WO1993020099A2 - Ligands pour les recepteurs de la cck et/ou la gastrine - Google Patents

Ligands pour les recepteurs de la cck et/ou la gastrine Download PDF

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Publication number
WO1993020099A2
WO1993020099A2 PCT/GB1993/000614 GB9300614W WO9320099A2 WO 1993020099 A2 WO1993020099 A2 WO 1993020099A2 GB 9300614 W GB9300614 W GB 9300614W WO 9320099 A2 WO9320099 A2 WO 9320099A2
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WIPO (PCT)
Prior art keywords
carbonyl
dihydroindole
tetrahydroisoquinoline
tert
butyloxycarbonyl
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Application number
PCT/GB1993/000614
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English (en)
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WO1993020099A3 (fr
Inventor
Hamish Ryder
David Alan Kendrick
Graeme Semple
Keiji Miyata
Andrzej Roman Batt
Elizabeth Alice Mathews
David Philip Rooker
Akito Nishida
Shinobu AZUZAWA
Michael Szelke
Original Assignee
Ferring B.V.
Yamanouchi Pharmaceutical Co. Ltd.
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Publication date
Application filed by Ferring B.V., Yamanouchi Pharmaceutical Co. Ltd. filed Critical Ferring B.V.
Publication of WO1993020099A2 publication Critical patent/WO1993020099A2/fr
Publication of WO1993020099A3 publication Critical patent/WO1993020099A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
    • C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl 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
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/0205—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)3-C(=0)-, e.g. statine or derivatives thereof
    • 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
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • 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
    • 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
    • C07K5/06156—Dipeptides with the first amino acid being heterocyclic and Trp-amino acid; Derivatives thereof
    • 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
    • C07K5/08—Tripeptides
    • C07K5/0821—Tripeptides with the first amino acid being heterocyclic, e.g. His, Pro, Trp
    • 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
    • C07K5/10—Tetrapeptides
    • C07K5/1024—Tetrapeptides with the first amino acid being heterocyclic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • This invention relates to novel compounds that bind to the CCK and/or gastrin receptor with high affinity, to processes for the preparation of these compounds, and to their use in the treatment of certain disease states.
  • Cholecystokinin (CCK) and gastrin are two members of a family of peptide hormones. They were originally discovered and described as agents acting oh organs of the gastrointestinal system. CCK stimulates the contraction of the gall bladder and the release of digestive enzymes from the pancreas. Gastrin stimulates the secretion of gastric acid. More recently CCK has been found in the brain, indicating that it may also act as a neurotransmitter or neuromodulator.
  • CCK and gastrin are biosynthesised as prepro-hormones.
  • the biologically active peptides are then released after a series of post-translational modifications.
  • CCK a number of active forms are produced which vary in the number of amino acid residues they contain. The smallest is a tetrapeptide (CCK-4) and the largest has 58 residues (CCK-58).
  • a variety of gastrins are also known, of which the 17-residue peptide (G-17) is probably one of the most important.
  • both CCK and gastrin have a tyrosine residue which is found as both the free phenol and as the O-sulphate. All the biologically active forms of both CCK and gastrin share a common tetrapeptide amide sequence at their C-terminus.
  • the C-terminal sequences of the two peptides are:
  • T Trp-Met-Asp-Phe-NH 2
  • CCK Apart from its actions on the gall bladder and pancreas mentioned above CCK also influences secretion, absorption and motility in the stomach and intestines, and causes the secretion of pancreatic hormones such as somatostatin. In the central nervous system CCK appears to be important in anxiogenesis. analgesia and appetite regulation.
  • Gastrin plays a fundamental part in the control of gastric acid secretion, although the precise mechanism by which this secretion is regulated remains in doubt. Gastrin causes the release of histamine from the ECL-cells in the stomach wall. Histamine then stimulates the parietal cells to secrete acid. It is possible that gastrin can directly stimulate the parietal cells, but this in particular is a point of controversy. Gastrin also increases the blood flow in the stomach wall, but this might also be an indirect effect mediated by histamine, and exerts a trophic effect on the gastric mucosa. (For a more complete review, and leading references, see ref. 1).
  • CCK and gastrin interact with their target organs through specific receptors located in the cell surface plasma membranes. It is generally agreed that there are two different CCK receptors.
  • the CCK-A (for alimentary) type is found in the peripheral tissue, and is the receptor which mediates the actions of CCK on the pancreas, gall bladder and intestines. It is also found in certain specific brain regions, where it might be involved in the control of appetite.
  • the CCK-B (for brain) receptor type is more widely distributed in the CNS, and is thought to be involved in anxiety and other central actions of CCK.
  • There is only one gastrin receptor type found particularly in the stomach wall. It appears to show very similar ligand specificity to the CCK-B receptor, and the CCK-B receptor is commonly used as a model for the less readily isolable gastrin receptor.
  • Tryptophan derivatives have been widely explored. The earliest compounds studied e.g. benzotript, were not very potent, but more recently disclosed compounds have demonstrated better affinity. 6 Perhaps the best example of this development is CI-988, a tryptophan "dipeptoid" from Parke-Davis. 7
  • Rhone-Poulenc has disclosed a number of compounds which have some analogy with the tryptophan analogues developed by Biomeasure but which lack the indolylmethyl side chain.8
  • Microbial metabolites are a traditional source of lead structures, and a number of compounds have been shown to have affinity for the CCK-receptor.10 Probably the most significant of these is asperlicin. It has inspired an enormous effort in the development of benzodiazepine derivatives as CCK ligands. This particular area is probably the most active single area of research into new compounds as CCK and gastrin antagonists. H
  • a number of groups have disclosed compounds which can be broadly described as small heterocycles with pendant aromatic substituents. 13 These compounds may bind in a similar manner to the benzodiazepines.
  • Cyclic nucleotide derivatives have been known for some time to be CCK antagonists. The best is dibutyryl cyclic GMP, but its affinity for the receptor is only modest compared with other types of compound. 14
  • the compounds of the present invention are ligands with a high affinity for CCK and/or gastrin receptors. They can be represented by the general formula A-B-C in which A, B and C are subunits as defined below and are linked by covalent bonds. It is presumed that the compounds of this invention achieve their potency by mimicking the C-terminal tetrapeptide which is common to CCK and gastrin, but this is not necessarily always the case.
  • the important features of A, B and C are represented schematically below as general structure a:
  • S 1 is an optional substituent group, but when present is a hydrophobic residue
  • S 2 is a mandatory substituent, and is always an aromatic (including heteroaromatic) residue
  • S 3 is also mandatory, and is generally a hydrophobic residue (but with the exceptions mentioned below)
  • S 4 is mandatory, and is a hydrophobic residue
  • S 5 is optional, and is generally a hydrophilic or polar residue
  • L 1 - L 5 are linking elements (covalent bonds or chains of atoms) which are optional with the proviso that if S 1 is present then L 2 must be present, and that at least one of L 3 and L 4 must be present.
  • S 5 when S 5 is absent S 3 can be a hydrophilic residue, and when B is a group such as a proline residue then L 3 can take the place of S 3 .
  • A is a unit that can have either one or two hydrophobic residues attatched. When only one is present then it is an aromatic system, and A is a group such as (substituted)phenyl carbamoyl, indoleacetyl or isoquinolinecarbonyl.
  • both hydrophobic residues are present and the linking unit L 1 is absent then A mimics a blocked aromatic amino-acid such as BOC-tryptophan or benzoyl-phenylglycine.
  • L 1 is present then A is cyclic.
  • the aromatic residue can either be pendant to this ring or fused to it, giving, for example, a phenylproline and an indoline respectively.
  • S 1 can be absent or it can be any hydrophobic group, for example a BOC- or a benzoyl group.
  • subunit B there are three possibilities.
  • B is analogous to an amino-acid. or a residue that can mimic an amino-acid, such as, for example O-benzyl-threonine or its "reduced" isostere.
  • L 3 is absent and L 4 is present then B can be considered to be an N-alkyl amino-acid analogue.
  • B is cyclic.
  • the ring can in itself constitute the hydrophobic residue S 3 , for example when B is a proline residue.
  • the residue can be a pendant group or, if it is cyclic, it can be fused to the ring of B, giving for example a substituted proline or an indoline respectively.
  • subunit C if L 5 is absent then the subunit is analogous to an N-alkylated amino-acid (as was B with L 3 absent and L 4 present).
  • S 3 must be present, and mimics the backbone of the amino-acid.
  • S 3 is extended and mimics a dipeptide chain.
  • S 5 can be absent, or if it is present it performs a function analogous to that just described.
  • S 4 can either be pendant to the ring so formed, or it can be fused with it.
  • the compounds of the present invention are derived from the amino-acid sequence of the naturally occuring hormones.
  • the starting point of our investigation was an amide described by Martinez et al. (Int. J. Peptide Protein Res., 28, 529-535, 1986).
  • Martinez et al. Int. J. Peptide Protein Res., 28, 529-535, 1986.
  • constraining the conformational freedom of the ester by cyclization gave compounds which retained some affinity for both CCK-A and CCK-B receptors. This key step is represented below.
  • A is a fused heteroaromatic substituted acyl residue, or an N ⁇ -blocked tryptophan residue
  • B is a hydrophobic amino-acid residue, or a surrogate of one
  • C is a benzo-fused piperidine or pyrrolidine, further substituted with a carboxyl or carboxyalkyl residue, which can be blocked as an ester, or extended, for example, by acylating an amino-acid residue.
  • this preferred embodiment of the invention includes;
  • A is a fused heteroaromatic substituted acyl residue, or an N ⁇ -blocked tryptophan residue
  • B is usually a hydrophobic amino-acid residue, or a similar surrogate, but may also be a hydrophilic amino-acid residue, or a similar surrogate;
  • C is a benzo-fused piperidine or pyrrolidine.
  • this preferred embodiment of the invention includes;
  • A is a substituted or unsubstituted phenylcarbamoyl residue (i.e. L 1 , L 2 and S 1 are absent);
  • B is a hydrophobic amino-acid, or a similar surrogate
  • C is a piperidine or pyrrolidine which may be benzo-fused or may have a pendant hydrophobic substituent, and which is further substituted with a carboxylor carboxyalkyl sidechain or a derivative thereof.
  • this embodiment of the invention includes:
  • A is a benzo-fused nitrogen heterocyclic acyl residue in which the nitrogen is substituted with a hydrophobic group (i.e. S 1 , S 2 , L 1 and L 2 all present);
  • B is a hydrophobic amino-acid residue or a similar surrogate, which preferably incorporates some degree of conformational restriction either through cyclization (as in f or by having a 3-amino-2-naphthoyl residue for B) or through N-substitution (as in g);
  • C is a benzo-fused piperidine or pyrrolidine which may optionally be substituted at up to three positions. If such substituents are present then at least one is hydrophilic (for example a carboxyl or carboxyalkyl).
  • this embodiment of the invention includes:
  • the second modification which yields potent and selective CCK-B/gastrin receptor ligands involves the deletion of L 5 (equivalent to the excision of the cyclic amide bond from b) to give a series of tertiary amides. In this series S 1 is not required and the compounds are structurally less complex (as in h).
  • A is an acyl residue with an aromatic substituent
  • B is a hydrophobic amino-acid or a similar surrogate
  • C is an N-substituted amino-acid or similar surrogate, where the N-substituent is an alkyl, cycloalkyl, aralkyl or aryl group, and the carboxy terminus may be the free acid or may be blocked as an ester or amide, or may be extended, for example, by acvlating another amino-acid residue.
  • this preferred embodiment of the invention includes:
  • salts include sodium, potassium and tetra-alkyl ammonium salts of acidic compounds, and chlorides, sulphates and acetates of basic compounds.
  • the compounds of the present invention contain a carboxylic acid moiety then these may be administered in pro-drug form as simple esters.
  • the synthesis of the compounds of the present invention can be considered as involving two stages.
  • Stage 1 the individual components A, B and C in general formula I are prepared from commercially available starting materials if they are not themselves available.
  • protecting groups may be introduced into A, B and C in order to obviate side reactions in Stage 2.
  • the second phase involves assembling the individual components into the finished compound.
  • Stage 2 apart from the crucial A-B and B-C bond forming reactions, selective manipulation of the protecting groups may be necessary.
  • final adjustments can be made to complete the synthesis.
  • pre- A - pre-C are commercially available precursors.
  • A-B fragment may be formed first and couple this to C.
  • C can be divided into two sub-fragments (e.g. when C is XIX, or XVI with R 14 is XXII). In these cases one of the sub-fragments can be introduced at a late stage. If C is composed of the subfragments C 1 -D then Stage 2 of the overall synthesis might be:
  • AAA Hydrolysis 6NHCl + phenol at 150°C for 1.5 hr.
  • Reagents were generally used as supplied without purification. Solvents were HPLC grade, except THF which was distilled from ⁇ a/benzophenone. Silica gel for flash chromatography was Merck Kieselgel 60 (230-400 mesh).

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Abstract

Cette invention concerne de nouveaux composés de la structure générale A-B-C et leurs sels acceptables sur le plan pharmaceutique, des compositions médicinales les contenant et l'utilisation de telles compositions médicinales pour le traitement de certaines maladies. Les composés de l'invention sont représentés schématiquement par A-B-C où S1-S4 sont d'une façon générale des groupements lipophiles, S5 est un groupement polaire ou hydrophile et L1-L5 sont des unités de liaison facultatives. Les composés de cette invention se fixent aux récepteurs de la cholécystokinine et/ou de la gastrine avec une très grande affinité et sont donc utiles pour le traitement de maladies découlant d'un dysfonctionnement d'un processus physiologique régulé par l'une ou l'autre de ces hormones.
PCT/GB1993/000614 1992-03-27 1993-03-25 Ligands pour les recepteurs de la cck et/ou la gastrine WO1993020099A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB929206757A GB9206757D0 (en) 1992-03-27 1992-03-27 Novel peptide receptor ligands
GB9206757.8 1992-03-27

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WO1993020099A2 true WO1993020099A2 (fr) 1993-10-14
WO1993020099A3 WO1993020099A3 (fr) 1993-11-25

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US5919829A (en) * 1993-08-10 1999-07-06 James Black Foundation Limited Gastrin and cck receptor ligands
WO1999033801A1 (fr) * 1997-12-23 1999-07-08 Institut National De La Sante Et De La Recherche Medicale (Inserm) Inhibiteur de tripeptidyl peptidase
US5955471A (en) * 1998-01-13 1999-09-21 Sk Corporation Tetrahydroisoquinolinealkanol derivatives and pharmaceutical compositions containing same
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US9000172B2 (en) 2011-10-14 2015-04-07 Bristol-Myers Squibb Company Substituted tetrahydroisoquinoline compounds as factor XIa inhibitors
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US9315519B2 (en) 2012-10-12 2016-04-19 Bristol-Myers Squibb Company Guanidine substituted tetrahydroisoquinoline compounds as factor XIa inhibitors
US9388199B2 (en) 2012-06-28 2016-07-12 Novartis Ag Pyrrolidine derivatives and their use as complement pathway modulators
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