 2,
wherein R*, R2, R5, and R6 are as defined above;
R9 is hydrogen or a straight or branched alkyl of from one to about six carbon atoms, -(CH2)nCO2R*, -(CH2)nOAr', - (CH2) nNR5R6, wherein n, R*, R5, and R6 are as defined above or taken from
R3 and Ar' is taken from Ar as defined below;
R12 and R13 are each independently hydrogen or are each independently taken with R3 and R4, respectively, to form a moiety doubly bonded to the carbon atom;
Ar is a mono- or polycyclic unsubstituted or substituted carbo- or heteroaromatic or carbo- or heterohydroaromatic moiety; and
Ar2 can be selected from Ar as defined above or the CH2Ar2 moiety of formula I is the sidechain of a biologically significant amino acid, with the proviso that Ar2 cannot be
Figure imgf000186_0002
Ar2 is also - (CH2) 2NHC (=NH)NHNO2, -(CH2)2NMe2, or -CH2CO2CH3.
2. A compound according to Claim 1 wherein:
R1 is a cycloalkyl or a polycycloalkyl of from about six to about ten carbon atoms with from zero to four substituents each independently selected from hydrogen, straight or branched alkyl of from one to six carbon atoms, CF3, NR5R6, - (CH2)nCO2R*, CN, F, Cl, Br, OR*, SR*, wherein R*, R5, and R6 are as defined in Claim 1 and n is an integer of from 1 to 3;
O
II
A is -NHCO-, OC(=O)-, -SO2-, -S (=O), -SC- or -CH2CO-;
R2 is CH3, -CH2CO2H or -CH2C≡CH;
R3 is -(CH2)n,-B-D or H;
R4 is -(CH2)n,-B-D or H;
R9 is hydrogen or methyl;
R12 is hydrogen;
R13 is hydrogen;
Ar is a monocyclic 5- or 6-member ring
having from 0 to 4 heteroatoms each independently nitrogen, oxygen, or sulfur, a bicyclic ring system wherein each ring is independently a 5- or 6-member ring containing from 0 to 3 heteroatoms each independently selected from nitrogen, oxygen, and sulfur,
a tricyclic ring system wherein each ring is independently a 5- or 6-member ring containing from 0 to 5 heteroatoms selected from nitrogen, oxygen, sulfur, or
a hydroaromatic ring;
Ar2 is a monocyclic 5- or 6-member ring having from 0 to 4 heteroatoms each
independently nitrogen, oxygen, or sulfur, a bicyclic ring system wherein each ring is independently a 5- or 6-member ring containing from 0 to
3 heteroatoms , each independently selected from nitrogen, oxygen, and sulfur,
a tricyclic ring system wherein each ring independently is a 5- or 6-member ring containing from 0 to 5 heteroatoms selected from nitrogen, oxygen, sulfur, a hydroaromatic ring,
an alkyl carboxylic acid, or
an alkyl amine with the proviso that Ar2 cannot be 2- or 3-indole. 3. A compound according to Claim 1 wherein
R1 is an unsubstituted or substitul cycloalkyl or polycycloalkyl
Figure imgf000188_0001
wherein W, X, Y, and Z are each independently hydrogen, a straight or branched alkyl of from one to six carbon atoms, CF3, NR5N6, - (CH2)nCO2R*, CN, F, Cl, Br, OR*, SR*, wherein R*, R5, and R6 are as defined in Claim 1 and n is an integer of from 1 to 3;
A is -NHCO-, OCO-, -SO2-, -S (=O) - or
-CH2CO-;
R2 is -CH3, -CH2CO2H, or -CH2C≡CH;
R3 is H, CH2OH, CH2OCOCH2CH2CO2H, CH2OCOCH=CHCO2H, CH2NHCOCH2CH2CO2H,
CH2NHCOCH=CHCO2H, -CH2SCH2CO2H, -CH2SCH2CH2CO2H, or -CH2CO2H,
R4 is H, -NHCOCH2CH2CO2H or NHCOCH=CHCO2H,
R9 is H or methyl,
R12 is hydrogen,
R13 is hydrogen,
Ar and Ar2 are as defined in Claim 1.
4. A compound according to Claim 1 wherein
R1 is 2-adamantyl, 1-(S)-2-endobornyl, or
2-methylcyclohexyl;
A is -OC (=O);
R2 is CH3;
R3 is H, CH2OH, CH2OCOCH2CH2CO2H,
CH2OCOCH=CHCO2H, CH2NHCOCH2CH2CO2H,
CH2NHCOCH=CHCO2H, CH2SCH2CO2H, or
CH2SCH2CH2CO2H,
R4 is H, -NHCOCH2CH2CO2H ([D] configuration) or NHCOCH=CHCO2H ( [D] configuration);
R9 is hydrogen or methyl;
R12 is hydrogen;
R13 is hydrogen;
Figure imgf000190_0001
Ar is as defined above for Ar, or the CH2Ar2 moiety of formula I is the sidechain of a
biologically significant amino acid, or
s.
Figure imgf000191_0001
Figure imgf000192_0001
each of the above moieties for Ar or Ar being independently unsubstituted, mono- or polysubstituted wherein the substituent is independently selected from NR5R6, halogen, alkyl, or alkoxy.
5. A compound according to Claim 1 wherein
R1 is an unsubstituted or substituted
cycloalkyl or polycycloalkyl
Figure imgf000193_0001
wherein W, X, Y, and Z are each independently hydrogen, a straight or branched alkyl of from one to six carbon atoms, CF3, NR5N6, - (CH2)nCO2R*, CN, F, Cl, Br, OR*, SR*, wherein R*, R5, and R6 are as defined in Claim 1 and n is an integer of from 1 to 3;
A is -NHCO-, OCO-, -SO2-, -S (=O) - or -CH2CO-;
R2 is -CH3, -CH2CO2H, or -CH2C≡CH;
R3 is H, CH2OH, CH2OCOCH2CH2CO2H,
CH2OCOCH=CHCO2H, CH2NHCOCH2CH2CO2H,
CH2NHCOCH=CHCO2H, -CH2SCH2CO2H, -CH2SCH2CH2CO2H, or -CH2CO2H,
R4 is H, -NHCOCH2CH2CO2H or NHCOCH=CHCO2H, R9 is H or methyl,
R12 is hydrogen,
B13 is hydrogen,
Ar is phenyl, substituted phenyl or pyridyl, and
Ar2 is 1-naphthyl or 2-naphthyl.
6. A compound according to Claim 1 wherein
R1 is an unsubstituted or substitul cycloalkyl or polycycloalkyl
Figure imgf000194_0001
wherein W, X, Y, and Z are each independently hydrogen, a straight or branched alkyl of from one to six carbon atoms, CF3, NR5N6, - (CH2) nCO2R*, CN, F, Cl, Br, OR*, SR*, wherein R*, R5, and R6 are as defined in Claim 1 and n is an integer of from 1 to 3;
A is -NHCO-, OCO-, -SO2-, -S (=O) - or
-CH2CO-;
R2 is -CH3, -CH2CO2H, or -CH2C≡CH;
R3 is H, CH2OH, CH2OCOCH2CH2CO2H,
CH2OCOCH=CHCO2H, CH2NHCOCH2CH2CO2H,
CH2NHCOCH=CHCO2H, -CH2SCH2CO2H, -CH2SCH2CH2CO2H, or -CH2CO2H, R4 is H, -NHCOCH2CH2CO2H or NHCOCH=CHCO2H, R9 is H or methyl,
R12 is hydrogen,
R13 is hydrogen,
Ar is phenyl, substituted phenyl or pyridyl; and
Ar2 is 3-benzo[b]thienyl, 3-(2-bromobenz[b]- furanyl) or 3-benzo[b]furanyl.
7. A compound according to Claim 1 wherein
R1 is an unsubstituted or substitul cycloalkyl or polycycloalkyl
Figure imgf000195_0001
wherein W, X, Y, and Z are each independently hydrogen, a straight or branched alkyl of from one to six carbon atoms, CF3, NR5N6, -(CH2)nCO2R*, CN, F, Cl, Br, OR*, SR*, wherein R*, R5, and R6 are as defined in Claim 1 and n is an integer of from 1 to 3;
A is -NHCO-, OCO-, -SO2-, -S(=O)- or -CH2CO-;
R2 is -CH3, -CH2CO2H, or -CH2C≡CH;
R3 is H, CH2OH, CH2OCOCH2CH2CO2H, CH2OCOCH=CHCO2H, CH2NHCOCH2CH2CO2H,
CH2NHCOCH=CHCO2H, -CH2SCH2CO2H,
-CH2SCH2CH2CO2H, or -CH2CO2H,
R4 is H, -NHCOCH2CH2CO2H or NHCOCH=CHCO2H, R9 is H or methyl,
R12 is hydrogen,
R13 is hydrogen,
Ar is phenyl, substituted phenyl or pyridyl; and
Ar2 is 2-(1-BOC-benzimidazolyl) or
2-benzimidazolyl.
8. A compound according to Claim 1 wherein
R1 is an unsubstituted or substituted
cycloalkyl or polycycloalkyl
Figure imgf000196_0001
wherein W, X, Y, and Z are each independently hydrogen, a straight or branched alkyl of from one to six carbon atoms, CF3, NR5N6, - (CH2)nCO2R*, CN, F, Cl, Br, OR*, SR*, wherein R*, R5, and R6 are as defined in Claim 1 and n is an integer of from 1 to 3;
A is -NHCO-, OCO-, -SO2-, -S(=O)- or
-CH2CO-; R2 is -CH3, -CH2CO2H, or -CH2C≡CH;
R3 is H, CH2OH, CH2OCOCH2CH2CO2H,
CH2OCOCH=CHCO2H, CH2NHCOCH2CH2CO2H,
CH2NHCOCH=CHCO2H, -CH2SCH2CO2H,
-CH2SCH2CH2CO2H, or -CH2CO2H,
R4 is H, -NHCOCH2CH2CO2H or NHCOCH=CHCO2H, R9 is H or methyl,
R12 is hydrogen,
R13 is hydrogen,
Ar is phenyl, substituted phenyl or pyridyl; and
Ar2 is 2-quinolinyl, 3-quinolinyl, or
4-quinolinyl.
9. A compound according to Claim 1 wherein
R1 is an unsubstituted or substitul cycloalkyl or polycycloalkyl
Figure imgf000197_0001
wherein W, X, Y, and Z are each independently hydrogen, a straight or branched alkyl of from one to six carbon atoms, CF3, NR5N6, - (CH2)nCO2R*, CN, F, Cl, Br, OR*, SR*, wherein R*, R5, and R6 are as defined in Claim 1 and n is an integer of from 1 to 3; A is -NHCO- , OCO- , -SO2-, -S ( =O) - or
-CH2CO-;
R2 is -CH3 , - CH2CO2H, or -CH2C≡CH
R3 is H, CH2OH, CH2OCOCH2CH2CO2H,
CH2OCOCH=CHCO2H, CH2NHCOCH2CH2CO2H,
CH2NHCOCH=CHCO2H, -CH2SCH2CO2H, -CH2SCH2CH2CO2H, or -CH2CO2H,
R4 is H, -NHCOCH2CH2CO2H or NHCOCH=CHCO2H, R9 is H or methyl,
R12 is hydrogen,
R13 is hydrogen,
Ar is phenyl, substituted phenyl or pyridyl; and
Ar2 is 2-pyridyl, 2-pyridyl-N-oxide, 3-pyridyl-N-oxide, 4-pyridy1-N-oxide,
3-pyridyl, or 4-pyridyl.
10. A compound according to Claim 1 wherein
R1 is an unsubstituted or substituted
cycloalkyl or polycycloalkyl
Figure imgf000198_0001
wherein W, X, Y, and Z are each independently hydrogen, a straight or branched alkyl of from one to six carbon atoms, CF3, NR5N6, - (CH2)nCO2R*, CN, F, Cl, Br, OR*, SR*, wherein R*, R5, and R6 are as defined in Claim 1 and n is an integer of from 1 to 3;
A is -NHCO-, OCO-, -SO2-, -S (=O) - or
-CH2CO-;
R2 is -CH3, -CH2CO2H, or -CH2C≡CH;
R3 is H, CH2OH, CH2OCOCH2CH2CO2H,
CH2OCOCH=CHCO2H, CH2NHCOCH2CH2CO2H,
CH2NHCOCH=CHCO2H, -CH2SCH2CO2H, -CH2SCH2CH2CO2H, or -CH2CO2H,
R4 is H, -NHCOCH2CH2CO2H or NHCOCH=CHCO2H, R9 is H or methyl,
R12 is hydrogen,
R13 is hydrogen,
Ar is phenyl, substituted phenyl or pyridyl; and
Ar2 is 3-indazolyl.
11. A compound according to Claim 1 named
Tricyclo[3.3.1.13'7]dec-2-yl [2-[[1- (hydroxymethyl)-2-phenylethyl]amino]-1-methyl-2- oxo-1-(9H-pyrido[3,4-b]indol-3-ylmethyl)ethyl]- carbamate (alanine center is RS, other center is
S),
Tricyclo[3.3.1.13'7]dec-2-yl [1-methyl-1-[[9- (methylsulfonyl)-9H-pyrido[3,4-b]indol-3- yl]methyl]-2-oxo-2-[(2-phenylethyl)amino]ethyl]- carbamate, and
Tricyclo[3.3.1.13'7]dec-2-yl [2-[[1- (hydroxymethyl)-2-phenylethyl]amino]-1-methyl-1- [[9-(methylsulfonyl)-9H-pyrido[3,4-b]indol-3- yl]methyl]-2-oxoethyl]carbamate (phenylmethyl center S, other center RS).
12. A compound according to Claim 1 named Tricyclo[3.3.1.13'7]dec-2-yl [2-[[1- (hydroxymethyl)-2-phenylethyl]amino]-1-methyl-1- (1-naphthalenylmethyl)-2-oxoethyl]carbamate
(naphthalenylmethyl center is RS, other center is
S),
Tricyclo[3.3.1.13'7]dec-2-yl [2-[[1- hydroxymethyl)-2-phenylethyl]amino]-1-methyl-1- (2-naphthalenylmethyl)-2-oxoethyl]carbamate
(naphthalene center is RS, hydroxymethyl center is S),
Tricyclo[3.3.1.13'7]dec-2-yl (±)-[1-methyl-1- (1-naphthalenylmethyl)-2-oxo-2-[(2-phenylethyl)- amino]ethyl]carbamate,
Tricyclo[3.3.1.13'7]dec-2-yl (±)-[1-methyl-1-
(2-naphthalenylmethyl)-2-oxo-2-[(2-phenylethyl)- amino]ethyl]carbamate, and
Tricyclo[3.3.1.13'7]dec-2-yl [2-[[1- (hydroxymethyl)-2-phenylethyl]amino]-1-methyl-1- (2-naphthalenylmethyl)-2-oxoethyl]carbamate
(hydroxy center is S, other center is R or S) (Isomer I).
13. A compound according to Claim 1 named
Tricyclo[3.3.1.13'7]dec-2-yl (±) [1-(3- benzofuranylmethyl)-1-methyl-2-oxo-2-[(2- phenylethyl)amino]ethyl]carbamate,
Tricyclo[3.3.1.13'7]dec-2-yl [1-(3- benzofuranylmethyl)-2-[[1-(hydroxymethyl)-2- phenylethyl]amino]-1-methyl-2-oxoethyl[carbamate (benzofuranylmethyl center is RS, other center is S),
Tricyclo[3.3.1.13'7]dec-2-yl [1-[(2-bromo-3- benzofuranyl)methyl]-2-[[1-(hydroxymethyl)-2- phenylethyl]amino]-1-methyl-2-oxoethyl]carbamate (benzofuran center is RS, hydroxymethyl center is S), and
Tricyclo [3.3.1.13'7] dec-2-yl (±)-[1-[(2-bromo-
3-benzofuranyl)methyl]-1-methyl-2-oxo-2-[(2- phenylethyl)amino]ethyl]carbamate.
14. A compound according to Claim 1 named
2-MethyIpropyl 2-[[2-methyl-1-oxo-3-(3- pyridinyl)-2-[[(tricyclo[3.3.1.13'7]dec-2- yloxy)carbonyl]amino]propyl]amino]-3-phenylpropyl carbonate (pyridine center is RS, other center is
S),
Tricyclo[3.3.1.13'7]dec-2-yl [2-[[1- hydroxymethyl)-2-phenylethyl]amino]-1-methyl-2- oxo-1-(3-pyridinylmethyl)ethyl]carbamate
(hydroxymethyl center is S, other is (±))
(Diastereomer I),
Tricyclo[3.3.1.13'7]dec-2-yl (±)-[1-methyl-2- oxo-2-[(2-phenylethyl)amino]-1-(4-pyridinyl- methyl)ethyl]carbamate,
Tricyclo[3.3.1.13'7]dec-2-yl [2-[[1-
(hydroxymethyl)-2-phenylethyl]amino]-1-methyl-2- oxo-1-(2-pyridinylmethyl)ethyl]carbamate
(hydroxymethyl center is S, other center is R or
S) (Diastereomer I), and
Tricyclo[3.3.1.13'7]dec-2-yl (±)-[1-methyl-2- oxo-2-[(2-phenylethyl)amino]-1-(2-pyridinyl)- methyl)ethyl]carbamate.
15. A compound according to Claim 1 named
Tricyclo[3.3.1.13'7]dec-2-yl (±)-[1- (2- aminophenyl)methyl]-1-methyl-2-oxo-2-[(2- phenylethyl)amino]ethyl]carbamate and Tricyclo[3.3.1.13'7]dec-2-yl (±)-[1-[(2- hydroxyphenyl)methyl]-1-methyl-2-oxo-2-[(2- phenylethyl)amino]ethyl]carbamate.
16. A compound according to Claim 1 named
Tricyclo[3.3.1.13'7]dec-2-yl (±)-[1-methyl-2- oxo-2-[(2-phenylethyl)amino]-1-[(2-quinolinyl)- methyl]ethyl]carbamate,
Tricyclo[3.3.1.13'7]dec-2-yl [2-[[1-
(hydroxymethyl)-2-phenylethyl]amino]-1-methyl-2- oxo-1-(4-quinolinylmethyl)ethyl]carbamate
(hydroxymethyl center is S, other center is RS),
Tricyclo[3.3.1.13'7]dec-2-yl) (±)-[1-methyl-2- oxo-2-[(2-phenylethyl)-amino]-1-(4-quinolinyl- methyl)ethyl]carbamic acid,
Tricyclo[3.3.1.13'7]dec-2-yl (±)-[1-methyl-2- oxo-2-[(2-phenylmethyl)amino]-1-(3-quinolinyl- methyl)ethyl]carbamate,
Tricyclo[3.3.1.13'7]dec-2-yl [2-[[1-(hydroxy- methyl)-2-phenylethyl]amino]-1-methyl-2-oxo-1-(2- quinolinylmethyl)ethyl[carbamate (alanine center is RS, other center is S),
Tricyclo[3.3.1.13'7]dec-2-yl [2-[(2-amino-2- phenylethyl)amino]-1-(1H-indazol-3-ylmethyl)-1- methy1-2-oxoethyl]carbamate,
4-[[2-[[2-methyl-1-oxo-3-(1,2,3,4- tetrahydro-2-quinolinyl)-2-[[(tricyclo- [3.3.1.13'7]dec-2-yloxy)carbonyl]amino]propyl]- amino]-1-phenylethyl]amino]-4-oxobutanoic acid compd. with 1-deoxy-1-(methylamino)-D-glucitol,
4-[[2-[[3-(1,2-dihydro-2-quinolinyl)-2- methyl-1-oxo-2-[[(tricyclo[3.3.1.13'7]dec-2- yloxy)carbonyl]amino]propyl]amino]-1- phenylethyl]amino]-4-oxobutanoic acid compd. with
1-deoxy-1-(methylamino)-D-glucitol, and 4-[[2-[[2-methyl-1-oxo-3-(4-quinolinyl)-2- [[(tricyclo[3.3.1.13'7]dec-2-yloxy)carbonyl]- amino]propyl]amino]-1-phenylethyl]amino]-4- oxobutanoic acid compd. with 1-deoxy-1-(methylamino)-D-glucitol.
17. A compound according to Claim 1 named
Tricyclo[3.3.1.13'7]dec-2-yl (±)-[1-(1H- indazol-3-ylmethyl)-1-methyl-2-oxo-2-[(2-phenylethyl)amino]ethyl]carbamate and
Tricyclo[3.3.1.13'7]dec-2-yl [2-[[1-(hydroxymethyl)-2-phenylethyl]amino]-1-(1H-indazol-3- ylmethyl)-1-methyl-2-oxoethyl]carbamate
(hydroxymethyl center is S, other center is RS).
18. A compound according to Claim 1 named
4-[[2-[3-(1H-indazol-3-yl)-2-methyl-1-oxo-2- [[(tricyclo[3.3.1.13'7]dec-2-yloxy)carbonyl]- amino]-propyl]amino]-1-phenylethyl]amino]-4- oxobutanoic acid (mixture of isomers).
19. A compound according to Claim 1 named
Tricyclo[3.3.1.13'7]dec-2-yl (±)-1-[1-(1H- benzimidazol-2-ylmethyl)-1-methyl-2-oxo-2-[(2- phenylethyl]amino]ethyl]carbamate and
Tricyclo[3.3.1.13'7]dec-2-yl [1-(1H- benzimidazol-2-ylmethyl)-2-[[1-(hydroxymethyl)-2- phenylethyl]amino]-1-methyl-2-oxoethyl]carbamate (hydroxy center is S, other center is RS).
20. A compound according to Claim 1 named
Tricyclo[3.3.1.13'7]dec-2-yl [1- (benzo[b]thien-3-ylmethyl)-2-[[1-(hydroxymethyl)- 2-phenylethyl]amino]-1-methyl-2-oxoethyl]- carbamate (benzothiophene center is RS,
hydroxymethyl center is S) and
Tricyclo[3.3.1.13'7]dec-2-yl (±)-[1- (benzo [b] thien-3-ylmethyl)-1-methyl-2-oxo-2-[(2- phenylethyl)amino]ethyl]carbamate.
21. A compound according to Claim 1 named
Tricyclo[3.3.1.13'7]dec-2-yl-(R or S, R)-[2- [[2-(2,5-dioxo-1-pyrrolidinyl)-2-phenylethyl]- amino]-1-(1H-indazol-3-ylmethyl)-1-methyl-2- oxoethyl]carbamate and
Tricyclo[3.3.1.13'7]dec-2-yl-(S or R, R)-[2- [[2-(2,5-dioxo-1-pyrrolidinyl)-2-phenylethyl]- amino]-1-(1H-indazol-3-ylmethyl)-1-methyl-2- oxoethyl]carbamate.
22. A compound according to Claim 1 named
Tricyclo[3.3.1.13'7]dec-2-yl [2-[[2-hydroxy- 1-(hydroxymethyl)-2-phenylethyl]amino]-1-methyl- 2-oxo-1-[[4-(phenylmethoxy)phenyl]methyl]ethyl]- carbamate.
23. A compound according to Claim 1 named
Tricyclo[3.3.1.13'7]dec-2-yl [2-[[2-hydroxy- 1-(hydroxymethyl)-2-phenylethyl]amino]-1-[(4- hydroxyphenyl)methyl]-1-methyl-2-oxoethyl]- carbamate (Mixture of [1S-[1R*(R*),2R*]] and
[1S-[1R*(S*),2R*]] isomers).
24. A compound according to Claim 1 named
Tricyclo[3.3.1.13'7]dec-2-yl [2-[[2-hydroxy- 1-(hydroxymethyl)-2-phenylethyl]amino]-1-[(4- methoxyphenyl)methyl]-1-methyl-2-oxoethyl]- carbamate (Mixture of [1S-[1R*(R*),2R*)]] and [1S-[1R*(S*),2R*]] isomers).
25. A compound according to Claim 1 named
Tricyclo[3.3.1.13'7]dec-1-yl [2-[[2-hydroxy- 1-(hydroxymethyl)-2-phenylethyl]amino]-1-methyl- 2-oxo-1-[[4-(phenylmethoxy)phenyl]methyl]ethyl]- carbamate (Mixture of [1S-[1R*(R*),2R*]] and
[1S-[1R*(S*),2R*]] isomers).
26. A compound according to Claim 1 named
Tricyclo[3.3.1.13'7]dec-2-yl (±)-[1-[(3,5- dimethyl-4-isoxazolyl)methyl]-1-methyl-2-oxo-2- [(2-phenylethyl)amino]ethyl]carbamate.
27. A compound according to Claim 1 named
Tricyclo[3.3.1.13'7]dec-2-yl (±)-[1-[[2- (acetylamino)-4-thiazolyl]methyl]-1-methyl-2-oxo- 2-[(2-phenylethyl)amino]ethyl]carbamate.
28. A compound according to Claim 1 named
Tricyclo[3.3.1.13'7]dec-2-yl (±)-[1-(1H- benzotriazol-1-ylmethyl)-1-methyl-2-oxo-2-[(2- phenylethyl)amino]ethyl]carbamate.
29. A compound according to Claim 1 named
Tricyclo[3.3.1.13'7]dec-2-yl (RS, S) [2-[[1- (hydroxymethyl)-2-phenylethyl]amino]-1-methyl-2- oxo-1-[[4-(1,2,3-thiadiazol-4-yl)phenyl]methyl]- ethyl]carbamate.
30. A compound according to Claim 1 named
Tricyclo[3.3.1.13'7]dec-2-yl (S or R, S)-[2- [[2-hydroxy-1-(hydroxymethyl)-2-phenylethyl]- amino]-1-methyl-2-oxo-1-[[4-(1,2,3-thiadiazol-4- yl)phenyl]methyl]ethyl]carbamate.
31. A compound according to Claim 1 named
Tricyclo[3.3.1.13'7]dec-2-yl-(S or R, R)-[2- [[2-(2,5-dioxo-1-pyrrolidinyl)-2- phenylethyl]amino]-1-(1H-indazol-3-ylmethyl)-1- methyl-2-oxoethyl] carbamate.
32. A compound according to Claim 1 named
4-[[2-[[2-Methyl-1-oxo-3-(4-pyridinyl)-2- [[(tricyclo[3.3.1.13'7]dec-2-yloxy)carbonyl]- amino]propyl]amino]-1-phenylethyl]amino]-4- oxobutanoic acid.
33. A compound according to Claim 1 named
4-[[2-[[3-(2,3-dihydro-1-methyl-5-phenyl-1H- benzodiazepin-2-yl)-2-methyl-1-oxo-2-[[(tricyclo- [3.3.1.13,7]dec-2-yloxy)carbonyl]amino]propyl]- amino]-1-phenylethyl]amino]-4-oxobutanoic acid compd. with 1-deoxy-1-(methylamino)-D-glucitol.
34. A compound according to Claim 1 named
Tricyclo[3.3.1.13'7]dec-2-yl [2-[[1- (hydroxymethyl)-2-phenylethyl]amino]-1-methyl-2- oxo-1-(2-pyridmylmethyl}ethyl]carbamate,
N-oxide.
35. A compound according to Claim 1 named
Tricyclo[3.3.1.13'7]dec-2-yl [1-[(2,3- dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2- yl)methyl]-1-methyl-2-[(2-phenylethyl)amino]-2- oxoethyl]carbamate.
36. A compound according to Claim 1 named
Tricyclo[3.3.1.13'7]dec-2-yl [2-[[1-hydroxy- methyl)-2-phenylethyl]amino]-1-methyl-2-oxo-1-(4- pyridinylmethyl)ethyl]carbamate.
37. A compound according to Claim 1 named
Tricyclo[3.3.1.13'7]dec-2-yl (±)-[1-methyl-2- oxo-2-[(2-phenylethyl)amino]-1-[(5,6,7,8-tetra- hydro-5,5,8,8-tetramethyl-2-naphthalenyl)methyl]- ethyl]carbamate.
38. A compound according to Claim 1 named
Tricyclo[3.3.1.13'7]dec-2-yl [1S-[1R*(R or S),2R*]]-[2-[[2-hydroxy-1-(hydroxymethyl)-2- phenylethyl]amino]-1-methyl-2-oxo-1-(1H- pyrrolo [2,3-b]pyridin-3-ylmethyl)ethyl]carbamate.
39. A compound according to Claim 1 named
Tricyclo[3.3.1.13,7] [1S-[1R*(S or R),2R*]]- [2-[[2-hydroxy-1-(hydroxymethyl)-2-phenylethyl]- amino]-1-methyl-2-oxo-1-(1H-pyrrolo[2,3-b]- pyridin-3-ylmethyl)ethyl]carbamate.
40. A compound according to Claim 1 named
Tricyclo[3.3.1.13'7]dec-2-yl [1S-[1R*(R or S),2R*]]-[2-[[2-hydroxy-1-(hydroxymethyl)-2- phenylethyl]amino]-1-methyl-2-oxo-1-(1H- pyrrolo[3,2-c]ρyridin-3-ylmethyl)ethyl]carbamate.
41. A compound according to Claim 1 named
Tricyclo[3.3.1.13,7] [1S-[1R*(S or R),2R*]]- [2-[[2-hydroxy-1-(hydroxymethyl)-2-phenylethyl]- amino]-1-methyl-2-oxo-1-(1H-pyrrolo[3,2-c]- pyridin-3-ylmethyl)ethyl]carbamate.
42. A compound according to Claim 1 named
Carbamic acid, [-[(2,3-dimethyl)-1H-pyrrol- 4-ylmethyl]-1-methyl-2-oxo-2-[(2-phenylethyl)- amino]ethyl-, tricyclo[3.3.1.13'7]dec-2-yl ester.
43. A compound according to Claim 1 named
Carbamic acid, [1-[(2,3-dimethyl)-1H-pyrrol- 4-ylmethyl]-2-[[1-(hydroxymethyl)-2-hydroxy-2- phenylethyl]amino]-1-methylethyl]-, tricyclo- [3.3.1.l3,7]dec-2-yl ester (mixture of isomers).
44. A compound according to Claim 1 named
Carbamic acid, [1-(imidazo[1,5-a]pyridin-3- ylmethyl)-2-oxo-2-[(2-phenylethyl)amino]ethyl]-, tricyclo[3.3.1.13'7]dec-2-yl ester.
45. A compound according to Claim 1 named
Carbamic acid, [2-[[1-(hydroxymethyl)-2- hydroxy-2-phenylethyl] amino]-1-(imidazo[1,5-a]- pyridin-3-ylmethyl)-1-methylethyl]-, tricyclo- [3.3.1.l3,7]dec-2-yl ester (mixture of isomers).
46. A pharmaceutical composition comprising an
amount of a compound according to Claim 1, effective to suppress the appetite in a mammal, and a pharmaceutically acceptable carrier.
47. A method of suppressing appetite in a mammal, comprising administering an effective appetite suppressing amount of a compound according to Claim 1.
48. A pharmaceutical composition comprising an amount of a compound according to Claim 1, effective to reduce gastric acid secretion in a mammal, and a pharmaceutically acceptable carrier.
49. A method of reducing gastric acid secretion in a mammal, comprising administering an effective gastric acid secretion reducing amount of a compound according to Claim 1.
50. A pharmaceutical composition comprising an amount of a compound according to Claim 1, effective to reduce anxiety in a mammal, and a
pharmaceutically acceptable carrier.
51. A method of reducing anxiety in a mammal,
comprising administering an effective anxiety reducing amount of a compound according to
Claim 1.
52. A pharmaceutical composition comprising an amount of a compound according to Claim 1 effective to treat gastrointestinal ulcers in a mammal, and a pharmaceutically acceptable carrier.
53. A method for treating gastrointestinal ulcers in a mammal comprising administering an effective gastrointestinal ulcer treating amount of a compound according to Claim 1.
54. A pharmaceutical composition comprising an amount of a compound according to Claim 1 effective to treat psychotic behavior in a mammal, and a pharmaceutically acceptable carrier.
55. A method of treating psychosis in a mammal,
comprising administering an effective psychosis treating amount of a compound according to
Claim 1.
56. A pharmaceutical composition comprising an amount of a compound according to Claim 1 effective to block the reaction caused by withdrawal from drug or alcohol use in a mammal, and a
pharmaceutically acceptable carrier.
57. A method of blocking drug or alcohol withdrawal reaction in a mammal comprising administering an effective withdrawal reaction blocking amount of a compound according to Claim 1.
58. A pharmaceutical composition comprising an amount of a compound according to Claim 1 effective to potentiate the effects of morphine and other opioids in treating pain.
59. A method of treating pain in a mammal, comprising administering an effective amount of a compound according to Claim 1.
60. A pharmaceutical composition comprising an amount of a compound according to Claim 1 effective to treat and/or prevent panic.
61. A method of treating and/or preventing panic in a mammal, comprising administering an effective amount of a compound according to Claim 1.
62. A compound of formula
Figure imgf000210_0001
PCT/US1991/006181 1990-08-31 1991-08-29 Amino acid analogs as cck antagonists WO1992004025A1 (en)

Applications Claiming Priority (4)

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US726,656 1985-04-24
US57630890A 1990-08-31 1990-08-31
US576,308 1990-08-31
US07/726,656 US5331006A (en) 1990-08-31 1991-07-12 Amino acid analogs as CCK antagonists

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WO (1) WO1992004025A1 (en)

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WO1993003721A1 (en) * 1991-08-20 1993-03-04 Warner-Lambert Company Cholecystokinin antagonists useful for treating depression
US5380872A (en) * 1992-07-14 1995-01-10 Glaxo Inc. Modulators of cholecystokinin
US5488056A (en) * 1994-10-31 1996-01-30 Eli Lilly And Company Method for treating anxiety
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WO2007026916A1 (en) 2005-08-30 2007-03-08 Takeda Pharmaceutical Company Limited 1-heterocyclylsulfonyl, 2-aminomethyl, 5- (hetero-) aryl substituted 1-h-pyrrole derivatives as acid secretion inhibitors
EP2364979A1 (en) 2007-02-28 2011-09-14 Takeda Pharmaceutical Company Limited Pyrrole compounds
US8592597B2 (en) 2008-08-27 2013-11-26 Takeda Pharmaceutical Company Limited Pyrrole compounds
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Publication number Priority date Publication date Assignee Title
WO1993003721A1 (en) * 1991-08-20 1993-03-04 Warner-Lambert Company Cholecystokinin antagonists useful for treating depression
US5380872A (en) * 1992-07-14 1995-01-10 Glaxo Inc. Modulators of cholecystokinin
US5508432A (en) * 1992-07-14 1996-04-16 Glaxo Wellcome Inc. Modulators of cholecystokinin
US5488056A (en) * 1994-10-31 1996-01-30 Eli Lilly And Company Method for treating anxiety
US8048909B2 (en) 2004-09-30 2011-11-01 Takeda Pharmaceutical Company Limited Proton pump inhibitors
WO2006036024A1 (en) 2004-09-30 2006-04-06 Takeda Pharmaceutical Company Limited Proton pump inhibitors
US10308605B2 (en) 2004-09-30 2019-06-04 Takeda Pharmaceutical Company Limited Proton pump inhibitors
EP2336107A2 (en) 2004-09-30 2011-06-22 Takeda Pharmaceutical Company Limited Proton pump inhibitors
WO2007026916A1 (en) 2005-08-30 2007-03-08 Takeda Pharmaceutical Company Limited 1-heterocyclylsulfonyl, 2-aminomethyl, 5- (hetero-) aryl substituted 1-h-pyrrole derivatives as acid secretion inhibitors
US8436187B2 (en) 2005-08-30 2013-05-07 Takeda Pharmaceutical Company Limited 1-heterocyclylsulfonyl, 3-aminomethyl, 5- (hetero-) aryl substituted 1-H-pyrrole derivatives as acid secretion inhibitors
US7977488B2 (en) 2005-08-30 2011-07-12 Takeda Pharmaceutical Company Limited 1-heterocyclylsulfonyl, 2-aminomethyl, 5-(hetero-) aryl substituted 1-H-pyrrole derivatives as acid secretion inhibitors
US8299261B2 (en) 2005-08-30 2012-10-30 Takeda Pharmaceutical Company Limited 1-heterocyclylsulfonyl, 3-aminomethyl, 5-(hetero-) aryl substituted 1-H-pyrrole derivatives as acid secretion inhibitors
US8338461B2 (en) 2005-08-30 2012-12-25 Takeda Pharmaceutical Company Limited 1-heterocyclylsulfonyl, 3-aminomethyl, 5-(hetero-)aryl substituted 1-H-pyrrole derivatives as acid secretion inhibitors
US8338462B2 (en) 2005-08-30 2012-12-25 Takeda Pharmaceuticals Company Limited 1-heterocyclylsulfonyl, 3-aminomethyl, 5- (hetero-) aryl substituted 1-H-pyrrole derivatives as acid secretion inhibitors
US8415368B2 (en) 2005-08-30 2013-04-09 Takeda Pharmaceutical Company Limited Acid secretion inhibitor
EP2327692A1 (en) 2005-08-30 2011-06-01 Takeda Pharmaceutical Company Limited 1-heterocyclylsulfonyl, 2-aminomethyl, 5-(hetero-)aryl substituted 1-H-pyrrole derivatives as acid secretion inhibitors
US8933105B2 (en) 2007-02-28 2015-01-13 Takeda Pharmaceutical Company Limited Pyrrole compounds
EP2364979A1 (en) 2007-02-28 2011-09-14 Takeda Pharmaceutical Company Limited Pyrrole compounds
US8592597B2 (en) 2008-08-27 2013-11-26 Takeda Pharmaceutical Company Limited Pyrrole compounds
US8969387B2 (en) 2008-08-27 2015-03-03 Takeda Pharmaceutical Company Limited Pyrrole compounds
US8993598B2 (en) 2008-08-27 2015-03-31 Takeda Pharmaceutical Company Limited Pyrrole compounds
US10759804B2 (en) 2015-06-29 2020-09-01 Imperial College Innovations Limited Compounds and their use as inhibitors of N-myristoyl transferase
US11466011B2 (en) 2015-06-29 2022-10-11 Imperial College Innovations Limited Compounds and their use as inhibitors of N-myristoyl transferase

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