EP0442878A1 - Derivatives of tryptophan as cck antagonists - Google Patents

Derivatives of tryptophan as cck antagonists

Info

Publication number
EP0442878A1
EP0442878A1 EP89905266A EP89905266A EP0442878A1 EP 0442878 A1 EP0442878 A1 EP 0442878A1 EP 89905266 A EP89905266 A EP 89905266A EP 89905266 A EP89905266 A EP 89905266A EP 0442878 A1 EP0442878 A1 EP 0442878A1
Authority
EP
European Patent Office
Prior art keywords
mmol
loweralkyl
substituted
aryl
hydrogen
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP89905266A
Other languages
German (de)
French (fr)
Other versions
EP0442878A4 (en
Inventor
James F. Kerwin, Jr.
Alex M. Nadzan
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Abbott Laboratories
Original Assignee
Abbott Laboratories
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Abbott Laboratories filed Critical Abbott Laboratories
Publication of EP0442878A1 publication Critical patent/EP0442878A1/en
Publication of EP0442878A4 publication Critical patent/EP0442878A4/en
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/02—Antidotes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/20—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals substituted additionally by nitrogen atoms, e.g. tryptophane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/0202—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-X-X-C(=0)-, X being an optionally substituted carbon atom or a heteroatom, e.g. beta-amino acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic

Definitions

  • the present invention relates to novel organic compounds and compositions which antagonize cholecystokinin and gastrin, processes for making such compounds, synthetic intermediates employed in these processes and a method for treating gastrointestinal disorders, central nervous system disorders, cancers of the pancreas and the gall bladder, hypoinsulinemia, or potentiating analgesia, or regulating appetite with such compounds.
  • CCK Cholecystokinins
  • CCK 8 the carboxyl terminal octapeptide fragment of CCK, is the smallest CCK fragment that remains fully biologically active.
  • CCK may be an important neuromodulator of memory, learning and control of primary sensory and motor functions.
  • CCK and its fragments are believed to play an important role in appetite regulation and satiety.
  • Della-Fera Science 206 471 (1979); Gibbs et al., Nature 289 599(1981); and Smith, Eating and Its Disorders, eds., Raven Press, New York, 67 (1984)).
  • CCK antagonists B.J. Gertz in Neurology and Neurobiology Vol 47, Cholecystokinin Antagonists, Wang and Schoenfeld eds., Alan R. Liss, Inc., New York, NY, 327-342, (1988); Silverman, et al., Am. J. Gastroent. 82 703-8 (1987)) are useful in the treatment and prevention of CCK-related disorders of the gastrointestinal (GI) (Lotti, et al., J. Pharm. Exp. Therap. 241 103-9 (1987)), central nervous (CNS) (Panerai, et al., Neuropharmacology 26 1285-87 (1987)) and appetite regulatory systems of animals, especially man.
  • GI gastrointestinal
  • CNS central nervous
  • CCK antagonists are also useful in potentiating and prolonging opiate induced analgesia and thus have utility in the treatment of pain.
  • CCK antagonists are also useful for the treatment of disorders of gastric emptying (Stenikar, et al., Arzn. Forsch./Drug Research 37(II) 1168-71 (1987)), gastroesophageal reflux disease, pancreatitis, pancreatic and gastric carcinomas (Douglas, et al., Gastroent.
  • the first class comprises derivatives of cyclic nucleotides as represented by dibutyryl cyclic GMP (N. Barlas et al., Am. J. Physiol., 242, G161 (1982) and references therein).
  • the second class is represented by C-terminal fragments of CCK (see Jensen et al. Biochem. Bioohys. Acta, 757, 250 (1983) and Spanarkel J. Biol. Chem. 258, 6746 (1983)).
  • the third class comprises amino acid derivatives of glutamic acid and tryptophan as indicated by proglumide and benzotript (see Hahne et al. Proc. Natl. Acad.
  • the fourth and most recent class is comprised of 3-substituted benzodiazepines, represented by L-364,718 (see: Evans et al. Proc. Natl. Acad. Sci. U.S.A., 83 4918 (1986)).
  • CCK antagonists are relatively weak antagonists of CCK demonstrating IC 50 s between 10 -4 and 10 -6 M.
  • the benzodiazepine CCK antagonists or their metabolites may have undesirable effects in vivo due to their interaction with benzodiazepine receptors.
  • the C-terminal pentapeptide fragment of CCK is the same as the C-terminal pentapeptide fragment of another polypeptide hormone, gastrin.
  • Gastrin like CCK, exists in both the GI system. Gastrin antagonists are useful in the treatment and prevention of gastrin-related disorders of the GI system such as ulcers, Zollinger-Ellison syndrome and central G cell hyperplasia. (Morley, Gut Pept. Ulcer Proc, Hiroshima Symp. 2nd, 1, (1983)). Bock,et al., J. Med. Chem. 32 13-16 (1989) discloses receptor antagonists of the in vitro effects of gastrin.
  • the compounds of the invention are antagonists of cholecystokinin (CCK) and bind specifically to CCK receptors.
  • CCK antagonists are useful in the treatment and prevention of CCK-related disorders of the gastrointestinal, central nervous and appetite regulatory systems of animals and humans.
  • CCK antagonists are useful in the treatment and prevention of gastrointestinal ulcers, cancers of the gall bladder and pancreas, pancreatitis, Zollinger-Ellison syndrome, central G cell hyperplasia, irritable bowel syndrome, the treatment or prevention of neurpleptic disorders, tardive dyskinesia, Parkinson's disease, psychosis, Gilles de la Tourette syndrome, disorders of appetite regulatory systems, the treatment of pain and the treatment of substance abuse.
  • cholecystokinin antagonists of the formula:
  • R 1 and R 2 are independently selected from i) hydrogen, ii) loweralkyl, iii) cycloalkyl, iv) loweralkenyl, v) adamantyl, vi) aryl, vii) substituted aryl, viii) heterocyclic group, ix) substituted alkyl, x) substituted amide, xi) functionalized carbonyl, and xii) nitrogen containing ring wherein R 1 ,
  • R 2 and the adjacent nitrogen atom form a ring.
  • R 6 and R 7 are independently selected from hydrogen, loweralkyl, cycloalkyl, loweralkenyl,
  • aryl group is substituted with one, two or three substituents independently selected from loweralkyl, alkoxy, thioalkoxy, carboxy, carboalkoxy, cyano, haloalkyl, -N 3 , -NHP 4 wherein P 4 is an N-protecting group , -O P 5 wherein P 5 is an O-protecting group, nitro, halogen, hydroxy, amino, alkylamino and dialkylamino; v) -(C(R 21 )(R 18 )) 1-4 aryl wherein R 21 is hydrogen, -(C 1 -C 8 loweralkyl), loweralkenyl,
  • R 1 8 is hydrogen , - ( C 1 -C 6 loweralkyl ) , loweralkenyl,
  • R 4 is independently as defined above, vi) -(C(R 21 )(R 18 )) 1-4 (substituted aryl) wherein R 21 and R 18 are defined independently as above, vii) -(C(R 21 )(R 18 )) 1-4 C(O)R 3 , wherein
  • R 21 and R 18 are independently as defined above and wherein R 3 is -OH, -OR 4 wherein
  • R 4 is independently as defined above,
  • R 6 and R 7 are independently as defined above, or -NHR 4 wherein R 4 is as defined above, with the proviso that when R 3 is NR 6 R 7 then R 21 , and R 18 are not both hydrogen and viii) -(C(R 21 )(R 18 )) 1-4 R 12 wherein
  • R 21 and R 18 are independently as defined above and R 12 is a heterocyclic group.
  • Substituted amide groups are selected from
  • R 6 and R 7 are independently selected from hydrogen, loweralkyl, cycloalkyl, loweralkenyl,
  • aryl group is substituted with one, two or three substituents independently selected from loweralkyl, alkoxy, thioalkoxy, carboxy, carboalkoxy, cyano, haloalkyl, -N 3 , -NHP 4 wherein P 4 is an N-protecting group, -OP 5 wherein P 5 is an Q-protecting group, nitro, halogen, hydroxy, amino, alkylamino and dialkylamino.
  • Functionalized carbonyl groups are selected from
  • R 3 is -OH, -OR 4 wherein R 4 is independently as defined above, -NR 6 R 7 wherein R 6 and R 7 are independently as defined above, or -NHR 4 wherein R 4 is independently as defined above.
  • Nitrogen containing rings wherein R 1 , R 2 and the adjacent nitrogen atom form a ring are represented by the formula
  • R 20 is i) hydrogen, ii) loweralkyl, or iii) loweralkenyl.
  • B is i) -(CH 2 ) m -, ii) substituted alkenylene, iii) -QCH 2 - wherein Q is O, S, or
  • Ar is a heterocyclic group , aryl or substituted aryl .
  • D is group of the formula
  • R 30 is hydrogen, loweralkyl, arylalkyl, (substituted aryl) alkyl, or an N-protecting group; and R 5 is independently as defined above.
  • the compounds of the invention are cholecystokinin antagonists of the formula:
  • R 6 and R 7 are independently selected from hydrogen, loweralkyl, cycloalkyl, loweralkenyl,
  • aryl group is substituted with one, two or three substituents independently selected from loweralkyl, alkoxy, thioalkoxy, carboxy, carboalkoxy, cyano, haloalkyl, -N 3 , -NHP 4 wherein P 4 is an N-protecting group, -OP 5 wherein P 5 is an O-protecting group, nitro, halogen, hydroxy, amino, alkylamino and dialkylamino; x) cyclic group wherein R 1 and R 2 taken together with the adjacent nitrogen atom form a heterocyclic group represented by the formula
  • R 5 is one, two or three of the substituents independently selected from the group -(C 1 -C 6 loweralkyl), loweralkenyl,
  • R 12 is a heterocyclic group; with the proviso that R 1 and R 2 are not both hydrogen;
  • R 11 is i) hydrogen, ii) loweralkyl, or iii) loweralkenyl
  • R 20 is i) hydrogen, ii) loweralkyl, or iii) loweralkenyl
  • R 18 are independently as def ined above , iii ) -QCH 2 - wherein Q is O , S , or
  • European Patent Application No. 0230151 published July 29, 1987, discloses the following compounds as CCK antagonists:
  • Ar is phenyl or phenyl substituted with one or two substituents independently selected from hydrogen, loweralkyl, alkoxy, hydroxy substituted alkyl, alkoxy substituted alkyl, halogen, amino, hydroxy, nitro, cyano, carboxy, ethoxycarbonyl and trihalomethyl; and R 1 is -(CH 2 ) phenyl wherein a is 1 to 4; and R 2 is loweralkyl, cycloalkyl, -(CH 2 ), aryl wherein b is 0 to 4, -(CH 2 ) b (substituted aryl) wherein b is 0 to 4 and substituted aryl is as defined above, or -(CH 2 ) c (CO)R 3 wherein c is 1 to 4 and R 3 is hydroxy, alkoxy, -O(CH 2 ) c aryl,
  • the “dashed” bond in the compound of Formula I indicates that the bond is a single bond or a double bond.
  • loweralkyl refers to straight or branched chain alkyl radicals containing from 1 to 6 carbon atoms including but not limited to methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 2 ,2-dimethylbutyl, and the like.
  • cycloalkyl refers to an alicyclic ring having 3 to 7 carbon atoms including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • loweralkenyl refers to a lower alkyl radical which contains at least one carbon-carbon double bond.
  • loweralkynyl refers to a lower alkyl radical which contains at least one carbon-carbon triple bond.
  • alkylene group refers to a (CH 2 ) y radical where y is 1 to 5, such as methylene, ethylene, propylene, tetramethylene and the like.
  • alkenylene group refers to a C 2 -C 5 chain of carbon atoms which contains at least one carbon-carbon double bond, such as vinylene,- propenylene, butenylene and the like.
  • halogen or halo as used herein refers to F, Cl, Br, I.
  • alkoxy and thioalkoxy refer to R 9 O- and R 9 S- respectively, wherein R 9 is a loweralkyl group.
  • alkoxyalkyl refers to an alkoxy group appended to a loweralkyl radical including, but not limited to, methoxymethyl, ethoxypropyl and the like.
  • alkylamino refers to -NHR 13 wherein R 13 is a loweralkyl group.
  • dialkylamino refers to -NR 14 R 15 - wherein R 14 and R 15 are independently selected from loweralkyl.
  • aminoalkyl refers to an amino group (-NH 2 ) appended to a loweralkyl radical including, but not limited to, aminomethyl, aminoethyl and the like.
  • aminoalkenyl refers to an amino group appended to a loweralkenyl radical, with the proviso that the amino group is not bonded directly to the double bond of the alkenyl group. Examples include, but are not limited to, 4-amino-but-2-enyl and the like.
  • aminocarbonyl refers to -C(O)NH 2 .
  • alkylaminocarbonyl refers to -C(O)NHR 19 wherein R 19 is a loweralkyl group.
  • dialkylaminocarbonyl refers to -C(O)NR 19 R 20 wherein R 19 and R 20 are independently selected from loweralkyl.
  • alkoxycarbonyl refers to -C(O)R 16 wherein R 16 is an alkoxy group.
  • Carboaryloxy refers to -C(O)R 17 wherein R 17 is an aryloxy group.
  • haloalkyl refers to a loweralkyl radical substituted by one or more halogens including, but not limited to, chloromethyl, 1,2-dichloroethyl, trifluoromethyl and the like.
  • aryl or "aryl group” as used herein refers to phenyl, naphthyl, indanyl, fluorenyl, (1,2,3,4)-tetrahydronaphthyl, indenyl or isoindenyl.
  • substituted aryl refers to an aryl group substituted with one, two or three substituents independently selected from the group including but not limited to loweralkyl, alkoxy, halogen, thioalkoxy, carboxy, carboalkoxy, cyano, haloalkyl, -N 3 , -NHP 4 wherein P 4 is an N-protecting group, -OP 5 wherein P 5 is an O-protecting group, nitro, hydroxy, amino, alkylamino and dialkylamino.
  • arylalkyl refers to an aryl group appended to a loweralkyl radical including, but not limited to, benzyl and the like.
  • (substituted aryl)alkyl refers to a substituted aryl group appended to a loweralkyl radical including, but not limited to, 4-methoxybenzyl and the like.
  • heterocyclic refers to any 5-, 6- or 7-membered ring containing from one to three heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur; wherein the 5-membered ring has 0-2 double bonds, 6-membered ring has 0-3 double bonds and the 7-membered ring has 0-3 double bonds; wherein the nitrogen and sulfur heteroatoms can be oxidized; wherein the nitrogen heteroatom can be quaternized; and including any bicyclic or tricyclic group in which the above-mentioned heterocyclic ring is fused to one or two benzene rings or one or two 5-membered or 6-membered heterocyclic rings as defined above.
  • heterocycles include, but are not limited to, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, oxatriazolyl, pyrrolidinyl, pyrrolmyl, imidazolidinyl, imidazolinyl, pyrazolidmyl, triazolyl, tetrahydrofuryl, pyranyl, pyronyl, pyridyl, pyrazinyl, pyridazinyl, piperidyl, piperazinyl, morpholinyl, thiazinyl, oxadiazinyl, azepinyl, thiapinyl, thionaphthyl, benzofuryl, isobenzofuryl, indolyl, oxyindolyl, isoin
  • the heterocyclic groups can be unsubstituted or substituted with one, two or three substituents independently selected from hydroxy, oxo, amino, alkylamino, dialkylamino, alkoxy, thioalkoxy, carboxyl, alkoxycarbonyl, halo, haloalkyl, loweralkyl, cyano, aminoalkyl, aminoalkenyl, azide, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, nitro, thiocyanate, alkenyloxy, thioalkenyloxy, aryloxy, thioaryloxy, -OP 1 and -NHP 2 wherein P 1 is an O-protecting group and P 2 is an N-protecting group.
  • aryloxy or “thioaryloxy” as used herein refers to R 10 O- or R 10 S-, respectively, wherein R 10 is an aryl or substituted aryl group.
  • N-protecting group or “N-protected” as used herein refers to those groups intended to protect the N-terminus of an amino acid or peptide or to protect an amino group against undersirable reactions during synthetic procedures or to prevent the attack of exopeptidases on the compounds or to increase the solubility of the compounds and includes but is not limited to sulfonyl, acyl, acetyl, pivaloyl, t-butyloxycarbonyl (Boc), carbonylbenzyloxy (Cbz), benzoyl or an L- or D-aminoacyl residue, which may itself be N-protected similarly.
  • O-protecting group refers to a substituent which protects hydroxyl groups against undesirable reactions during synthetic procedures and includes but is not limited to substituted methyl ethers, for example methoxymethyl, benzylozymethyl, 2-methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, benzyl and triphenylmethyl; tetrahydropyranyl ethers; substituted ethyl ethers, for example, 2,2,2-trichloroethyl and t-butyl; and silyl ethers, for example, trimethylsilyl, t-butyldimethylsilyl and t-butyldiphenylsi lyl .
  • Trp refers to tryptophan
  • Exemplary compounds of the invention include, but are not limited to:
  • N-(2'-Indolylcarbonyl)-R-Tryptophan-di-n-pentylamide N-(3'-Quinolylcarbonyl)-R-Tryptophan-benzylamide, N-(2'-Indolylcarbonyl)-Tryptophan-(1',R-phenylethyl)amide, N-(3'-Quinolylcarbonyl)-R-Tryptophan-di-n-pentylamide, Methyl N-(2'-Indolylcarbonyl)-R-Tryptophyl-S-Phenylglycinate, Ethyl N-(2'-Indolylcarbonyl)-R-Tryptophyl-S- Phenylglycinate,
  • Preferred compounds of the invention include N-(2'-Indolylcarbonyl)-R-Tryptophan-di-n-pentylamide, N-(3'-Qumolylcarbonyl)-R-Tryptophan-di-n-pentylamide, N-(3'-Quinolylcarbonyl)-R-(beta-Oxindolyl)Alanine-di-n-pentylamide
  • the compounds of the invention may be made as shown in Scheme I. Compounds with DL (R,S), L, or D configuration may be used in the synthetic schemes.
  • N-protected derivatives of tryptophan 1 are coupled with primary and secondary amines of the type HNR 1 R 2 (preferably dialkyl, diaryl, or arylalkyl amines or amino acid esters) using bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOPCl) or other standard coupling techniques (i.e., isobutylchloroformate (IBCF), phosphorus pentachloride (PCl 5 ), dicyclohexylcarbodiimide (DCC), or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) with hydroxybenzotriazole (HOBt)).
  • BOPCl bis(2-oxo-3-oxazolidinyl)phosphinic chloride
  • IBCF isobutylchloroformate
  • PCl 5 phosphorus pentachloride
  • DCC dicyclohexylcarbodiimi
  • Both the salt 3 and the free base 4 are coupled to an appropriate arylcarboxylic acid or heteroarylcarboxylic acid (preferably quinoline-3-carboxylic acid or indole-2-carboxylic acid) using standard techniques to provide product 5 .
  • 5 can be obtained from the coupl ing of 3 or 4 with the appropriate acid chloride or activated ester form of the aryl- or heteroarylcarboxylic acids. Further substitution of the nitrogem atom can be achieved via prior alkylation.
  • the amine 4 or its hydrochloride 3 is either directly alkylated with R 11 X (where X is chloride, bromide, iodide), an activated form of the alcohol R 11 OH or reductively alkylated with an appropriate aldehyde in the presence of a reducing agent such as sodium cyanoborohydride or sodium borohydride, to provide the same product 6.
  • Product 5 can then be coupled in a fashion analogous to 3 and 4 to provide the key compound 5 .
  • Compound 5 can be treated directly with aryl- or alkylsulfenyl chlorides (R 10 SCl or R 9 SCl) in a variety of solvents to provide the thioaryl or thioalkyl substituted tryptophans 1 .
  • the tricyclic intermediate 17 can be produced from 5 via the action of t-butylhypochlorite and an amine base and the tricyclic 17 reacted with thiols R 10 SH or R 9 SH to provide the substituted analogs 7 .
  • the product 5 can also be treated with base (sodium hydride, sodium hydroxide under phase transfer conditions, or lithium hexamethyldisilazide in dimethylformamide (DMF)) followed by an alkylating or acylating agent represented by R 30 X, to provide the derivatized products 8.
  • base sodium hydride, sodium hydroxide under phase transfer conditions, or lithium hexamethyldisilazide in dimethylformamide (DMF)
  • R 30 X alkylating or acylating agent represented by R 30 X
  • the amine hydrochloride 3 or it substituted analog 6 can likewise be coupled with aryl- or heteroarylsulfonylchlorides (ArSO 2 Cl) to provide the products 9.
  • aryl- or heteroarylsulfonylchlorides ArSO 2 Cl
  • one familiar with the art could use the sulfonic acids and standard coupling methodology to provide 9.
  • the amines 3 and 6 may also be coupled in standard fashion to the beta aryl- or beta heteroaryl substituted acrylic acids ( or their corresponding acid chlorides) to yield the unsaturated derivatives 10.
  • Compound 11 is obtained through direct oxidation of the parent 5 with hydrochloric acid in dimethylsulfoxide (DMSO). Alternatively, controlled hydrolysis of intermediate 17 yields compound 11.
  • Indoline derivatives of the type 12 are obtained by the catalytic hydrogenation of 5 followed by an acylation or an alkylation.
  • Compounds of the type 1 are obtained by an alkylation sequence starting from compound 13.
  • Compound 14 is alkylated directly with R 11 X utilizing phase transfer conditions (methylene chloride, or other suitable organic solvent, and 10-50% sodium or potassium hydroxide solutions or potassium carbonate) with a tetraalkylammonium salt present, preferably tetrabutylammonium hydrogensulfate (NBu 4 HSO 4 ).
  • a tetraalkylammonium salt present, preferably tetrabutylammonium hydrogensulfate (NBu 4 HSO 4 ).
  • the product 15 is deprotected with aqueous acid and subsequently the free amine or its salt is protected with CbzCl or di-t-butyldicarbonate (Boc 2 O) to yield the ester 16.
  • Ester 16 is saponified in a standard fashion (NaOH) to provide 1 (R 11 not H) for subsequent reaction including conversion to products of types 5, 7 , 8 , 9 and 10.
  • R 4 and R 4 are independently selected from i) hydrogen, ii) C 1 -C 6 loweralkyl, iii) cycloalkyl, iv) loweralkenyl, v) -(CH 2 ) m cycloalkyl.
  • R 4 and R 4 are independently selected from i) hydrogen, ii) C 1 -C 6 loweralkyl, iii) cycloalkyl, iv) loweralkenyl, v) -(CH 2 ) m cycloalkyl.
  • vi) -(CH 2 ) m CN, vii) alkoxyalkyl, viii) adamantyl, ix) -(CH 2 ) m (C O) r NR 6 R 7 wherein
  • R 6 and R 7 are independently selected from hydrogen, loweralkyl, cycloalkyl, loweralkenyl,
  • aryl group is substituted with one, two or three substituents independently selected from loweralkyl, alkoxy, thioalkoxy, carboxy, carboalkoxy, cyano, haloalkyl, -N 3 , -NHP 4 wherein P 4 is an N-protecting group, -OP 5 wherein P 5 is an 0-protecting group, nitro, trihalomethyl, halogen, hydroxy, amino, alkylamino and dialkylamino; x) cyclic groups wherein R 1 and R 2 taken together with the adjacent nitrogen atom form a heterocyclic group represented by the formula
  • R 21 and R 18 are independently selected from the group hydrogen
  • R 21 and R 18 are independently as defined above and -OR 4 wherein R 4 is independently as defined above, -NR 6 R 7 wherein R 6 and R 7 are independently as defined above, or -NHR 4 wherein R 4 is independently as defined above, with the proviso that when R 3 is NR 6 R 7 then R 21 and R 18 are not both hydrogen and xiv) -(C(R 21 )(R 18 )) m R 12 wherein R 21 and R 18 are independently as defined above and
  • R 12 is a heterocyclic group; with the proviso that R 1 and R 2 are not both hydrogen; R 11 is i) hydrogen, ii) loweralkyl, or iii) loweralkenyl;
  • R 20 is i) hydrogen, ii) loweralkyl, or iii) loweralkenyl; the subscripts are independently selected at each occurrence from the values n is 1 to 3; m is 0 to 4; p is 0 to 2; q is 0 or 1; r is 0 to 1; and t is 0 to 1; and P 3 and P 6 are independently selected from hydrogen and an N-protecting group.
  • Ar is a heterocyclic group, aryl or substituted aryl wherein substituted aryl is as defined above; m is 0 to 4; and q is 0 or 1.
  • Activating groups are those functional groups which activate a carboxylic acid or sulfonic acid group toward coupling with an amine to form an amide or sulfonamide bond.
  • Activating groups Z' include, but are not limited to -OH, -SH, alkoxy, thioalkoxy, halogen, formic and acetic acid derived anhydrides, anhydrides derived from alkoxycarbonyl halides such as isobutyloxycarbonylchloride and the like, N-hydroxysuccinimide derived esters, N-hydroxyphthalimide derived esters, N-hydroxybenzotriazole derived esters,
  • N-hydroxy-5-norbornene-2,3-dicarboxamide derived esters 4-nitrophenol derived esters, 2,4,5-trichlorophenol derived esters and the like.
  • N-t-Butyloxycarbonyl-R-Tryptophan (10 g, 33 mmol) was stirred at 0°C in 160 mL of methylene chloride (CH 2 Cl 2 ) with bis(2-oxo-3-oxazolidnyl )phosphinic chloride (BOPCl, 8.6 g, 34 mmol), 4.5mL (32 mmol) of triethylamine (TEA).
  • di-n-pentylamine 18 mL, 89 mmol
  • the mixture was stirred overnight and allowed to warm to room temperature.
  • An additional equivalent of BOPCl was added after 18 hrs and the reaction stirred an additional day at ambient temperature.
  • reaction sequence was performed similarly to that in example 7 utilizing 90 mg of the hydrochloride salt of example 6, indole-2-carboxylic acid (80 mg), EDCI(120 mg), HOBt (55 mg), and TEA (125 ⁇ L ).
  • EDCI (1.91 g, 10 mmol) was added to a cooled (4°C) solution containing quinoline-3-carboxylic acid (1.73 g, 10 mmol), tryptophan methyl ester hydrochloride (2.55 g, 10 mmol), and (2.8 mL, 20 mmol) in 50 mL of methylene chloride. After 4 hrs, the solvent was evaporated and the residue dissolved in ethylacetate and extracted three times with 1 M H 3 PO 4 (phosphoric acid), three times with 1 M Na 2 CO 3 (sodium carbonate), three times with brine and then dried over MgSO 4 . The solution was filtered and concentrated.
  • EDCI 190 mg, 1.0 mmol was added to a cooled (4°C) solution of N-(3'-Quinolylcarbonyl)-R-Tryptophan (360 mg, 1.0 mmol), 3-methyl-5-phenylpyrazole (200 mg), HOBt (130 mg, 1.0 mmol), and TEA (140 ⁇ L , 1.0 mmol) in CH 2 Cl 2 (20 mL). The reaction was allowed to attain room temperature overnight. The solvents were evaporated and the residue was dissolved in EtOAc and extracted with 1 M H 3 PO 4 (3x), H 2 O (3x) then dried over MgSO 4 , filtered and concentrated in vacuo.
  • EDCI (191 mg, 1.0 mmol) was added to a cooled solution (4°C) of Boc-R-Tryptophan (304 mg, 1.0 mmol), S-Phenylglycine me thyl ester (202 mg, 1.0 mmol), HOBt (135 mg, 1.0 mmol) and TEA (279 ⁇ L, 2.0 mmol) in dry CH 2 Cl 2 (10 mL).
  • the reaction was allowed to reach ambient temperature overnight.
  • the solvents were evaporated in vacuo and the residue was dissolved in EtOAc and extracted successively with 1 M H 3 PO 4 (3x), 1 M Na 2 CO 3 (3x), brine (3x) then dried over MgSO 4 , filtered and the filtrate concentrated in vacuo.
  • EDCI 75 mg, 0.39 mmol was added to a cooled (4°C) solution of indole-2-carboxylic acid (63 mg, 0.39 mmol), methyl R-Tryptophyl-S-Phenyglycinate hydrochloride (150 mg, 0.39 mmol), HOBt (53 mg, 0.39 mmol), and TEA (112 ⁇ L , 0.8 mmol) in CH 2 Cl 2 (10 mL). The reaction was allowed to attain ambient temperature overnight. Additional indole-2-carboxylic acid (6 mg), EDCI (8 mg) and TEA (12 ⁇ L ) were added and the reaction was continued 6 hours.
  • Boc-R-Tryptophan (1.43 g, 4.7 mmol), ethyl N-benzylglycinate (1.04 g, 5.4 mmol), EDCI (1.05 g, 5.48 mmol), and HOBt (500 mg, 3.7 mmol) were stirred in 10 mL of DMF at 0°C and TEA (700 ⁇ L ) was added. The reaction was allowed to stir overnight and warm to ambient temperature. The reaction mixture was treated in an analogous fashion to that in example 23 and chromatography with EtOAc/hexane as the elutant mixture provided 1.43 g of an oily product after evaporation of the solvents in vacuo.
  • EDCI (82 mg, 0.43 mmol) was added to a cooled (4°C) solution of indole-2-carboxylic acid (69 mg, 0.43 mmol) ethyl R-Tryptophan-(N-benzyl )glycinate hydrochloride (104 mg, 0.43 mmol), HOBt (58 mg, 0.43 mmol), and TEA (120 ⁇ L , 0.86 mmol) in CH 2 Cl 2 (10 mL). The reaction was allowed to attain ambient temperature overnight. Additional EDCI (8 mg) and TEA (12 ⁇ L ) were added after 1 day.
  • EDCI 104 mg, 0.54 mmol was added to a cooled (4°C) solution of quinoline-3-carboxylic acid (94 mg, 0.54 mmol), ethyl R-Tryptophan-(N-benzyl)glycinate hydrochloride (217 mg, 0.54 mmol), and TEA (151 ⁇ L , 1.08 mmol) in CH 2 Cl 2 (10 mL).
  • the reaction was allowed to attain ambient temperature overnight. After 5 hours, the solvent was evaporated and the residue was dissolved in EtOAc and extracted with 1 M H 3 PO 4 (3x), 1 M Na 2 CO 3 (3x), brine (3x) the dried over MgSO 4 , filtered and the filtrate concentrated.
  • EDCI 27 mg, 0.14 mmol was added to a cooled (4°C) solution of N-(3'-Qumolylcarbonyl)-R-Tryptophan (50 mg, 0.14 mmol), methyl R-Phenylglycinate hydrochloride (28 mg, 0.14 mmol), HOBt (19 mg, 0.14 mmol), and TEA (39 ⁇ L, 0.28 mmol) in CH 2 Cl 2 (5 mL).
  • MS(FAB) m/e 507(m+H) + , 342, 334, 314.
  • EDCI 27 mg, 0.14 mmol was added to a cooled (4°C) solution of N-(3'-Quinolylcarbonyl)-R-Tryptophan (50 mg, 0.14 mmol), methyl S-Phenylglycinate hydrochloride (28 mg, 0.14 mmol), HOBt (19 mg, 0.14 mmol), and TEA (39 ⁇ L, 0.28 mmol) in CH 2 Cl 2 (5 mL). The reaction was allowed to attain room temperature overnight. The reaction mixture was not homogeneous and an additional quantity of TEA (4 ⁇ L ) was added.
  • Crop 1 12 mg, 0.024 mmol, 17%.
  • BOPCl (128 mg, 0.50 mmol) was added to a cooled (4°C) solution of N-(3'-Quinolylcarbonyl)-R-Tryptophan (180 mg, 0.50 mmol), N-methylbenzylamine (130 ⁇ L , 1.0 mmol), and HOBt (68 mg, 0.50 mmol) in CH 2 Cl 2 (10 mL). The reaction was allowed to attain room temperature overnight. An additional quantity of BOPCl (13 mg) was added and the reaction was continued.
  • BOPCl 255 mg, 1.0 mmol was added to a cooled solution (4°C) of Boc-R-Tryptophan (304 mg, 1.0 mmol), S- ⁇ -methylbenzylamine (129 ⁇ L , 1.0 mmol), HOBt (135 mg, 1.0 mmol) and TEA (140 ⁇ L , 1.0 mmol) in dry THF (15 mL). After 2 hours, the solvents were evaporated in vacuo and the residue was dissolved in EtOAc and extracted successively with 1 M H 3 PO 4 (3x), 1 M Na 2 CO 3 (3x), brine (3x) then dried over MgSO 4 , filtered and the filtrate concentrated in vacuo.
  • BOPCl 255 mg, 1.0 mmol was added to a cooled solution (4°C) of Boc-R-Tryptophan (304 mg, 1.0 mmol), R- ⁇ -methylbenzylamine (129 ⁇ L, 1.0 mmol), HOBt (135 mg, 1.0 mmol) and TEA (140 ⁇ L , 1.0 mmol) in dry THF (15 mL).
  • the reaction was allowed to reach ambient temperature overnight.
  • the solvents were evaporated in vacuo and the residue was dissolved in EtOAc and extracted successively with 1 M H 3 PO 4 (3x), 1 M Na 2 CO 3 (3x), brine (3x) then dried over MgSO 4 , filtered and the filtrate concentrated in vacuo.
  • Boc-R-Tryptophan-(1',R-phenylethyl)amide 200 mg, 0.49 mmol was mixed with HCl-Dioxane (1.2 mL, 4.9 mmol, pre-cooled to 4°C) under an N 2 atmosphere at ambient temperature. After 2 hours, the volatiles were evaporated in vacuo and placed under high vacuum overnight to provide the product.
  • BOPCl (152 mg, 0.60 mmol) was added to a cooled (4°C) solution of N-(3'-quinolylcarbonyl)-R-Tryptophan (200 mg, 0.56 mmol), perhydroisoquinoline (192 mg, 1.4 mmol, prepared by catalytic reduction of isoquinoline (cf. Witkop J Am Chem Soc, 70, 2617-19, 1948), TEA (84 ⁇ L, 0.6 mmol) and HOBt (81 mg , 0.60 mmol) in THF (10 mL). The reaction was allowed to attain room temperature overnight. The solvents were evaporated and the residue treated as in example 18.
  • BOPCl (152 mg, 0.60 mmol) was added to a cooled (4°C) solution of N-(3'-quinolylcarbonyl)-R-Tryptophan (200 mg, 0.56 mmol), dibenzylamine (268 ⁇ L , 1.4 mmol), TEA (84 ⁇ L , 0.6 mmol) and HOBt (81 mg, 0.60 mmol) in THF (10 mL). The reaction was allowed to attain room temperature overnight. The solvent was evaporated and the residue was treated as in example 18. The product was purified by chromatography on silica eluted with 2:1 to 1:1 hexanes-EtOAc to provide 100 mg of product, 0.186 mmol (33%).
  • BOPCl 255 mg, 1.0 mmol was added to a cooled solution (4°C) of Boc-S-Tryptophan (304 mg, 1.0 mmol), 3-aminoquinoline (144 mg, 1.0 mmol), HOBt (13 mg, 0.1 mmol) and TEA (140 ⁇ L , 1.0 mmol) in dry CH 2 Cl 2 (10 mL). The reaction was allowed to reach ambient temperature overnight. The solvents were evaporated in vacuo and the residue was treated as in example 18. The residue was purified by chromatography on silica gel eluted with a 2:1 to 1:1 hexanes-EtOAc gradient. Yield: 195 mg, 0.45 mmol, (45%).
  • Boc-S-Tryptophan-N-(3'-quinolyl)amide 164 mg, 0.38 mmol was mixed with HCl-Dioxane (3 mL, 12 mmol, pre-cooled to 4 C) under an N 2 atmosphere at ambient temperature. After 2 hours, the volatiles were evaporated in vacuo and placed under high vacuum overnight to provide the product. MS(CI) m/e 331(m+H) + .
  • BOPCl (152 mg, 0.60 mmol) was added to a cooled (4°C) solution of N-(3'-quinolylcarbonyl)-R-Tryptophan (200 mg, 0.56 mmol), 3-aminoquinoline (173 mg, 1.2 mmol, recrystallized from hexanes), TEA (167 ⁇ L , 1.2 mmol) and HOBt (81 mg, 0.60 mmol) in CH-Cl 2 (15 mL). The reaction was allowed to attain room temperature. After 5 hours, the solvents were evaporated and the residue was treated as in example 18. The crude product was crystallized from aqueous ethanol to provide 60 mg, 0.12 mmol (21% yield).
  • EDCI 80 mg, 0.42 mmol was added slowly over -3 hours to a cooled (4°C) solution of quinoline-3-carboxylic acid (73 mg, 0.42 mmol), S-(p-hydroxyphenyl)glycine methyl ester hydrochloride (170 mg, 0.42 mmol), HOBt (6 mg, 0.04 mmol), and TEA (117 ⁇ L , 0.84 mmol) in CH 2 Cl 2 (15 mL). After 2 days, an additional 10% equivalent amount of EDCI and TEA were added and the reaction was continued for one day.
  • R,S-5-benzyloxytryptophan (2.0 g) was treated with di-t-butyldicarbonate (1.7 g) in a 50% solution of saturated sodium bicarbonate in dioxane at 0°C. The reaction was allowed to warm to ambient temperature and stir overnight. The solvents were evaporated in vacuo and residue partioned between NaOH (1.0 N) and EtOAc. The aqueous portion was then acidified to pH 2.0 using concentrated HCl and the solution extracted with ethylacetate. The EtOAc was dried over MgSO 4 and filtered.
  • Example 57 N-(2'-(3'-Methylindenyl)carbonyl)-R-Tryptophan-di-n-pentylamide EDCI (50 mg, 0.26 mmol) was added to a cooled (4°C) solution of 3-methylindene-2-carboxylic acid (45 mg, 0.26 mmol), hydrochloride of example 2 (100 mg, 0.30 mmol), HOBt (7 mg, 0.05 mmol), and TEA (73 ⁇ L, 0.53 mmol) in CH 2 Cl 2 (5 mL). The reaction was allowed to attain ambient temperature overnight. The solvents were evaporated and the residue was treated as in example 18.
  • EDCI 57 mg, 0.3 mmol
  • 4-hydroxy-3-iodobenzoic acid 79 mg, 0.30 mmol
  • hydrochloride of example 2 100 mg, 0.30 mmol
  • HOBt 13 mg, 0.1 mmol
  • TEA 84 ⁇ L, 0.6 mmol
  • CH 2 Cl 2 5 mL
  • the reaction was allowed to attain ambient temperature overnight.
  • the solvents were evaporated and the residue was treated as in example 18.
  • Example 72 The product of example 72 was treated with 1.0 N NaOH in dioxane at ambient temperature. When tlc indicated that the starting material had been consumed, the reaction mixture was concentrated in vacuo and partioned between water and ethylacetate. The aqueous portion was separated and acidified to pH 2.0 and extracted sucessively with EtOAc. The extracts were dried over MgSO 4 and the solution filtered and concentrated. The crude product was treated directly as in example 51 to provide product after chromatography using EtOAc/hexanes as the elutant.
  • Example 74 N-(3'-Quinolylcarbonyl)- ⁇ -allyl-Tryptophan-di-n-pentylamide
  • example 73 was treated with 4.5 N HCl in dioxane as in example 2 to provide product which was used directly in a coupling reaction analogous to that described in example 21.
  • the product was purified by chromatography using EtOAc and hexane.
  • N ⁇ -Quinoline-3-(N-hydroxysuccinimide) ester (95 mg, 0.35), and the product of example 76 (0.3 mmol assumed) were dissolved in 10 mL of methylene chloride and treated with TEA (49 ⁇ L , 0.35 mmol). Additional ester (95 mg) and TEA (49 ⁇ L) were added after 1 and again at 2 days. The solvents were evaporated and the residue was extracted as in example 67 and then purified by chromatography eluting with 90:10:0.5 methylene chloride-ethanol-ammonium hydroxide to provide 71 mg, 0.13 mmol (37%) as a yellow glass.
  • Di-t-butyldicarbonate (327 mg, 1.5 mmol) was added to 5-hydroxy-R-Tryptophan (250 mg, 1.14 mmol) and TEA (167 ⁇ L, 1.2 mmol) in 10 mL THF and 5 mL of water. After 1 day, the solvent was evaporated and the residue in ethylacetate was extracted with 0.1 M citric acid and water then dried over MgSO 4 and the filtrate concentrated. The product was used directly in the next step.
  • N ⁇ -(3'-Quinolylcarbonyl)-R-Tryptophan 360 mg, 1.0 mmol
  • 3,5-dimethylpyrazole 96 mg, 1.0 mmol
  • HOBt 270 mg, 2.0 mmol
  • TEA 140 ⁇ L , 1.0 mmol
  • EDCI 20 mg
  • the solvents were evaporated and the residue was extracted and purified as in example 67.
  • N ⁇ -(3'-Quinolylcarbonyl)-R-Tryptophan 150 mg, 0.49 mmol
  • diethanolamine 240 ⁇ L , 2.5 mmol
  • BOPCl 127 mg, 0.50 mmol
  • the solvents were evaporated and the residue was purified by chromatography on silica gel eluted with 20:1 methylene chloride-ethanol to provide 144 mg, 0.32 mmol (66%).
  • R f 0.52 (80:20:1 chloroform-methanol-ammonium hydroxide).
  • Boc-S-Tryptophan (1 g, 3.3 mmol), dipentylamine (1.6 mL, 8.2 mmol) and HOBt (446 mg, 3.3 mmol) were dissolved in 25 mL of methylene chloride and treated with BOPCl (841 mg, 3.3 mmol). After 1 day, TEA (460 ⁇ L ) and additional BOPCl (168 mg) were added. After 3 days, the solvents were evaporated and the residue in ethylacetate was extracted with 0.1 M citric acid, 0.1 M NaHCO 3 , and water. After drying over MgSO 4 and concentration of the filtrate, the residue was purified by chromatography on silica gel eluted with 9:1 to 2:1 hexane-ethylacetate step gradient.
  • Phenanthrene-3-carboxylic acid 100 mg, 0.45 mmol
  • the product of example 2 172 mg, 0.45 mmol
  • the crude residue was purified by chromatography on silica gel eluted with a 9:1 to 2:1 hexane-ethylacetate step gradient to yield 92 mg, 0.18 mmol (40%).
  • MS(CI) m/e 548(m+H) + , 418, 326.
  • 5-Fluoroindole-2-carboxylic acid (269 mg, 1.5 mmol), the product of example 2 (500 mg, 1.31 mmol) were coupled as in example 58 with the following modifications: 10% more EDCI and TEA were added at 6 hours, and 50% more EDCI and TEA were added at 1 day. After 2 days, the reaction mixture was processed as in example 100 to yield 546 mg, 1.08 mmol (82%). MS(CI) m/e 505(m+H) + , 348, 326.
  • Example 108 N-(p-Chloropheny1aminothiocarbonyl)-R-Tryptophan-di-n-pentylamide
  • the product of example 2 (100 mg, 0.26 mmol) was reacted with 4-chlorophenylisothiocyanate as in example 107 to yield 62 mg, 0.12 mmol (46%).
  • mp 138-140°C.
  • MS(CI) m/e 513(m+H) + , 356, 344, 326.
  • the compounds of Formula I antagonize CCK which makes the compounds useful in the treatment and prevention of disease states wherein CCK or gastrin may be involved, for example, gastrointestinal disorders such as irritable bowel syndrome, ulcers, excess pancreatic or gastric secretion, acute pancreatitis, motility disorders, pain (potentiation of opiate analgesia), central nervous system disorders caused by CCK's interaction with dopamine such as neuroleptic disorders, tardive dyskinesia, Parkinson's disease, psychosis or Gilles de la Tourette Syndrome, disorders of appetite regulatory systems, Zollinger-Ellison syndrome, and central G cell hyperplasia.
  • gastrointestinal disorders such as irritable bowel syndrome, ulcers, excess pancreatic or gastric secretion, acute pancreatitis, motility disorders, pain (potentiation of opiate analgesia), central nervous system disorders caused by CCK's interaction with dopamine such as neuroleptic disorders, tardive dyskinesia, Parkinson's disease,
  • CCK 8 [Asp-Tyr(SO 3 H)-Met-Gly-Trp-Met-Asp-Phe-NH 2 ] was purchased from Beckman Instruments (Palo Alto, CA) and Peptide International (Louisville, KY). Chymostatin, L-Try-Gly, puromycin, bestatin, EGTA, HEPES and BSA were purchased from Sigma Chemical Co. (St. Louis, MO). [ 125 I]BH-CCK 8 (specific activity, 2200 Ci/mmol) and Aquasol-2 scintillation cocktail were obtained from New England Nuclear (Boston, MA). Male guinea pigs, 250 to 325 g, were obtained from Scientific Small Animal Laboratory and Farm (Arlington Heights, IL). Collagenase, 300 units per mg, was purchased from Worthington (Frehold, N.J.) Protocol For Radioligand Binding Experiments
  • Cortical and pancreatic membrances were prepared as described (Lin and Miller; J. Pharmacol. Exp. Ther. 232, 775-780, 1985). In brief, cortex and pancreas were removed and rinsed with ice-cold saline. Visible fat and connective tissues were removed from the pancreas. Tissues were weighed and homogenized separately in approximately 25 mL of ice-cold 50 mM Tris-HCl buffer, pH 7.4 at 4°C, with a Brinkman Polytron for 30 sec, setting 7. The homogenates were centrifuged for 10 min at 1075 x g and pellets were discarded, the supernatants were saved and centrifuged at 38,730 x g for 20 min.
  • the resultant pellets were rehomogenized in 25 mL of 50 mM Tris-HCl buffer with a Teflon-glass homogenizer, 5 up and down strokes.
  • the homogenates were centrifuged again at 38,730 x g for 20 min.
  • Pellets were then resuspended in 20 mM HEPES, containing 1 mM EGTA, 118 mM NaCl, 4.7 mM KCl, 5 mM MgCl 2 , 100 uM bestatin, 3 uM phosphoramidon, pH 7.4 at 22°C, with a Teflon-glass homogenizer, 15 up and down strokes.
  • Resuspension volume for the cortex was 15-18 mL per gm of original wet weight and 60 mL per gm for the pancreas. 2. Incubation Conditions
  • [ 125 I]Bolton-Hunter CCK 8 and test compounds were diluted with HEPES-EGTA-salt buffer (see above) containing 0.5% bovine serum albumin (BSA).
  • BSA bovine serum albumin
  • the cortical tissues were incubated at 30°C for 150 min and pancreatic tissues were incubated at 37°C for 30 min. Incubations were terminated by filtration using Skatron Cell
  • Guinea pig acini were prepared by the method of Bruzzone et al. (Biochem. J. 226, 621-624, 1985) as follows. Pancreas was dissected out and connective tissues and blood vessels were removed. The pancreas was cut into small pieces (2mm) by a scissor and placed in a 15 mL conical plastic tube containing 2.5 mL of Krebs-Ringer HEPES (KRH) buffer plus 400 units per mL of collagense.
  • KRH Krebs-Ringer HEPES
  • the composition of the KRH buffer was: HEPES, 12.5 mM: NaCl, 118 mM; KCl, 4.8 mM; CaCl 2 , 1 mM; KH 2 PO 4 , 1.2 mM; MgSO 4 , 1.2 mM; NaHCO 3 , 5 mM; glucose, 10 mM, pH 7.4.
  • the buffer was supplemented with 1% MEM vitamins, 1% MEM amino acids and 0.001% aprotinin.
  • the tube was shaken by hand until the suspension appeared homogeneous, usually 5 to 6 min. 5 mL of the KRH, without collagenase and with 0.1% BSA, were added and the tube was centrifuged at 50 x g for 35 sec.
  • acini were resuspended in 100 volumes of KRH-3SA buffer, containing 3 uM phosohoramidon and 100 M bestatin. While stirring, 400 uL of acini were added to 1.5 mL microcentrifuge tubes containing 50 uL of CCK 8 , buffer, or test compounds. The final assay volume was 500 uL. Tubes were vortexed and placed in a 37°C waterbath, under 100% O 2 , for 30 min. Afterward, tubes were centrifuged at 10,000 g for 1 min.
  • Amylase activity in the supernatant and the cell pellet were separately determined after appropriate dilutions in 0.1% Tr iton X-100, 10 mM NaH 2 PO 4 , pH 7.4 by Abbott Amylase A-gent test using the Abbott Bichromatic Analyzer 200.
  • mice Three fasted mice are dosed (p.o.) with the test compound.
  • CCK 8 80 ug/kg s.c. is administered with
  • charcoal meal 0.1 ml of 10% suspension
  • the animals are sacrificed within an additional 5 minutes.
  • Gastric emptying defined as the presence of charcoal within the intestine beyond the pyloric sphincter, is inhibited by CCK 8 . Gastric emptying observed in more than one mouse indicates antagonism of
  • mice Male mice, 20-30 g, are used in all experiments. The animals are fed with laboratory lab chow and water ad libitum. The compound of Formula I (1-100 mg/kg in 0.2 ml of 0.9% saline) was administered i.p. Ten minutes later CCK 8 (0.2 to 200 nmole/kg in 0.2 ml of 0.9% saline) or saline is injected into the tail vein. Two minutes later the animals are sacrificed and blood is collected into 1.5 ml heparinized polypropylene tubes. The tubes are centrifuged at 10,000 x g for 2 minutes. Insulin levels are determined in the supernatant (plasma) by an RIA method using kits from Radioassy Systems Laboratory (Carson, CA.) or Novo Biolabs (MA.).
  • mice Male Swiss CD-I mice (Charles River) (22-27 g) were provided with ample food (Purina Lab Chow) and water until the time of their injection with the test compound.
  • ICV injections were given by a free-hand method similar to that previously described (Haley and McCormick, Br. J. Pharmacol. Chemother. 12 12-15 (1957)).
  • the animals were placed on a slightly elevated metal grid and restrained by the thumb and forefinger at the level of the shoulders, thus immobilizing their heads.
  • Injections were made with a 30 gauge needle with a "stop" consisting of a piece of tygon tubing to limit penetration of the needle to about 4.5 mm below the surface of the skin.
  • the needle was inserted perpendicular to the skull at a midline point equidistant from thje eye and an equal distance posterior from the level of the eyes such that the injection site and the two eyes form an equilateral triangle.
  • the injection volme (5 ul) was expelled smoothly over a period of approximately 1 second.
  • mice were placed in their cages and allowed a 15 minute recovery period prior to the beginning of the behavioral observations.
  • mice were placed in clear plastic cages. Each cage measured 19 ⁇ 26 ⁇ 15 centimeters and contained a 60-tube polypropylene test tube rack (NALGENE #5970-0020) placed on end in the center of the cage to enhance exploratory activity. Observations were made evcery 30 seconds for a period of 30 minutes. Behavior was compared between drug and CCK 8 treated mice; CCK 8 treated mice; a;nd mice treated with an equal volume of carrier (usually 0.9% saline or 5% dimethylsulfoxide in water). Locomotion as reported here consisted of either floor locomotion or active climbing on the rack. Differences among groups were analyzed by Newman-Kewels analysis and a probability level of p ⁇ 0.05 was accepted as significant.
  • carrier usually 0.9% saline or 5% dimethylsulfoxide in water
  • MED minimally effective doses
  • the compounds of the present invention can be used in the form of salts derived from inorganic or organic acids.
  • These salts include but are not limited to the following: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate, lactate, maleate, methanesulfonate.
  • nicotinate 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, and undecanoate.
  • the basic nitrogen-containing groups can be guaternized with such agents as loweralkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides, and others. Water or oil-soluble or dispersible products are thereby obtained.
  • loweralkyl halides such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides
  • dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates
  • long chain halides
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the compounds of Formula I which contain a basic or acidic moiety by conventional chemical methods. Generally, the salts are prepared by reacting the free base or acid with stoichiometric amounts or with an excess of the desired salt forming inorganic or organic acid or base in a suitable solvent or various combinations of solvents.
  • acids which may be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, sulphuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, succinic acid and citric acid.
  • Other salts include salts with alkali metals or alkaline earth metals, such as sodium, potassium, calcium or magnesium or with organic bases.
  • the pharmaceutically acceptable salts of the acid of Formula I are also readily prepared by conventional procedures such as treating an acid of Formula I with an appropriate amount of a base, such as an alkali or alkaline earth metal hydroxide e.g. sodium, potassium, lithium, calcium, or magnesium, or an organic base such as an amine, e.g., dibenzylethylenediamine, trimethylamine, piperidine, pyrrolidine, benzylamine nd the like, or a quaternary ammonium hydroxide such as tetramethylammonium hydroxide and the like.
  • a base such as an alkali or alkaline earth metal hydroxide e.g. sodium, potassium, lithium, calcium, or magnesium
  • an organic base such as an amine, e.g., dibenzylethylenediamine, trimethylamine, piperidine, pyrrolidine, benzylamine nd the like, or a quaternary ammonium hydroxide such as tetramethylammonium hydrox
  • the total daily dose administered in single or divided doses may be in amounts, for example, from 0.001 to 1000 mg a day and more usually 1 to 1000 mg.
  • Dosage unit compositions may contain such amounts of submultiples thereof to make up the daily dose.
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated, the particular treatment and the particular mode of administration.
  • the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the severity of the particular disease undergoing therapy.
  • the compounds of the present invention may be administered orally, parenterally, by inhalation spray, rectally, or topically in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired.
  • parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection, or infusion techniques.
  • sterile injectable preparations for example, sterile injectable aqueous or oleagenous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable prepartion may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable nonirritating excipient such as cocoa butter and polyethylene glycols which are solid at ordinary temperatures but l iquid at the rectal temperature and will therefore melt in the rectum and release the drug.
  • Solid dosage forms for oral administration may include capsules, tablets, pills, powders, and granules.
  • the active compound may be admixed with at least one inert diluent such as sucrose lactose or starch.
  • Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate.
  • the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.
  • Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsion, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water.
  • Such compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.
  • liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used.
  • the present compositons in liposome form can contain, in addition to the compounds of the present invention, stabilizers, preservatives, excipients and the like.
  • the preferred lipids are the phospholipids and the phophatidyl cholines (lecithins), both natural and synthetic. Methods to form liposomes are known in the art. See, for example, Prescott, ed., Methods in Cell Biology, Vol. XIV, Academic Press, New York, N.Y. pp. 33- (1976).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Psychiatry (AREA)
  • Pain & Pain Management (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Toxicology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Indole Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention concerne un composé de la formule (I), dans laquelle R1 et R2 sont sélectionnés indépendamment parmi l'hydrogène, un alkyle inférieur, un cycloalkyle, un alkényle inférieur, un adamantyle, un aryle, un aryle substitué, un groupe hétérocyclique, un alkyle substitué, un amide substitué, un carbonyle fonctionnalisé et un cycle contenant de l'azote dans lequel R1, R2 et l'atome d'azote adjacent forment un cycle; R11 représente un hydrogène, un alkyle inférieur ou un alkényle inférieur; R20 représente un hydrogène, un alkyle inférieur ou un alkényle inférieur; B représente -(CH2)m-, un alkénylène substitué, -QCH2- où Q représente O, S, NH ou un amino substitué, -CH2Q- où Q est tel qu'il est défini ci-dessus ou B représente NH; Z représente C=O, S(O)2, ou C=S; Ar est un groupe hétérocyclique, un aryle ou un aryle substitué; D est un oxindol-3-yl, indolin-3-yl ou indol-3-yl substitué ou non-substitué; et m est compris entre 0 et 4; ou un sel pharmaceutiquement acceptable de ce composé.The invention relates to a compound of formula (I), in which R1 and R2 are independently selected from hydrogen, lower alkyl, cycloalkyl, lower alkenyl, adamantyl, aryl, substituted aryl, heterocyclic group , substituted alkyl, substituted amide, functionalized carbonyl and a nitrogen-containing ring in which R1, R2 and the adjacent nitrogen atom form a ring; R11 represents hydrogen, lower alkyl or lower alkenyl; R20 represents hydrogen, lower alkyl or lower alkenyl; B represents - (CH2) m-, a substituted alkenylene, -QCH2- where Q represents O, S, NH or a substituted amino, -CH2Q- where Q is as defined above or B represents NH; Z represents C = O, S (O) 2, or C = S; Ar is a heterocyclic group, aryl or substituted aryl; D is a substituted or unsubstituted oxindol-3-yl, indolin-3-yl or indol-3-yl; and m is between 0 and 4; or a pharmaceutically acceptable salt of this compound.

Description

DERIVATIVES OF TRYPTOPHAN AS CCK ANTAGONISTS
Technical Field
This is a continuation-in-part of U.S. patent application Serial No. 177,715, filed April 5, 1988.
The present invention relates to novel organic compounds and compositions which antagonize cholecystokinin and gastrin, processes for making such compounds, synthetic intermediates employed in these processes and a method for treating gastrointestinal disorders, central nervous system disorders, cancers of the pancreas and the gall bladder, hypoinsulinemia, or potentiating analgesia, or regulating appetite with such compounds.
Background of the Invention
Cholecystokinins (CCK) are a family of amino acid polypeptide hormones. CCK and a 33 amino acid fragment of CCK (CCK33) were first isolated from hog intestine. (Matt and Jorpes, Biochem. J. 125 628 (1981)). Recently the CCK33 fragment has been found in the brain, where it appears to be the precursor of two smaller fragments, an octapeptide CCK8 and a
tetrapeptide CCK4. (Dockray, Nature 264 4022 (1979)).
CCK8, the carboxyl terminal octapeptide fragment of CCK, is the smallest CCK fragment that remains fully biologically active. (Larsson and Rehfeld, Brain Res. 165 201-218 (1979)). The localization of CCK fragments in the cortex of the brain suggests that CCK may be an important neuromodulator of memory, learning and control of primary sensory and motor functions. CCK and its fragments are believed to play an important role in appetite regulation and satiety. (Della-Fera, Science 206 471 (1979); Gibbs et al., Nature 289 599(1981); and Smith, Eating and Its Disorders, eds., Raven Press, New York, 67 (1984)).
CCK antagonists (B.J. Gertz in Neurology and Neurobiology Vol 47, Cholecystokinin Antagonists, Wang and Schoenfeld eds., Alan R. Liss, Inc., New York, NY, 327-342, (1988); Silverman, et al., Am. J. Gastroent. 82 703-8 (1987)) are useful in the treatment and prevention of CCK-related disorders of the gastrointestinal (GI) (Lotti, et al., J. Pharm. Exp. Therap. 241 103-9 (1987)), central nervous (CNS) (Panerai, et al., Neuropharmacology 26 1285-87 (1987)) and appetite regulatory systems of animals, especially man. CCK antagonists are also useful in potentiating and prolonging opiate induced analgesia and thus have utility in the treatment of pain. (Faris et al., Science 226 1215 (1984); Rovati, et al., Clinical Research 34 406A (1986); Dourish, et al, European J. Pharmacology 147 469-72 (1988)). CCK antagonists are also useful for the treatment of disorders of gastric emptying (Stenikar, et al., Arzn. Forsch./Drug Research 37(II) 1168-71 (1987)), gastroesophageal reflux disease, pancreatitis, pancreatic and gastric carcinomas (Douglas, et al., Gastroent. 96 4629 (1989); Beauchamp, et al., Am. Surg. 202 313-9 (1985)), disorders of bowel motility, biliary dyskinesia, anorexia nervosa, hypoglycemia (Rossetti, Diabetes 36 1212-15 (1987); Reagan, Eur. J. Pharmacol. 14 241-3 (1987), gallbladder disease, and the like.
Previously four distinct chemical classes of CCK receptor antagonists have been reported. The first class comprises derivatives of cyclic nucleotides as represented by dibutyryl cyclic GMP (N. Barlas et al., Am. J. Physiol., 242, G161 (1982) and references therein). The second class is represented by C-terminal fragments of CCK (see Jensen et al. Biochem. Bioohys. Acta, 757, 250 (1983) and Spanarkel J. Biol. Chem. 258, 6746 (1983)). The third class comprises amino acid derivatives of glutamic acid and tryptophan as indicated by proglumide and benzotript (see Hahne et al. Proc. Natl. Acad. Sci. U.S.A., 78, 6304 (1981) and Jensen et al. Biochem. Biophys. Acta. 761, 269 (1983)). The fourth and most recent class is comprised of 3-substituted benzodiazepines, represented by L-364,718 (see: Evans et al. Proc. Natl. Acad. Sci. U.S.A., 83 4918 (1986)).
Most of the previously known CCK antagonists are relatively weak antagonists of CCK demonstrating IC50s between 10-4 and 10-6 M. The benzodiazepine CCK antagonists or their metabolites may have undesirable effects in vivo due to their interaction with benzodiazepine receptors.
The C-terminal pentapeptide fragment of CCK is the same as the C-terminal pentapeptide fragment of another polypeptide hormone, gastrin. Gastrin, like CCK, exists in both the GI system. Gastrin antagonists are useful in the treatment and prevention of gastrin-related disorders of the GI system such as ulcers, Zollinger-Ellison syndrome and central G cell hyperplasia. (Morley, Gut Pept. Ulcer Proc, Hiroshima Symp. 2nd, 1, (1983)). Bock,et al., J. Med. Chem. 32 13-16 (1989) discloses receptor antagonists of the in vitro effects of gastrin.
Summary of the Invention
It has now been found that the compounds of the invention are antagonists of cholecystokinin (CCK) and bind specifically to CCK receptors. These CCK antagonists are useful in the treatment and prevention of CCK-related disorders of the gastrointestinal, central nervous and appetite regulatory systems of animals and humans. These compounds are useful in the treatment and prevention of gastrointestinal ulcers, cancers of the gall bladder and pancreas, pancreatitis, Zollinger-Ellison syndrome, central G cell hyperplasia, irritable bowel syndrome, the treatment or prevention of neurpleptic disorders, tardive dyskinesia, Parkinson's disease, psychosis, Gilles de la Tourette syndrome, disorders of appetite regulatory systems, the treatment of pain and the treatment of substance abuse.
Disclosure of the Invention
In accordance with the present invention, there are cholecystokinin antagonists of the formula:
R1 and R2 are independently selected from i) hydrogen, ii) loweralkyl, iii) cycloalkyl, iv) loweralkenyl, v) adamantyl, vi) aryl, vii) substituted aryl, viii) heterocyclic group, ix) substituted alkyl, x) substituted amide, xi) functionalized carbonyl, and xii) nitrogen containing ring wherein R1,
R2 and the adjacent nitrogen atom form a ring.
Substituted alkyl groups are selected from the group consisting of i) -(CH2)1-4cycloalkyl, ii) -(CH2)1-4CN, iii) alkoxyalkyl, iv) -(CH2)1-4(C=O)rNR6R7 wherein
R6 and R7, are independently selected from hydrogen, loweralkyl, cycloalkyl, loweralkenyl,
-(CH2)maryl,
-(CH2)m(substituted aryl) wherein the aryl group is substituted with one, two or three substituents independently selected from loweralkyl, alkoxy, thioalkoxy, carboxy, carboalkoxy, cyano, haloalkyl, -N3, -NHP4 wherein P4 is an N-protecting group , -O P5 wherein P5 is an O-protecting group, nitro, halogen, hydroxy, amino, alkylamino and dialkylamino; v) -(C(R21)(R18))1-4aryl wherein R21 is hydrogen, -(C1-C8loweralkyl), loweralkenyl,
-(O)t(CH2)mcarboxyl,
-(O)t(CH2)mcarboalkoxy,
-(O)t(CH2)mcarboaryloxy, haloalkyl, nitro, alkoxy, aryloxy, thioalkoxy, thloaryloxy, halogen, CN, -OH, -NH2, -NR6R wherein R6 and R7 are independently as defined above, -(CH 2)mOR4, and
-(CH2)mSR4 wherein R4 is hydrogen, -(C=O)rloweralkyl,
-(C=O)rloweralkenyl, -(C=O)rcycloalkyl,
-(C=O)r(CH2)maryl or
-(C=O)r(CH2)m(substituted aryl); and R1 8 is hydrogen , - ( C1-C6 loweralkyl ) , loweralkenyl,
-(O)t(CH2)mcarboxyl,
-(O)t(CH2)mcarboalkoxy,
-(O)t(CH2)mcarboaryloxy, haloalkyl, nitro, alkoxy, aryloxy, thioalkoxy, thioaryloxy, halogen, CN, -OH, -NH2, -NR6R7 wherein R6 and R7 are independently as defined above, -(CH2)mOR4 wherein R is independently as defined above, and
-(CH2)mSR4 wherein R4 is independently as defined above, vi) -(C(R21)(R18))1-4(substituted aryl) wherein R21 and R18 are defined independently as above, vii) -(C(R21)(R18))1-4C(O)R3, wherein
R21 and R18 are independently as defined above and wherein R3 is -OH, -OR4 wherein
R4 is independently as defined above,
-NR6R7 wherein R6 and R7 are independently as defined above, or -NHR4 wherein R4 is as defined above, with the proviso that when R3 is NR6R7 then R21, and R18 are not both hydrogen and viii) -(C(R21)(R18))1-4R12 wherein
R21 and R18 are independently as defined above and R12 is a heterocyclic group.
Substituted amide groups are selected from
-(C=O)NR6R7 wherein
R6 and R7, are independently selected from hydrogen, loweralkyl, cycloalkyl, loweralkenyl,
-(CH2)maryl,
-(CH2)m(substituted aryl) wherein the aryl group is substituted with one, two or three substituents independently selected from loweralkyl, alkoxy, thioalkoxy, carboxy, carboalkoxy, cyano, haloalkyl, -N3, -NHP4 wherein P4 is an N-protecting group, -OP5 wherein P5 is an Q-protecting group, nitro, halogen, hydroxy, amino, alkylamino and dialkylamino. Functionalized carbonyl groups are selected from
-C(O)R3, wherein
R3 is -OH, -OR4 wherein R4 is independently as defined above, -NR6R7 wherein R6 and R7 are independently as defined above, or -NHR 4 wherein R4 is independently as defined above.
Nitrogen containing rings wherein R1, R2 and the adjacent nitrogen atom form a ring are represented by the formula
wherein E and J are independently selected from -(CH2)p-, -(CH=CH)r-,
-YCH2-, -CH2Y-, -C(O)Y- and -YC(O)- wherein Y is S, O, CH2, or -N(R8)-, wherein R8 is selected from hydrogen,
-(C=O)r(C1-C6loweralkyl), -(C=O)r- cycloalkyl, -(C=O)rloweralkenyl,
-(C=O)r(CH2)maryl,
-(C=O)r(CH2)m(substituted aryl) wherein substituted aryl is as defined above,
-(CH2)mSR4, and -(CH2)mOR4 wherein R4 is hydrogen, -(C=O)rloweralkyl,
-(C=O)rloweralkenyl, -(C=O)rcycloalkyl,
-(C=O)r(CH2)maryl or
-(C=O)r(CH2)m(substituted aryl) wherein substituted aryl is as defined above, and wherein R5 is hydrogen or R5 is one, two or three of the substituents independently selected from the group -(C1-C6loweralkyl), loweralkenyl,
-(O)t(CH2)mcarboxyl,
-(O)t(CH2)mcarboalkoxy,
-(O)t(CH2)mcarboaryloxy, haloalkyl, nitro, alkoxy, cyano, -N3, -NHP4, -OP5, alkylaminocarbonyl, dialkylaminocarbonyl, aryloxy, thioalkoxy, thioaryloxy, halogen, CN, -OH, -NH2, -NR6R7 wherein R6 and R7 are independently as defined above, -(CH 2)mOR4 wherein R4 is independently as defined above, and -(CH2)mSR4 wherein R4 is independently as defined above. R11 is i) hydrogen, ii) loweralkyl, or iii) loweralkenyl.
R20 is i) hydrogen, ii) loweralkyl, or iii) loweralkenyl.
B is i) -(CH2)m-, ii) substituted alkenylene, iii) -QCH2- wherein Q is O, S, or
-N(R8)- wherein R8 is as defined above, iv) -CH2Q- wherein Q is as defined above, or v) NH.
Substituted alkenylene is represented by the formula -(CR21=CR18)q wherein R21 and R18 are independently as defined above.
Z is i) C=O, ii) S (O) 2 , or iii ) C=S .
Ar is a heterocyclic group , aryl or substituted aryl . D is group of the formula
or
wherein R30 is hydrogen, loweralkyl, arylalkyl, (substituted aryl) alkyl, or an N-protecting group; and R5 is independently as defined above.
The subscripts, are independently selected at each occurrence from the following values: n is 1 to 3; m is 0 to 4; p is 0 to 2; q is o to 1; r is 0 to 1; and t is 0 to 1. In particular the compounds of the invention are cholecystokinin antagonists of the formula:
wherein a) R1 and R2 are independently selected from i) hydrogen, ii) C1-C6 loweralkyl, iii) cycloalkyl, iv) loweralkenyl, v) -(CH2)mcycloalkyl, vi) -(CH2)mCN, vii) alkoxyalkyl, viii) adamantyl, ix) -(CH2)m(C=O)rNR6R7 wherein
R6 and R7 , are independently selected from hydrogen, loweralkyl, cycloalkyl, loweralkenyl,
-(CH2)maryl,
-(CH2)m(substituted aryl) wherein the aryl group is substituted with one, two or three substituents independently selected from loweralkyl, alkoxy, thioalkoxy, carboxy, carboalkoxy, cyano, haloalkyl, -N3, -NHP4 wherein P4 is an N-protecting group, -OP5 wherein P5 is an O-protecting group, nitro, halogen, hydroxy, amino, alkylamino and dialkylamino; x) cyclic group wherein R1 and R2 taken together with the adjacent nitrogen atom form a heterocyclic group represented by the formula
wherein E and J are independently selected from -(CH2)P-' -(CH=CH)r-, -YCH2-, -CH2Y-, -C(O)Y- and -YC(O)- wherein Y is S, O, CH2, or -N(R8)-, wherein R8 is selected from hydrogen, -(C=O)r(C1-C6loweralkyl), -(C=O)r- cycloalkyl, -(C=O)rloweralkenyl, -(C=O)r(CH2)maryl,
-(C=O)r(CH2)m(substituted aryl) wherein substituted aryl is as defined above, -(CH 2)mSR4 and
-(CH2)mOR4 wherein R4 is hydrogen, -(C=O)rloweralkyl,
-(C=O)rloweralkenyl, -(C=O)rcycloalkyl,
-(C=O)r(CH2)maryl or
-(C=O)r(CH2)m(substituted aryl) wherein substituted aryl is as defined above, and wherein R5 is hydrogen or
R5 is one, two or three of the substituents independently selected from the group -(C1-C6loweralkyl), loweralkenyl,
-(O)t(CH2)mcarboxyl,
-(O)t(CH2)mcarboalkoxy,
-(O)t(CH2)mcarboaryloxy, haloalkyl, nitro, cyano, -N3, -NHP4, -OP5, alkylaminocarbonyl, dialkylaminocarbonyl, alkoxy, aryloxy, thioalkoxy, thioaryloxy, halogen, CN, -OH, -NH2, -NR6R7 wherein R6 and R7 are independently as defined above, -(CH 2)mOR4 wherein R4 is independently as defined above, and -(CH 2)mSR4 wherein R4 is independently as defined above; xi) -(C(R21)(R18))maryl wherein R21 and R18 are independently selected from the group hydrogen, -(C1-C6loweralkyl), loweralkenyl,
-(O)t(CH2)mcarboxyl,
-(O)t(CH2)mcarboalkoxy,
-(O)t(CH2)mcarboaryloxy, haloalkyl, nitro, alkoxy, aryloxy, thioalkoxy, thioaryloxy, halogen, CN, -OH, -NH2, -NR6R7 wherein R6 and R7 are independently as defined above, -(CH2)mOR4 wherein R is independently as defined above, and -(CH2)mSR4 wherein R is independently as defined above, xii) -(C(R21)(R18))m(substituted aryl) wherein R21 and R18 are independently defined as above, and substituted aryl is as defined above, xiii) -(C(R21)(R18))mC(O)R3, wherein R21 and R18 are independently as defined above and wherein R3 is -OH ,
-OR4 wherein R4 is indep-endently as defined above, -NR6R7 wherein R6 and R7 are independently as defined above, or -NHR4 wherein R4 is independently as defined above, with the proviso that when R3 is NR6R7 then R21 and R18 are not both hydrogen and xiv) -(C(R21)(R18))mR12 wherein R21 and R18 are independently as defined above and
R12 is a heterocyclic group; with the proviso that R1 and R2 are not both hydrogen;
b) R11 is i) hydrogen, ii) loweralkyl, or iii) loweralkenyl; c) R20 is i) hydrogen, ii) loweralkyl, or iii) loweralkenyl; d) B is i) -(CH2)m-, ii) -(CR21=CR18)q- wh erein R21 and
R 18 are independently as def ined above , iii ) -QCH2- wherein Q is O , S , or
-N(R8)- wherein R8 is independently as defined above, iv) -CH2Q- wherein Q is as defined above, or v) NH; e) Z is i) C=O, ii) S(O)2 , or iii) C=S; f) Ar is a heterocyclic group, aryl or substituted aryl wherein substituted aryl is as defined above; the subscripts n. m, p, q, r and t are independently selected at each occurrence from the values n is 1 to 3; m is 0 to 4; p is 0 to 2; q is 0 or 1; r is 0 to 1; and t is 0 to 1; or a pharmaceutically acceptable salt thereof. European Patent Application No. 0230151, published July 29, 1987, discloses the following compounds as CCK antagonists:
wherein Ar is phenyl or phenyl substituted with one or two substituents independently selected from hydrogen, loweralkyl, alkoxy, hydroxy substituted alkyl, alkoxy substituted alkyl, halogen, amino, hydroxy, nitro, cyano, carboxy, ethoxycarbonyl and trihalomethyl; and R1 is -(CH2) phenyl wherein a is 1 to 4; and R2 is loweralkyl, cycloalkyl, -(CH2), aryl wherein b is 0 to 4, -(CH2)b(substituted aryl) wherein b is 0 to 4 and substituted aryl is as defined above, or -(CH2)c(CO)R3 wherein c is 1 to 4 and R3 is hydroxy, alkoxy, -O(CH2)caryl,
-O(CH2)c(substituted aryl) wherein c is 1 to 4, or NR 6R7 wherein R6 and R7 are independently selected from hydrogen and loweralkyl.
The "dashed" bond in the compound of Formula I indicates that the bond is a single bond or a double bond.
The term "loweralkyl" as used herein refers to straight or branched chain alkyl radicals containing from 1 to 6 carbon atoms including but not limited to methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 2 ,2-dimethylbutyl, and the like.
The term "cycloalkyl" as used herein refers to an alicyclic ring having 3 to 7 carbon atoms including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
The term "loweralkenyl" as used herein refers to a lower alkyl radical which contains at least one carbon-carbon double bond.
The term "loweralkynyl" as used herein refers to a lower alkyl radical which contains at least one carbon-carbon triple bond.
The term "alkylene group" as used herein refers to a (CH2)y radical where y is 1 to 5, such as methylene, ethylene, propylene, tetramethylene and the like.
The term "alkenylene group" as used herein refers to a C2-C5 chain of carbon atoms which contains at least one carbon-carbon double bond, such as vinylene,- propenylene, butenylene and the like.
The term "halogen" or "halo" as used herein refers to F, Cl, Br, I.
The terms "alkoxy" and "thioalkoxy" as used herein refer to R9O- and R9S- respectively, wherein R9 is a loweralkyl group.
The term "alkoxyalkyl" as used herein refers to an alkoxy group appended to a loweralkyl radical including, but not limited to, methoxymethyl, ethoxypropyl and the like.
The term "alkylamino" as used herein refers to -NHR13 wherein R13 is a loweralkyl group. The term "dialkylamino" as used herein refers to -NR14R15- wherein R14 and R15 are independently selected from loweralkyl.
The term "aminoalkyl" as used herein refers to an amino group (-NH2) appended to a loweralkyl radical including, but not limited to, aminomethyl, aminoethyl and the like.
The term "aminoalkenyl" as used herein refers to an amino group appended to a loweralkenyl radical, with the proviso that the amino group is not bonded directly to the double bond of the alkenyl group. Examples include, but are not limited to, 4-amino-but-2-enyl and the like.
The term "aminocarbonyl" as used herein refers to -C(O)NH2.
The term "alkylaminocarbonyl" as used herein refers to -C(O)NHR19 wherein R19 is a loweralkyl group.
The term "dialkylaminocarbonyl" as used herein refers to -C(O)NR19R20 wherein R19 and R20 are independently selected from loweralkyl.
The terms "alkenyloxy" and "thioalkenyloxy" as used herein refer to -OR17 and -SR17, respectively, wherein R17 is a loweralkenyl group, with the the proviso that the oxygen or sulfur atom is not bonded to the double bond of the loweralkenyl group. Examples include, but are not limited to CH =CHCH2O-, CH2=CHCH2S- and the like.
The term "alkoxycarbonyl" as used herein refers to -C(O)R16 wherein R16 is an alkoxy group.
The term "carboaryloxy" as used herein refers to -C(O)R17 wherein R17 is an aryloxy group. The term "haloalkyl" as used herein refers to a loweralkyl radical substituted by one or more halogens including, but not limited to, chloromethyl, 1,2-dichloroethyl, trifluoromethyl and the like.
The term "aryl" or "aryl group" as used herein refers to phenyl, naphthyl, indanyl, fluorenyl, (1,2,3,4)-tetrahydronaphthyl, indenyl or isoindenyl.
The term "substituted aryl" as used herein refers to an aryl group substituted with one, two or three substituents independently selected from the group including but not limited to loweralkyl, alkoxy, halogen, thioalkoxy, carboxy, carboalkoxy, cyano, haloalkyl, -N3, -NHP4 wherein P4 is an N-protecting group, -OP5 wherein P5 is an O-protecting group, nitro, hydroxy, amino, alkylamino and dialkylamino.
The term "arylalkyl" as used herein refers to an aryl group appended to a loweralkyl radical including, but not limited to, benzyl and the like.
The term "(substituted aryl)alkyl" as used herein refers to a substituted aryl group appended to a loweralkyl radical including, but not limited to, 4-methoxybenzyl and the like.
The term "heterocyclic" or "heterocyclic group" as used herein refers to any 5-, 6- or 7-membered ring containing from one to three heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur; wherein the 5-membered ring has 0-2 double bonds, 6-membered ring has 0-3 double bonds and the 7-membered ring has 0-3 double bonds; wherein the nitrogen and sulfur heteroatoms can be oxidized; wherein the nitrogen heteroatom can be quaternized; and including any bicyclic or tricyclic group in which the above-mentioned heterocyclic ring is fused to one or two benzene rings or one or two 5-membered or 6-membered heterocyclic rings as defined above. Exemplary heterocycles include, but are not limited to, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, oxatriazolyl, pyrrolidinyl, pyrrolmyl, imidazolidinyl, imidazolinyl, pyrazolidmyl, triazolyl, tetrahydrofuryl, pyranyl, pyronyl, pyridyl, pyrazinyl, pyridazinyl, piperidyl, piperazinyl, morpholinyl, thiazinyl, oxadiazinyl, azepinyl, thiapinyl, thionaphthyl, benzofuryl, isobenzofuryl, indolyl, oxyindolyl, isoindolyl, indazolyl, indolinyl, 7-azaindolyl, isoindazolyl, anthranyl, benzopyranyl, coumarinyl, isocoumarinyl, quinolyl, isoquinolyl, naphthyridinyl, cinnolinyl, quinazolinyl, pyridopyridyl, benzoxazinyl, diazepinyl, quinoxadinyl, chromenyl, chromanyl, isochromanyl, carbolinyl, xanthenyl, and acridinyl.
The heterocyclic groups can be unsubstituted or substituted with one, two or three substituents independently selected from hydroxy, oxo, amino, alkylamino, dialkylamino, alkoxy, thioalkoxy, carboxyl, alkoxycarbonyl, halo, haloalkyl, loweralkyl, cyano, aminoalkyl, aminoalkenyl, azide, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, nitro, thiocyanate, alkenyloxy, thioalkenyloxy, aryloxy, thioaryloxy, -OP1 and -NHP2 wherein P1 is an O-protecting group and P2 is an N-protecting group.
The term "aryloxy" or "thioaryloxy" as used herein refers to R10O- or R10S-, respectively, wherein R10 is an aryl or substituted aryl group. The term "N-protecting group" or "N-protected" as used herein refers to those groups intended to protect the N-terminus of an amino acid or peptide or to protect an amino group against undersirable reactions during synthetic procedures or to prevent the attack of exopeptidases on the compounds or to increase the solubility of the compounds and includes but is not limited to sulfonyl, acyl, acetyl, pivaloyl, t-butyloxycarbonyl (Boc), carbonylbenzyloxy (Cbz), benzoyl or an L- or D-aminoacyl residue, which may itself be N-protected similarly.
The term "O-protecting group" as used herein refers to a substituent which protects hydroxyl groups against undesirable reactions during synthetic procedures and includes but is not limited to substituted methyl ethers, for example methoxymethyl, benzylozymethyl, 2-methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, benzyl and triphenylmethyl; tetrahydropyranyl ethers; substituted ethyl ethers, for example, 2,2,2-trichloroethyl and t-butyl; and silyl ethers, for example, trimethylsilyl, t-butyldimethylsilyl and t-butyldiphenylsi lyl .
The term "Trp" as used herein refers to tryptophan.
Exemplary compounds of the invention include, but are not limited to:
N-(2'-Indolylcarbonyl)-R-Tryptophan-di-n-pentylamide, N-(3'-Quinolylcarbonyl)-R-Tryptophan-benzylamide, N-(2'-Indolylcarbonyl)-Tryptophan-(1',R-phenylethyl)amide, N-(3'-Quinolylcarbonyl)-R-Tryptophan-di-n-pentylamide, Methyl N-(2'-Indolylcarbonyl)-R-Tryptophyl-S-Phenylglycinate, Ethyl N-(2'-Indolylcarbonyl)-R-Tryptophyl-S- Phenylglycinate,
Ethyl N-(3'-Qumolylcarbonyl)-R-Tryptophyl-(N-benzyl)- Glycinate,
Methyl N-(3'-Qumolylcarbonyl)-Tryptophyl-S-Phenyl- glycinate.
Ethyl N-(3'-Quinolylcarbonyl)-Tryptophyl-S-Phenyl- glycinate,
N-(3'-Quinolylcarbonyl)-R-Tryptophan-(1',R-phenylethyl)- amide,
Methyl N-(3'-Qumolylcarbonyl)-R-Tryptophyl-S- (p-methoxyphenyl)glycinate,
N-(3'-Qumolylcarbonyl)-R-5-Benzyloxytryptophan-di-n-pentylamide,
N-(3'-Qumolylcarbonyl)-R-5-Fluorotryptophan-di-n-pentylamide,
N-(2'-Indolylcarbonyl)-R-5-Fluorotryptophan-di-n-pentylamide,
N-(3'-Quinolylcarbonyl)-R-(beta-Oxindolyl)Alanine-di-n-pentylamide,
N(alpha)-(3'-Qumolylcarbonyl)-R-5-Hydroxytryptophan-di-n-pentylamide,
N(alpha)-(3'-Quinolylcarbonyl)-R-Tryptophan-bis-(ethoxyethyl)amide,
N(alpha)-(3'-Qumolylcarbonyl)-R-Tryptophan-(N-3-Methoxy-n-propyl, N-n-pentyl)amide,
N-(4',8'-Dihydroxy-2'-qumolylcarbonyl)-R-Tryptophan-di-n-pentylamide,
N-(6'-Quinolylcarbonyl)-R-Tryptophan-di-n-pentylamide, N-(4'-Hydroxy-2'-quinolylcarbonyl)-R-Tryptophan-di-n-pentylamide,
N-(5'-Fluoro-2'-indolylcarbonyl ) -R-Tryptophan-di-n-pentylamide , N-(3'-Quinolylcarbonyl)-R-Tryptophan-di-n-pentylamide mesylate salt
N-4',8'-Dihydroxy-2'-quinolylcarbonyl)-R-Tryptophan-(1',R-phenylethyl)amide,
Methyl N-(4',8'-Dihydroxy-2'-quinolylcarbonyl)-R- Tryptophyl-S-(p-Methoxyphenyl)glycinate,
N-(4',8'-Dihydroxy-2'-quinolylcarbonyl)-R-Benzyloxy-tryptophan-di-n-pentylamide,
N-(4',8'-Dihydroxy-2'-qumolylcarbonyl)-R-5-Fluorotryptophan-di-n-pentylamide,
N-(4",8'-Dihydroxy-2'-quinolylcarbonyl)-R-(beta- Oxindolyl)Alanine-di-n-pentylamide,
N(alpha)-(4',8'-Dihydroxy-2'-quinolylcarbonyl)-R-5- Hydroxytryptophan-di-n-pentylamide,
N(alpha)-(4',8'-Dihydroxy-2'-qumolylcarbonyl)-R- Tryptophan-bis-(ethoxyethyl) amide,
Methyl N-(4',8'-Dihydroxy-2'-qumolylcarbonyl)-R- Tryptophyl-S-Phenylglycinate,
Ethyl N-(4',8'-Dihydroxy-2'-quinolylcarbonyl)-R- Tryptophyl-S-Phenylglycinate,
Ethyl N-(4',8'-Dihydroxy-2'-quinolylcarbonyl)-R- Tryptophyl-(N-benzyl)Glycinate, and N(alpha)-(4',8'-Dihydroxy-2'-quinolylcarbonyl)-R- Tryptophan-(N-3-methoxy-n-propyl, N-n-pentyl)amide
Preferred compounds of the invention include N-(2'-Indolylcarbonyl)-R-Tryptophan-di-n-pentylamide, N-(3'-Qumolylcarbonyl)-R-Tryptophan-di-n-pentylamide, N-(3'-Quinolylcarbonyl)-R-(beta-Oxindolyl)Alanine-di-n-pentylamide
N(alpha)-(3'-Quinolylcarbonyl)-R-5-Hydroxytryptophan-di-n-pentylamide, N-(4',8'-Dihydroxy-2'-quinolylcarbonyl)-R-Tryptophan-di-n- pentylamide, and
N(alpha)-(4',8'-Dihydroxy-2'-quinolylcarbonyl)-R-5-Hydroxytryptophan-di-n-pentylamide.
The compounds of the invention may be made as shown in Scheme I. Compounds with DL (R,S), L, or D configuration may be used in the synthetic schemes.
N-protected derivatives of tryptophan 1 are coupled with primary and secondary amines of the type HNR1R2 (preferably dialkyl, diaryl, or arylalkyl amines or amino acid esters) using bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOPCl) or other standard coupling techniques (i.e., isobutylchloroformate (IBCF), phosphorus pentachloride (PCl5), dicyclohexylcarbodiimide (DCC), or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) with hydroxybenzotriazole (HOBt)). The product amide 2 is deprotected with hydrochloric acid in dioxane to provide the hydrochloride salt 3 in the case where P = Boc (t-butoxycarbonyl) and with hydrogenolysis over palladium on carbon or other solid supports to provide amine 4 in the case where P = Cbz (carbobenzyloxy) . Both the salt 3 and the free base 4 are coupled to an appropriate arylcarboxylic acid or heteroarylcarboxylic acid (preferably quinoline-3-carboxylic acid or indole-2-carboxylic acid) using standard techniques to provide product 5 . Alternatively, 5 can be obtained from the coupl ing of 3 or 4 with the appropriate acid chloride or activated ester form of the aryl- or heteroarylcarboxylic acids. Further substitution of the nitrogem atom can be achieved via prior alkylation. In these cases the amine 4 or its hydrochloride 3 is either directly alkylated with R11X (where X is chloride, bromide, iodide), an activated form of the alcohol R11OH or reductively alkylated with an appropriate aldehyde in the presence of a reducing agent such as sodium cyanoborohydride or sodium borohydride, to provide the same product 6. Product 5 can then be coupled in a fashion analogous to 3 and 4 to provide the key compound 5 . Compound 5 can be treated directly with aryl- or alkylsulfenyl chlorides (R10SCl or R9SCl) in a variety of solvents to provide the thioaryl or thioalkyl substituted tryptophans 1 .
Alternatively, the tricyclic intermediate 17 can be produced from 5 via the action of t-butylhypochlorite and an amine base and the tricyclic 17 reacted with thiols R10SH or R9SH to provide the substituted analogs 7 .
The product 5 can also be treated with base (sodium hydride, sodium hydroxide under phase transfer conditions, or lithium hexamethyldisilazide in dimethylformamide (DMF)) followed by an alkylating or acylating agent represented by R30X, to provide the derivatized products 8. The amine hydrochloride 3 or it substituted analog 6 can likewise be coupled with aryl- or heteroarylsulfonylchlorides (ArSO2Cl) to provide the products 9. Alternatively, one familiar with the art could use the sulfonic acids and standard coupling methodology to provide 9. In addition, the amines 3 and 6 may also be coupled in standard fashion to the beta aryl- or beta heteroaryl substituted acrylic acids ( or their corresponding acid chlorides) to yield the unsaturated derivatives 10. Compound 11 is obtained through direct oxidation of the parent 5 with hydrochloric acid in dimethylsulfoxide (DMSO). Alternatively, controlled hydrolysis of intermediate 17 yields compound 11. Indoline derivatives of the type 12 are obtained by the catalytic hydrogenation of 5 followed by an acylation or an alkylation. Compounds of the type 1 are obtained by an alkylation sequence starting from compound 13. Compound 13 is first reacted with benzaldehyde under dehydrating conditions to provide 14 (Q=H) or with benzophenone imine to provide 14 (Q=phenyl). Compound 14 is alkylated directly with R11X utilizing phase transfer conditions (methylene chloride, or other suitable organic solvent, and 10-50% sodium or potassium hydroxide solutions or potassium carbonate) with a tetraalkylammonium salt present, preferably tetrabutylammonium hydrogensulfate (NBu4HSO4). The product 15 is deprotected with aqueous acid and subsequently the free amine or its salt is protected with CbzCl or di-t-butyldicarbonate (Boc2O) to yield the ester 16. Ester 16 is saponified in a standard fashion (NaOH) to provide 1 (R11 not H) for subsequent reaction including conversion to products of types 5, 7 , 8 , 9 and 10.
Intermediates for the preparation of compounds of the formula I include compounds of the formula: wherein R4 and R4 are independently selected from i) hydrogen, ii) C1-C6 loweralkyl, iii) cycloalkyl, iv) loweralkenyl, v) -(CH2)mcycloalkyl. vi) -(CH2)mCN, vii) alkoxyalkyl, viii) adamantyl, ix) -(CH2)m(C=O)rNR6R7 wherein
R6 and R7, are independently selected from hydrogen, loweralkyl, cycloalkyl, loweralkenyl,
-(CH2)maryl,
-(CH2)m(substituted aryl) wherein the aryl group is substituted with one, two or three substituents independently selected from loweralkyl, alkoxy, thioalkoxy, carboxy, carboalkoxy, cyano, haloalkyl, -N3, -NHP4 wherein P4 is an N-protecting group, -OP5 wherein P5 is an 0-protecting group, nitro, trihalomethyl, halogen, hydroxy, amino, alkylamino and dialkylamino; x) cyclic groups wherein R1 and R2 taken together with the adjacent nitrogen atom form a heterocyclic group represented by the formula
wherein E and J are independently selected from -(CH2)p-, -(CH=CH)r-, -YCH2-, -CH2Y-, -C(O)Y- and -YC(O)- wherein Y is S, O, CH2, or -N(R8)-, wherein R8 is selected from hydrogen, -(C=O)r(C1-C6loweralkyl), -(C=O)r- cycloalkyl, -(C=O)rloweralkenyl, -(C=O)r(CH2)maryl, -(C=O)r(CH2)m(substituted aryl) wherein substituted aryl is as defined above, -(CH2)mSR4 and -(CH2)mOR4 wherein R4 is hydrogen, -(C=O)rloweralkyl, -(C=O)rloweralkenyl, -(C=O)rcycloalkyl, -(C=O)r(CH2)maryl or -(C=O)r(CH2)m(substitut:ed aryl) wherein substituted aryl is as defined above, and wherein R5 is hydrogen orR5 is one, two or three of the substituents independently selected from the group -(C1-C6loweralkyl), loweralkenyl,
-(O)t(CH2)mcarboxyl,
-(O)t(CH2)mcarboalkoxy,
-(O)t(CH2)mcarboaryloxy, haloalkyl, nitro, cyano, -N3, -NHP4, -OP5, alkylaminocarbonyl, dialkylaminocarbonyl, alkoxy, aryloxy, thioalkoxy, thioaryloxy, halogen, CN, -OH, -NH2, -NR6R7 wherein R6 and R7 are independently as defined above, -(CH2)mOR4 wherein R4 is independently as defined above, and -(CH2)mSR4 wherein R4 is independently as defined above; xi) -(C(R21)(R18))maryl wherein
R21 and R18 are independently selected from the group hydrogen,
-(C1-C6loweralkyl), loweralkenyl,
-(O)t(CH2)mcarboxyl,
-(O)t(CH2)mcarboalkoxy,
-(O)t(CH2)mcarboaryloxy, haloalkyl, nitro, alkoxy, aryloxy, thioalkoxy, thioaryloxy, halogen, CN, -OH, -NH2, -NR6R7 wherein R6 and R7 are independently as defined above, -(CH 2)mOR4 wherein R4 is independently as defined above, and -(CH 2)mSR4 wherein R4 is independently as defined above, xii) -(C(R21)(R18))m(substituted aryl) wherein R21 and R18 are independently defined as above, and substituted aryl is as defined above, xiii) -(C(R21)(R18))mC(O)R3, wherein R21 and R18 are independently as defined above and wherein R3 is -OH,
-OR4 wherein R4 is independently as defined above, -NR 6R7 wherein R6 and R7 are independently as defined above, or -NHR4 wherein R4 is independently as defined above, with the proviso that when R3 is NR6R7 then R21 and R18 are not both hydrogen and xiv) -(C(R21)(R18))mR12 wherein R21 and R18 are independently as defined above and
R12 is a heterocyclic group; with the proviso that R1 and R2 are not both hydrogen; R11 is i) hydrogen, ii) loweralkyl, or iii) loweralkenyl;
R20 is i) hydrogen, ii) loweralkyl, or iii) loweralkenyl; the subscripts are independently selected at each occurrence from the values n is 1 to 3; m is 0 to 4; p is 0 to 2; q is 0 or 1; r is 0 to 1; and t is 0 to 1; and P3 and P6 are independently selected from hydrogen and an N-protecting group.
Other intermediates for the preparation of compounds of the formula I incude compounds of the formula:
Ar-B-Z-Z'
wherein B is i) -(CH2)m-, ii) -(CR21=CR18)q- wherein R21 and R18 are independently as defined above, iii) -QCH2- wherein Q is O, S, or
-N(R8)- wherein R8 is independently as defined above, or iv) -CH2Q- wherein Q is as defined above,
Z is i) C=O, ii) S(O)2 , or iii) C=S; Z' is an activating group; or B-Z-Z' taken together represent -N=C=O, -N=C=S, -CH2-N=C=O or -CH2-N=C=S; Ar is a heterocyclic group, aryl or substituted aryl wherein substituted aryl is as defined above; m is 0 to 4; and q is 0 or 1. Activating groups are those functional groups which activate a carboxylic acid or sulfonic acid group toward coupling with an amine to form an amide or sulfonamide bond. Activating groups Z' include, but are not limited to -OH, -SH, alkoxy, thioalkoxy, halogen, formic and acetic acid derived anhydrides, anhydrides derived from alkoxycarbonyl halides such as isobutyloxycarbonylchloride and the like, N-hydroxysuccinimide derived esters, N-hydroxyphthalimide derived esters, N-hydroxybenzotriazole derived esters,
N-hydroxy-5-norbornene-2,3-dicarboxamide derived esters, 4-nitrophenol derived esters, 2,4,5-trichlorophenol derived esters and the like.
The following examples will serve to further illustrate preparation of the novel compounds of the invention. Example 1 N-(t-Butyloxycarbonyl)-R-Tryptophan-di-n-pentylamide
N-t-Butyloxycarbonyl-R-Tryptophan (10 g, 33 mmol) was stirred at 0°C in 160 mL of methylene chloride (CH2Cl2) with bis(2-oxo-3-oxazolidnyl )phosphinic chloride (BOPCl, 8.6 g, 34 mmol), 4.5mL (32 mmol) of triethylamine (TEA). To this reaction mixture was added di-n-pentylamine (18 mL, 89 mmol). The mixture was stirred overnight and allowed to warm to room temperature. An additional equivalent of BOPCl was added after 18 hrs and the reaction stirred an additional day at ambient temperature. The solvents were evaporated in vacuo and the residue taken up in ethylacetate (EtOAc) and washed with water, 1 N hydrochloric acid (HCl) solution, saturated sodium bicarbonate solution (NaHCO3), water and then the organic solution was dried over magnesium sulfate (MgSO4). After filtration and concentration of the filtrate in vacuo, the residue was purified by chromatography using ethylacetate-hexane as the solvent system in the ratio (1:4). The product was isolated as an oil in 57% yield (8.2 g). MS(CI) m/e 444(m+H)+, 326. 1H NMR( CDCl3,300MHz) δ 0.78(t,J=7Hz,3H), 0.88(t,J=6Hz,3H), 0.9-1.2 (m,8H), 1.25(m,4H), 1.45(s,9H), 2.7-3.08(m,3H), 3.1(d,J=9Hz ,2H), 3.33(m,1H), 4.9(q,J-12Hz,1H), 5.4(d,J=9Hz,1H), 7.05(s,1H), 7.15(m,2H), 7.34(d,J=9Hz,1H), 7.7(d,J=9Hz,1H), 8.1(s,1H).
Example 2 R-Tryptophan-di-n-pentylamide hydrochloride
The product of example 1 (2.0 g, 4.4 mmol) was dissolved in 4 N HCl in dioxane (12 mL) and stirred under inert atmosphere (N2) for an hour. When the reaction was complete by tic the solvents were evaporated in vacuo and hexane and diethylether added. The residue was triturated with these two solvents and the solvents again removed in vacuo. This procedure was repeated several times until the product was obtained as a glassy solid in quantitative yield. Example 3 N-(2'-Indolylcarbonyl)-R-Tryptophan-di-n-pentylamide
The hydrochloride of example 2 (135 mg, 0.36 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDCI, 100 mg), HOBt (48 mg) and indole-2-carboxylic acid (110mg) were stirred at 0°C under nitrogen in 5 mL of anhydrous dimethylfomamide (DMF). To this mixture was added 250 μL of TEA and the mixture was stirred overnight with warming to ambient temperature. The reaction mixture was poured into ethylacetate and water and the organic extract was washed successively with water, 10% citric acid solution, and saturated aqueous sodium bicarbonate. The solution was dried over magnesium sulfate, filtered and concentrated. The residue was purified by chromatography using ethylacetate and hexane as the elutant mixture to provide 130 mg of product (75% yield) after removal of the volatiles. mp 75-8°C. [α]D= -16.2° (c=0.105, MeOH). MS(CI) m/e 487(m+H)+, 358, 329, 217. 1H NMR( CDCl3,300MHz) δ 9.2(bs,1H), 8.0(bs,1H), 7.77(d,J=7.5Hz,1H), 7.66(d,J=7.5Hz,1H), 7.13-7.44(m,7H), 7.05(d,J=2Hz,1H), 6.93(m,1H), 5.43(apparent q,J=7.5Hz,1H), 3.35-3.45(m,1H), 3.32(d,J=7Hz,2H), 2.95-3.08(m,2H), 2.75-2.85(m,1H), 0.95-1.45(m,12H), 0.88(t,J=7Hz,3H), 0.78(t,J=7Hz,3H). C,H,N analysis calculated for C30H38N4O2, 0.5 H2O: C 72.68, H 7.94, N 11.31; found: C 72.62, H 7.82, N 11.2
Example 4 N-(p-Chlorobenzoyl)-R-Tryptophan-di-n-pentylamide
To a mixture of the hydrochloride of example 2 (41 mg) and triethylamine (30 μL ) stirred in 3 mL of methylene chloride at 0°C was added 20 μL of p-chlorobenzoylchloride. When tlc analysis indicated the consumption of starting material, the mixture was taken up in ethylacetate and washed three times with portions of water. The organic extract was dried over MgSO4, then filtered. Concentration of the filtrate and chromatography of the residue using ethylacetate and hexane as the elutant mixture provided 30 mg of product. mp 63-5 C. MS(CI) m/e 482(m+H)+, 448, 262, 173, 158. 1H NMR( CDCl3,300MHz) δ 8.02(bs,1H), 7.77(bd,J=7.5Hz,1H), 7.72(d,J=7Hz,1H), 7.38(d,J=7Hz,1H), 7.34(bd,J=7.5Hz,1H), 7.17(dt,J=1,7Hz,1H), 7.10-7.15(m,4H), 7.05(d,J=2Hz,1H), 5.41(m,1H), 3.35-3.45(m,1H), 3.28(m,2H), 2.93-3.05 (m,2H), 2.80(m,1H), 0.95-1.45 (m,12H), 0.88(t,J=7Hz,3H), 0.79(t,J=7Hz,3H). C,H,N analysis calculated for C28H36ClN3O2: C 69.74, H 7.53, N 8.71; found: C 69.28, H 7.57, N 8.60.
Example 5 N-(t-Butyloxycarbonyl)-R-Tryptophan-benzylamide
To a solution of N-t-Butyloxycarbonyl-R-Tryptophan (365 mg), HOBt (155 mg), and EDCI (269 mg) stirred at 0°C in CH2Cl2 (10 mL) was added benzylamine (140 μL ) and TEA (140 μL ) . The reaction mixture was allowed to warm to ambient temperature overnight. The mixture was treated in a fashion similar to that in example 1 and provided 290 mg (61% yield) of product after chromatography. mp= 142.5-143.5°C. [α]D= +6.0° (c=0.25, 1:1 DMF-MeOH). MS(CI) m/e 394(m+H)+, 338, 294, 276. 1H NMR(CDCl3,300MHz) δ 8.03(bs,1H), 7.68 (d,J=7.5Hz,1H), 7.37(dd,J=0.5,8.5Hz,1H), 7.1-7.25(m,5H), 6.97(bm,3H), 5.96(bs,1H), 5.16(bs,1H), 4.47(m,1H), 4.25-4.35(m,2H), 3.35(dd,J=5.5,14.5Hz,1H), 3.16 (dd,J=7.5,14.5Hz,1H), 1.41(bs,9H). C,H,N analysis calculated for C23H27N3O3: C 70-19, H 6.92, N 10.68; found: C 69.97, H 7.04, N 10.60.
Example 6 R-Tryptophan-benzylamide hydrochloride
The product of example 5 (290 mg) was stirred under inert atmosphere at 0°C in 4 mL of a 4.5 M solution of hydrogen chloride in dioxane. After completion of reaction by tlc analysis the volatiles were removed in vacuo and the product was triturated with anhydrous diethylether and hexane. Product was collected by filtration providing 232 mg (95% yield). mp= 189-91°C. MS(CI) m/e 294(m+H)+. 1H NMR(DMSOd6 ,300MHz) δ 11.07(s,1H), 9.01(bt,J=6Hz,1H), 8.26(bs,2H), 7.67(d,J=7.5Hz,1H), 7.38(d,J=7.5Hz,1H), 7.2-7.3(m,4H), 7.08-7.15(m,3H), 7.01(t,J=7Hz,1H), 4.28(m,2H), 4.03(bt,J=7.5Hz,1H), 3.26(dd,J=7,14Hz,1H), 3.15(dd,J=7,14Hz,1H).
Example 1 N-(3'-Quinolylcarbonyl)-R-Tryptophan-benzylamide
The hydrochloride salt of example 6 (70 mg), quinoline-3-carboxylic acid (63 mg), EDCI (110 mg), and hydroxybenzotriazole (HOBt, 110 mg) were stirred in 3 mL of anhydrous DMF at 0°C under nitrogen. To this mixture was added TEA (110 μL ) and the mixture was stirred overnight with warming to ambient temperature. The reaction mixture was taken up in ethylacetate and washed several times with water. The organic extract was dried over MgSO4, filtered, and concentrated in vacuo. Chromatography of the residue using ethylacetate and hexane as the elutant mixture provided 67 mg (70% yield) of product. mp= 211-12°C. [α]D= +45.5° (c=0.09, 1:1 DMF-MeOH). MS(CI) m/e 449(m+H)+, 342, 314. 1H NMR(DMSOd6,300MHz) δ 10.82(bs,1H), 9.23(d,J=2Hz,1H), 9.0(bd,J=8.5Hz,1H), 8.81(d,J=2Hz,1H), 8.73(bt,J=7Hz,1H), 8.09(s,1H), 8.06(s,1H), 7.87(dt,J=1,7Hz,1H), 7.72(m,2H), 7.2-7.35(m,7H), 7.06(bt,J=7Hz,1H), 6.99(bt,J=7Hz,1H), 4.85(m,1H), 4.34(d,J=7Hz,2H). C,H,N analysis calculated for C28H24N4O2: C 74.97, H 5.40, N 12.50; found: C 74.94, H 5.50, N 12.50.
Example 8 N-(2'-Indolylcarbonyl)-R-Tryptophan-benzylamide
The reaction sequence was performed similarly to that in example 7 utilizing 90 mg of the hydrochloride salt of example 6, indole-2-carboxylic acid (80 mg), EDCI(120 mg), HOBt (55 mg), and TEA (125 μL ). Product was isolated in an identical manner mp= 207-8°C. [α]D= +55.7° (c-0.07, 1:1 DMF-MeOH). MS(CI) m/e 437(m+H)+, 330, 302, 276. 1H NMR(DMSOd6 ,300MHz) δ 11.52(bs,1H), 10.8(bs,1H), 8.71(t,J=7Hz,1H), 8.58(d,J=9Hz,1H), 7.72(d,J=7.5Hz,1H), 7.62(d,J=7.5Hz,1H), 7.40(d,J=7.5Hz,1H), 7.15-7.32(m,9H), 6.95-7.08(m,3H), 4.80(m,1H), 4.32(d,J=6Hz,2H), 3.15-3.25(m,2H). C,H,N analysis calculated for C27H24N4O2: C 74.28, H 5.55, N 12.84; found: C 73.95, H 5.72, N 12.47.
Example 9 N-(2'-Pyrrolylcarbonyl)-R-Tryptophan-di-n-pentylamide
The hydrochloride salt of example 2 (0.38 g, 1.0 mmol) was stirred in 5 mL of methylene chloride with N-methylmorpholine (NMM, 0.22 mL, 2 mmol) under nitrogen at 0°C. EDCI (0.2 g, 1.0 mmol) and HOBt (0.27 g, 2 mmol) were added followed by the addition of pyrrole-2-carboxylic acid (0.112 g, 1.0 mmol). The reaction mixture was allowed to stir overnight with warming to ambient temperature. The solvents were evaporated in vacuo and the residue taken up in ethylacetate and washed successively with water, saturated NaHCO,, a saturated solution of citric acid, water, and brine. The organic solution was dried over MgSO4 and then filtered. Solvents were evaporated in vacuo and the crude product subjected to flash chromatography using ethylacetate and hexane as the elutant mixture. The product was crystallized from ethylacetate and hexane to provide 0.36 g (81%). mp= 108-110°C. [α]D= -2.4° (c-1.0, MeOH). MS(CI) m/e 437(m+H)+. 1H NMR(CDCl3, 300MHz) δ 0.75(t,J=7Hz,3H), 0.88(t,J=7Hz,3H), 0.9-1.22(m,6H), 1.25-1.45(m,6H), 2.7-2.85(m,1H), 2.9-3.05(m,2H), 3.28(d,J=6Hz,2H), 3.3-3.4(m,1H), 5.4(apparent q,J=9Hz,1H), 6.22(m,1H), 6.65(m,1H), 6.(m,2H), 7.03(d,J=3Hz,1H), 7.1-7.2(m,2H), 7.35(d,J=9Hz,1H), 7.8(d,J=9Hz,1H), 8.03(s,1H), 9.6(bs,1H). C,H,N analysis calculated for C26H36N4O2, 0.25 H2O: C 70-79, H 8-34, N 12.70; found: C 70.51, H 8.26, N 12.71. Example 10 N-(1'-Isoquinolylcarbonyl)-R-Tryptophan-di-n-pentylamide
The hydrochloride salt of example 2 (0.38 g, 1.0 mmol) was stirred in 10 mL of methylene chloride with N-methylmorpholine (NMM, 0.2 mL, 2.0 mmol) under N2 at 0°C. EDCI (0.2 g, 1.1 mmol and HOBt (0.27 g, 2.0 mmol) was added to the mixture, followed by the addition of isoquinoline-1-carboxylic acid (0.17 g, 1.0 mmol). The reaction mixture was treated as in example 9 and a crystalline product resulted in 55% yield (0.28 g). mp= 87.5-89°C. [α]D= +16.7° (c=0.5, MeOH). MS(CI) m/e 499(m+H)+, 342. 1H NMR(CDCl3,300MHz) δ 0.78(t,J=7Hz,3H), 0.85(t,J=7Hz,3H), 0.95-1.2(m,8H), 1.25-1.45(m,4H), 2.85-3.1(m,3H), 3.3-3.45(m,3H), 5.5(apparent q,J=7Hz,1H), 7.1-7.2(m,3H), 7.35(d,J=9Hz,1H), 7.65(m,2H), 7.78(d,J=6Hz,1H), 7.85(d,J=9Hz,2H), 8.05(s,1H), 8.5(d,J=6Hz,1H), 8.85(d,J=9Hz,1H), 9.55(d,J=9Hz,1H). C,H,N analysis calculated for C31H38N4O2: C 74.66, H 7-68, N 11.24; found: C 75.05, H 7.74, N 11.19.
Example 11 N-(3' -(2'-Chloropyridylcarbonyl))-R-Tryptophan-di-n-pentylamid
The hydrochloride of example 2 (0.38 g, 1.0 mmol) was stirred tetrahydrofuran (THF, 10 mL) with NMM ( 0 .2 mL , 2 . 0 mmol ) unde r nitrogen atmosphe re at 0°C . EDCI (0.2 g, 1.0 mmol), HOBt (0.27 g, 2.0 mmol), and 2-chloronicotinic acid (0.16 g, 1.0 mmol) were added. The reaction mixture was allowed to stir at ambient temperature overnight. The solvents were removed in vacuo and ethylacetate and water added to the residue. The organic extract was separated and washed with citric acid, NaHCO3 solution, water, brine and then dried over MgSO4. The solution was filtered and concentrated in vacuo and the residue subjected to chromatography using ethylacetate and hexane as the elutant mixture to provide 0.31 g (64%) of oily product which crystallized under vacuum. mp= 81-2°C. [α]D= -54.5° (c-1.1, MeOH). MS(CI) m/e 483(m+H)+, 326. 1H NMR(CDCl3,300MHz) δ 0.8(t,J=7Hz,3H), 0.9(t,J=7Hz,3H), 0.95-1.2(m,8H), 1.25-1.45(m,4H), 2.7-2.85(m,1H), 2.9-3.1(m,2H), 3.25-3.4(m,3H), 5.4(q,J=6Hz,1H), 7.1(d,J=3Hz,1H), 7.15(m,2H), 7.25-7.4(m,3H), 7.78(d,J=9Hz,1H), 7.95(dd,J=3,7Hz,1H), 8.05(bs,1H), 8.45(dd,J=3,6Hz,1H). C,H,N analysis calculated for
C27H35ClN4O2, 0.5 H2O: C 65-90, H 7-38, N 11.39; found: C 66.11, H 7.09, N 11.26.
Example 12 N-(4'-Cinnolinylcarbonyl)-R-Tryptophan-di-n-pentylamide
The hydrochloride salt of example 2 (0.38 g, 1.0 mmol) was stirred in THF (8 mL) with NMM (0.2 mL, 2 mmol) under N2 atmosphere at 0°C. To the mixture was added EDCI (0.2 g, 1.1 mmol), HOBt (0.27 g, 2 mmol), and cinnolinic acid (0.18 g, 1.0 mmol). The reaction mixture was allowed to stir overnight reaching ambient temperature. The solvents were evaporated in vacuo. The residue was processed in a similar fashion as in example 11 to provide 0.41 g (83%) of pure product. mp= 63.5-65°C. [α]D= -2.2° (c=1.1, MeOH). MS(CI) m/e 500(m+H)+, 326. 1H NMR(CDCl3,300MHz) δ 0.86(m,6H), 1.0-1.35(m,8H), 1.4-1.58(m,4H), 2.95(m,1H), 3.0-3.2(m,2H), 3.35-3.5(m,3H), 5.5(m,1H), 7.15(m,2H), 7.2(t,J=7Hz,2H), 7.4(d,J=9Hz,1H), 7.75(t,J=7Hz,1H), 7.78(d,J=9Hz,1H), 7.85(t,J=7Hz,1H), 8.15(d,J=9Hz,2H), 8.6(d,J=9Hz,1H), 9.2(s,1H). C,H,N analysis calculated for C30H37N5O2, 0.66 H2O: C 70-41, H 7.29, N 13.69; found: C 70.44, H 7.39, N 13.37.
Example 13 Methyl N-(3'-Quinolylcarbonyl)-R-Tryptophanate
EDCI (1.91 g, 10 mmol) was added to a cooled (4°C) solution containing quinoline-3-carboxylic acid (1.73 g, 10 mmol), tryptophan methyl ester hydrochloride (2.55 g, 10 mmol), and (2.8 mL, 20 mmol) in 50 mL of methylene chloride. After 4 hrs, the solvent was evaporated and the residue dissolved in ethylacetate and extracted three times with 1 M H3PO4 (phosphoric acid), three times with 1 M Na2CO3 (sodium carbonate), three times with brine and then dried over MgSO4. The solution was filtered and concentrated. The solid residue was recrystallized from EtOAc to yield 2.62 g (73%). Rf= 0.13 (1:1 hexanes-EtOAc); 0.80 (80:20:1 CHCl3-MeOH-NH4OH). mp= 205-6°C. [α] = +87.5° (c-0.16, 1:1 DMF-MeOH). MS ( FAB ) m/e 374(m+H)+, 277, 201. H NMR( CDCl3 ,300MHz ) δ 9.17(bs,1H), 8.42(d,J=1.4Hz,1H), 8.13(d,J=9Hz,1H), 7.81(m,2H), 7.62(m,2H), 7.40(d,J=8.5Hz,1H), 7.22(bt,J=7.5Hz,1H), 7.11(t,J=7Hz,1H), 7.06(s,1H), 7.0(bs,1H), 5.21(m,1H), 3.79(s,3H), 3.52(m,2H). C,H,N analysis calculated for C22H19N3O3: C 70-75, H 5-13, N 11.26; found: C 70.59, H 5.25, N 11.19.
Example 14 N-(3'-Quinolylcarbonyl)-R-Tryptophan
The product of example 13 ( 2 . 5 g , 6 .7 mmol ) and 1 N NaOH solution (6.7 mL) were dissolved in 100 mL of MeOH and 50 mL o dioxane. An additional 0.67 mL of 1 N NaOH solution was added 2 and again at 4 hrs and the reaction stirred overnight at ambient temperature. The solvents were evaporated and the residue partitioned between EtOAc and water. The aqueous fraction was separated and acidified and then extracted with EtOAc. These organic washings were combined and washed until neutral (pH~7) then dried over MgSO4. The solution was filtere and concentrated. The resulting solid was dissolved in hot EtOAc-ethanol and this solution was cooled, an equal volume of hexanes was added and the resulting precipitate collected to provide 0.79 g (33%) of product. The filtrate was concentrated to provide 0.77 g (32%) of product. The original EtOAc solutio containing residual ester was resubjected to NaOH in the same fashion to provide an additional 0.84 g (35%) of product. mp= 42-3°C. [α]D= +100° (c=0.08, 1:1 DMF-MeOH). MS(CI) m/e 360(m+H)+, 342, 314, 296, 213. 1H NMR( DMSOd6 ,300MHz ) δ 3.21-3.4(m,2H), 4.72-4.78(m,1H), 6.98-7.09(m,2H), 7.26(d,J=2Hz,1H), 7.32(d,J=8Hz,1H), 7.64(d,J=7Hz,1H), 7.70(dt,J=1,8Hz,1H), 7.87(dt,J=1,7Hz,1H), 8.08(bs,1H), 8.11(bs,1H), 8.80(d,J=3Hz,1H), 9.08(d,J=8Hz,1H), 9.22(d,J=2Hz,1H), 10.85(bs,1H), 12.85(bs,1H).
Example 15 N-(3'-Quinolylcarbonyl)-R-Tryptophanamide
Ester from example 13 (68 mg) was treated with a saturated solution of ammonia in methanol (5 mL) at -78°C. The reaction vessel was sealed and allowed to warm to ambient temperature overnight. Product (37 mg) was isolated via chromatography of the residue after removal of the volatiles in vacuo. mp= 228-30°C. [α]D= +90° (c-0.16, 1:1 DMF-MeOH). MS(CI) m/e 359(m+H)+, 314, 230, 212, 173. 1H NMR(DMSOd6,300MHz) δ 10.8(S,1H), 9.21(d,J-2Hz,1H), 8.86(d,J=8Hz,1H), 8.78(d,J=2Hz,1H), 8.06(bd,J=8Hz,2H), 7.86(m,1H), 7.71(m,3H), 7.30(d,J=7.5Hz,1H), 7.24(s,1H), 7.17(s,1H), 7.05(dt,J=1,7Hz,1H), 6.98(bt,J=7Hz,1H), 4.76(m,1H), 3.35(bs,H2O), 3.1-3.3(m,2H).
C,H,N analysis calculated for C21H18N4O2, 0.5 H2O: C 68-64, H 5.22, N 15.26; found: C 68.23, H 5.16, N 14.65.
Example 16 Methyl N-(2'-Indolylcarbonyl)-R-Tryptophanate
EDCI (10 mmol) was added to a cooled solution (4°C) containing indole-2-carboxylic acid (1.61 g, lOmmol), R-tryptophan methyl ester hydrochloride (2.55 g, 10 mmol), HOBt (10 mmol) and TEA (2.8 mL) in CH2Cl2 (50 mL). Reaction conditions and purificati of product proceeded as in example 13 to provide 1.59 g (44%). mp= 220-221°C. [α]D= +96.4° (c=1.08, 1:1 DMF-MeOH). MS(CI) m 362(m+H)+. 1H NMR(DMSOd6,300MHz) δ 3.15(s,3H), 3.19-3.25(m,2H), 4.20-4.27(m,1H), 6.97-7.08(m,3H), 7.15(dt,J=1,7Hz,1H), 7.22(d,J=2Hz,2H), 7.33(d,J=7Hz,1H), 7.40(dd,J=1,8Hz,1H), 7.58(d,J=7Hz,1H), 7.62(d,J=8Hz,1H), 8.81(d,J=8Hz,1H), 10.84(bd,J=1Hz,1H), 11.55(s,1H). C,H,N analysis calculated for C21H1gN3O3: C 69.79, H 5.30, N 11.63; found: C 69.76, H 5.39, N 11.51.
Example 17 N-(2'-Indolylcarbonyl)-R-Tryptophan
The product of example 16 (1.5 g) and 4.2 mL of 1.0 N NaOH solution were dissolved in 100 mL of methanol. Reaction and processing continued as in example 14. A precipitate was collected (0.50 g) 34% and the filtrate provided an additional 0.44 g (30% yield) of product. Rf= 0.24 (70:30:1 CHCl3-MeOH-NH4OH). MS ( FAB ) m/e 348(m+H)+. 1H NMR(DMSOd6,300MHz) δ 3.18-3.4(m,2H), 4.66-4.72(m,1H), 6.96-7.08(m,3H), 7.14-7.22(m,3H), 7.32(d,J=8Hz,1H), 7.40(dd,J=1,8Hz,1H), 7.62(d,J=8Hz,2H), 8.66(d,J=8Hz,1H), 10.83(d,J=2Hz,1H), 11.54(d,J=1Hz,1H), 12.8(bs,1H).
Example 18 N-(2'-Indolylcarbonyl)-Tryptophan-(1',R-phenylethyl)amide
EDCI (191 mg, 1.0 mmol) was added to a cooled solution (4°C) containing the product of example 17 (374 mg, 1.0 mmol), R-α-methylbenzyl amine (0.129 mL, 1.0 mmol), HOBt (135 mg) , a TEA (0.139 mL) in 15 mL of CH2Cl2. The reaction was stirred overnight and reached ambient temperature. After 2 days the solvent had evaporated. The residue was dissolved in EtOAc an extracted with 0.1 M H3PO4, 0.1 M Na2CO3, H2O then dried over MgSO4 and filtered. The- crude product obtained from concentration of the filtrate was recrystallized from 80% aqueous ethanol. HPLC (high pressure liquid chromatography) indicated two components in an apparently equal ratio. Rf= 0.31; 0.36 (1:1 hexanes-EtOAc). mp= 215-19°C. [α]D= +5.6° (c=0.78, 1:1 DMF-MeOH). MS ( CI ) m/e 451(m+H)+, 330. 1H NMR(DMSOd6,300MHz) δ 1.29(d,J=7Hz,1.5H), 1.39(d,J=7Hz,1.5H), 3.04-3.26(m,2H), 4.77-4.89(m,1H), 4.91-5.03(m,1H), 6.95-7.08(m,3H), 7.12-7.42(m,10H), 7.61(dd,J=3,8Hz,1H), 7.71-7.76(m,1H), 8.51(dd,J=3,8Hz,1H), 8.57(d,J=8Hz,0.5H), 8.66(d,J=8Hz,0.5H), 10.79(dd,J=2,5Hz,1H), 11.54(bs,1H). C,H, analysis calculated for C28H26N4O2: C 74-64, H 5.82, N 12.44; found: C 74.75, H 5.92, N 12.42.
Example 19 N-(2'-Indolylcarbonyl)-Tryptophan-(1' ,S-phenylethyl)amide
BOPCl (255 mg, 1.0 mmol) was added to a cooled (4°C) solution N-(2'-Indolylcarbonyl)-R-Tryptophan (347 mg, 1.0 mmol), S-α-methylbenzylamine (129μL, 1.0 mmol), HOBt (203 mg, 1.5 mmol), and TEA (139 μL , 1.0 mmol) in THF (20 mL). The reactio was allowed to attain room temperature overnight. The solvent was evaporated and the residue was dissolved in EtOAc and extracted with 1 M H3PO4 (3x), 1 M Na2CO3 (3x), brine (3x) the dried over MgSO4, filtered and the solvent evaporated in vacuo. The crude product was recrystallized from aqueous EtOH to provide 205 mg, 0.46 mmol (46%). Tic indicated two components, (1:1 hexanes-EtOAc). The product was purified further by chromatography to yield 12 mg of isomer a (mp= 216-18ºC), 32 mg of isomer b (mp= 245-7°C) and 107 mg of mixed fractions (mp= 212-14°C). Isomer a: MS(CI) m/e 451(m+H)+, 373, 330. 1H NMR(DMSOd6,300MHz) δ 1.38 (d,J=5Hz,3H), 3.10(dd,J=6,8Hz,1H), 3.18(dd,J=3,8Hz,1H), 4.84-4.87(m,1H), 4.98(m,1H), 6.97-7.06(m,3H), 7.15-7.22(m,4H), 7.24-7.31(m,5H), 7.40(dd,J=<1,5Hz,1H), 7.62(d,J=5Hz,1H), 7.73(d,J=5Hz,1H), 8.48(dd,J=1,5Hz,1H), 8.63(d,J=5Hz,1H), 10.77(d,J=1Hz,1H), 11.53(bs,1H). Isomer b: MS(CI) m/e 451(m+H)+. 1H NMR(DMSOd6,300MHz) δ 1.28(d,J=4Hz,3H), 3.13-3.27(m,2H), 3.34(s,H2O), 4.77-4.83(m,1H), 4.92-4.97(m,1H), 6.98-7.07(m,3H), 7.16(t,J=4Hz,1H), 7.19-7.22(m,2H), 7.26(s,1H), 7.30(t,J=4Hz,3H), 7.35(d,J=4Hz,2H), 7.38(dd,J=1,5Hz,1H), 7.60(d,J=5Hz,1H), 7.73(d,J=5Hz,1H), 8.49(bd,J=5Hz,0.5H), 8.55(d,J=5Hz,0.5H), 10.78(bs,0.5H), 11.52(s,0.5H). Mixture: 1H NMR(DMSOd6,300MHz) 1.28(d,J=7Hz,1.65H), 1.39(d,J=7Hz,1.35H), 3.06-3.28(m,2H), 3.28(s,H2O), 4.87(m,1H), 4.89-5.03(m,1H), 6.95-7.07(m,3H), 7.13-7.37(m,9H), 7.40(dd,J=1,4Hz,4H), 7.61(dd,J=2,7Hz,1H), 7.72(dd,J=3,8Hz,1H), 8.40-8.47(m,1.5H), 8.55(d,J=8Hz,0.5H), 10.74(dd,J=1,5Hz,1H), 11.48(s,1H). C,H,N analysis calculated for C28H26N4O2, 0.5 H2O (mixture of isomers): C 73.18, H 5.92, N 12.19; found: C 73.23, H 5.88, N 12.15.
Example 20 N-(3'-Quinolylcarbonyl)-Tryptophyl-3'-methyl-5'-phenylpyrazylide
EDCI (190 mg, 1.0 mmol) was added to a cooled (4°C) solution of N-(3'-Quinolylcarbonyl)-R-Tryptophan (360 mg, 1.0 mmol), 3-methyl-5-phenylpyrazole (200 mg), HOBt (130 mg, 1.0 mmol), and TEA (140 μL , 1.0 mmol) in CH2Cl2 (20 mL). The reaction was allowed to attain room temperature overnight. The solvents were evaporated and the residue was dissolved in EtOAc and extracted with 1 M H3PO4 (3x), H2O (3x) then dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica eluted with a gradient from CHCl3 to 18:1 CHCl3-EtOH. The pure fractions were combined, concentrated and the product crystallized from aqueous EtOH to provide 94 0.17 mmol (17%). [α]D= +0.7° (c-0.54, DMF). MS ( FAB ) m/e 500(m+H)+, 342, 314. 1H NMR( DMSOd6,300MHz) δ 2.62(s,3H), 3.29-3.38(m,1H), 3.38(s,H2O), 3.54(dd,J=4,14Hz,1H), 6.12-6.19(m,1H), 7.02-7.06(m,2H), 7.12(dt,J=1,8Hz,1H), 7.36(d,J=8Hz,1H), 7.42(d,J=2Hz,1H), 7.48-7.51(m,3H), 7.72 (dt,J=1,7Hz,1H), 7.90(dt,J=1,7Hz,1H), 7.95(d,J=7Hz,2H), 8.02(dd,J=1,8Hz,2H), 8.12(dt,J=1,7Hz,2H), 8.87(d,J=2Hz,1H), 9.26(d,J=2Hz,1H), 9.36(d,J=8Hz,1H), 10.89 (d,J=2Hz,1H). C,H,N analysis calculated for C31H25N5O2, 0.33 H2O: C 73.63, H 5.12, N 13.85; found: C 73.71, H 5.24, N 13.77.
Example 21 N-(3'-Quinolylcarbonyl)-R-Tryptophan-di-n-pentylamide
EDCI (440 mg, 2.3 mmol) was added to a cooled (4°C) solution of Quinoline-3-carboxylic acid (398 mg, 2.3 mmol), R-Tryptophan-dipentylamide hydrochloride (840 mg, 2.2 mmol), HOBt (68 mg, 0.50 mmol), and TEA (641 μL, 4.6 mmol) in CH2Cl2 (50 mL). The reaction was allowed to attain room temperature overnight. The solvent was evaporated and the residue was dissolved in EtOAc and extracted with 0.1 M H3PO4 (3x), 0.1 M Na2CO3 (3x), H2O (3x), brine (lx) then dried over MgSO4, filtered and the filtrate concentrated in vacuo. The residue was purified by chromatography on silica and eluted with a step gradient from CHCl3 to 1% EtOH in CHCl3. Yield: 873 mg, 1.75 mmol (76%). Rf= 0.39 (30:1 CHCl3-EtOH). mp= 67-72°C. [α]D= -21.9° (c=0.57, CHCl3). MS(CI) m/e 499(m+H)+, 386, 369, 342, 326. 1H NMR(CDCl3,300MHz) δ 0.82(t,J=7Hz,3H), 0.89(t,J=7Hz,3H), 1.0-1.48(m,12H), 2.79-2.89(m,1H), 2.99-3.12(m,2H), 3.37(d,J=7Hz,2H), 3.42-3.52(m,1H), 5.45-5.53(m,1H), 7.08(d,J=2Hz,1H), 7.12-7.23(m,2H), 7.34(bt,J=7Hz,2H), 7.62(dt,J=1,7Hz,1H), 7.78-7.88(m,3H), 8.05(bs,1H), 8.16(d,J=8Hz,1H), 8.50(d,J=2Hz,1H), 9.32(d,J=2Hz,1H). C,H,N analysis calculated for C31H38N4O2, 0.25 H2O: C 74.00, H 7.71, N 11.14; found: C 74.08, H 7.76, N 11.16.
Example 22 Methyl S-Phenylglycinate hydrochloride
S-Phenylglycine (5 g, 33mmol) was refluxed for 4 hours in methanol saturated with HCl gas (50 mL). The solvent was then evaporated and the residue triturated with ether to yield 6.0 g,
30 mmol (91%) of product, mp 224-6°C(dec). [α]D= 137° (c=1.0,
MeOH). 1H NMR(DMSOd6,300MHz) δ 3.72(s,3H), 5.27(s,1H), 7.45-7.48(m,3H), 7.50-7.54(m,m3H), 9.14(s,3H).
Example 23 Methyl N-(t-Butyloxycarbonyl)-R-Tryptophyl-S-Phenylglycinate
EDCI (191 mg, 1.0 mmol) was added to a cooled solution (4°C) of Boc-R-Tryptophan (304 mg, 1.0 mmol), S-Phenylglycine me thyl ester (202 mg, 1.0 mmol), HOBt (135 mg, 1.0 mmol) and TEA (279 μL, 2.0 mmol) in dry CH2Cl2 (10 mL). The reaction was allowed to reach ambient temperature overnight. The solvents were evaporated in vacuo and the residue was dissolved in EtOAc and extracted successively with 1 M H3PO4 (3x), 1 M Na2CO3 (3x), brine (3x) then dried over MgSO4, filtered and the filtrate concentrated in vacuo. Yield: 385 mg, 0.85 mmol (85%). Rf= 0.41 (1:1 hexanes-EtOAc); 0.35 (18:1 CHCl3-EtOH). MS(CI) m/e 452(m+H)+, 469(m+NH4)+, 413, 396, 352, 334, 304. 1H NMR(CDCl3,300MHz) δ 1.42(bs,9H), 3.17(dd,J=8,15Hz,1H), 3.30(bdd,J=5,15Hz,1H), 3.66(s,3H), 4.52(bs,1H), 5.12(bs,1H), 5.46(bd,J=5Hz,1H), 6.72(d,J=7Hz,1H), 6.90(s,1H), 7.10-7.14(m,3H), 7.21(dt,J=1,7Hz,1H), 7.28-7.31(m,4H), 7.35(d,J=8Hz,1H), 7.63(d,J=7Hz,1H), 7.97(bs,1H).
Example 24 Methyl R-Tryptophyl-S-Phenylglycinate hydrochloride
Methyl Boc-R-Tryptophyl-S-Phenylglycinate (380 mg, 0.84 mmol) was mixed with HCl-Dioxane (4 mL, 16 mmol, pre-cooled to 4°C) under an N2 atmosphere at ambient temperature. After 60 minutes, the reaction was quenched with ether and the resulting solid collected and dried in vacuo. Yield: 299 mg, 0.77 mmol (92%).
Example 25 Methyl N-(2'-Indolylcarbonyl)-R-Tryptophyl-S-Phenylglycinat
EDCI (75 mg, 0.39 mmol) was added to a cooled (4°C) solution of indole-2-carboxylic acid (63 mg, 0.39 mmol), methyl R-Tryptophyl-S-Phenyglycinate hydrochloride (150 mg, 0.39 mmol), HOBt (53 mg, 0.39 mmol), and TEA (112 μL , 0.8 mmol) in CH2Cl2 (10 mL). The reaction was allowed to attain ambient temperature overnight. Additional indole-2-carboxylic acid (6 mg), EDCI (8 mg) and TEA (12 μL ) were added and the reaction was continued 6 hours. The solvent was evaporated and the residue was dissolved in EtOAc and extracted with 1 M H3PO4 (3x), 1 M Na2CO3 (3x), brine (3x). The organic extracts were dried over MgSO4, filtered, and then concentrated. The crude residue was purified by chromatography on silica eluted with 2:1 hexane/EtOAc. The combined product fractions were evaporated and crystallized from aqueous EtOH to provide the product, 65 mg, 0.13 mmol (34%). Rf= 0.30 (18:1 CHCl3-EtOH). mp= 190-1°C. [α]D= +76.7° (c=1.0, 1:1 DMF-MeOH). MS(FAB+) m/e 495(m+H)+, 334, 330. 1H NMR(DMSOd6,300MHz) δ 3.06-3.22(m,2H), 3.64(s,3H), 4.93-5.02(m,1H), 5.51(dd,J=3,3Hz,1H), 6.96(dt,J=1,8Hz,1H), 7.0-7.06(m,2H), 7.13-7.22(m,3H), 7.28(d,J=7Hz,1H), 7.35-7.41(m,6H), 7.62(d,J=8Hz,1H), 7.72(d,J=7Hz,1H), 8.52(d,J=8Hz,1H), 9.14(d,J=7Hz,1H), 10.77(d,J=1Hz,1H), 11.55(bs,1H). C,H,N analysis calculated for C29H26N4O4: C 70.43, H 5.30, N 11.33; found: C 70.16, H 5.42, N 11.23.
Example 26 Ethyl N-(Butyloxycarbonyl)-R-Tryptophyl-(N-benzyl)Glycinate
Boc-R-Tryptophan (1.43 g, 4.7 mmol), ethyl N-benzylglycinate (1.04 g, 5.4 mmol), EDCI (1.05 g, 5.48 mmol), and HOBt (500 mg, 3.7 mmol) were stirred in 10 mL of DMF at 0°C and TEA (700 μL ) was added. The reaction was allowed to stir overnight and warm to ambient temperature. The reaction mixture was treated in an analogous fashion to that in example 23 and chromatography with EtOAc/hexane as the elutant mixture provided 1.43 g of an oily product after evaporation of the solvents in vacuo. MS (FAB) m/e 480(m+H)+, 380, 362, 347, 294. 1H NMR( DMSOd6 ,300MHz) δ 10.82(bd,J=5.5Hz,1H), 7.5(d,J=7.5Hz,0.5H), 6.85-7.35(m,10.5H) 4.35-4.85(m,4H), 4.08(m,2H), 3.91(m,1H), 2.90-3.05(m,2H), 1.33(s,4.5H), 1.28(s,4.5H), 1.15(m,3H).
Example 27 Ethyl R-Tryptophyl-(N-benzyl)Glycinate hydrochloride
Ethyl Boc-R-Tryptophan-(N-benzyl)glycinate (353 mg, 0.76 mmol) was mixed with HCl-Dioxane (5 mL, 20 mmol, precooled to 4°C) under an N2 atmosphere and allowed to attain ambient temperature. After 1 hour, the solvent was evaporated and the residue was triturated with ether and filtered to give 257 mg, 0.76 mmol (84%) of product. MS(FAB) m/e 380(m+H)+, 347. 1H NMR(DMSOd6,300MHz) δ 1.13 (t,J=7Hz,1.5H), 1.18(t,J=7Hz,1.5H), 3.15-3.22(m,2H), 3.79-4.62(m,7H), 6.96-7.03(m,1H), 7.08-7.19(m,3H), 7.24-7.66(m,6H), 8.34(bs,3H),
11.11(d,J=2Hz,0.5H), 11.15(d,J=2Hz,0.5H).
Example 28 Ethyl N-(2'-Indolylcarbonyl)-R-Tryptophyl-(N-benzyl)Glycinate
EDCI (82 mg, 0.43 mmol) was added to a cooled (4°C) solution of indole-2-carboxylic acid (69 mg, 0.43 mmol) ethyl R-Tryptophan-(N-benzyl )glycinate hydrochloride (104 mg, 0.43 mmol), HOBt (58 mg, 0.43 mmol), and TEA (120 μL , 0.86 mmol) in CH2Cl2 (10 mL). The reaction was allowed to attain ambient temperature overnight. Additional EDCI (8 mg) and TEA (12 μL ) were added after 1 day. After 4 days, the solvents were evaporated and the residue was dissolved in EtOAc and extracted with 1 M H3PO4 (3x), 1 M Na2CO3 (3x), brine (3x) then dried over MgSO4, filtered and the filtrate concentrated. The residue (which indicated two products by tlc) was purified by chromatography on silica gel eluted with 30:1 CHCl3-EtOH. Early fractions gave 102 mg, 0.2 mmol (45%) of desired product. Rf= 0.44 (18:1 CHCl3). [α]D= +17.8° (c=1.0, MeOH). MS(FAB) m/e 523(m+H)+, 507, 436, 393, 362, 330, 302, 285. 1H NMR(CDCl3,300MHz) 2 amide bond isomers in a 65:35 ratio: δ 1.11(t,J=7Hz,1.1H), 1.23(t,J=7Hz,1.9H), 3.31-3.50(m,2H), 3.73-3.92(m,1.3H), 4.0(q,J=7Hz,0.7H), 4.12-4.20(m,2H), 4.38(d,J=16Hz,0.6H), 4.53-4.62(m,1H), 4.70(d,J=15Hz,0.4H), 5.31-5.38(m,0.4H), 5.57-5.65(m,0.6H), 6.84-6.86(m,0.6H), 6.91-6.92(m,0.4H), 6.98-7.29(m,11H), 7.3-7.40(m,2H), 7.62-7.66(m,1.3H), 7.72(d,J=8Hz,0.7H), 8.01(s,0.4H), 8.08(s,0.6H), 9.18(s,0.4H), 9.21(s,0.6H). C,H,N analysis calculated for C31H30N4O4, 0.25 H2O: C 70.64, H 5.83, N 10.63; f ound : C 70 . 46 , H 5 . 67 , N 10 . 55 .
Later fractions provided 36 mg, 0.11 mmol, 25% of undesired diketopiperazine. Rf= 0.18 (18:1 CHCl3-EtOH). [α]D= -39.3° (c-0.60, DMF). mp= 204-6°C. MS(CI) m/e 334(m+H)+. 1H NMR(CDCl3,300MHz) δ 3.08(dd,J=1,18Hz,1H), 3.31-3.45(m,2H), 3.53(dd,J=1,18Hz,1H), 4.14(d,J=15Hz,1H), 4.37-4.41(m,1H), 4.62(d,J=15Hz,1H), 6.0(bs,1H), 7.03(d,J=2Hz,1H), 7.05-7.08(m,2H), 7.13-7.22(m,2H), 7.25-7.30(m,3H), 7.39(dt,J=8,1Hz,1H), 7.65(bd,J=8Hz,1H), 8.12(bs,1H). C,H,N analysis calculated for C20H19N3O, 0.25 CHCl3: C 67.23, H 5.34, N 11.57; found: C 66.87, H 5.49, N 11.44.
Example 29 Ethyl N-(3'-Quinolylcarbonyl)-R-Tryptophyl-(N-benzyl)Glycinate
EDCI (104 mg, 0.54 mmol) was added to a cooled (4°C) solution of quinoline-3-carboxylic acid (94 mg, 0.54 mmol), ethyl R-Tryptophan-(N-benzyl)glycinate hydrochloride (217 mg, 0.54 mmol), and TEA (151 μL , 1.08 mmol) in CH2Cl2 (10 mL). The reaction was allowed to attain ambient temperature overnight. After 5 hours, the solvent was evaporated and the residue was dissolved in EtOAc and extracted with 1 M H3PO4 (3x), 1 M Na2CO3 (3x), brine (3x) the dried over MgSO4, filtered and the filtrate concentrated. The residue (which indicated two products by tlc) was purified by chromatography on silica gel eluted with a solvent gradient of 50:1 to 30:1 CHCl3-EtOH. Early fractions provided 64 mg, 0.12 mmol, 22% yield of desired product. Rf= 0.15 (30:1 CHCl3-EtOH). mp= 82-85°C. [α]D= +37.0° (c=0.50, DMF). MS(FAB) m/e 535(m+H)+, 391, 362, 342. 1H NMR( CDCl3,300MHz), 2 amide bond isomers in a 2:1 ratio: δ 1.17(t,J=7Hz,1H), 1.26(t,J=7Hz,2H), 3.38-3.45(m,0.67H), 3.54(dd,J=7,14Hz,0.33H), 3.76(d,J=17Hz,0.67H), 3.86(d,J=12Hz,0.33H), 4.03-4.28(m,2H), 4.43(d,J=16Hz,0.67H), 4.54(d,J=15Hz,0.33H), 4.71(d,J=7Hz,0.67H), 4.76(d,J=7Hz,0.33H), 5.34-5.42(m,0.33H), 5.63-5.71(m,0.67H), 7.04-7.12(m,3H), 7.18(dt,J=1,7Hz,2H), 7.23-7.30(m,4H), 7.38(bd,J=8Hz,1H), 7.57-7.68(m,2H), 7.73-7.88(m,2H), 8.07(bs,0.33H), 8.12-8.18(m,1.67H), 8.36(d,J=2Hz,0.67H), 8.43(d,J=2Hz,0.33H), 9.22(d,J=2Hz,0.67H), 9.28(d,J=2Hz,0.33H). Analysis calculated for C32H30N4O4, 1.1 CHCl3: C 59.70, H 4.71, N 8.41; found: C 60.07, H 4.91, N 8.41.
Later fractions provided 116 mg, 0.35 mmol, 65% of undesired diketopiperazine identical to that isolated in example 28. Rf= 0.06 (30:1 CHCl3-EtOH).
Example 30 Methyl R-Phenylglycinate hydrochloride
R-Phenylglycine (5 g, 33 mmol) was refluxed for 2 hours in methanol (50 mL) saturated with HCl gas. The solvent was then evaporated and the residue triturated with ether to give 6.3 g, 31 mmol (94%) of product. mp= 243-5°C. [α]D = +140° (c=1.0, MeOH).
Example 31 Methyl N-(3'-Quinolylcarbonyl)-Tryptophyl-R-Phenylglycinate
EDCI (27 mg, 0.14 mmol) was added to a cooled (4°C) solution of N-(3'-Qumolylcarbonyl)-R-Tryptophan (50 mg, 0.14 mmol), methyl R-Phenylglycinate hydrochloride (28 mg, 0.14 mmol), HOBt (19 mg, 0.14 mmol), and TEA (39 μL, 0.28 mmol) in CH2Cl2 (5 mL). After 6 hours, the solvents were evaporated and the residue was dissolved in EtOAc and extracted with 1 M H3PO4 (3x), H2O (3x) then the solution was concentrated without drying and the residue was recrystallized from aqueous EtOH to give 17.4 mg, 0.034 mmol (24%). The mother liquor was evaporated to give 28 mg, 0.06 mmol (39%). Tlc Rf= 0.25 (2:1 hexanes-EtOAc). HPLC: crop 1 shows two peaks in a 46/54 ratio, crop 2 shows a 92/8 ratio (normal phase silica, solvents: hexane, EtOAc in a gradient from 5% to 70% over 10 minutes). Crop 1 (1/1 mixturre of diastereomers): mp= 235-7°C. MS(FAB) m/e 507(m+H)+, 342, 334, 314. 1H NMR(DMSOd6,300MHz) δ 3.10-3.28 (m,2H), 3.63(s,1.5H), 3.66(s,1.5H), 4.98-5.08(m,1H), 5.50(m,1H), 6.95-7.08(m,2H), 7.24-7.32(m,2H), 7.36-7.46(m,5H), 7.66-7.89(m,4H), 8.04-8.08(m,2H), 8.73(d,J=2Hz,0.5H), 8.78(d,J=2Hz,0.5H), 8.92-8.96(m,1H), 9.13-9.21(m,2H), 10.79-10.82(m,1H). C,H,N analysis calculated for C30H26N4O4, 0.5 H2O: C 69.89, H 5.28, N 10.87; found: C 70.18, H 5.01, N 10.83. Crop 2 (predominately one diastereomer): mp= 214-16ºC [α]D= -42.6° (c=0.5, DMF). 1H NMR(DMSOd6, 300MHz) δ 3.22(dd,J=10,14Hz,1H), 3.33(dd,J=5,14Hz,1H), 3.64(s,3H), 4.97-5.05(m,1H), 5.49(d,J=7Hz,1H), 6.97-7.08(m,2H), 7.28-7.46(m,8H), 7.68(dt,J=1,7Hz,1H), 7.78(d,J=7Hz,1H), 7.86(dt,J=1,7Hz,1H), 8.06(dt,J=1,7Hz,1H), 8.74(d,J=2Hz,1H), 8.87(d,J=8Hz,1H), 9.03(d,J=7Hz,1H), 9.17(d,J=2Hz,1H), 10.78(bd,J=1Hz,1H).
Example 32 Methyl N-(3'-Quinolylcarbonyl)-Tryptophyl-S-Phenylglycinate
EDCI (27 mg, 0.14 mmol) was added to a cooled (4°C) solution of N-(3'-Quinolylcarbonyl)-R-Tryptophan (50 mg, 0.14 mmol), methyl S-Phenylglycinate hydrochloride (28 mg, 0.14 mmol), HOBt (19 mg, 0.14 mmol), and TEA (39 μL, 0.28 mmol) in CH2Cl2 (5 mL). The reaction was allowed to attain room temperature overnight. The reaction mixture was not homogeneous and an additional quantity of TEA (4 μL ) was added. After 2 hours, the solvent was evaporated and the residue was dissolved in EtOAc and extracted with 1 M H3PO4 (3x, some solid was present and was filtered and dried in vacuo, crop 1), 1 M Na2CO3 (3x), brine (3x), then dried over MgSO4, filtered and the solvent evaporated to give crop 2. Crop 1: 12 mg, 0.024 mmol, 17%. Rf= 0.24 (18:1 CHCl3-EtOH); 0.28 (2:1 hexanes-EtOAc). mp= 252-4°C. Crop 2: [α]D= +75.5° (c=0.47, DMF). MS(CI) m/e 507(m+H)+. 1H NMR(DMSOd6,300MHz) δ 3.06-3.23(m,2H), 3.64(s,3H), 4.95-5.05(m,1H), 5.47-5.53(m,1H), 6.93-7.06(m,3H), 7.13-7.21(m,3H), 7.28(d,J=8Hz,1H), 7.34-7.42(m,6H), 7.62(d,J=8Hz,1H), 7.72(d,J=7Hz,1H), 8.50(d,J=8Hz,1H), 9.10(d,J=7Hz,1H), 10.75(d,J=1Hz,1H), 11.54(d,J=1Hz,1H) C,H,N analysis calculated for C30H26N4O4, 0.33 H2O: C 70.29, H 5.24, N 10.93; found: C 70.08, H 5.23, N 10.74.
Example 33 N-(3'-Quinolylcarbonyl)-Tryptophan-(N-methyl,N-benzyl)amide
BOPCl (128 mg, 0.50 mmol) was added to a cooled (4°C) solution of N-(3'-Quinolylcarbonyl)-R-Tryptophan (180 mg, 0.50 mmol), N-methylbenzylamine (130 μL , 1.0 mmol), and HOBt (68 mg, 0.50 mmol) in CH2Cl2 (10 mL). The reaction was allowed to attain room temperature overnight. An additional quantity of BOPCl (13 mg) was added and the reaction was continued. After 3 days, the solvents were evaporated and the residue was dissolved in EtOAc and extracted with 1 M H3PO4 (3x), 1 M Na2CO3 (3x), brine (3x) the dried over MgSO4, filtered and the filtrate concentrated in vacuo to provide 148 mg, 0.33 mmol (66% crude yield). The product was purified by chromatography on silica eluted with 2:1 hexanes-EtOAc to pure EtOAc. Purified yield: 64 mg. [α]D= -5.6° (c-0.55, DMF). MS(FAB) m/e 463(m+H)+, 342, 314, 307. 1H NMR(CDCl3,300MHz) δ 2.67(s,2H), 2.86(s,1H), 3.38-3.45(m,2H), 4.47(d,J=14Hz,1H), 4.56(d,J=14Hz,1H), 5.52-5.62(m,1H), 6.95(d,J=7Hz,0.33H), 7.01(dd,J=2,7Hz,0.67H), 7.09-7.43(m,9H), 7.57-7.65(m,1H), 7.74-7.90(m,3H), 8.01(bs,0.67H), 8.10(bs,0.33H), 8.16(bd,J=8Hz,1H), 8.48(d,J=2Hz,0.33H), 8.51(d,J=2Hz,0.67H), 9.28(d,J=3Hz,0.33H), 9.32(d,J=2Hz,0.67H); (2 amide bond isomers coalesced upon heating in DMSOd6 at 125°C). C,H,N analysis calculated for C29H26N4O2, 0.5 EtOAc 0.5 H2O: C 72.21, H 6.06,.N 10.87; found: C 72.06, H 5.87, N 11.09.
Example 34 N-(t-Butyloxycarbonyl)-R-Tryptophan-(1',S-phenylethyl)amide
BOPCl (255 mg, 1.0 mmol) was added to a cooled solution (4°C) of Boc-R-Tryptophan (304 mg, 1.0 mmol), S-α-methylbenzylamine (129 μL , 1.0 mmol), HOBt (135 mg, 1.0 mmol) and TEA (140 μL , 1.0 mmol) in dry THF (15 mL). After 2 hours, the solvents were evaporated in vacuo and the residue was dissolved in EtOAc and extracted successively with 1 M H3PO4 (3x), 1 M Na2CO3 (3x), brine (3x) then dried over MgSO4, filtered and the filtrate concentrated in vacuo. The residue was purified by chromatography on silica gel eluted with a 10:1 to 1:1 hexanes-EtOAc gradient. Yield: 199 mg, 0.49 mmol, 49%. Rf= 0.25 (2:1 hexanes-EtOAc); 0.59 (1:1 hexanes-EtOAc). mp= 80-83°C. MS(CI) m/e 408(m+H)+, 425(m+NH4)+, 352, 308, 290. 1H NMR(CDCl3,300MHz) δ 1.10-1.18(bs,3H), 1.42(s,9H), 3.14(dd,J=8,14Hz,1H), 3.34(dd,J=5,14Hz,1H), 4.4-4.48(bd,J=5Hz,1H), 4.88-4.97(m,1H), 5.18(bs,1H), 5.86(bd,J=7Hz,1H), 6.98(s,1H), 7.03(d,J=2Hz,1H), 7.07(d,J=2Hz,1H), 7.12-7.25(m,6H), 7.38(dt,J=8,<1Hz,1H), 7.69(d,J=7Hz,1H), 8.08(s,1H).
Example 35 R-Tryptophan-(1',S-phenylethyl)amide hydrochloride
Boc-R-Tryptophan-(1,S-phenylethyl)amide (144 mg, 0.36 mmol) was mixed with HCl-Dioxane (2 mL, 8 mmol, pre-cooled to 4°C) under an N2 atmosphere at ambient temperature. After 1 hour, the reaction was evaporated in vacuo and placed under high vacuum overnight. Rf= 0.59 (80:20:1 CHCl3-MeOH-NH4OH).
Example 36 N-(3'-Quinolylcarbonyl)-R-Tryptophan-(1',S-phenylethyl)amide
EDCI (76 mg, 0.40 mmol) was added to a cooled (4°C) solution of quinoline-3-carboxylic acid (69 mg, 0.40 mmol), hydrochloride of example 35 ( 0.36 mmol assumed), and TEA (112 μL , 0.8 mmol) in CH2Cl2 (10 mL). After 5 hours, an additional 10% equivalent amount of the acid, EDCI and TEA were added. After 1 day, the solvents were evaporated and the mixture treated as in example 19. The concentrated residue was purified by chromatography on silica eluted with 2:1 to 1:2 hexanes-EtOAC to provide 60 mg, 0.13 mmol, 36% of product. Rf= 0.27 (2:1 hexanes-EtOAc). mp= 246-9°C. [α]D= +15.3° (c=0.59, 1:1 DMF-MeOH). MS(CI) m/e 463(m+H)+, 342, 290. 1H NMR(DMSOd6,300MHz) δ 1.28(d,J=7Hz,3H) 3.18-3.35(m,2H), 4.83-4.99(m,2H), 6.97-7.19(m,2H), 7.19-7.37(m,5H), 7.68(dt,J=1,7Hz,1H), 7.76(d,J=8Hz,1H), 7.86(dt,J=1,7Hz,1H), 8.04(s,1H), 8.08(s,1H), 8.59(d,J=8Hz,1H), 8.79(d,J=2Hz,1H), 8.92(d,J=7Hz,1H), 9.21(d,J=2Hz,1H), 10.83(s,1H). C,H,N analysis calculated for C29H26N4O2, 0.25 H2O: C 74.58, H 5.72, N 12.00; found: C 74.25, H 5.82, N 11.69.
Example 37 N-(t-Butyloxycarbonyl)-R-Tryptophan-(1',R-phenylethyl)amide
BOPCl (255 mg, 1.0 mmol) was added to a cooled solution (4°C) of Boc-R-Tryptophan (304 mg, 1.0 mmol), R-α-methylbenzylamine (129 μL, 1.0 mmol), HOBt (135 mg, 1.0 mmol) and TEA (140 μL , 1.0 mmol) in dry THF (15 mL). The reaction was allowed to reach ambient temperature overnight. The solvents were evaporated in vacuo and the residue was dissolved in EtOAc and extracted successively with 1 M H3PO4 (3x), 1 M Na2CO3 (3x), brine (3x) then dried over MgSO4, filtered and the filtrate concentrated in vacuo. The residue was purified by chromatography on silica gel eluted with a 10:1 to 1:1 hexanes-EtOAc gradient. Yield: 225 mg, 0.56 mmol, 56%. Rf= 0.20 (2:1 hexanes-EtOAc); 0.59 (1:1 hexanes-EtOAc). mp= 80-84°C. MS(CI) m/e 408(m+H)+, 425(m+NH4)+, 352, 308, 290. 1H NMR( CDCl3 ,300MHz) δ 0.82(d,J=7Hz,3H), 0.93(s,9H), 3.11(bdd,J=8,14Hz,1H), 3.31(ddd,J<1;5,14Hz,1H), 4.42(bs,1H), 4.92-5.08(m,1H), 5.2(bs,1H), 5.86(bd,J=6Hz,1H), 6.83(s,1H), 7.02(bs,2H), 7.11-7.27(m,6H), 7.69(d,J=8Hz,1H), 7.84(d,J=8Hz,1H), 7.90(s,1H).
Example 38 R-Tryptophan-(1',R-phenylethyl)amide hydrochloride
Boc-R-Tryptophan-(1',R-phenylethyl)amide (200 mg, 0.49 mmol) was mixed with HCl-Dioxane (1.2 mL, 4.9 mmol, pre-cooled to 4°C) under an N2 atmosphere at ambient temperature. After 2 hours, the volatiles were evaporated in vacuo and placed under high vacuum overnight to provide the product.
Example 39 N-(3'-Quinolylcarbonyl)-R-Tryptophan-(1',R-phenylethyl)amide
EDCI (86 mg, 0.45 mmol) was added to a cooled (4°C) solution of quinoline-3-carboxylic acid (78 mg, 0.45 mmol), hydrochloride of example 38 (140 mg, 0.41 mmol), HOBt (13 mg, 0.10 mmol), and (125 μL , 0.9 mmol) in CH2Cl2 (15 mL). The reaction was allowed to attain ambient temperature overnight. The solvents were evaporated and the residue treated as in example 19. The crude yield was 174 mg, 0.38 mmol, (92%). Product was recrystallized from 80% aqueous ethanol to provide 67 mg of pure material. 0.25 (1:2 hexanes-EtOAc). MS(CI) m/e 463(m+H)+, 173. 1H NMR(CDCl3, 300MHz) δ 1.38(d,J=7Hz,3H), 3.18(dd,J=9,14Hz,1H), 3.50(dd,J=4,14Hz,1H), 4.96-5.10(m,2H), 5.83(d,J=8Hz,1H), 6.72(d,J=2Hz,1H), 7.03-7.06(m,2H), 7.15-7.37(m,7H), 7.62(dt,J=1,7Hz,1H), 7.78-7.89(m,4H), 8.16(d,J=8Hz,1H), 8.50(d,J=2Hz,1H), 9.32(d,J=2Hz,1H). C,H,N analysis calculated for C29H26N4O2, 0.75 H2O: C 73.17, H 5.82, N 11.77; found: C 73.40, H 5.85, N 11.50.
Example 40 N-(3'-Quinolylcarbonyl)-Tryptophan-perhydroisoquinolylamide
BOPCl (152 mg, 0.60 mmol) was added to a cooled (4°C) solution of N-(3'-quinolylcarbonyl)-R-Tryptophan (200 mg, 0.56 mmol), perhydroisoquinoline (192 mg, 1.4 mmol, prepared by catalytic reduction of isoquinoline (cf. Witkop J Am Chem Soc, 70, 2617-19, 1948), TEA (84 μL, 0.6 mmol) and HOBt (81 mg , 0.60 mmol) in THF (10 mL). The reaction was allowed to attain room temperature overnight. The solvents were evaporated and the residue treated as in example 18. The crude product was purified by chromatography on silica eluted with CHCl3 to 18:1 CHCl3-EtoH to provide 153 mg, 0.32 mmol (57% yield). mp= 124-35°C. MS(CI) m/e 481(m+H)+, 385, 352, 314, 296. 1H NMR( DMSOd6 ,300Hz ,120°C) δ 1.2-1.8(m,12H), 3.05-3.24(m,3H), 3.28-3.36(m,1H), 3.65-3.82(m,2H), 5.29-5.45(m,1H), 6.96-7.09(m,2H), 7.17(t,J=2Hz,1H), 7.32-7.37(m,1H), 7.62-7.70(m,2H), 7.84(dt,J=1,7Hz,1H), 8.02-8.09(m,2H), 8.50-8.61(m,1H), 8.75-8.79(m,1H), 9.23-9.27(m,1H), 10.48(vbs,1H). C,H,N analysis calculated for C30H32N4O2, 0.83 H2O: C 72.65, H 6.90, N 11.30; found: C 72.66, H 6.80, N 10.96.
Example 41 N-(3'-Quinolylcarbonyl)-Tryptophan-dibenzylamide
BOPCl (152 mg, 0.60 mmol) was added to a cooled (4°C) solution of N-(3'-quinolylcarbonyl)-R-Tryptophan (200 mg, 0.56 mmol), dibenzylamine (268 μL , 1.4 mmol), TEA (84 μL , 0.6 mmol) and HOBt (81 mg, 0.60 mmol) in THF (10 mL). The reaction was allowed to attain room temperature overnight. The solvent was evaporated and the residue was treated as in example 18. The product was purified by chromatography on silica eluted with 2:1 to 1:1 hexanes-EtOAc to provide 100 mg of product, 0.186 mmol (33%). MS(FAB) m/e 539(m+H)+, 366, 342, 314. 1H NMR( CDCl3,300MHz) δ 3.38(s,1H), 3.41(s,1H), 4.20-4.23(m,1H), 4.26(bs,2H), 4.46(d,J=16Hz,1H), 4.89(d,J=14Hz,1H), 5.61(apparent q,J=7Hz,1H), 6.86(d,J=2Hz,1H), 7.02-7.22(m,6H), 7.23-7.36(m,7H), 7.58-7.64(m,2H), 7.78-7.86(m,2H), 7.99(s,1H), 8.15(d,J=8Hz,1H), 8.43(d,J=2Hz,1H), 9.26(d,J=2Hz,1H). C,H,N analysis calculated for C35H30N4O2, 0.5 H2O: C 76.76, H 5.71, N 10.23; found: C 76.88, H 5.66, N 10.09.
Example 42 N-(t-Butyloxycarbonyl)-S-Tryptophan-N-(3'-quinolyl)amide
BOPCl (255 mg, 1.0 mmol) was added to a cooled solution (4°C) of Boc-S-Tryptophan (304 mg, 1.0 mmol), 3-aminoquinoline (144 mg, 1.0 mmol), HOBt (13 mg, 0.1 mmol) and TEA (140 μL , 1.0 mmol) in dry CH2Cl2 (10 mL). The reaction was allowed to reach ambient temperature overnight. The solvents were evaporated in vacuo and the residue was treated as in example 18. The residue was purified by chromatography on silica gel eluted with a 2:1 to 1:1 hexanes-EtOAc gradient. Yield: 195 mg, 0.45 mmol, (45%). Rf= 0.25 (1:1 hexanes-EtOAc). MS(CI) m/e 431(m+H)+, 331. 1H NMR(CDCl3,300MHz) δ 1.48(s,9H), 3.28(dd,J=8,15Hz,1H), 3.46(dd,J=6,15Hz,1H), 4.69(m,1H), 5.28(bs,1H), 7.10-7.15(m,2H), 7.22(dt,J=1,7Hz,1H), 7.38(d,J=8Hz,1H), 7.52(dt,J<1,8Hz,1H), 7.62(dt,J=1,8Hz,1H), 7.71(d,J=7Hz,1H), 7.78(d,J=8Hz,1H), 7.98(s,1H), 8.03(s,1H), 8.20(s,1H), 8.31(d,J=2Hz,1H), 8.58(d,J=1Hz,1H).
Example 43 S-Tryptophan-N-(3'-quinolyl)amide hydrochloride
Boc-S-Tryptophan-N-(3'-quinolyl)amide (164 mg, 0.38 mmol) was mixed with HCl-Dioxane (3 mL, 12 mmol, pre-cooled to 4 C) under an N2 atmosphere at ambient temperature. After 2 hours, the volatiles were evaporated in vacuo and placed under high vacuum overnight to provide the product. MS(CI) m/e 331(m+H)+. 1H NMR(CD3OD,300MHz) δ 3.42-3.58(m,2H), 4.4(t,J=7Hz,1H), 6.85(dt,J=1,7Hz,1H), 7.02(dt,J=1,7Hz,1H), 7.32(s,1H), 7.35(d,J=7Hz,1H), 7.58(d,J=8Hz,1H), 7.94(dt,J=1,7Hz,1H), 8.08(dt,J=1,7Hz,1H), 8.20(m,J=7Hz,2H), 8.41(d,J=2Hz,1H), 9.26(d,J=2Hz,1H).
Example 44 N-Diphenylacetyl-S-Tryptophan-N-(3'-quinolyl)amide
EDCI (67 mg, 0.35 mmol) was added to a cooled (4°C) solution of diphenylacetic acid (74 mg, 0.35 mmol), S-Tryptophan-N-(3'-quinolyl)amide hydrochloride ( 0.32 mmol) and TEA (89 μL, 0.64 mmol) in CH2Cl2 (10 mL). The reaction was allowed to attain ambient temperature overnight. The solvents were evaporated and the residue was treated as in example 18. The crud eproduct was purified by chromatography on silica eluted with 1:1 hexanes-EtOAc. mp= 233-35°C. [α]D= +17.7° (c=1.03, 1:1 DMF-MeOH). MS(CI) m/e 525(m+H)+, 381, 353, 331, 313, 277, 257. 1H NMR(CDCl3,300MHz) δ 3.26(dd,J=7,14Hz,1H), 3.38(dd,J=7,14Hz,1H), 4.93(s,1H), 5.06(apparent q,J=7Hz,1H), 6.41(d,J=7Hz,1H), 6.87(d,J=2Hz,1H), 7.06-7.16(m,5H), 7.2-7.31(m,7H), 7.38(d,J=8Hz,1H), 7.49(dt,J=1,7Hz,1H), 7.58-7.64(m,2H), 7.72(dd,J=1,8Hz,1H), 7.99(d,J=8Hz,1H), 8.12(s,1H), 8.36(d,J=2Hz,1H), 8.49(d,J=2Hz,1H), 8.56(s,1H).
Analysis calculated for C34H28N4O2, H2O: C 75.25, H 5.57, N 10.33; found: C 75.13, H 5.14, N 10.07.
Example 45 N-(3'-Quinolylcarbonyl)-2-(2'-nitrophenylsulfenyl)- R-Tryptophan-di-n-pentylamide
2-Nitrophenylsulfenylchloride (3.4 mg, 0.02 mmol) was added to N-(3'-quinolylcarbonyl)-R-Tryptophan-dipentylamide (10 mg, 0.02 mmol) in CHCl3. After 3 hours, the reaction mixture was purified by chromatography on silica eluted with CHCl3 to 1% EtOH in CHCl3 to provide 13 mg, 0.02 mmol (100%) of yellow product. MS(CI) m/e 652(m+H)+. 1H NMR(CDCl3,300MHz) δ 0.81-0.90(m,6H), 1.04-1.37(m,9H), 1.43-1.58(m,4H), 3.12-3.25(m,2H), 3.31-3.48(m,4H), 5.38-5.45(m,1H), 6.33(dd,J=1,7Hz,1H), 7.08-7.18(m,2H), 7.21-7.36(m,4H), 7.58(dt,J=1,7Hz,1H), 7.75-7.83(m,3H), 8.10(d,J=8Hz,1H), 8.13(dd,J=1,8Hz,1H), 8.33(d,J=2Hz,1H), 8.38(s,1H), 9.10(d,J=2Hz,1H). C,H,N analysis calculated for C37H41N5O4S: C 68.18, H 6.34, N 10.75; found: C 67.88, H 6.41, N 10.65.
Example 46 N-(3'-Quinolylcarbonyl)-Tryptophan-N-(3'-quinolyl)amide
BOPCl (152 mg, 0.60 mmol) was added to a cooled (4°C) solution of N-(3'-quinolylcarbonyl)-R-Tryptophan (200 mg, 0.56 mmol), 3-aminoquinoline (173 mg, 1.2 mmol, recrystallized from hexanes), TEA (167 μL , 1.2 mmol) and HOBt (81 mg, 0.60 mmol) in CH-Cl2 (15 mL). The reaction was allowed to attain room temperature. After 5 hours, the solvents were evaporated and the residue was treated as in example 18. The crude product was crystallized from aqueous ethanol to provide 60 mg, 0.12 mmol (21% yield). Rf= 0.17 (EtOAc). mp= 268-70°C. MS(CI) m/e 486(m+H)+, 385, 342. 1H NMR( CDCl3-CD3OP,500MHz) δ 3.50(dd,J=4,8Hz,1H), 3.58(dd,J=4,8Hz,1H), 5.28(t,J=4Hz,1H), 7.03(dt,J=<1,4Hz,1H), 7.13(dt,J=<1,8Hz,1H), 7.21(s,1H), 7.39(d,J=5Hz,1H), 7.56-7.59(m,1H), 7.65-7.72(m,3H), 7.82(d,J=5Hz,1H), 7.85-7.88(dt,J=1,5Hz,1H), 7.98(m,2H), 8.11(d,J=5Hz,1H), 8.59(d,J=1Hz,1H), 8.68(d,J=1Hz,1H), 8.71(d,J=2Hz,1H), 9.25(d,J=2Hz,1H). Analysis calculated for
C30H23N5O2, H2O: C 71.55, H 5.00, N 13.91; found: C 71.56, H 5.01, N 13.51.
Example 47 Methyl S-(p-Hydroxyphenyl)glycinate hydrochloride
S-(p-Hydroxyphenyl)glycine (3 g, 18 mmol) was heated to reflux with saturated HCl in MeOH (50 mL ) for 3 hours. After evaporation of the solvents, the residue was triturated with ether to give 3.6 g (14 mmol, 77% yield) of product. mp= 192-3°C(dec). [α]D= +147° (c=1.0, MeOH).
Example 48 Methyl N-(t-Butyloxycarbonyl)-R-Tryptophyl-S- (p-hydroxyphenyl)glycinate
BOPCl (254 mg, 1.0 mmol) was added to a cooled solution (4°C) of Boc-R-Tryptophan (304 mg, 1.0 mmol), methyl
S-(p-hydroxyphenyl)glycinate (129 μl , 1.0 mmol), HOBt (135 mg, 1.0 mmol) and TEA (279 μl , 2.0 mmol) in dry THF (10 mL). The reaction was allowed to reach ambient temperature overnight. After one day, additional BOPCl (25 mg) and TEA (28μL) were added. After two days, another 109 mg of methyl S-(p-hydroxyphenyl)glycinate, BOPCl (127 mg) and TEA (140μL) were added. After three days, the solvents were evaporated in vacuo and the residue was dissolved in EtOAc and extracted successively with 0.1 M H3PO4 (3x), brine (3x) then dried over MgSO4, filtered and the filtrate concentrated in vacuo to provide 323 mg of product, 0.69 mmol (69%). Rf= 0.14 (1:1 hexanes-EtOAc). mp= 83-7°C. MS(CI) m/e 468(m+H)+, 412, 368, 350. 1H NMR(DMSOd6,500MHz) δ 1.31(s,9H), 2.90(dd,J=5,8Hz,1H), 3.03(dd,J=3,8Hz,1H), 3.62(s,3H), 4.30-4.34(m,1H), 5.24(d,J=4Hz,1H), 6.72-6.75(m,3H), 6.96(t,J=5Hz,1H), 7.05(t,J=5Hz,1H), 7.09-7.12(m,3H), 7.31(d,J=5Hz,1H), 7.54(d,J=5Hz,1H), 8.51(d,J=4Hz,1H), 9.53(s,1H).
Example 49 Methyl R-Tryptophyl-5-(p-hydroxyphenyl)glycinate hydrochloride
Methyl Boc-R-Tryptophan-S-(p-hydroxyphenyl)glycinate (222 mg, 0.47 mmol) was mixed with HCl-Dioxane (3 mL, 12 mmol, pre-cooled to 4°C ) under an N2 atmosphere at ambient temperature. After 2 hours, the reaction mixture was concentrated in vacuo and placed under high vacuum overnight to provide product.
Example 50 Methyl N-(3'-Quinolylcarbonyl)-R-Tryptophyl-S-(p-hydroxyphenyl) glycinate
EDCI (80 mg, 0.42 mmol) was added slowly over -3 hours to a cooled (4°C) solution of quinoline-3-carboxylic acid (73 mg, 0.42 mmol), S-(p-hydroxyphenyl)glycine methyl ester hydrochloride (170 mg, 0.42 mmol), HOBt (6 mg, 0.04 mmol), and TEA (117 μL , 0.84 mmol) in CH2Cl2 (15 mL). After 2 days, an additional 10% equivalent amount of EDCI and TEA were added and the reaction was continued for one day. The solvents were evaporated and the residue was dissolved in EtOAc and extracted with 0.1 M H3PO4 (3x), H2O (3x), and dried over MgSO4. The filtrate was concentrated and the residue purified by chromatography using 1% EtOH in CH2Cl2 as the elutant mixture provide product 28 mg (0.048 mmol, 11% yield). MS(CI) m/e 523(m+H)+, 540(m+NH4)+. 1H NMR( CD3OD,300MHz) δ 3.24-3.43 (m,2H), 3.68(s,3H), 5.07(t,J=7Hz,1H), 5.25(s,1H), 6.71(d,J=8Hz,1H), 6.94-7.02(m,3H), 7.08-7.12(m,2H), 7.33(d,J=7Hz,1H), 7.62(d,J=8HZ,1H), 7.68(dt,J=1,7Hz,1H), 7.87(dt,J=1,7Hz,1H), 7.99(d,J=8Hz,1H), 8.07(d,J=8Hz,1H), 8.63(d,J=2Hz,1H), 9.13(d,J=2Hz,1H). C,H,N analysis calculated for C30H26N4O5, 0.2 H2O, 0.2 CH2Cl2: C 66.78, H 4.97, N 10.32; found: C 66.83, H 4.73, N 10.14.
Example 51 N-(t-Butyloxycarbonyl)-R,S-5-benzyloxytryptophan- di-n-pentylamide
R,S-5-benzyloxytryptophan (2.0 g) was treated with di-t-butyldicarbonate (1.7 g) in a 50% solution of saturated sodium bicarbonate in dioxane at 0°C. The reaction was allowed to warm to ambient temperature and stir overnight. The solvents were evaporated in vacuo and residue partioned between NaOH (1.0 N) and EtOAc. The aqueous portion was then acidified to pH 2.0 using concentrated HCl and the solution extracted with ethylacetate. The EtOAc was dried over MgSO4 and filtered. Evaporation of the volatiles gave 1.12 g which was stirred with dipentylamine (2.5 mL) and BOPCl (1.0 g) in 20 mL of CH2Cl2 a 0°. After stirring overnight with warming to ambient temperature the reaction mixture was treated as in example 1. The product was purified by crystallization from EtOAc/hexane to provide 997 mg of a white powder. MS(FAB) m/e 550(m+H)+, 450, 433, 360, 265, 236. 1H NMR( CDCl3 ,300MHz) δ 7.88(bs,1H), 7.52(bd,J=7.5Hz,2H), 7.2-7.4(m,5H), 7.02(d,J=2Hz,1H), 6.93(dd,J=2,9Hz,1H), 5.40(bd,J=7.5Hz,1H), 5.13(s,2H), 4.87(m,1H), 3.32(m,1H), 2.82-3.12(m,5H), 1.42(s,9H), 0.95-1.4(m.12H), 0.87(t,J=7Hz,3H), 0.78(t,J=7Hz,3H).
Example 52 R,S-5-Benzyloxytryptophan-di-n-pentylamide hydrochloride
The product of example 51 (800 mg, 1.5 mmol) was mixed with 4.0 N HCl-Dioxane (7 mL, 28 mmol, pre-cooled to 4°C) under an N2 atmosphere at ambient temperature. After 1 hour, the reaction mixture was evaporated in vacuo and placed under high vacuum overnight to provide the product. MS(FAB) m/e 450(m+H)+, 433, 265, 236, 213. 1H NMR(DMSOd6,300MHz) δ 0.73(t,J=7Hz,3H), 0.84(t,J=7Hz,3H), 0.96-1.3(m,12H), 2.56-2.66(m,1H), 2.72-2.81(m,1H), 2.87-2.96(m,1H), 3.07(dd,J=8,14Hz,1H), 3.17-3.23(m,1H), 3.36(s,H2O), 4.32(bs,1H), 5.09(s,2H), 6.83(dd,J=2,8Hz,1H), 7.12(d,J=2Hz,1H), 7.25-7.28(m,2H), 7.32-7.42(m,3H), 7.46-7.49(m,2H), 8.33(bs,2H), 10.91(d,J=2Hz,1H).
Example 53 N-(3'-Quinolylcarbonyl)-R,S-5-benzyloxytryptophan- di-n-pentylamide
EDCI (154 mg, 0.80 mmol) was added to a cooled (4°C) solution of quinoline-3-carboxylic acid (139 mg, 0.80 mmol), hydrochlorid salt of example 52 (0.78 mmol) and TEA (223 μL , 1.6 mmol) in CH2Cl2 (5 mL). The reaction was allowed to attain ambient temperature overnight. The solvents were evaporated and the residue was treated as in example 18. Chromatography of the residue utilizing 1% EtOH in CHCl3 as the elutant mixture provided product 239 mg (0.4 mmol, 51%). Rf= 0.19 (30:1 CHCl3-EtOH). MS(FAB) m/e 605(m+H)+, 448, 432, 420. 1H NMR(CDCl3,300MHz) δ 0.82(t,J=7Hz,3H), 0.89(t,J=7Hz,3H), 1.02-1.35(m,10H), 1.40-1.50(m,2H), 2.82-2.92(m,1H), 3.02-3.13(m,2H), 3.32(s,1H), 3.34(s,1H), 3.41-3.51(m,1H), S.01(d,J=14Hz,1H), 5.07(d,J=14Hz,1H), 5.43-5.52(m,1H), 6.93(dd,J=2,12Hz,1H), 7.06(d,J=2Hz,1H), 7.23(s,0.5H), 7.27-7.45(m,7.5H), 7.61(dt,J=1,8Hz,1H), 7.78-7.82(m,1H), 7.87(bd,J=8Hz,1H), 7.96(s,1H), 8.16(bd,J=8Hz,1H), 8.49(d,J=2Hz,1H), 9.32(s,J=2Hz,1H). Analysis calculated for C38H44N4O3, 1.5 H2O: C 72.24, H 7.50, N 8.87; found: C 71.91, H 7.12, N 8.63.
Example 54 N-(3'-(3''-Pyridyl)prop-2-enoyl)-R-Tryptophan-di-n-pentylamide
To a solution of the hydrochloride of example 2 (0.2 g, 0.53 mmol) and N-methylmorpholine (0.11 mL) in CH2Cl2 (10 mL) at 0°C was added HOBt (0.15 g, 1.06 mmol) and 3-(3'-pyridyl)acrylic acid (0.08 g, 0.53 mmol) followed by EDCI (0.11 g, 0.57 mmol). The reaction mixture was stirred overnight at ambient temperature. The solvents were evaporated in vacuo and after the addition of water the mixture was extracted with ethylacetate. The combined ethylacetate extracts were washed with a saturated solution of citric acid, water, a saturated solution of sodium bicarbonate, and brine. The solution was dried over MgSO4 and filtered. Concentration of the solution and chromatography of the residue using ethylacetate and hexane as the elutants provided 0.09 g (37%) of product. [α]D= +5.1° (c=0.75, MeOH). MS(CI) m/e 475(m+H)+, 344, 280. 1H NMR(CDCl3,300MHz) δ 0.8(t,J=7Hz,3H), 0.9(t,J=7Hz,3H), 1.08-1.3(m,8H), 1.32(m,4H), 2.8(m,1H), 2.9(m,1H), 3.05(m,1H), 3.25(d,J=6Hz,2H), 3.35(m,1H), 5.4(apparent q,J=6Hz,1H), 6.5(d,J=15Hz,1H), 6,8(d,J=9Hz,1H), 7.05(d,J=3Hz,1H), 7.15(m,2H), 7.3(m,2H), 7.63(d,J=15Hz,1H), 7.75(m,2H), 8.12(s,1H), 8.55(d,J=5Hz,1H), 8.7(s,1H). C,H,N analysis calculated for C29H38N4O2, 0.33 H2O: C 72.47, H 8.11, N 11.66; found: C 72.12, H 8.14, N 11.55.
Example 55 N-(3'-Pyridylcarbonyl)-R-Tryptophan-di-n-pentylamide
The hydrochloride of example 2 (0.15g, 0.4 mmol) was stirred in methylene chloride (CH2Cl2, 8 mL) with NMM (0.05 mL, 0.4 mmol) under nitrogen atmosphere at 0°C. EDCI (0.095g, 0.5 mmol), HOBt (0.1g, 0.8 mmol) and nicotinic acid (0.05g, 0.4 mmol) were added. The reaction mixture was allowed to stir at ambient temperature overnight. The solvents were removed in vacuo and ethylacetate and water added to the residue. The organic extract was separated and washed with citric acid, NaHCO3 solution, water, brine and then dried over MgSO4. The solution was filtered and concentrated in vacuo and residue subjected to chromatography using ethylacetate and hexane as the eluant mixture to provide 0.085 g (46%) of pure oily product. [α]D= -1.1° (c=0.9, MeOH). MS(CI) m/e 449(m+H)+, 158. 1H NMR(CDCl3,300MHZ) δ 0.8(t,J=7Hz,3H), 0.9(t,J=7Hz,3H), 0.95-1.4(m,12H), 2.75-2.8(m,1H), 2.95-3.1(m,2H), 3.3(d,J=6Hz,1H), 3.4(m,2H), 5.45(apparent q,J=6Hz,1H), 7.1(d,J=3Hz,1H), 7.15(m,2H), 7.3-7.4(m,3H), 7.8(d,J=9Hz,1H), 8.05(dt,J=3,6Hz,1H), 8.25(bs,1H), 8.7(dd,J=3,6Hz,1H), 9.0(d,J=2Hz,1H). C,H,N analysis calculated for C27H36N4O2, 0.75 H2O: C 70.17, H 8.18, N 12.13; found: C 70.04, H 8.16, N 12.53.
Example 56 N-(9'-Fluorenylidenylacetyl)-R-Tryptophan-di-n-pentylamide
EDCI (50 mg, 0.26 mmol) was added to a cooled (4°C) solution of fluorenylidene acetic acid (66 mg, 0.30 mmol), hydrochloride of example 2 (100 mg, 0.30 mmol), HOBt (7 mg, 0.05 mmol), and TEA (73 μL , 0.52 mmol) in CH2Cl2 (5 mL). The reaction was allowed to attain ambient temperature overnight. The solvents were evaporated and the residue was treated as in example 18. to provide the product. mp= 68-74°C. [α]D= +29.9° (c-1.08, MeOH).
MS(CI) m/e 548(m+H) +. 1H NMR(CDCl3,300MHz) δ 0.82(t,J=7Hz,3H),
0.88(t,J=7Hz,3H), 1.01-1.45(m,12H), 2.82-2.92(m,1H),
3.00-3.12(m,2H), 3.29-3.41(m,3H), 5.43-5.50(m,1H), 6.72(s,1H),
6.86(d,J=8Hz,1H), 7.09-7.28(m,6H), 7.33-7.40(m,3H),
7.62(bt,J=7Hz,2H), 7.78(dd,J=1,7Hz,1H), 8.02(s,1H),
8.14(d,J=8Hz,1H). C,H,N analysis calculated for C36H41N3O2: C
78.94, H 7.55, N 7.67; found: C 78.94, H 7.73, N 7.58.
Example 57 N-(2'-(3'-Methylindenyl)carbonyl)-R-Tryptophan-di-n-pentylamide EDCI (50 mg, 0.26 mmol) was added to a cooled (4°C) solution of 3-methylindene-2-carboxylic acid (45 mg, 0.26 mmol), hydrochloride of example 2 (100 mg, 0.30 mmol), HOBt (7 mg, 0.05 mmol), and TEA (73μL, 0.53 mmol) in CH2Cl2 (5 mL). The reaction was allowed to attain ambient temperature overnight. The solvents were evaporated and the residue was treated as in example 18. The crude product was purified by chromatography provide 86.5 mg, 0.17 mmol (67%). mp= 60-64°C. [α]D= -12.9° (c=1.11, MeOH). MS(CI) m/e 500(m+H)+, 326. 1H NMR(CDCl3,300MHz) δ 0.79(t,J=7Hz,3H), 0.88(t,J=7Hz,3H), 0.92-1.03(m,1H), 1.06-1.44(m,11H), 2.53(t,J=2Hz,3H), 2.76-2.86(m,1H), 2.95-3.06(m,2H), 3.28-3.31(m,2H), 3.33-3.45(m,1H), 3.59(t,J=2Hz,2H), 5.38-5.44(m,1H), 6.72(d,J=8Hz,1H), 7.06(d,J=2Hz,1H), 7.09-7.21(m,2H), 7.28-7.37(m,3H), 7.43-7.47(m,2H), 7.78(d,J=8Hz,1H), 8.06(s,1H).
C,H,N analysis calulated for C32H41N3O2, 0.25 H2O: C 76.23, H 8.30, N 8.33; found: C 76.38, H 8.23, N 8.30.
Example 58 N-(2'-(5'-Methoxy)indolylcarbonyl)-R-Tryptophan-di-n-pentylamide
EDCI (57 mg, 0.3 mmol) was added to a cooled (4°C) solution of 5-methoxyindole-2-carboxylic acid (57 mg, 0.3 mmol), hydrochloride of example 2 (100 mg, 0.30 mmol), HOBt (7 mg, 0.05 mmol), and TEA (84μL, 0.6 mmol) in CH2Cl2 (5 mL). The reaction was allowed to attain ambient temperature overnight. The solvents were evaporated and the residue was treated as in example 18. The crude product was purified by chromatography with 2:1 hexanes-EtOAc as the elutant (Rf= 0.54). Chloroform was used to transfer and consolidate fractions. mp= 73-82°C. [α]D= -18.0° (c=0.50, MeOH). MS(CI) m/e 517(m+H)+, 388, 329. 1H NMR(CDCl3,300MHz) δ 0.78(t,J=7Hz,3H), 0.88(t,J=7Hz,3H), 0.95-1.43(m,12H), 2.28-2.37(m,1H), 2.93-3.08(m,2H), 3.30(s,1H), 3.33(s,1H), 3.35-3.45(m,1H), 3.86(s,3H), 5.4-5.47(m,1H), 6.85(d,J=2Hz,1H), 6.94(dd,J=2,8Hz,1H), 7 . 05 ( t , J=3Hz , 2H ) , 7 . 11-7 .22 ( m,3H ) , 7 . 28 ( m , 2H ) ,
7.77(dd,J<1,7Hz,1H), 8.01(bs,1H), 9.18(bs,1H). C,H,N analysis calulated for C31H40N4O3, CHCl3: C 60.42, H 6.50, N 8.81; found: C 60.33, H 6.57, N 8.88.
Example 59 N-(4'-Hydroxy-3'-iodobenzoyl)-R-Tryptophan-di-n-pentylamide
EDCI (57 mg, 0.3 mmol) was added to a cooled (4°C) solution of 4-hydroxy-3-iodobenzoic acid (79 mg, 0.30 mmol), hydrochloride of example 2 (100 mg, 0.30 mmol), HOBt (13 mg, 0.1 mmol), and TEA (84μL, 0.6 mmol) in CH2Cl2 (5 mL). The reaction was allowed to attain ambient temperature overnight. The solvents were evaporated and the residue was treated as in example 18. The crude product was purified by chromatography on silica eluted with 2:1 to 1:1 hexanes-EtOAc. Chloroform was used to transfer the fractions. mρ= 71-80°C. [α]D= -2.8° (c=0.78, 1:1 DMF-MeOH). MS(CI) m/e 590(m+H)+, 464, 335. 1H NMR(CDCl3,300MHz) δ 0.81(t,J=8Hz,3H), 0.88(t,J=8Hz,3H), 1.01-1.08(m,2H), 1.10-1.52(m,10H), 2.93-3.18(m,3H), 3.28(s,1H), 3.31(s,1H), 3.38-3.46(m,1H), 5.32(apparent q,J=6Hz,1H), 6.84(d,J=7Hz,2H), 7.07(d,J=2Hz,1H), 7.13-7.22(m,2H), 7.34(d,J=6Hz,1H), 7.47(dd,J=2,7Hz,1H), 7.75(d,J=6Hz,1H), 7.98(d,J=2Hz,1H), 8.10(bs,1H). C,H,N analysis calculated for
C28H36IN3O3, 0.5 CHCl3: C 52.00, H 5.74, N 6.38; found: C 52.13, H 5.72, N 6.27.
Example 60 N-(t-Butyloxycarbonyl)-R,S-5-fluorotryptophan
In a manner similar to that in example 51 R,S-5-fluorotryptophan (2.0 g) was treated with 2.3 g of di-t-butyldicarbonate and after the standard workup provided 2.45 g (89%) of the desired product. MS (FAB) m/e 323(m+H)+, 295, 279, 267, 223. 1H NMR(CD3OD,300MHz) δ 7.27(dd,J=4,9.5Hz,1H), 7.22(dd,J=2.5,9.5Hz,1H), 7.14(s,1H), 6.85(dt,J=2.5,9Hz,1H), 4.88(bs,3H), 4.39(m,1H), 3.25(dd,J=5,14Hz,1H), 3.06(dd,J=7.5,14Hz,IH), 1.46(bs,9H).
Example 61 N-(t-Butyloxycarbonyl)-R,S-5-fluorotryptophan-di-n-pentylamide
In a manner similar to that in example 51, using the product of example 60 (879 mg), dipentyl amine (2 mL), and BOPCl (1.0 g), the product was obtained after standard purification (919 mg, 73%). mp= 134-5°C. MS(CI) m/e 462(m+H)+, 406, 362, 344. 1H NMR(CDCl3,300MHz) δ 8.03(bs,1H), 7.32(bdd,J=2,9.5Hz,1H), 7.2-7.25(m,1H), 7.07(d,J=2Hz,1H), 6.94(dt,J=2,9Hz,1H), 5.39(bd,J=9Hz,1H), 4.83(m,1H), 3.34(m,1H), 2.85-3.15(m,5H), 1.42(s,9H), 1.05-1.4(m,12H), 0.87(t,J=7Hz,3H), 0.80(t,J=7Hz,3H)
C,H,N analysis calculated for C26H40FN3O3: C 67.63, H 8.74, N 9.10; found: C 67.63, H 8.79, N 8.96.
Example 62 R,S-5-Fluorotryptophan-di-n-pentylamide hydrochloride
Employing similar procedures as in example 2 and using the product of example 61 (491 mg) and 8.0 mL of 4.5 M HCl in dioxane, the product hydrochloride salt was obtained in quantitative yield.
Example 63 N-(3'-Quinolylcarbonyl)-R,S-5-fluorotryptophan-di-n-pentylamide
In a fashion analogous to that in example 3, using the hydrochloride salt of example 62 (200 mg), EDCI (300 mg), HOBt (50 mg), quinoline-3-carboxylic acid (180 mg), and TEA (280 μL) in a DMF solution, the desired product (153 mg) was isolated in 59% yield after standard chromatography with EtOAc/hexane as th elutant mixture. mp= 62-5°C. MS(FAB) m/e 517(m+H)+, 362, 344, 332, 229. 1H NMR(CDCl3,300MHz) δ 9.30(d,J=2dz,1H), 8.52(d,J=2Hz,1H), 8.15(d,J=8.5Hz,1H), 8.10(bs,1H), 7 . 88 ( dd, J=0 . 7 , 8Hz , 1H ) , 7 . 80 ( d-t , J=1 . 5 , 7Hz , 1H ) ,
7.62(dt,J=1,7Hz,1H), 7.42(dd,J=2.5,9Hz,1H), 7.33(bd,J=8Hz,1H), 7.27(dd,J=4,9Hz,1H), 7.12(d,J=2.5Hz,1H), 6.94(dt,J=2.5,9Hz,1H), 5.45(m,1H), 3.42-3.50(m,1H), 3.32(m,2H), 3.03-3.13(m,2H), 2.85-2.95(m,1H), 1.05-1.5(m,12H), 0.84(t,J=7.5Hz,3H), 0.89(t,J=7.5Hz,3H). C,H,N analysis calculated for C31H37FN4O2: C 72.05, H 7.22, N 10.85; found: C 72.17, H 7.31, N 10.78.
Example 64 N-(2'-Indolylcarbonyl)-R,S-5-fluorotryptophandi-n-pentylamide
In a fashion analogous to that in example 3 using the hydrochloride salt of example 62 (200 mg), EDCI (300 mg), HOBt (50 mg) indole-2-carboxylic acid (150 mg), and TEA (280 μL ) in a DMF solution, the desired product (17 mg) was isolated in 62% yield after standard chromatography with EtOAc/hexane as the elutant mixture. mp= 78-82°C. MS(FAB) m/e 505(m+H)+, 362, 344, 320, 217. 1H NMR(CDCl3,300MHz) δ 9.30(bs,1H), 8.02(bs,1H), 7.65(bd,J=7.5Hz,1H), 7.41(m,2H), 7.22-7.30(m,3H), 7.14(t,J=7.5Hz,1H), 7.09(d,J=2Hz,1H), 6.92(dt,J=2.5,9Hz,2H), 5.39(m,1H), 3.37-3.45(m,1H), 3.27(m,2H), 3.0-3.1(m,2H), 2.85-2.95(m,1H), 1.0-1.45(m,12H), 0.87(t,J=7Hz,3H), 0.80(t,J=7Hz,3H). C,H,N anaysis calculated for C30H37FN4O2: C 71.39, H 7.40, N 11.10; found: C 71.14, H 7.43, N 10.97.
Example 65 (Nα,Ni-Dimethyl)-N-(3'-quinolylcarbonyl)-R-Tryptophan-di-n- pentylamide
The product from example 21 (10 mg, 0.02 mmol) was dissolved in
DMF (1 mL), cooled to 0°C and treated with lithium bis(trimethylsilyl)amide ( 60μL , 0.06 mmol, 1 M in THF) in one portion. After five minutes, methyliodide (3.7 μL , 0.06 mmol) was added in one portion. Additional lithium bis(trimethylsilyl)amide (30 μL ) and methyliodide (3.7 μL ) were added after 1 hour and the temperature was allowed to reach room temperature overnight. The solvents were evaporated and the residue was purified by chromatography on silica eluted with a step gradient from 4:1 to 2:1 hexanes-ethylacetate to provide the product. MS(CI) m/e 527(m+H)+, 370, 340. 1H NMR(CDCl3,300MHz) δ 0.80(t,J=7Hz,3H), 0.91(t,J=7Hz,3H), 1.13-1.58(m,12H), 3.07(s,3H), 3.16-3.26(m,2H), 3.31-3.58(m,4H) 3.76(s,3H), 6.04( t,J=8Hz,1H), 7.02(s,1H), 7.17(dt,J=1,8Hz,1H), 7.24-7.33(m,2H), 7.59(t,J=7Hz,1H), 7.73-7.82(m,2H), 7.87(d,J=1Hz,1H), 8.12(d,J=9Hz,1H), 8.75(d,J=1Hz,1H).
Example 66 N-(p-Toluenesulfonyl)-R-Tryptophan-di-n-pentylamide
The product of example 2 (50 mg, 0.13 mmol) was dissolved in methylene chloride (2 mL) and treated with p-toluenesulfonyl chloride (25 mg, 0.13 mmol) and TEA (18 μL , 0.13 mmol). After 5 hours, additional TEA (18 μL ) was added and the reaction was left overnight. The solvent was evaporated to provide 67 mg of crude product. Rf= 0.23 (18:1 CHCl3-EtOH); 0.62 (1:1 hexanes-ethylacetate). MS(CI) m/e 498(m+H)+, 515(m+NH4)+, 344. 1H NMR(CDCl3,300MHz) δ 0.88(t,J=7Hz,3H), 0.96(t,J=7Hz,3H), 0.98-1.22(m,12H), 2.38(s,3H), 2.52-2.75(m,2H), 2.84-2.96(m,1H), 2.99-3.08(m,1H), 3.10(s,1H), 3.12(s,1H), 4.33-4.42(m,1H), 5.77(d,J=12Hz,1H), 7.05-7.14(m,2H), 7.18(d,J=7Hz,2H), 7.26(s,2H), 7.32(dt,J=8,1Hz,1H), 7.50(bd,J=7Hz,1H), 7.67(d,J=8Hz,2H), 8.0(s,1H).
Example 67 N-(p-Chlorobenzenesulfonyl)-R-Tryptophan-di-n-pentylamide
The product from example 2 (500 mg, 1.31 mmol) was treated with p-chlorobenzene sulfonylchloride (277 mg, 1.31 mmol) and TEA (362 μL, 2.6 mmol) in methylene chloride (15 mL) at room temperature overnight. The solvents were evaporated and the residue in ethylacetate was extracted with 0.1% citric acid, 0.1 M sodium bicarbonate and water, then dried over magnesium sulfate and the filtrate concentrated. Rf= 0.88 (1:1 hexanes-ethylacetate). The crude residue was crystallized from aqueous ethanol to provide 478 mg, 0.95 mmol (73%). MS ( FAB ) m/e 518(m+H)+, 484, 344, 326. 1H NMR( DMSOd6 ,300MHz ) δ 0.71(t,J=7Hz,3H), 0.82(t,J=7Hz,5H), 0.91-1.27(m,10H), 2.65-3.07(m,6H), 4.21-4.29(m,1H), 6.93(t,J=7Hz,1H), 7.02-7.07(m,3H), 7.25-7.31(m,2H), 7.53(d,J=8Hz,2H), 7.70(d,J=8Hz,1H), 8.50(d,J=9Hz,1H), 10.83(bs,1H). C,H,N analysis calculated for C27H36ClN3O3S, 0.1 H2O: C 62.38, H 7.02, N 8.08; found: C 62.26, H 6.86, N 8.10.
Example 68 N-(p-Chlorobenzoyl)-Ni-acetyl-2,3-dihydro-R-Tryptophan- di-n-pentylamide
The product from example 4 (500 mg, 1.0 mmol) was treated with 10% Pd/C (200 mg) in acetic acid (30 ml) under 3 atmospheres of hydrogen gas overnight in a Paar shaker. After filtration of the catalyst, the solution was treated with excess acetic anhydride (283 μL , 3.0 mmol). After completion of the acetylation, the solvent was evaporated and the residue was purified by chromatography on silica gel to provide the product.
Example 69 N-(3'-Quinolylcarbonyl)-R-(β-oxyindolyl)Ala-di-n-pentylamide
The product of example 78 (121 mg, 0.24 mmol) was dissolved in dioxane (10 mL) and treated with concentrated hydrochloric acid (1 mL). A red colored solution formed immediately which bleached in 10-15 seconds to provide a colorless solution. After several hours, the reaction mixture was poured into EtOAc and washed until neutral then dried over MgSO4. The crude product was purified by chromatography on silica eluted with a step gradient from 1-5% EtOH in CH2Cl2 to provide product 97 mg (0.19 mmol, 79% yield). MS(CI) m/e 515(m+H)+, 369, 358. 1H NMR(CDCl3,300MHz) δ 0.85-0.96 m,6H), 1.24-1.38(m,8H), 1.48-1.61(m,4H), 1.69(s,H2O), 2.16(ddd,J=3,8,14Hz,0.6H), 2.32(ddd,J=3,8,14Hz,0.4H), 2.50-2.62(m,1H), 3.03-3.16(m,0.6H), 3.18-3.29(m,0.4H), 3.34-3.45(m,1H), 3.51-3.64(m,1.6H), 3.92(m,1H), 5.32 (dt,J=2,8Hz,0.4H), 5.53 (dt,J=2,10Hz,0.6H), 6.82(d,J=7Hz,0.6H), 6.37(d,J=7Hz,0.4H), 6.98-7.06(m,1H), 7.12(t,J=7Hz,1H), 7.20(t,J=8Hz,1H), 7.45(d,J=7Hz,0.6H), 7.52-7.58(m,0.4H), 7.62(t,J=8Hz,1H), 7.72-7.88(m,2H), 8.02(d,J=8Hz,0.4H), 8.08(d,J=8Hz,0.6H), 8.12-8.15(m,1H), 8.37(s,0.4H), 8.42(d,J=2Hz,0.6H), 8.62(d,J=2Hz,0.4H), 9.20(d,J=2Hz,0.6H), 9.34(d,J=2Hz,0.4H). C,H,N analysis calculated for C31H38N4O3, 0.3 H2O: C 71.59, H 7.48, N 10.77; found: C 71.55, H 7.40, N 10.61.
Example 70 Methyl N-(Diphenylmethylene)-R-Tryptophanate
Benzophenone imine (1.0 g, 5.5 mmol) and R-Tryptophan methyl ester hydrochloride (5.5 mmol) were stirred in 20 mL of anhydrous CH2Cl2 overnight. The ammonium hydrochloride was filtered away and the solvents removed in vacuo. The residue was taken up in diethylether and filtered and the filtrate washed with water and dried over MgSO4. The solution was filtered, concentrated and the remainder crystallized from diethylether/hexane. mp= 112-112.5°C. MS(EI) m/e 382(m)+, 323, 253, 193. 1H NMR(CDCl3,300MHz) δ 7.92(bs,1H), 7.59(m,2H), 7.10-7.40(m,9H), 6.97(bd,J=3Hz,1H), 6.92(m,1H), 6.60(bd,J=7Hz,2H), 4.41(dd,J=5,8.5Hz,1H), 3.72(s,3H), 3.47(dd,J=5,15Hz,1H), 3.23(dd,J=8.5,15Hz,1H) C,H,N analysis calculated for C25H22N2O2: C 78.50, H 5.80, N 7.33; found: C 78.22, H 5.89, N 7.05.
Example 71 Methyl N-(Diphenylmethylene)-α-allyl-Tryptophanate
The product of example 70 (222 mg), potassium carbonate (260 mg), and tetrabutylammonium hydrogensulfate (27 mg) were stirred at ambient temperature in 4 mL of CH2Cl2. To this mixture was added allylbromide (60 μL ) and the reaction stirred overnight. The mixture was partitioned between water and ethylacetate and the ethylacetate solution was dried over MgSO4 and filtered. Concentration of the filtrate and chromatography of the residue using ethylacetate and hexane as the elutants provided product.
Example 72 Methyl N-(t-Butyloxycarbonyl)-α-allyl-Tryptophanate
The product of example 71 was stirred in dioxane (2 mL) and 3.0 N HCl (3.0 mL) was added to the solution. When tlc analysis indicated that the product had fully reacted, the mixture was carefully neutralized with solid NaHCO3 while cooling. The reaction was made slightly basic and an excess of di-t-butyldicarbonate was added. After an hour at ambient temperature the mixture was partioned between water and ethylacetate. The ethylacetate was dried over MgSO4 and filtered. Chromatography of the concentrated residue yielded product. 1H NMR(CDCl3,300MHz) δ 7.55(bd,J=7.5Hz,1H), 7.25(m,1H), 7.20(dt,J=1,7Hz,1H), 7.10(bt,J=7Hz,1H), 6.90(bs,1H), 5.97(ddt,J=5,10.5,16.5Hz,1H), 5.18(bd,J=10.5Hz,1H), 5.06(m,2H), 4.68(m,3H), 3.68(s,3H), 3.28(m,2H), 1.42(bs,9H).
Example 73 N-(t-Butyloxycarbonyl)-α-allyl-Tryptophan-di-n-pentylamide
The product of example 72 was treated with 1.0 N NaOH in dioxane at ambient temperature. When tlc indicated that the starting material had been consumed, the reaction mixture was concentrated in vacuo and partioned between water and ethylacetate. The aqueous portion was separated and acidified to pH 2.0 and extracted sucessively with EtOAc. The extracts were dried over MgSO4 and the solution filtered and concentrated. The crude product was treated directly as in example 51 to provide product after chromatography using EtOAc/hexanes as the elutant. Example 74 N-(3'-Quinolylcarbonyl)-α-allyl-Tryptophan-di-n-pentylamide
The product of example 73 was treated with 4.5 N HCl in dioxane as in example 2 to provide product which was used directly in a coupling reaction analogous to that described in example 21. The product was purified by chromatography using EtOAc and hexane.
Example 75 Nα-t-Butyloxycarbonyl-Ni(t-butyloxycarbonylmethyl)-R-Tryptophan- di-n-pentylamide
The product of example 1 (150 mg, 0.34 mmol) was dissolved in 6 mL of DMF and treated with lithium bis(trimethylsilyl) amide (340 μL, 0.34 mmol, 1.0 M in THF ) followed by t-butylbromoacetate (65 μL, 0.4 mmol). After two hours, the reaction was quenched with saturated ammonium chloride and then poured into ethylacetate and extracted and purified as in example 67 to provide a quantitative yield of product. Rf= 0.5
(2:1 hexane-ethylacetate). MS(CI) m/e 558(m+H) , 502, 458, 440.
1H NMR(CDCl3,300MHz) δ 0.78(t,J=7Hz,3H), 0.88(t,J=7Hz,3H), 1.05-1.44(m,30H), 1.44(s,H2O), 2.7-2.8(m,1H), 2.85-3.08(m,2H), 3.12-3.15(m,2H), 3.26-3.38(m,1H), 4.65(s,2H), 4.83-4.92(m,1H), 5.42(d,J=8Hz,1H), 6.91(s,1H), 7.08-7.20(m,3H), 7.69(d,J=7Hz,1H)
Example 76 Ni-(Carboxymethyl)-R-Tryptophan-di-n-pentylamide hydrochloride
The product of example 75 (225 mg, 0.4 mmol) was dissolved in 20 mL of 4 N HCl in dioxane. After 5 hours, an additional 20 mL of acid was added and the reaction was continued overnight. The excess reagent was evaporated and the residue was used directly in the next step. Rf= 0.16 (10:3 EtOAc-PAW). PAW= (20:11:6 pyridine-H2O-acetic acid). Example 77 Nα-Quinolylcarbonyl-Ni-(carboxymethyl)-R-Tryptophan di-n-pentylamide
Nα-Quinoline-3-(N-hydroxysuccinimide) ester (95 mg, 0.35), and the product of example 76 (0.3 mmol assumed) were dissolved in 10 mL of methylene chloride and treated with TEA (49 μL , 0.35 mmol). Additional ester (95 mg) and TEA (49 μL) were added after 1 and again at 2 days. The solvents were evaporated and the residue was extracted as in example 67 and then purified by chromatography eluting with 90:10:0.5 methylene chloride-ethanol-ammonium hydroxide to provide 71 mg, 0.13 mmol (37%) as a yellow glass. Rf= 0.3 (80:20:1 chloroform-methanol-ammonium hydroxide). MS(CI) m/e 557(m+H)+, 400, 372, 340. 1H NMR(DMSOd6,300MHz) δ 0.76(t,J=7Hz,3H), 0.83(t,J=7Hz,3H), 1.03-1.42(m,12H), 3.05-3.4(m,6H), 3.4(bs,H2O), 4.73(s,2H), 5.14(m,1H), 7.02(t,J=7Hz,1H), 7.08(t,J=7Hz,1H), 7.18(s,1H), 7.28(d,J=7Hz,1H), 7.55(d,J=7Hz,1H), 7.71(d,J=8Hz,1H), 7.86(dt,J=1,7Hz,1H), 8.10(t,J=7Hz,1H), 8.88(d,J=2Hz,1H), 9.20(d,J=8Hz,1H), 9.26(d,2Hz,1H). C,H,N analysis calculated for
C33H40N4O4, 0.5 NH3, 1.9 H2O: C 66.12, H 7.62, N 10.52; found: C 66.18, H 7.24, N 10.58.
Example 78 2,3-Dihydro-1-(3'-quinolylcarbonyl)-pyrrolo[2,3-b]indole- (2R)-dipentylcarboxamide
The product of example 21 (2.5 g, 5.0 mmol) was dissolved in 50 mL of methylene chloride and cooled to 4°C. Then TEA (2.8 mL, 20 mmol) was added in one portion followed by the addition of t-butylhypochlorite (0.57 mL, 5.0 mmol) over 10 minutes (cf. Ohne, Spande and Witkop J Amer Chem Soc, 92(2), 343, 1970). The reaction was allowed to attain room temperature overnight. The reaction solution was washed with water then dried over MgSO4. The solution was filtered and the filtrate concentrated. The residue was mixed with 4:1 hexane-ethylacetate and the resulting solid was filtered to provide 1.43 g, 2.9 mmol (58%). mp= 145-53°C. [α]D= +172° (c=1.04, CH2Cl2). MS(CI) m/e 497(m+H)+. 1H NMR(CDCl3,300MHz) δ 0.74(t,J=7Hz,3H), 0.78(t,7Hz,3H), 0.85-1.13(m,12H), 1.26-1.34(m,1H), 2.85-2.94(m,3H), 3.05-3.13(m,3H), 5.50(dd,J=3,10Hz,1H), 7.11-7.13(m,2H), 7.32-7.39(m,2H), 7.52(t,J=7Hz,1H), 7.8(dt,J=1,7Hz,1H), 7.86(d,J=7Hz,1H), 8.13(d,J=8Hz,1H), 8.35(d,J=2Hz,1H), 9.06(d,J=2Hz,1H), 9.38(s,1H). C,H,N analysis calculated for
C31H36N4O2, 0.4 H2O: C 73.90, H 7.36, N 11.12; found: C 73.92, H 7.40, N 11.21.
Example 79 Nα-(3'-Quinolylcarbonyl)-R-(2-phenylthio)Tryptophan di-n-pentylamide
The product of example 78 (50 mg, 0.1 mmol), NH4HCO3 (0.5M, 400 μL , 0.2 mmol) and thiophenol (103 μL , 1.0 mmol) were dissolved in 1 mL of dioxane and stirred overnight at 55°C. The reaction was poured into 0.1 M citric acid and extracted with ethylacetate then washed with water, dried over MgSO4, filtered and the filtrate concentrated. The residue was then purified by chromatography on silica gel eluted with a methylene chloride to 20:1 methylene chloride-ethanol step gradient to provide 14.5 mg, 0.024 mmol (24%). MS(CI) m/e 607(m+H)+, 497, 158; MS ( FAB) m/e 607(m+H)+, 422, 325. 1H NMR( CDCl3 ,300MHz) δ 0.74-0.83(m,6H), 1.0-1.45(m,12H), 2.94-3.11(m,2H), 3.18-3.42(m,4H), 5.4(apparent q,J=8Hz,1H), 6.96-7.27(m,7H), 7.51(dt,J=1,7Hz,1H), 7.67-7.73(m,3H), 8.04(dd,J=1,8Hz,1H), 8.28(d,J=2Hz,2H), 9.10(d,J=2Hz,1H).
Example 80 Nα-(3'-Quinolylcarbonyl)-R-(2-butylthio)Tryptophan- di-n-pentylamide
The product of example 78 (250 mg, 0.5 mmol), sodium bicarbonate (63 mg, 0.75 mmol) and n-butanethiol (5 mL, 47 mmol) were dissolved in 5 mL DMF and warmed to 60°C for 4 days. The solvent was evaporated and the residue in ethylacetate was extracted as in example 67. The residue was purified by chromatography on silica gel eluted with a 10:1 to 4:1 methylene chloride-ethylacetate step gradient to provide 89 mg, 0.15 mmol (30%) and 121 mg (48%) of recovered starting material. MS(CI) m/e 587(m+H)+, 325. 1H NMR( CDCl3 ,300MHz) δ 0.84-0.91(m,9H), 1.1-1.62(m,16H), 2.78(dt,J=1,8Hz,2H), 2.96-3.06(m,1H), 3.09-3.30(m,2H), 3.34-3.45(m,3H), 5.45(apparent q,J=7Hz,1H), 7.12(dt,J=1,8Hz,1H), 7.19(dt,J=1,8Hz,1H), 7.31(t,J=7Hz,2H), 7.59(dt,J=1,8Hz,1H), 7.73-7.85(m,3H), 8.10(s,1H), 8.13(d,J=8Hz,1H), 8.41(d,J=2Hz,1H), 9.23(d,J=2Hz,1H). C,H,N analysis calculated for C35H46N4O2S: C 71.63, H 7.90, N 9.55; found: C 71.54, H 7.97, N 9.42.
Example 81 Nα-t-Butyloxycarbonyl-R-5-hydroxytryptophan
Di-t-butyldicarbonate (327 mg, 1.5 mmol) was added to 5-hydroxy-R-Tryptophan (250 mg, 1.14 mmol) and TEA (167 μL, 1.2 mmol) in 10 mL THF and 5 mL of water. After 1 day, the solvent was evaporated and the residue in ethylacetate was extracted with 0.1 M citric acid and water then dried over MgSO4 and the filtrate concentrated. The product was used directly in the next step.
Example 82 Nα-t-Butyloxycarbonyl-R-5-hydroxytryptophan-di-n-pentylamide
The product of example 81 (1.5 mmol assumed) and dipentylamine (760 μL, 3.75 mmol) were dissolved in 20 mL methylene chloride and treated with BOPCl (382 mg, 1.5 mmol) overnight. The solvents were evaporated and the residue was extracted as in example 81 followed by chromatography on silica gel eluted with a 4:1 to 1:1 hexane-ethylacetate step gradient to provide 288 mg, 0.63 mmol (42% yield). mp= 60-65°C. MS(CI) m/e 460(m+H)+, 404, 360, 342. 1H NMR( CDCl3 ,300MHz) δ 0.77(t,J=7Hz,3H), 0.85(t,J=7Hz,3H), 0.95-1.38(m,12H), 1.43(s,9H), 2.68-2.78(m,1H), 2.82-2.93(m,1H), 2.98-3.15(m,3H), 3.26-3.36(m,1H), 4.83-4.92(m,1H), 5.52(d,J=8Hz,1H), 5.80(s,1H), 6.78(dd,J=2,8Hz,1H), 6.98(d,J=2Hz,1H), 7.16(s,1H), 7.18(d,J=8Hz,1H), 7.93(s,1H).
Example 83 R-5-Hydroxytryptophan-di-n-pentylamide hydrochloride
The product of example 82 (270 mg, 0.59 mmol) was treated with 5 mL of 4 N HCl/dioxane for 1 hour. The excess acid and solvents were evaporated and the residue was placed on high vacuum overnight to provide 243 mg, 0.6 mmol, quantitative yield.
Example 84 Nα-(3'-Quinolylcarbonyl)-R-5-hydroxytryptophan-di-n-pentylamide
Quinoline-3-carboxylic acid (26 mg , 0.15 mmol), the product of example 83 (50 mg, 0.13 mmol) and TEA (21 μL , 0.15 mmol) were dissolved in 5 mL of 1:1 THF and treated with EDCI (29 μL , 0.15 mmol) overnight. The solvent was evaporated and the residue in ethylacetate was extracted with 0.1 M citric acid and water. After drying over MgSO4, the filtered solution was concentrated and then placed under high vacuum overnight to provide 72 mg, 0.14 mmol (93%) as a glass. mp= 78-90°C. MS(CI) m/e 515(m+H)+, 358, 342, 330. 1H NMR( CDCl3 ,300MHz) δ 0.69(t,J=7Hz,3H), 0.76(t,J=7Hz,3H), 0.82-1.28(m,12H), 2.84-3.12(m,3H), 3.22(dd,J=4,14Hz,1H), 3.51(d,J=2Hz,1H), 3.60(dd,J=10,14Hz,1H), 5.43(dt,J=4,8Hz,1H), 6.88(dd,J=2,8Hz,1H), 7.10(d,J=2Hz,1H), 7.22(d,J=8Hz,1H), 7.40(d,J=2Hz,1H), 7.62(dt,J=1,7Hz,1H), 7.82(dt,J-l,7Hz,1H), 7.90(dd,J=1,8Hz,1H), 8.01(d,J=2Hz,1H), 8.23(d,J=8Hz,1H), 8.49(d,J=8Hz,1H), 8.62(s,1H),
8.72(d,J=1Hz,1H), 9.62(d,J=2Hz,1H). C,H,N analysis calculated for C31H38N4O3, 0.5 H2O: C 71.10, H 7.51, N 10.70; found: C 71.23, H 7.50, N 10.45. Example 85 Nα-(3'-Quinolylcarbonyl)-R-Tryptophyl-3,5-dimethylpyrazylide
Nα-(3'-Quinolylcarbonyl)-R-Tryptophan (360 mg, 1.0 mmol), 3,5-dimethylpyrazole (96 mg, 1.0 mmol) and HOBt (270 mg, 2.0 mmol) were dissolved in 10 mL of methylene chloride and treated with EDCI (197 mg, 1.0 mmol) at 4°C and allowed to attain room temperature overnight. TEA (140 μL , 1.0 mmol) was added after 1 day as well as additional pyrazole (10 mg) and EDCI (20 mg). After 2 days, the solvents were evaporated and the residue was extracted and purified as in example 67. MS(FAB) m/e 438(m+H)+, 342, 314, 265. 1H NMR(DMSOd6,300MHz) δ 2.12(s,2H), 2.36(S,3H), 2.52(s,3H), 3.22-3.49(m,2H), 5.96-6.02(m,1H), 6.32(s,1H), 7.02-7.11(m,2H), 7.32-7.36(m,2H), 7.71(dt,J=1,8Hz,1H), 7.38(dt,J=1,7Hz,1H), 7.94(dd,J=1,7Hz,1H), 8.10(dt,J=<1,7Hz,2H), 8.83(d,J=2Hz,1H), 9.21-9.24(m,2H), 10.85(d,J=1Hz,1H). C,H,N analysis calculated for C26H23N5O2, 0.5 H2O: C 69.94, H 5.42, N 15.69; found: C 70.11, H 5.47, N 15.23.
Example 86
Nα-(3'-Quinolylcarbonyl)-R-Tryptophan(bis(2'-hydroxyethyl))amide
Nα-(3'-Quinolylcarbonyl)-R-Tryptophan (150 mg, 0.49 mmol) and diethanolamine (240 μL , 2.5 mmol) were dissolved in 10 mL THF and treated with BOPCl (127 mg, 0.50 mmol) and stirred overnight. The solvents were evaporated and the residue was purified by chromatography on silica gel eluted with 20:1 methylene chloride-ethanol to provide 144 mg, 0.32 mmol (66%). Rf= 0.52 (80:20:1 chloroform-methanol-ammonium hydroxide). MS(CI) m/e 447(m+H)+, 429, 342, 274. 1H NMR(CDCl3-D2O,300MHz) δ 3.20(s,1H), 3.23-3.40(m,3H), 3.44-3.52(m,4H), 3.54-3.62(m,2H), 5.27(dd,J=6,8Hz,1H), 7.02(t,J-7Hz,1H), 7.11(t,J=7Hz,1H), 7.27(s,1H), 7.37(d,J=8Hz,1H), 7.71(d,J=8Hz,1H), 7.76(d,J=7Hz,1H), 7.93(dt,J=1,7Hz,1H), 8.10(d,J=8Hz,2H), 8.29(d,J=2Hz,1H), 9.17(d,J=2Hz,1H). C,H,N analysis calculated for C25H26N4O4, 0.7 H2O: C 65.40, H 6.02, N 12.20; found: C 65.58, H 6.03, N 11.89.
Example 87 Nα-(3'-Quinolylcarbonyl)-R-Tryptophan(N-ethoxyethyl, N-2'hydroxyethyl)amide
The product of example 86 (50 mg, 0.112 mmol) was dissolved in 5 mL of DMF and treated with lithium bis(trimethlysilyl)amide (220 μL , 0.110 mmol, 0.5 M in toluene) and ethyliodide (38 μL, 0.48 mmol). The crude reaction mixture was purified by chromatography on silica gel eluted with 1% ethanol in methylene chloride to provide product. mp= 195-8°C. [α]D= +38.4 (c=0.63, DMF). MS (FAB) m/e 475(m+H)+. 1H NMR( CDCl3 ,300MHz) δ 1.42(t,J=7Hz,3H), 3.08(dq,J=2,15Hz,1H), 3.35-3.80(m,9H), 4.06(bs,1H), 4.13(q,J=7Hz,2H), 4.95-5.03(m,1H), 7.13(dt,J=1,7Hz,2H), 7.2-7.27(m,2H), 7.35(d,J=8Hz,1H), 7.56(dt,J=1,7Hz,1H), 7.72(t,J=7Hz,1H), 7.79(dt,J=1,7Hz,1H), 7.92(d,J=7Hz,1H), 8.11(d,J=8Hz,1H), 8.33(d,J=2Hz,1H), 9.22(d,J=2Hz,1H). C,H,N analysis calculated for C27H30N4O4, 1.0 H2O: C 65.84, H 6.55, N 11.37; found: C 65.64, H 6.02, N 11.13.
Example 88
Nα-(3'-Quinolylcarbonyl)-R-Tryptophan-(bis(ethoxyethyl)amide
The product of example 86 (60 mg, 0.134 mmol) was dissolved in 5 mL of DMF and treated with lithium bis(trimethylsilyl)amide (540 μL , 0.27 mmol, 0.5 M in toluene) and ethyliodide (43 μL , 0.54 mmol). After 2 hours, additional base (270 μL ) and ethyliodide (43 μL ) were added and the reaction was stirred overnight. The solvents were evaporated and the residue was treated as in example 81 to provide 68 mg, 0.14 mmol (quantitative). MS(CI) m/e 503(m+H)+, 485, 457, 398, 330. 1H NMR( CDCl3 ,300MHz) δ 1.06(t,J=7Hz,1.5H), 1.15(t,J-7Hz,1.-H), 1.37-1.46(m,3H), 3.2-3.68(m,12H), 4.13(q,J=7Hz,2H), 5.47-5.59(m,1H), 7.05-7.38(m,5H), 7.57-7.87(m,5H), 8.08-8.17(m,1H), 8.43(d,J=2Hz,0.5H), 8.50(d,J=2Hz,0.5H), 9.25(d,J=2Hz,0.5H), 9.32(d,J=2Hz,0.5H).
Example 89 Nα-(3'-Quinolylcarbonyl)-R-Tryptophan-(N-benzyloxyethyl, N-hydroxyethyl)amide (a) Nα-(3'-Quinolylcarbonyl)-R-Tryptophan-(bis(benzyloxyethyl)amide
(b)
The product of example 86 (50 mg, 0.112 mmol) was alkylated with benzylbromide (13 μL , 0.11 mmol) as in example 87. Chromatography on silica gel eluted with a 1% to 5% ethanol in methylene chloride in a step gradient to provide 8.0 mg of dialkylated (b) and 23.2 mg of monoalkylated (a) product. Monoalkylated (a): MS(FAB) m/e 537(m+H)+, 307, 220, 185. 1H NMR(CDCl3,300MHz) δ 3.03(dq,J=3,15Hz,1H), 3.4-3.68(m,8Hz), 3.76-3.86(m,2H), 4.02(bs,1H), 4.60(bs,1H), 5.23(s,2H), 5.50(apparent q,J=7Hz,1H), 7.01-7.22(m,7H), 7.30(d,J=8Hz,1H), 7.49-7.56(m,2H), 7.72(d,J=8Hz,1H), 1.74-7.79(m,1H), 8.06(dd,J=<1,8Hz,1H), 8.16(d,J=2Hz,1H), 8.38(d,J=7Hz,1H), 9.16(d,J=2Hz,1H). C,H,N analysis calculated for C32H32N4O4, 3.5 H2O: C 64.09, H 6.56, N 9.34; found C 64.36, H 5.55, N 8.99. Dialkylated (b): MS(FAB) m/e 627(m+H)+, 460, 404, 307, 220. 1H NMR(CDCl3,300MHz) δ 3.30-3.45(m,5H), 3.5-3.66(m,5H), 4.26(d,J=14Hz,0.5H), 4.32(d,J=14Hz,0.5H), 4.37(s,1H), 5.22(s,1H), 5.23(s,1H), 5.47-5.56(m,1H), 7.03-7.38(m,16H), 7.56-7.63(m,1H), 7.70-7.84(m,3H), 8.12-8.17(m,1H), 8.38(d,J=2Hz,0.5H), 8.42(d,J=2Hz,0.5H), 9.22(d,J=2Hz,0.5H), 9.28(d,J=2Hz,0.5H).
Example 90 N'(8'-Hydroxy-2'-quinolylcarbonyl)-R-Tryptophan-di-n-pentylamide
In a manner similar to example 58, 8-Hydroxyquinoline-2- carboxylic acid (50 mg, 0.26 mmol) was coupled to the product of example 2 (100 mg, 0.26 mmol). The concentrated residue after extraction and drying was crystallized from ethylacetate-hexane to provide 86 mg, 0.16 mmol (60% yield). Rf= 0.4 (30:1 methylene chloride-ethanol). MS(CI) m/e 515(m+H)+, 189, 158. 1H NMR(CDCl3, 300MHz) δ 0.80(t,J=7Hz,3H), 0.85(t,J=7Hz,3H), 1.0-1.32(m,9H), 1.35-1.5(m,3H), 2.85-3.12(m,3H), 3.38(S,1H), 3.41(s,1H), 3.43-3.52(m,1H), 5.45-5.53(m,1H), 7.10-7.23(m,4H), 7.33(t,J=1Hz,1H), 7.37(t,J=1Hz,1H), 7.52(t,J=8Hz,1H), 7.81(d,J=7Hz,1H), 8.02(s,1H), 8.07(s,1H), 8.23(s,2H), 8.85(d,J=8Hz,1H). C,H,N analysis calculated for C31H38N4O3: C 72.34, H 7.44, N 10.89; found: C 72.38, H 7.61, N 10.66
Example 91 N-(4',8'-Dihydroxy-2'-quinolylcarbonyl)-R-Tryptophan- di-n-pentylamide
In a manner similar to example 58, 4,8-dihydroxyquinoline-2-carboxylic acid (205 mg, 1.0 mmol) was coupled to the product of example 2 (380 mg, 1.0 mmol). After 3 days, the reaction mixture was concentrated and the crude product residue was purified by chromatography on silica gel eluted with 1% to 6% ethanol in methylene chloride step gradient to provide 59 mg, 0.11 mmol (11%). Rf= 0.41 (18:1 methylene chloride-ethanol). MS(FAB+) m/e 531(m+H)+, 375, 346, 328. 1H NMR( CD3OD, 300MHz) δ 0.77(t,J=7Hz,3H), 0.87(t,J=7Hz,3H), 0.94-1.45(m,12H), 2.97-3.13(m,3H), 3.23-3.45(m,3H), 5.33-5.39(m,1H), 7.01-7.15(m,4H), 7.32-7.40(m,3H), 7.65-7.72(m,2H). C,H,N analysis calculated for C31H38N4O4, 0.5 H2O: C 68.99, H 7.28, N 10.38; found: C 69.06, H 7.24, N 10.30.
Example 92 N-(6'-Acetoxy-2'-naphthoyl)-R-Tryptophan-di-n-pentylamide
In a manner similar to example 58, 6-Acetoxynaphthalene-2-carboxylic acid (230 mg, 1.0 mmol), the product of example 2 (380 mg, 1.0 mmol) were coupled with EDCI. After 2 days, the solvents were evaporated and the residue was extracted with 0.1 M citric, 0.1 M NaHCO3, H2O and dried over MgSO4. The residue from evaporation of the volatiles was purified by chromatography on silica gel eluted with 20:1 methylene chloride-ethanol solvent system to provide 467 mg, 0.87 mmol (87% yield). MS(CI) m/e 556(m+H)+, 514. 1H NMR( CDCl3,300MHz) δ 0.79(t,J=7Hz,3H), 0.89(t,J=7Hz,3H), 0.97-1.48(m,12H), 2.38(s,3H), 2.78-2.88(m,1H), 2.96-3.08(m,2H), 3.32-3.48(m,3H), 5.43-5.52(m,1H), 7.07(d,J=3Hz,1H), 7.12(dt,J=1,7Hz,1H), 7.19(dt,J=1,7Hz,1H), 7.26-7.36(m,3H), 7.59(d,J=2Hz,1H), 7.80-7.92(m,4H), 8.06(s,1H), 8.28(s,1H). C,H,N analysis calculated for C34H41N3O4, H2O: C 73.22, H 7.77, N 7.53; found: C 72.92, H 7.52, N 7.42.
Example 93 N-(6'-Hydroxy-2'-naphthoyl)-R-Tryptophan-di-n-pentylamide
The product of example 92 (200 mg, 0.37 mmol) was dissolved in 10 mL methanol and treated with 1 N NaOH (37 μL, 0.37 mmol). After 3 hours, the solvents were evaporated and the residue was extracted with 0.1% citric acid and water then dried over MgSO4. The cocentrated filtrate was purified by chromatography on silica gel eluted with 4:1 hexanes-ethylacetate to provide a quantitative yield of product. MS(CI) m/e 514(m+H)+, 327, 158. 1H NMR(CDCl3,300MHz) δ 0.82(t,J=7Hz,3H), 0.91(t,J=7Hz,3H), 1.03-1.37(m,9H), 1.44-1.62(m,3H), 3.08-3.24(m,3H), 3.38-3.51(m,3H), 5.41(apparent q,J=8Hz,1H), 6.91(d,J=1Hz,1H), 6.92(d,J=8Hz,1H), 7.03(dd,J=2,9Hz,1H), 7.10(d,J=2Hz,1H), 7.14-7.26(m,3H), 7.29(d,J=9Hz,1H), 7.35-7.44(m,2H), 7.57(d,J=1Hz,1H), 7.82(dd,J=1,7Hz,1H), 8.16(d,J=2Hz,1H), 9.22(s,1H). C,H,N analysis calculated for C32H39N3O3: C 74.79, H 7.50, N 8.18; found: C 74.76, H 7.71, N 8.12.
Example 94 N-Benzyloxycarbonyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid 1,2,3,4-Tetrahydro-isoquinoline-3-carboxylic acid (500 mg, 2.3 mmol) and Cbz-OSu (874 mg, 3.5 mmol) were dissolved in 30 mL of 1:1:1 dioxane-water-methanol treated with TEA (641 μL, 4.6 mmol) and left stirring overnight. The mixture was concentrated and the residue was extracted with 0.1 M H3PO4, H2O then dried over MgSO4, filtered and the filtrate concentrated. The crude material yield was quantitative and was used directly in the next step. 1H NMR(DMSOd6 ,300MHz ) δ 3.17(d,J=5Hz,2H), 4.44-4.73(m,2H), 4.86-4.94(m,1H), 5.08-5.26(m,2H), 7.16-7.24(m,4H), 7.32-7.42(m,6H).
Example 95 N-(N-Benzyloxycarbonyl-1,2,3,4-tetrahydroisoquinolyl-3-carbonyl) -R-Tryptophan-di-n-pentylamide
The product of example 94 (400 mg, 1.29 mmol), the product of example 2 (464 mg, 1.29 mmol), HOBt (176 mg, 1.3 mmol) and TEA (181 μL, 1.3 mmol) were dissolved in 10 mL methylene chloride and treated with EDCI (248 mg, 1.3 mmol) at 4°C and allowed to reach room temperature overnight. The solvents were evaporated and the residue was purified by chromatography to provide product. Rf= 0.32 (18:1 methylene chloride-ethanol). MS(CI) m/e 637(m+H)+, 508, 503, 478, 391, 326. 1H
NMR(DMSOd6,300MHz,145°C) δ 0.84-0.88(m,3H), 1.10-1.40(m,15H), 2.82(s,H2O), 2.85-3.23(m,8H), 4.53(dd,J=2,15Hz,1H), 4.76(dd,J=8,15Hz,1H), 4.87(t,J=5Hz,1H), 4.93-5.02(m,1H), 5.15-5.27(m,2H), 6.96-7.03(m,2H), 7.08-7.12(m,2H), 7.17-7.22(m,4H), 7.34-7.47(m,6H), 7.55-7.58(m,1H), 10.35(s,1H). C,H,N analysis calculated for C39H48N4O4: C 73.55, H 7.60, N 8.80; found: C 73.31, H 7.66, N 8.74.
Example 96 N-(3'-Isoguinolylcarbonyl)-R-Tryptophan-di-n-pentylamide
The product of example 95 (260 mg, 0.41 mmol) was dissolved in 25 mL of decalin and treated with 10 mg of 10% Pd/C at reflux for 5 hours. The reaction was cooled and the mixture was filtered. After concentration of the filtrate, the residue was purified by chromatography on silica gel eluted with a 4:1 to 2:1 hexane-ethylacetate step gradient to yield 121 mg, 0.24 mmol (59%). Rf= 0.5 (1:1 hexane-ethylacetate). MS(CI) m/e 499 (m+H)+. 1H NMR(CDCl3,300 MHz) δ 0.77(t,J=7Hz,3H), 0.86(t,J=7Hz,3H), 0.94-1.44(m,12H), 2.86-3.10(m,3H), 3.33-3.44(m,3H), 5.47-5.54(m,1H), 7.11-7.20(m,3H), 7.32(dd,J=1,7Hz,1H), 7.67-7.78(m,2H), 7.83(dd,J=1,7Hz,1H), 7.96(d,J=8Hz,1H), 8.03(d,J=7Hz,1H), 8.15(s,1H), 8.59(s,1H), 9.02(d,J=9Hz,1H), 9.18(s,1H). C,H,N analysis calculated for
C31H38N4O2, H2O: C 72.06, H 7.80, N 10.84; found: C 72.09, H 7.44, N 10.74.
Example 97 N-(6'-Quinolylcarbonyl)-R-Tryptophan-di-n-pentylamide
Quinoline-6-carboxylic acid (52 mg, 0.30 mmol), the product of example 2 (100 mg, 0.26 mmol) and TEA ( 31 μL , 0.3 mmol) were dissolved in 5 mL of methylene chloride and treated with EDCI (51 mg, 0.26 mmol) at room temperature. The reaction became homogeneous within 1 hour. After 12 hours, the solvents were evaporated and the residue in EtOAc was extracted with 0.1 M citric acid, 0.1 M Na2CO3, and water. The solution was dried over MgSO4, filtered, and the filtrate concentrated. The residue after concentration was purified by chromatography on silica gel eluted with a 4:1 to 1:1 hexane-ethylacetate step gradient to yield 79 mg, 0.16 mmol (53%). MS(CI) m/e 499(m+H)+, 370. 1H NMR(CDCl3,300MHz) δ 0.81(t,J=7Hz,3H), 0.89(t,J=7Hz,3H), 0.97-1.46(m,12H), 2.78-2.88(m,1H), 2.98-3.08(m,2H), 3.30-3.49(m,3H), 5.45-5.53(m,1H), 7.08(d,J=2Hz,1H), 7.13(dt,J=1,7Hz,1H), 7.19(dt,J=1.7Hz,1H), 7.32-7.38(m,2H), 7.46{dd,J=4,8Hz,1H), 7.82(d,J=8Hz,1H), 8.08-8.15(m,3H), 8.21(dd,J=1,8Hz,1H), 8.25(d,J=2Hz,1H), 8.99(dd,J=1,5Hz,1H). C,H,N analysis calculated for C31H38N4O2, 0.4 H2O: C 73.60, H 7.73, N 11.08; found: C 73.51, H 7.66, N 10.91. Example 98 N-Butyloxycarbonyl-S-Tryptophan-di-n-pentylamide
Boc-S-Tryptophan (1 g, 3.3 mmol), dipentylamine (1.6 mL, 8.2 mmol) and HOBt (446 mg, 3.3 mmol) were dissolved in 25 mL of methylene chloride and treated with BOPCl (841 mg, 3.3 mmol). After 1 day, TEA (460 μL ) and additional BOPCl (168 mg) were added. After 3 days, the solvents were evaporated and the residue in ethylacetate was extracted with 0.1 M citric acid, 0.1 M NaHCO3, and water. After drying over MgSO4 and concentration of the filtrate, the residue was purified by chromatography on silica gel eluted with 9:1 to 2:1 hexane-ethylacetate step gradient.
Example 99 S-Tryptophan-di-n-pentylamide hydrochloride
The product of example 98 (435 mg, 0.98 mmol) was dissolved in 3 mL of 4 N HCl in dioxane at 4°C and allowed to reach room temperature. After 2 hours, the excess reagent was evaporated and the residue was placed under high vacuum overnight. The product was used directly in the next step.
Example 100 N-(3'-Quinolylcarbonyl)-S-Tryptophan-di-n-pentylamide
Quinoline-3-carboxylic acid (69 mg, 0.4 mmol) and the product of example 99 (150 mg, 0.4 mmol) were coupled and extracted as in example 97. The concentrated residue was purified by chromatography on silica gel eluted with a 4:1 to 2:1 hexane-ethylacetate step gradient to yield 151 mg, 0.31 mmol (78%). MS(CI) m/e 499(m+H)+. 1H NMR(CDCl3,300MHz) δ 0.82(t,J=7Hz,3H), 0.90(t,J=7Hz,3H), 1.0-1.5(m,12H), 2.79-2.89(m,1H), 2.99-3.11(m,2H), 3.34(s,1H), 3.37(s,1H), 3.42-3.52(m,1H), 5.50(apparent q,J=7Hz,1H), 7.04(d,J=2Hz,1H), 7.11-7.23(m,2H), 7.32-7.38(m,2H), 7.62(dt,J=1,8Hz,1H), 7.78-7.83(m,2H), 7.86(dd,J=1,8Hz,1H), 8.04(s,1H), 8.16(d,J=8Hz,1H), 8.48(d,J=2Hz,1H), 9.31(d,J=2Hz,1H). C,H,N analysis calculated for C31H38N4O2, 0.4 H2O: C 73.60, H 7.73, N 11.08; found: C 73.67, H 7.75, N 10.97.
Example 101 N-(7'-Chloro-4'-hydroxy-3'-quinolylcarbonyl)-R-Tryptophan- di-n-pentylamide
7-Chloro-4-hydroxyquinoline-3-carboxylic acid (590 mg, 2.6 mmol) and the product of example 2 (1.0 g, 2.6 mmol) were coupled in a manner similar to example 58. After 2 days, the reaction mixture was treated as in example 92 and the residue was crystallized from hot 80% aqueous ethanol to yield 668 mg, 1.2 mmol (47%). MS(FAB+) m/e 549(m+H)+, 571(m+Na)+, 419, 392, 364, 326. 1H NMR(DMSOd6,300MHz) δ 0.73(t,J=7Hz,3H), 0.83(t,J=7Hz,3H), 0.90-1.17(m,7H), 1.18-1.4(m,5H), 2.92-3.09(m,4H), 3.12-3.33(m,2H), 5.22-5.31(m,1H), 6.98(dt,J=1,8Hz,1H), 7.04-7.09(m,2H), 7.33(d,J=8Hz,1H), 7.53(dd,J=2,8Hz,1H), 7.68(d,J=7Hz,1H), 7.75(d,J=2Hz,1H), 8.27(d,J=8Hz,1H), 8.81(s,1H), 10.38(d,J=8Hz,1H), 10.85(d,J=2Hz,1H), 12.74(s,1H). C,H,N analysis calculated for
C31H37ClN4O3: C 67.80, H 6.79, N 10.20; found: C 68.13, H 6.86, N 10.27.
Example 102 N-(3'-Phenanthrylcarbonyl)-R-Tryptophan-di-n-pentylamide
Phenanthrene-3-carboxylic acid (100 mg, 0.45 mmol) and the product of example 2 (172 mg, 0.45 mmol) were coupled and treated as in example 100 after 3 days reaction time. The crude residue was purified by chromatography on silica gel eluted with a 9:1 to 2:1 hexane-ethylacetate step gradient to yield 92 mg, 0.18 mmol (40%). MS(CI) m/e 548(m+H)+, 418, 326. 1H NMR(CDCl3,300MHz) δ 0.82(t,J=7Hz,3H), 0.88(t,J=7Hz,3H), 1.0-1.08(m,2H), 1.10-1.36(m,8H), 1.38-1.48(m,2H), 2.82-2.93(m,1H), 3.0-3.11(m,2H), 3.38-3.52(m,3H), 5.52-5.54(m,1H), 7.10(d,J=2Hz,1H), 7.12-7.23(m,2H), 7.34-7.41(m,2H), 7.61-7.98(m,8H), 8.05(m,1H), 8.72(d,J=8Hz,1H), 9.15(s,1H). C,H,N analysis calculated for C36H41N3O2: C 78.94, H 7.55, N 7.67; found: C 78.69, H 7.67, N 7.51.
Example 103 N-(5'-Nitro-2'-quinolylcarbonyl)-R-Tryptophan-di-n-pentylamide
5-Nitroquinoline-2-carboxylic acid (172 mg, 1.0 mmol) and the product of example 2 (380 mg, 1.0 mmol) were coupled as in example 100. After evaporation of the volatiles, the residue was purified by chromatography on silica gel eluted with a 4:1 to 2:1 hexane-ethylacetate step gradient to yield 387 mg, 0.73 mmol (73%). Rf= 0.7 (1:1 hexane-ethylacetate). MS(CI) m/e 544(m+H)+, 414, 344, 326. 1H NMR(CDCl3,300MHz) δ 0.78(t,J=7Hz,3H), 0.88(t,J=7Hz,3H), 0.95-1.48(m,12H), 2.81-2.91(m,1H), 2.95-3.07(m,2H), 3.38-3.49(m,3H), 5.46-5.53(m,1H), 7.11(d,J=2Hz,1H), 7.12-7.22(m,2H), 7.34(dd,J=1,7Hz,1H), 7.8-7.89(m,2H), 8.07(s,1H), 8.44-8.52(m,3H), 8.93(d,J=8Hz,1H), 9.18(dd,J=1,8Hz,1H). C,H,N analysis calculated for C31H37N5O4, 0.5 H2O: C 67.37, H 6.93, N 12.67; found: C 67.48, H 6.82, N 12.57.
Example 104 N-(4'-Hydroxy-2'-quinolylcarbonyl)-R-Tryptophan-di-n-pentylamide
4-Hydroxyquinoline-2-carboxylic acid (284 mg, 1.5 mmol), the product of example 2 (500 mg, 1.3 mmol) and TEA (209 μL , 1.5 mmol) were dissolved in 10 mL DMF and treated with EDCI (287 mg, 1.5 mmol). After 1 day, additional EDCI (287 mg) and TEA (209 μL) as well as HOBt (202 mg ) were added. The solvents were evaporated after 3 days and the residue in ethylacetate was extracted as in example 100. The crude product was purified by chromatography on silica gel eluted with a 20:1 to 9:1 methylene chloride-ethanol step gradient to yield 74 mg, 0.014 mmol (1.1%). MS(FAB+) m/e 515(m+H)+, 330. 1H NMR( DMSOd6,300MHz) δ 0.74-0.91(m,6H), 1.12-1.62(m,12H), 3.08-3.35(m,6H), 5.0-5.08(m,1H), 6.88(s,1H), 6.98(t,J=7Hz,1H), 7.06(t,J=7Hz,1H), 7.21(s,1H), 7.34(d,J=10Hz,2H), 7.62-7.69(m,2H), 7.90(d,J=8Hz,1H), 8.06(d,J=8Hz,1H), 9.42(d,J=7Hz,1H), 10.88(s,1H), 11.78(s,1H). C,H,N analysis calculated for
C31H38N4O3, 0.5 H2O: C 71.10, H 7.51, N 10.70; found: C 71.37, H 7.62, N 10.14.
Example 105 N-(5'-Methyl-2'-indolylcarbonyl)-R-Tryptophan-di-n-pentylamide
5-Methylindole-2-carboxylic acid (262 mg, 1.5 mmol), the product of example 2 (500 mg, 1.31 mmol) and TEA (209 μL, 1.5 mmol) were dissolved in 15 mL methylene chloride and treated with EDCI (287 mg, 1.5 mmol) at room temperature overnight. The solvents were evaporated and the residue was extracted as in example 100. The crude product was purified by chromatography on silica gel eluted with a 3:1 to 1:1 hexane-ethylacetate step gradient to yield 550 mg, 1.1 mmol (84%). MS(CI) m/e 501(m+H)+, 371, 344, 326. 1H NMR(CDCl3,300MHz) δ 0.77(t,J=7Hz,3H), 0.87(t,J=7Hz,3H), 0.91-1.45(m,13H), 2.43(s,3H), 2.78-2.88(m,1H), 2.93-3.09(m,2H), 3.31(s,1H), 3.33(s,1H), 3.34-3.45(m,1H), 5.44(apparent q,J=8Hz,1H), 6.86(d,J=1Hz,1H), 7.04(d,J=2Hz,1H), 7.06-7.14(m,2H), 7.18(dt,J=1,6Hz,1H), 7.29(d,J=8Hz,2H), 7.33(d,J=7Hz,1H), 7.42(d,J<1Hz,1H), 7.76(d,J=8Hz,1H), 8.02(s,1H), 9.38(s,1H). C,H,N analysis calculated for
C31H40N4O2: C 74.36, H 8.05, N 11.19; found: C 74.07, H 8.05, N 10.98.
Example 106 N-(5'-Fluoro-2'-indolylcarbonyl)-R-Tryptophan-di-n-pentylamide
5-Fluoroindole-2-carboxylic acid (269 mg, 1.5 mmol), the product of example 2 (500 mg, 1.31 mmol) were coupled as in example 58 with the following modifications: 10% more EDCI and TEA were added at 6 hours, and 50% more EDCI and TEA were added at 1 day. After 2 days, the reaction mixture was processed as in example 100 to yield 546 mg, 1.08 mmol (82%). MS(CI) m/e 505(m+H)+, 348, 326. 1H NMR( CDCl3,300MHz) δ 0.75(t,J=7Hz,3H), 0.86(t,J=7Hz,3H), 0.92-1.47(m,13H), 2.82-2.92(m,1H), 2.96-3.11(m,2H), 3.32(s,1H), 3.34(s,1H), 3.38-3.46(m,1H), 5.44(apparent q,J=7Hz,1H), 6.90(d,J=2Hz,1H), 6.98(dt,J=2,12Hz,1H), 7.05(d,J=2Hz,1H), 7.08-7.35(m,4H), 7.54(d,J=8Hz,1H), 7.73(d,J=7Hz,1H), 8.06(s,1H), 9.76(s,1H).
C,H,N analysis calculated for C30H37FN4O2, H2O, 0.3 EtOAc: C 68.25, H 7.60, N 10.20; found: C 68.13, H 7.25, N 10.11.
Example 107 N-(p-Chlorophenylaminothiocarbonyl)-S-Tryptophandi-n-pentylamide
4-Chlorophenylisothiocyanate (1 equiv) was added to the product of example 99 (100 mg, 0.26 mmol) and TEA (1.1 equiv) in THF and left stirring overnight. The reaction mixture was poured into ethylacetate and extracted with 0.1% citric acid, 0.1 M NaHCO3 and water. The organic layer was then dried over MgSO4, filtered and diluted with hexanes until slightly cloudy then left overnight to precipitate. The resulting solid was collected and rinsed with fresh hexanes to yield 89 mg, 0.173 mmol (67%). mp= 140-141°C. MS(CI) m/e 513(m+H)+, 356, 344, 329, 326. 1H NMR(CDCl3,300MHz) δ 0.82-0.88(m,6H), 1.02-1.48(m,11H), 1.46-1.54(m,1H), 2.80-3.10(m,3H), 3.26-3.43(m,3H), 5.77-5.83(m,1H), 7.00(d,J=2Hz,1H), 7.03(d,J=8Hz,2H), 7.12(dt,J=1,7Hz,1H), 7.19(dt,J=1,7Hz,1H), 7.23-7.25(m,2H), 7.30(s,1H), 7.33(dd,J=<1,8Hz,1H), 7.81(d,J=8Hz,1H), 7.93(s,1H), 8.02(s,1H). C,H,N analysis calculated for C28H37ClN4OS, 0.2 H2O: C 65.08, H 7.30, N 10.84; found: C 65.14, H 7.18, N 10.79.
Example 108 N-(p-Chloropheny1aminothiocarbonyl)-R-Tryptophan-di-n-pentylamide The product of example 2 (100 mg, 0.26 mmol) was reacted with 4-chlorophenylisothiocyanate as in example 107 to yield 62 mg, 0.12 mmol (46%). mp= 138-140°C. MS(CI) m/e 513(m+H)+, 356, 344, 326. 1H NMR( CDCl3,300MHz) δ 0.82(t,J=7Hz,3H), 0.83(t,J=7Hz,3H), 1.02-1.48(m,11H), 1.46-1.54(m,1H), 2.80-3.10(m,3H), 3.26-3.43(m,3H), 5.77-5.83(m,1H), 7.01(d,J=2Hz,1H), 7.07(d,J=8Hz,2H), 7.12(dt, 3=1 ,7Hz,1H), 7.19(dt,J=1,7Hz,1H), 7.23-7.25(m,2H), 7.33(d,J=8Hz,1H), 7.46(bd,J=5Hz,1H), 7.81(d,J=8Hz,1H), 8.02(s,1H), 8.09(s,1H). C,H,N analysis calculated for C28H37ClN4OS, 0.2 H2O: C 65.08, H 7.30, N 10.84; found: C 65.09, H 7.24, N 10.75.
Example 109 N-(3'-Methylphenylaminocarbonyl)-S-Tryptophan-di-n-pentylami
The product of example 99 (77 mg, 0.23 mmol) was reacted with 3-methylphenylisocyanate as in example 107 to yield 47 mg, 0.10 mmol (47%). mp= 158-159°C. MS(CI) m/e 477(m+H)+, 344, 329. 1H NMR(CDCl3,300MHz) δ 0.78(apparent q,J=7Hz,6H),
0.95-1.38(m,12H), 2.32(s,3H), 2.98-3.12 (m,3H), 3.28(d,J=7Hz,2H), 3.33-3.40(m,1H), 5.31 (apparent q,J=7Hz,1H), 6.82-6.88(m,2H), 7.02(d,J=2Hz,1H), 7.05-7.18(m,4H), 7.28-7.32(m,2H), 7.71(s,1H), 7.75(d,J=7Hz,1H), 8.0(d,J=1Hz,1H). C,H,N analysis calculated for C29H40N4O2: C 73.06, H 8.46, N 11.76; found: C 73.36, H 8.47, N 11.73.
Example 110 N-(3'-Methylphenylaminocarbonyl)-R-Tryptophan-di-n-pentylamide
The product of example 2 (200 mg, 0.53 mmol) was reacted with 3-methylphenylisocyanate as in example 107 to yield 159 mg, 0.33 mmol (63%). mp= 155-6°C. MS(CI) m/e 477(m+H)+, 344, 329. 1H NMR(CDCl3,300MHz) δ 0.78(apparent q,J=7Hz,6H), 0.95-1.38(m,12H), 2.32(s,3H), 2.98-3.12(m,3H), 3.28(d,J=7Hz,2H), 3.33-3.40(m,1H), 5.31(apparent q,J=7Hz,1H), 6.82-6.86(m,2H), 7.02(d,J=2Hz,1H), 7.05-7.18(m,4H), 7.28-7.32(m,2H), 7.69(s,1H), 7.75(d,J=7Hz,1H), 8.0(d,J=1Hz,1H). C,H,N analysis calculated for C29H40N4O2, 0.2 H2O: C 72.53, H 8.48, N 11.67; found: C 72.58, H 8.49, N 11.54.
Example 111 N-(4'-Methylphenylaminocarbonyl)-S-Tryptophan-di-n-ρentylamide
The product of example 99 (100 mg, 0.26 mmol) was reacted with p-tolylisocyanate as in example 107 to yield 72 mg, 0.15 mmol (58%). mp= 140-1°C. MS(CI) m/e 477(m+H)+, 370, 344, 326, 320. 1H NMR(CDCl3,300MHz) δ 0.78(t,J=7Hz,3H), 0.82(t,J=7Hz,3H), 0.95-1.48(m,12H), 2.30(s,3H), 2.96-3.09(m,3H), 3.26(d,J=7Hz,2H), 3.31-3.40(m,1H), 5.28(apparent q,J=7Hz,1H), 6.72(d,J=8Hz,1H), 7.02(d,J=2Hz,1H), 7.04-7.17(m,6H), 7.21-7.32(m,2H), 7.58(s,1H), 7.73(d,J=7Hz,1H), 8.01(s,1H). C,H,N analysis calculated for
C29H40N4O2, 0.2 H2O: C 72.53, H 8.48, N 11.67; found: C 72.42, H 8.38, N 11.63.
Example 112 N-(4'-Methylphenylaminocarbonyl)-R-Tryptophan-di-n-pentylamide
The product of example 2 (100 mg, 0.26 mmol) was reacted with p-tolylisocyanate as in example 107 to yield 91 mg, 0.19 mmol (73%). mp= 136-8°C. MS(CI) m/e 477(m+H)+, 370, 344, 326, 320. 1H NMR(CDCl3,300MHz) δ 0.78(t,J=7Hz,3H), 0.82(t,J=7Hz,3H), 0.95-1.48(m,12H), 2.30(s,3H), 2.96-3.09(m,3H), 3.26(d,J=7Hz,2H), 3.31-3.40(m,1H), 5.28(apparent q,J=7Hz,1H), 6.63(d,J=8Hz,1H), 7.02(d,J=2Hz,1H), 7.04-7.17(m,6H), 7.21(m,2H), 7.51(s,1H), 7.73(d,J=7Hz,1H), 8.01(s,1H). C,H,N analysis calculated for
C29H40N4O2, 0.2 H2O: C 72.53, H 8.48, N 11.67; found: C 72.41, H 8.45, N 11.61.
Example 113 N-(4'-Chlorophenylaminocarbonyl)-S-Tryptophan-di-n-pentylamide
The product of example 99 (80 mg, 0.21 mmol) was reacted with 4-chlorophenylisocyanate as in example 107 to yield 89 mg, 0.18 mmol (85%). mp= 87-8°C. MS(CI) m/e 497(m+H)+, 370, 344, 326. 1H NMR(CDCl3,300MHz) δ 0.76-0.83(m,6H), 0.96-1.42(m,12H), 2.99-3.12(m,3H), 3.27(d,J=7Hz,2H), 3.32-3.39(m,1H), 5.28(apparent q,J=7Hz,1H), 6.95(d,J=8Hz,1H), 7.02(d,J=2Hz,1H), 7.07(dt,J=1,7Hz,1H), 7.13-7.20(m,3H), 7.25-7.32(m,4H), 7.72(d,J=7Hz,1H), 7.97(s,1H), 8.03(s,1H). C,H,N analysis calculated for C28H37ClN4O2, 0.3 H2O: C 66.93, H 7.54, N 11.15 found: C 66.80, H 7.33, N 11.12.
Example 114 N(4'-Chlorophenylaminocarbonyl)-R-Tryptophan-dipentylamide
The product of example 2 (100 mg, 0.30 mmol) was reacted with 4-chlorophenylisocyanate as in example 107 to yield product. mp= 73-75°C. MS(CI) m/e 497(m+H)+, 344, 326. 1H NMR(CDCl3,300MHz) δ 0.76-0.83(m,6H), 0.96-1.42(m,12H), 2.99-3.12(m,3H), 3.27(d,J=7Hz,2H), 3.32-3.39(m,1H), 5.28(apparent q,J=7Hz,1H), 6.98(d,J=8Hz,1H), 7.02(d,J=2Hz,1H), 7.07(dt,J=1,8Hz,1H), 7.13-7.20(m,3H), 7.25-7.32(m,4H), 7.72(d,J=7Hz,1H), 7.97(s,1H), 8.03(s,1H). C,H,N analysis calculated for C28H37ClN4O2, 0.3 H2O: C 66.93, H 7.54, N 11.15 found: C 66.80, H 7.24, N 11.12.
Example 115 N-(3'-Chlorophenylaminocarbonyl)-S-Tryptophan-di-n-pentylamid
The product of example 99 (77 mg, 0.21 mmol) was reacted with 3-chlorophenylisocyanate as in example 107 to yield 61 mg, 0.12 mmol (58%). mp= 125-127°C. MS(CI) m/e 497(m+H)+, 463, 370, 344. 1H NMR(CDCl3,300MHz) δ 0.79(t,J=7Hz,6H), 0.98-1.12(m,9H), 1.18-1.38(m,3H), 2.99-3.13(m,3H), 3.30(d,J=7Hz,2H), 3.33-3.41(m,1H), 5.31(apparent q,J=7Hz,1H),
6.96(m,1H), 7.02(d,J=2Hz,1H), 7.05-7.18(m,4H), 7.22-7.26(m,1H) 7.32(d,J=8Hz,1H), 1 .49(t,J=1Hz,1H), 7.73(d,J=8Hz,1H), 8.03(d,J=1Hz,1H), 8.18(s,1H). C,H,N analysis calculated for C28H37ClN4O2: C 67-65, H 7.50, N 11.27; found: C 67.62, H 7.5 N 11 . 16 .
Example 116 N-(3'-Chlorophenylaminocarbonyl)-R-Tryptophan-di-n-pentylamide
The product of example 2 (100 mg, 0.26 mmol) was reacted with 3-chlorophenylisocyanate as in example 107 to yield 75 mg, 0.15 mmol (71%). mp= 118-121°C. MS(CI) m/e 497(m+H)+, 370, 344, 326. 1H NMR(CDCl3,300MHz) δ 0.79(t,J=7Hz,6H), 0.98-1.12(m,9H), 1.18-1.38(m,3H), 2.99-3.13(m,3H), 3.30(d,J=7Hz,2H), 3.33-3.41(m,1H), 5.31(apparent q,J=7Hz,1H), 6.93-6.98(m,1H), 7.02(d,J=2Hz,1H), 7.05-7.09(m,2H), 7.12-7.19(m,2H), 7.23-7.26(m,1H), 7.32 ( d,J=8Hz ,1H), 7.49(t,J=1Hz,1H), 7.73(d,J=8Hz,1H), 8.03(s,1H), 8.10(s,1H). C,H,N analysis calculated for C28H37ClN4O2, 0.3 H2O: C 66.93, H 7.54, N 11.15; found: C 66.99, H 7.40, N 11.12.
Example 117 N-(3'-Quinolylcarbonyl)-R-Tryptophan-di-n-pentylamide mesylat salt
The product of example 21 (1.0 g, 2.0 mmol) was dissolved in 15 mL of isopropanol and treated with methanesulfonic acid (269μL, 4.0 mmol). A yellow-orange color developed immediately. Hexane was added until cloudiness persisted in the solution. As an oil began to settle the mixture was gently warmed on a steam bath and a solid formed. The mixture was cooled and the solid collected by filtration and washed with fresh hexane. The solid was dried in vacuo to yield 1.06 g, 1.78 mmol (89%). mp= 163-5°C. [α]D= -24.0° (c=1.15, MeOH). MS(CI) m/e 499(m+H)+, (free base). 1H NMR(DMSOd6,300MHz) δ 0.76(t,J=7Hz,3H), 0.83(t,J=7Hz,3H), 1.05-1.3(m,9H), 1.33-1.55(m,3H), 2.36(s,3H), 3.06-3.20(m,3H), 3.23-3.32(m,3H), 5.20(apparent q,J=7Hz,1H0, 6.99(dt,J<1Hz,7Hz,1H), 7.06(dt,J<1,7Hz,1H), 7.20(d,J=2Hz,1H), 7.32(d,J=7HZ,1H), 7.67(d,=7Hz,1H), 7.81(dt,J<1,8Hz,1H), 7.99(dt,J<1,7Hz,1H), 8.16(d,J=8Hz,1H), 8.20(dd,J<1,8Hz,1H), 9.13(d,J=1Hz,1H), 9.31(d,J=8Hz,1H), 9.40(d,J=2HZ,1H), 10.88(d,J=1Hz,1H). C,H,N analysis calculated for C32H42N4O5S, 0.5 H2O: C 63.66, H 7.18, N 9.28; found: C 63.57, H 7.19, N 9.22.
The compounds of Formula I antagonize CCK which makes the compounds useful in the treatment and prevention of disease states wherein CCK or gastrin may be involved, for example, gastrointestinal disorders such as irritable bowel syndrome, ulcers, excess pancreatic or gastric secretion, acute pancreatitis, motility disorders, pain (potentiation of opiate analgesia), central nervous system disorders caused by CCK's interaction with dopamine such as neuroleptic disorders, tardive dyskinesia, Parkinson's disease, psychosis or Gilles de la Tourette Syndrome, disorders of appetite regulatory systems, Zollinger-Ellison syndrome, and central G cell hyperplasia.
In Vitro Test Methods and Results
The ability of the compounds of Formula I to interact with CCK receptors and to antagonize CCK can be demonstrated in vitro using the following protocols.
CCK8 [Asp-Tyr(SO3H)-Met-Gly-Trp-Met-Asp-Phe-NH2] was purchased from Beckman Instruments (Palo Alto, CA) and Peptide International (Louisville, KY). Chymostatin, L-Try-Gly, puromycin, bestatin, EGTA, HEPES and BSA were purchased from Sigma Chemical Co. (St. Louis, MO). [125I]BH-CCK8 (specific activity, 2200 Ci/mmol) and Aquasol-2 scintillation cocktail were obtained from New England Nuclear (Boston, MA). Male guinea pigs, 250 to 325 g, were obtained from Scientific Small Animal Laboratory and Farm (Arlington Heights, IL). Collagenase, 300 units per mg, was purchased from Worthington (Frehold, N.J.) Protocol For Radioligand Binding Experiments
1. Guinea Pig Cerebral Cortical and Pancreatic Membrane Preparations
Cortical and pancreatic membrances were prepared as described (Lin and Miller; J. Pharmacol. Exp. Ther. 232, 775-780, 1985). In brief, cortex and pancreas were removed and rinsed with ice-cold saline. Visible fat and connective tissues were removed from the pancreas. Tissues were weighed and homogenized separately in approximately 25 mL of ice-cold 50 mM Tris-HCl buffer, pH 7.4 at 4°C, with a Brinkman Polytron for 30 sec, setting 7. The homogenates were centrifuged for 10 min at 1075 x g and pellets were discarded, the supernatants were saved and centrifuged at 38,730 x g for 20 min. The resultant pellets were rehomogenized in 25 mL of 50 mM Tris-HCl buffer with a Teflon-glass homogenizer, 5 up and down strokes. The homogenates were centrifuged again at 38,730 x g for 20 min. Pellets were then resuspended in 20 mM HEPES, containing 1 mM EGTA, 118 mM NaCl, 4.7 mM KCl, 5 mM MgCl2, 100 uM bestatin, 3 uM phosphoramidon, pH 7.4 at 22°C, with a Teflon-glass homogenizer, 15 up and down strokes. Resuspension volume for the cortex was 15-18 mL per gm of original wet weight and 60 mL per gm for the pancreas. 2. Incubation Conditions
[125I]Bolton-Hunter CCK8, and test compounds were diluted with HEPES-EGTA-salt buffer (see above) containing 0.5% bovine serum albumin (BSA). To 1 mL Skatron polystyrene tubes were added 25 uL of test compounds, 25 uL of [125I]BH-CCK8, and 200 uL of membrane suspension, the final BSA concentration was 0.1%. The cortical tissues were incubated at 30°C for 150 min and pancreatic tissues were incubated at 37°C for 30 min. Incubations were terminated by filtration using Skatron Cell
Harvester and SS32 microfiber filter mats. The specific binding of [125I]BH- CCK8, defined as the difference between binding in the absence and presence of 1 uM CCK8, was 85-90% of total binding in cortex and 90-95% in pancreas. IC50's were determined from the Hill analysis. The results of these binding assays are shown in Table 1.
Protocol for Amylase
This assay was performed using the modified protocol of Lin et al., J. Pharmacol. Exp. Ther. 236, 729-734, 1986.
1. Guinea Pig Acini Preparation
Guinea pig acini were prepared by the method of Bruzzone et al. (Biochem. J. 226, 621-624, 1985) as follows. Pancreas was dissected out and connective tissues and blood vessels were removed. The pancreas was cut into small pieces (2mm) by a scissor and placed in a 15 mL conical plastic tube containing 2.5 mL of Krebs-Ringer HEPES (KRH) buffer plus 400 units per mL of collagense. The composition of the KRH buffer was: HEPES, 12.5 mM: NaCl, 118 mM; KCl, 4.8 mM; CaCl2, 1 mM; KH2PO4, 1.2 mM; MgSO4, 1.2 mM; NaHCO3, 5 mM; glucose, 10 mM, pH 7.4. The buffer was supplemented with 1% MEM vitamins, 1% MEM amino acids and 0.001% aprotinin. The tube was shaken by hand until the suspension appeared homogeneous, usually 5 to 6 min. 5 mL of the KRH, without collagenase and with 0.1% BSA, were added and the tube was centrifuged at 50 x g for 35 sec. The supernatant was discarded and 6 mL of the KRH were added to the cell pellet. Cells were triturated by a glass pipet and centrifuged at 50 x g for 35 sec. This wash procedure was repeated once. The cell pellet from the last centrifugation step was then resuspended in 15 mL of KRH containing 0.1% BSA. The contents were filtered through a dual nylon mesh, size 275 and 75 um. The filtrate, containing the acini, were centrifuged at 50 x g for 3 min. The acini were then resuspended in 5 mL of KRH-BSA buffer for 30 min at 37°C, under 100% O2, with a change of fresh buffer at 15 min. 2. Amylase Assay
After the 30 min incubation time, the acini were resuspended in 100 volumes of KRH-3SA buffer, containing 3 uM phosohoramidon and 100 M bestatin. While stirring, 400 uL of acini were added to 1.5 mL microcentrifuge tubes containing 50 uL of CCK8, buffer, or test compounds. The final assay volume was 500 uL. Tubes were vortexed and placed in a 37°C waterbath, under 100% O2, for 30 min. Afterward, tubes were centrifuged at 10,000 g for 1 min. Amylase activity in the supernatant and the cell pellet were separately determined after appropriate dilutions in 0.1% Tr iton X-100, 10 mM NaH2PO4, pH 7.4 by Abbott Amylase A-gent test using the Abbott Bichromatic Analyzer 200. The reference concentration for CCK8 in determining the
IC50's of the compounds of Formula I was 3×10 -10M. The results of this assay are shown in Tabee 2.
TABLE 1
IC50 (nM)
Compound of [125I]-BH-CCK8 [125I]-BH-CCK8
Example Pancreas Cortex
3 51 8,000
4 330 >10,000
7 350 >10,000
8 420 >10,000
18 680 10,000
19 1,000 >10,000
21 14 15,000
25 150 10,000
28 280 10,000
29 88 9,200
31 300 >10,000
32 120 >10,000
33 530 10 , 000
36 380 >10,000
39 110 >10,000
40 1,000 10,000
45 1,500 >10,000
50 1,200 >10,000
53 67 >10,000
57 750 >10,000
63 62 >10,000
64 330 10,000
69 10 4,100
78 370 >10,000
84 2.6 <10,000
90 230 >10,000
91 5 4,200
96 630 >10,000
97 180 >10,000
100 670 6,300
105 620 >10,000
106 82 10,000
117 17 13,000
TABLE 2
IC50 (nM)
Compound of Inhibition of
Example Amylase Release
3 670
7 <30,000
8 <10,000
18 <30,000
19 <10,000 21 42
25 <10,000
28 <10,000
29 <10,000
31 <100,000
32 < 30,000
33 <30,000 36 <10,000
39 <10,000
40 <100,000 46 <10,000 54 < 100,000 93 100,000
96 < 100,000
97 < 100 , 000 100 < 100,000
The results of the assays indicate that the compounds of the invention inhibit specific
[125I]-BH-CCK-8 receptor binding in the concentration range of 10-9 to 10-6 M and that the compounds antagonize the actions of CCK..
In Vivo Test Methods and Results
The ability of the compounds of Formula I to interact with CCK receptors and to antagonize CCK in vivo can be dmonstrated using the following protocols.
Inhibition of CCK Induced Gastric Emptying
Three fasted mice are dosed (p.o.) with the test compound. CCK8 (80 ug/kg s.c.) is administered with
60 minutes and charcoal meal (0.1 ml of 10% suspension) is given orally 5 minutes later. The animals are sacrificed within an additional 5 minutes.
Gastric emptying, defined as the presence of charcoal within the intestine beyond the pyloric sphincter, is inhibited by CCK8. Gastric emptying observed in more than one mouse indicates antagonism of
CCK8.
Measurement of Plasma Insulin Level Following Treatment with CCK8 and a Compound of Formula I
The ability of the compounds of Formula I to antagonize CCK induced hyperinsulinemia can be demonstrated in vivo using the following protocol.
Male mice, 20-30 g, are used in all experiments. The animals are fed with laboratory lab chow and water ad libitum. The compound of Formula I (1-100 mg/kg in 0.2 ml of 0.9% saline) was administered i.p. Ten minutes later CCK8 (0.2 to 200 nmole/kg in 0.2 ml of 0.9% saline) or saline is injected into the tail vein. Two minutes later the animals are sacrificed and blood is collected into 1.5 ml heparinized polypropylene tubes. The tubes are centrifuged at 10,000 x g for 2 minutes. Insulin levels are determined in the supernatant (plasma) by an RIA method using kits from Radioassy Systems Laboratory (Carson, CA.) or Novo Biolabs (MA.).
Antagonism of CCK Mediated Behavioral Effect in Mice with Compounds of Formula I
Male Swiss CD-I mice (Charles River) (22-27 g) were provided with ample food (Purina Lab Chow) and water until the time of their injection with the test compound.
ICV injections were given by a free-hand method similar to that previously described (Haley and McCormick, Br. J. Pharmacol. Chemother. 12 12-15 (1957)). The animals were placed on a slightly elevated metal grid and restrained by the thumb and forefinger at the level of the shoulders, thus immobilizing their heads. Injections were made with a 30 gauge needle with a "stop" consisting of a piece of tygon tubing to limit penetration of the needle to about 4.5 mm below the surface of the skin. The needle was inserted perpendicular to the skull at a midline point equidistant from thje eye and an equal distance posterior from the level of the eyes such that the injection site and the two eyes form an equilateral triangle. The injection volme (5 ul) was expelled smoothly over a period of approximately 1 second.
Immediately after the injections, the mice were placed in their cages and allowed a 15 minute recovery period prior to the beginning of the behavioral observations.
For the behavioral observations, the mice were placed in clear plastic cages. Each cage measured 19 × 26 × 15 centimeters and contained a 60-tube polypropylene test tube rack (NALGENE #5970-0020) placed on end in the center of the cage to enhance exploratory activity. Observations were made evcery 30 seconds for a period of 30 minutes. Behavior was compared between drug and CCK8 treated mice; CCK8 treated mice; a;nd mice treated with an equal volume of carrier (usually 0.9% saline or 5% dimethylsulfoxide in water). Locomotion as reported here consisted of either floor locomotion or active climbing on the rack. Differences among groups were analyzed by Newman-Kewels analysis and a probability level of p<0.05 was accepted as significant. Each group tested consisted of 10 animals. The results of this test indicate that compounds of Formula I are antagonists of CCK in vivo. Minimally effective doses (MED) are defined as that dose at which a statistically significant reversal of CCK-induced inactivity was observed when the test compound of Formula I and CCK8 were coadministered.
Compound of Dose of
Example CCK8 MED
21 3 nmol 0.3 nmol
The compounds of the present invention can be used in the form of salts derived from inorganic or organic acids. These salts include but are not limited to the following: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate, lactate, maleate, methanesulfonate. nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, and undecanoate. Also, the basic nitrogen-containing groups can be guaternized with such agents as loweralkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides, and others. Water or oil-soluble or dispersible products are thereby obtained.
The pharmaceutically acceptable salts of the present invention can be synthesized from the compounds of Formula I which contain a basic or acidic moiety by conventional chemical methods. Generally, the salts are prepared by reacting the free base or acid with stoichiometric amounts or with an excess of the desired salt forming inorganic or organic acid or base in a suitable solvent or various combinations of solvents.
Examples of acids which may be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, sulphuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, succinic acid and citric acid. Other salts include salts with alkali metals or alkaline earth metals, such as sodium, potassium, calcium or magnesium or with organic bases.
The pharmaceutically acceptable salts of the acid of Formula I are also readily prepared by conventional procedures such as treating an acid of Formula I with an appropriate amount of a base, such as an alkali or alkaline earth metal hydroxide e.g. sodium, potassium, lithium, calcium, or magnesium, or an organic base such as an amine, e.g., dibenzylethylenediamine, trimethylamine, piperidine, pyrrolidine, benzylamine nd the like, or a quaternary ammonium hydroxide such as tetramethylammonium hydroxide and the like.
When a compound of Formula I is used as an antagonist of CCK or gastrin in a human subject, the total daily dose administered in single or divided doses may be in amounts, for example, from 0.001 to 1000 mg a day and more usually 1 to 1000 mg. Dosage unit compositions may contain such amounts of submultiples thereof to make up the daily dose.
The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated, the particular treatment and the particular mode of administration.
It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the severity of the particular disease undergoing therapy.
The compounds of the present invention may be administered orally, parenterally, by inhalation spray, rectally, or topically in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection, or infusion techniques.
Injectable preparations, for example, sterile injectable aqueous or oleagenous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable prepartion may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In additon, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable nonirritating excipient such as cocoa butter and polyethylene glycols which are solid at ordinary temperatures but l iquid at the rectal temperature and will therefore melt in the rectum and release the drug. Solid dosage forms for oral administration may include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound may be admixed with at least one inert diluent such as sucrose lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.
Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsion, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Such compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.
The present agents can also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The present compositons in liposome form can contain, in addition to the compounds of the present invention, stabilizers, preservatives, excipients and the like. The preferred lipids are the phospholipids and the phophatidyl cholines (lecithins), both natural and synthetic. Methods to form liposomes are known in the art. See, for example, Prescott, ed., Methods in Cell Biology, Vol. XIV, Academic Press, New York, N.Y. pp. 33- (1976).
The foregoing is merely illustrative of the invention and is not intended to limit the invention to the disclosed compounds. Variations and changes which are obvious to one skilled in the art are intended to be within the scope and nature of the invention which are defined in the appended claims.

Claims

CLAIMSWhat is claimed is:
1. A compound of the formula:
wherein
R1 and R2 are independently selected from i) hydrogen, ii) loweralkyl, iii) cycloalkyl, iv) loweralkenyl, v) adamantyl, vi) aryl, vii) substituted aryl, viii) heterocyclic group, ix) substituted alkyl, x) substituted amide, xi) functionalized carbonyl, and xii) nitrogen containing ring wherein R1,
R2 and the adjacent nitrogen atom form a ring;
R10 is i) hydrogen, ii) loweralkyl, or iii) loweralkenyl; R20 is i) hydrogen, ii) loweralkyl, or iii) loweralkenyl;
B is i) -(CH2)m-, ii) substituted alkenylene, iii) -QCH2- wherein Q is O, S, or
-N( R8)- wherein R8 is selected from hydrogen, -(C=O)r(C1-C8loweralkyl), -(C=O)r-, cycloalkyl, -(C=O)rloweralkenyl
-(C=O)r(CH2)maryl,
-(C=O)r(CH2)m(substituted aryl) wherein substituted aryl is as defined above,
-(CH2)mSR4 and -(CH2)mOR4 wherein
R4 is hydrogen, -(C=O)rloweralkyl, -(C=O)rloweralkenyl, -(C=O)rcycloalkyl,
-(C=O)r(CH2)maryl or
-(C=O)r(CH2)m(substituted aryl), iv) -CH2Q- wherein Q is as defined above, or v) NH;
Z is i) C=O, ii) S(O)2 , or iii) C=S ;
Ar is a heterocyclic group, aryl or substituted aryl; D is unsubstituted or substituted indol-3-yl, indolin-3-yl or oxindol-3-yl; and
m is 0 to 4 and r is 0 or 1; or a pharmaceutically acceptable salt thereof; with the proviso that when the compound is of the formula:
wherein Ar is phenyl or phenyl substituted with one or two substituents independently selected from hydrogen, loweralkyl, hydroxy substituted alkyl, alkoxy substituted alkyl, alkoxy, halogen, amino, hydroxy, nitro, cyano, carboxy, ethoxycarbonyl and trihalomethyl; and R1 is -(CH2)aphenyl wherein a is 1 to 4; then
R2 is not loweralkyl, cycloalkyl, -(CH2)baryl wherein b is 0 to 4, -(CH2)b(substituted aryl) wherein b is 0 to 4 and substituted aryl is as defined above, or -(CH2)c(CO)R3 wherein c is 1 to 4 and R3 is hydroxy, alkoxy, -O(CH2)caryl, -O(CH2)c(substituted aryl) wherein c is 1 to 4, or -NR6R7 wherein R6 and R7 are independently selected from hydrogen and loweralkyl.
2. The compound of Claim 1 wherein R1 and R2 are independently selected from loweralkyl; Z is C=O; B is absent; R., is hydrogen or loweralkyl; D is indol-3-yl, hydroxy-substituted indol-3-yl or halo-substituted indol-3-yl; and Ar is a heterocyclic group selected from indolyl, quinolyl, naphthyl and substituted derivatives thereof.
3. The compound of Claim 1 wherein R1 is loweralkyl; R2 is -(CH2)sO(loweralkyl) wherein s is 1 to 4; Z is C=O; B is absent; R11 is hydrogen or loweralkyl; D is indol-3-yl, hydroxy-substituted indol-3-yl or halo-substituted indol-3-yl; and Ar is a heterocyclic group selected from indolyl, quinolyl, naphthyl and substituted derivatives thereof.
4. The compound of Claim 1 wherein R1 is hydrogen or -(CH2)s(C=O)O(loweralkyl) wherein s is 1 to 4; R2 is benzyl or -CHR'R" wherein R' is carboalkoxy or loweralkyl and R" is phenyl; Z is C=O; B is absent; R10 is hydrogen or loweralkyl; D is indol-3-yl, hydroxy-substituted indol-3-yl or halo-substituted indol-3-yl; and Ar is indolyl, quinolyl or naphthyl.
5. A compound selected from the group cons i sting of:
N-(2'-Indolylcarbonyl)-R-Tryptophan-di-n-pentylamide, N-(3'-Quinolylcarbonyl)-R-Tryptophan-di-n-pentylamide, N-(3'-Quinolylcarbonyl)-R-(beta-Oxindolyl)Alanine-di-n-pentylamide
N(alpha)-(3'-Quinolylcarbonyl)-R-5-Hydroxytryptophan-di-n-pentylamide,
N-(4',8'-Dihydroxy-2'-quinolylcarbonyl)-R-Tryptophan-di-n-pentylamide, and
N(alpha)-(4',8'-Dihydroxy-2'-quinolylcarbonyl)-R-5-Hydroxytryptophan-di-n-pentylamide.
6. A pharmaceutical composition for antagonizing CCK, comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of Claim 1.
7. A method for antagonizing CCK comprising administering to a host in need of such treatment a therapeutically effective amount of a compound of Claim 1.
8. A method for the treatment and prevention of gastrointestinal ulcers, cancers of the gall bladder and pancreas, pancreatitis, Zollinger-Ellison syndrome, central G cell hyperplasia, irritable bowel syndrome, the treatment or prevention of neuroleptic disorders, tardive dyskinesia, Parkinson's disease, psychosis, Gilles de la Tourette syndrome, disorders of appetite regulatory systems, the treatment of pain and the treatment of substance abuse comprising administering to a host in need of such treatment a therapeutically effective amount of a compound of Claim 1.
9. A pharmaceutical composition for the treatment and prevention of gastrointestinal ulcers, cancers of the gall bladder and pancreas, pancreatitis, Zollinger-Ellison syndrome, central G cell hyperplasia, irritable bowel syndrome, the treatment or prevention of neuroleptic disorders, tardive dyskinesia, Parkinson's disease, psychosis, Gilles de la Tourette syndrome, disorders of appetite regulatory systems, the treatment of pain and the treatment of substance abuse comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of Claim 1.
10. A process for the preparation of a compound of the formula:
wherein
R1 and R2 are independently selected from i) hydrogen, ii) loweralkyl, iii) cycloalkyl, iv) loweralkenyl, v) adamantyl, vi) aryl, vii) substituted aryl, viii) heterocyclic group, ix) substituted alkyl, x) substituted amide, xi) functionalized carbonyl, and xii) nitrogen containing ring wherein R1,
R2 and the adjacent nitrogen atom form a ring;
R10 is i) hydrogen, ii) loweralkyl, or iii) loweralkenyl;
R20 is i) hydrogen, ii) loweralkyl, or iii) loweralkenyl;
B is i) -(CH2)m-, ii) substituted alkenylene, iii) -QCH2- wherein Q is O, S, or -N( R8)- wherein R8 is selected from hydrogen, -(C=O)r(C1-C6loweralkyl), -(C=O)r-, cycloalkyl, -(C=O)rloweralkenyl,
-(C=O)r(CH2)maryl, -(C=O)r(CH2) (substituted aryl) wherein substituted aryl is as defined above,
-(CH2)mSR4 and -(CH2)mOR4, wherein
R1 is hydrogen, -(C=O)rloweralkyl, -(C=O)rloweralkenyl, -(C=O)rcycloalkyl, -(C=O)r(CH2)maryl or -(C=O)r(CH2)m(substituted aryl), iv) -CH2Q- wherein Q is as defined above, or v) NH;
Z is i) C=O, ii) S(O)2 , or iii) C=S ;
Ar is a heterocyclic group, aryl or substituted aryl;
D is unsubstituted or substituted indol-3-yl, indolin-3-yl or oxindol-3-yl; and
m is 0 to 4 and r is 0 ro 1; or a pharmaceutically acceptable salt thereof; comprising coupling an amine of the formula a)
;
wherein P3 is hydrogen with a compound of the formula
Ar-B-Z-Z'
wherein Z' is an activating group; or
-B-Z-Z' taken together represent -N=C=O, -N=C=S,
-CH2-N=C=O or -CH2-N=C=S.
11. A process for the preparation of a compound of the formula
wherein
R1 and R2 are independently selected from i) hydrogen, ii) loweralkyl, iii) cycloalkyl, iv) loweralkenyl, v) adamantyl, vi) aryl, vii) substituted aryl, viii) heterocyclic group, ix) substituted alkyl, x) substituted amide, xi) functionalized carbonyl, and xii) nitrogen containing ring wherein R1,
R2 and the adjacent nitrogen atom form a ring;
R5 is hydrogen or R5 is one, two or three of the substituents independently selected from the group -(C1-C6loweralkyl), loweralkenyl, -(O)t(CH2)mcarboxyl,
-(O)t(CH2)mcarboalkoxy,
-(O)t(CH2)mcarboaryloxy, haloalkyl, nitro, alkoxy, cyano, -N3, -NHP1 wherein P4 is an N-protecting group, -OP5 wherein P5 is an O-protecting group, alkylaminocarbonyl, dialkylaminocarbonyl, aryloxy, thioalkoxy, thioaryloxy, halogen, CN, -OH, -NH2, -NR6R7 wherein R 6 and R7 are indep-endentlyselected from hydrogen, loweralkyl, cycloalkyl, loweralkenyl, - ( CH2 ) maryl ,
-(CH2)m(substituted aryl) wherein the aryl group is substituted with one, two or three substituents independently selected from loweralkyl, alkoxy, thioalkoxy, carboxy, carboalkoxy, cyano, haloalkyl, -N3, -NHP4 wherein P4 is an N-protecting group, -OP5 wherein P5 is an O-protecting group, nitro, halogen, hydroxy, amino and -NH(loweralkyl);
-(CH2)mOR4 wherein R4 is hydrogen, -(C=O)rloweralkyl, -(C=O)rloweralkenyl, -(C=O)rcycloalkyl,
-(C=O)r(CH2)maryl or -(C=O)r(CH2) (substituted aryl), and
-(CH2)mSR4 wherein R4 is independently as defined above; R11 is i) hydrogen, ii) loweralkyl, or iii) loweralkenyl;
R20 is i ) hydrogen, ii) loweralkyl, or iii) loweralkenyl;
B is i) -(CH2)m-, ii) substituted alkenylene, iii) -QCH2- wherein Q is O, S, or -N(R8)- wherein R8 is selected from hydrogen, -(C=O)r(C1-C6loweralkyl), -(C=O)r-, cycloalkyl, -(C=O)rloweralkenyl,
-(C=O)r(CH2)maryl,
-(C=O)r(CH2)m(substituted aryl) wherein substituted aryl is as defined above,
-(CH2-)mSR4, and -(CH2)mOR4 wherein R4 is hydrogen, -(C=O)rloweralkyl, -(C=O)rloweralkenyl, -(C=O)rcycloalkyl, -(C=O)r(CH2)maryl or -(C=O)r(CH2)m(substituted aryl), iv) -CH2Q- wherein Q is as defined above, or v) NH;
Z is i) C=O, ii) S(O)2 , or iii) C=S;
Ar is a heterocyclic group, aryl or substituted aryl;
R30 is hydrogen, loweralkyl, arylalkyl, (substituted aryl) alkyl or an N-protecting group;
R31 is loweralkyl, aryl or substituted aryl;
and m, t and r are independently selected at each occurrence from the values m is 0 to 4, t is 0 or and r is 0 or 1; or a pharmaceutically acceptable salt thereof; comprising reacting a compound of the formula
wherein P6 is an N-protecting group; and
R1, R2, R4, R11 and R30 are independently as defined above, with a compound of the formula R31SH wherein R31 is loweralkyl, aryl or substituted aryl
EP19890905266 1988-04-05 1989-04-04 Derivatives of tryptophan as cck antagonists Withdrawn EP0442878A4 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US17771588A 1988-04-05 1988-04-05
US177715 1988-04-05

Publications (2)

Publication Number Publication Date
EP0442878A1 true EP0442878A1 (en) 1991-08-28
EP0442878A4 EP0442878A4 (en) 1991-10-23

Family

ID=22649698

Family Applications (2)

Application Number Title Priority Date Filing Date
EP19890105864 Pending EP0336356A3 (en) 1988-04-05 1989-04-04 Derivatives of tryptophan as cck antagonists
EP19890905266 Withdrawn EP0442878A4 (en) 1988-04-05 1989-04-04 Derivatives of tryptophan as cck antagonists

Family Applications Before (1)

Application Number Title Priority Date Filing Date
EP19890105864 Pending EP0336356A3 (en) 1988-04-05 1989-04-04 Derivatives of tryptophan as cck antagonists

Country Status (3)

Country Link
EP (2) EP0336356A3 (en)
JP (1) JPH03503650A (en)
WO (1) WO1989010355A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5684156A (en) * 1994-02-08 1997-11-04 Pierce; David R. Process for preparation of clonidine derivatives

Families Citing this family (51)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA1326108C (en) * 1988-04-12 1994-01-11 Sun Hyuk Kim Cck antagonists
US5580896A (en) * 1989-06-29 1996-12-03 Warner-Lambert Company Treatment of pain and colorectal cancer with dipeptoids of α-substituted Trp-Phe derivatives
US5278316A (en) * 1989-06-29 1994-01-11 Warner-Lambert Company N-substituted cycloalkyl and polycycloalkyl alpha-substituted Trp-Phe- and phenethylamine derivatives
US5631281A (en) * 1989-06-29 1997-05-20 Warner-Lambert Company N-substituted cycloalkyl and polycycloalkyl α-substituted Trp-Phe- and phenethylamine derivatives
IE902295A1 (en) * 1989-07-07 1991-01-16 Abbott Lab Amino acid analog cck antagonists
JPH05504968A (en) * 1990-03-07 1993-07-29 ローン―プーラン・ロレ・ソシエテ・アノニム Glycinamide derivatives, their production and pharmaceuticals containing them
FR2667066B2 (en) * 1990-03-07 1993-06-25 Rhone Poulenc Sante N-HETEROCYCLYL GLYCINAMIDES, THEIR PREPARATION AND THE MEDICINAL PRODUCTS CONTAINING THEM.
US5593967A (en) * 1990-08-31 1997-01-14 Warner-Lambert Company Cholecystokinin antagonists, their preparation and therapeutic use
CA2088980C (en) * 1990-08-31 2002-04-16 David C. Horwell Pro-drugs for cck antagonists
US5340825A (en) * 1990-08-31 1994-08-23 Warner-Lambert Company Pro drugs for CCK antagonists
US5244905A (en) * 1990-08-31 1993-09-14 Warner-Lambert Company N-substituted cycloalkyl and polycycloalkyl polyhydro-β-carboline-phenylalanine- and phenethylamine derivatives
US5244915A (en) * 1990-08-31 1993-09-14 Warner-Lambert Company Amico acid derivatives cyclized at the c-terminal
JPH06502627A (en) * 1990-08-31 1994-03-24 ワーナー―ランバート・コンパニー Novel cholecystokinin antagonists, their manufacture and therapeutic use
WO1994004494A1 (en) * 1992-08-13 1994-03-03 Warner-Lambert Company Tachykinin antagonists
US5264419A (en) * 1990-08-31 1993-11-23 Warner-Lambert Company N-substituted cycloalkyl and polycycloalkyl α-substituted TRP derivatives
US5075313A (en) * 1990-09-13 1991-12-24 Eli Lilly And Company 3-aryl-4(3H)quinazolinone CCK antagonists and pharmaceutical formulations thereof
FR2694006A1 (en) * 1992-07-22 1994-01-28 Esteve Labor Dr New amide derivs. of benzo-hetero cyclic cpds. - for treating gastrointestinal disorders, including ulcers and gastric hypersecretion
JP3419539B2 (en) 1993-02-17 2003-06-23 中外製薬株式会社 Indoline-2-one derivatives
US6869957B1 (en) 1993-11-17 2005-03-22 Eli Lilly And Company Non-peptide tachykinin receptor antagonists
US6403577B1 (en) 1993-11-17 2002-06-11 Eli Lilly And Company Hexamethyleneiminyl tachykinin receptor antagonists
ES2135695T3 (en) * 1994-01-24 1999-11-01 Fujisawa Pharmaceutical Co AMINO ACID DERIVATIVES AND THEIR USE AS PHOSPHOLIPASE A2 INHIBITORS.
GB2303369B (en) * 1994-05-09 1998-05-27 Black James Foundation Cck and gastrin receptor ligands
GB9409150D0 (en) * 1994-05-09 1994-06-29 Black James Foundation Cck and gastrin receptor ligands
JPH10501228A (en) * 1994-06-06 1998-02-03 ワーナー−ランバート・コンパニー Tachykinin (NK1) receptor antagonist
JPH08325263A (en) * 1995-05-31 1996-12-10 Sumitomo Metal Ind Ltd New 2-amino-3-phenylpropionic acid derivative
KR100241643B1 (en) 1995-06-06 2000-03-02 디. 제이. 우드 Substituted N- (indole-2-carbonyl) -β-alanimamide and its derivatives for treating diabetes
DK0832065T3 (en) * 1995-06-06 2001-11-19 Pfizer Substituted N- (indole-2-carbonyl) glycinamides and derivatives as glycogen phosphorylase inhibitors
DE69522718T2 (en) 1995-06-06 2002-02-07 Pfizer SUBSTITUTED N- (INDOL-2-CARBONYL) AMIDES AND DERIVATIVES AS GLYCOGEN PHOSPHORYLASE INHIBITORS
CA2360740A1 (en) 1999-03-02 2000-09-08 Boehringer Ingelheim Pharmaceuticals, Inc. Compounds useful as reversible inhibitors of cathepsin s
US6420364B1 (en) 1999-09-13 2002-07-16 Boehringer Ingelheim Pharmaceuticals, Inc. Compound useful as reversible inhibitors of cysteine proteases
US6277877B1 (en) 2000-08-15 2001-08-21 Pfizer, Inc. Substituted n-(indole-2-carbonyl)glycinamides and derivates as glycogen phosphorylase inhibitors
US8415354B2 (en) 2004-04-29 2013-04-09 Abbott Laboratories Methods of use of inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme
US20100222316A1 (en) 2004-04-29 2010-09-02 Abbott Laboratories Inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme
US7880001B2 (en) 2004-04-29 2011-02-01 Abbott Laboratories Inhibitors of the 11-beta-hydroxysteroid dehydrogenase Type 1 enzyme
KR101496190B1 (en) 2005-01-05 2015-02-26 애브비 인코포레이티드 Adamantyl derivatives as inhibitors of the 11-beta-hydroxysteroid dehydrogenase Type 1 enzyme
EP2835367A1 (en) 2005-01-05 2015-02-11 AbbVie Inc. Inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme
US8198331B2 (en) 2005-01-05 2012-06-12 Abbott Laboratories Inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme
US20090192198A1 (en) 2005-01-05 2009-07-30 Abbott Laboratories Inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme
JP5736098B2 (en) 2007-08-21 2015-06-17 アッヴィ・インコーポレイテッド Pharmaceutical composition for treating central nervous system disorders
AU2009293750C1 (en) * 2008-09-18 2016-02-04 Nippon Zoki Pharmaceutical Co., Ltd. Amino acid derivative
PL228037B1 (en) * 2009-03-23 2018-02-28 Marciniak Agnieszka Maria Application of kynurenic acid and its derivatives in preventing or treatment of pancreas diseases
CN102020588B (en) * 2009-09-16 2014-01-29 深圳微芯生物科技有限责任公司 Tricyclic compound with histone deacetylases inhibition activity and preparation method and application thereof
CA2860187C (en) * 2011-12-22 2020-11-10 Connexios Life Sciences Pvt. Ltd. Cyclic amide derivatives as inhibitors of 11-beta-hydroxysteroid dehydrogenase and uses thereof
EP2994142A4 (en) * 2013-05-08 2017-03-29 Colorado Seminary, Which Owns and Operates The University of Denver Antibiotic and anti-parasitic agents that modulate class ii fructose 1,6-bisphosphate aldolase
CN104628616B (en) * 2015-02-12 2016-06-01 佛山市赛维斯医药科技有限公司 Containing N-diamantane amides, the Preparation Method And The Use of p-nitrophenyl
CN104628617B (en) * 2015-02-12 2016-04-06 佛山市赛维斯医药科技有限公司 N-diamantane amides glucokinase activators, preparation method and its usage
CN104628615B (en) * 2015-02-12 2016-04-06 佛山市赛维斯医药科技有限公司 Containing N-diamantane amides, the Its Preparation Method And Use of halogeno-benzene
CN104693084B (en) * 2015-02-12 2016-03-16 佛山市赛维斯医药科技有限公司 The N-diamantane amides of nitrile group-containing phenyl, Preparation Method And The Use
CN111093372B (en) * 2017-09-13 2022-05-27 先正达参股股份有限公司 Microbicidal quinoline (thio) carboxamide derivatives
ES2904910T3 (en) * 2017-09-13 2022-04-06 Syngenta Participations Ag Microbiocidal quinoline (thio)carboxamide derivatives
US20220298138A1 (en) * 2019-08-21 2022-09-22 Kalvista Pharmaceuticals Limited Enzyme inhibitors

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2224130A1 (en) * 1971-05-18 1972-11-30 Rotta Research Laboratorium S.P.A., San Fruttuoso Di Monza, Mailand (Italien) Tryptophan derivatives
DE2726276A1 (en) * 1976-10-12 1978-04-13 Ici Ltd POLYPEPTIDE
DE3236484A1 (en) * 1981-10-02 1983-04-21 Richter Gedeon Vegyészeti Gyár R.T., 1103 Budapest TRIPEPTIDES, METHOD FOR PRODUCING THE SAME AND MEDICINAL PRODUCTS CONTAINING THEM
US4472305A (en) * 1983-05-17 1984-09-18 Sterling Drug Inc. Hexapeptide amides
EP0230151A2 (en) * 1985-12-31 1987-07-29 Biomeasure, Inc. Cholecystokinin antagonists
EP0250148A2 (en) * 1986-06-16 1987-12-23 Merck & Co. Inc. Amino acid analogs as CCK-antagonists

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS588051A (en) * 1981-07-03 1983-01-18 Toyama Chem Co Ltd Novel dipeptide compound and its preparation
US4482567A (en) * 1982-10-07 1984-11-13 Research Foundation For Mental Hygiene, Inc. N-hexanoyl to n-heptadecanoyl 5-hydroxy tryptophan-5-hydroxytryptophanamides and use as analgesics
US4642315A (en) * 1982-11-18 1987-02-10 E. R. Squibb & Sons, Inc. Carboxy and substituted carboxy alkanoyl and cycloalkanoyl peptides
US4604402A (en) * 1984-03-30 1986-08-05 E. R. Squibb & Sons, Inc. Hydroxy substituted ureido amino and imino acids

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2224130A1 (en) * 1971-05-18 1972-11-30 Rotta Research Laboratorium S.P.A., San Fruttuoso Di Monza, Mailand (Italien) Tryptophan derivatives
DE2726276A1 (en) * 1976-10-12 1978-04-13 Ici Ltd POLYPEPTIDE
DE3236484A1 (en) * 1981-10-02 1983-04-21 Richter Gedeon Vegyészeti Gyár R.T., 1103 Budapest TRIPEPTIDES, METHOD FOR PRODUCING THE SAME AND MEDICINAL PRODUCTS CONTAINING THEM
US4472305A (en) * 1983-05-17 1984-09-18 Sterling Drug Inc. Hexapeptide amides
EP0230151A2 (en) * 1985-12-31 1987-07-29 Biomeasure, Inc. Cholecystokinin antagonists
EP0250148A2 (en) * 1986-06-16 1987-12-23 Merck & Co. Inc. Amino acid analogs as CCK-antagonists

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of WO8910355A1 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5684156A (en) * 1994-02-08 1997-11-04 Pierce; David R. Process for preparation of clonidine derivatives

Also Published As

Publication number Publication date
JPH03503650A (en) 1991-08-15
EP0336356A2 (en) 1989-10-11
EP0336356A3 (en) 1991-09-25
WO1989010355A1 (en) 1989-11-02
EP0442878A4 (en) 1991-10-23

Similar Documents

Publication Publication Date Title
EP0442878A1 (en) Derivatives of tryptophan as cck antagonists
US5346907A (en) Amino acid analog CCK antagonists
US5340802A (en) Peptide analog type-B CCK receptor ligands
KR100504449B1 (en) Cell adhesion inhibitors
US4971978A (en) Derivatives of D-glutamic acid and D-aspartic acid
KR890003603B1 (en) Process for preparing renin inhibitors containing 5-amino-2,5-disubstituted-4-hydroxypentanoic acid residues
IE902295A1 (en) Amino acid analog cck antagonists
KR19980703151A (en) Lactam-containing hydroxamic acid derivatives, their preparation and their use as inhibitors of matrix metalloproteases
JP2004523529A (en) Melanocortin receptor agonist
KR19990087322A (en) Useful isoquinolines as analgesics
US5270302A (en) Derivatives of tetrapeptides as CCK agonists
EP0405506A1 (en) Tetrapeptide type-B CCK receptor ligands
CA2348159A1 (en) Aromatic amine derivatives, their production and use
JPS6124551A (en) Acylaminophenyl ketone and amine
US5128346A (en) Derivatives of D-glutamic acid and D-aspartic acid
JP6333267B2 (en) Azaindoline
KR20150065718A (en) Indolines
US5380872A (en) Modulators of cholecystokinin
KR20060130123A (en) Ornithine derivatives as prostaglandin e2 agonists or antagonists
WO1993017032A1 (en) Techniques and intermediates for preparing non-peptide peptidomimetics
EP0136720B1 (en) Enkephalin analogs
JP2002533338A (en) Non-peptide NK1 receptor antagonist
WO1990006937A1 (en) Derivatives of tetrapeptides as cck agonists
EP0207680B1 (en) Chemical compounds
JPS60105698A (en) Novel enkephalin derivative

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 19901001

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): BE CH DE FR GB IT LI NL SE

A4 Supplementary search report drawn up and despatched

Effective date: 19910830

AK Designated contracting states

Kind code of ref document: A4

Designated state(s): BE CH DE FR GB IT LI NL SE

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: ABBOTT LABORATORIES

RBV Designated contracting states (corrected)

Designated state(s): BE CH DE ES FR GB GR IT LI NL SE

XX Miscellaneous

Free format text: VERBUNDEN MIT 89105864.6/0336356 (EUROPAEISCHE ANMELDENUMMER/VEROEFFENTLICHUNGSNUMMER) DURCH ENTSCHEIDUNG VOM 06.08.92.

17Q First examination report despatched

Effective date: 19921015

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 19951003