EP0912551A1 - Agonistes et antagonistes de la somatostatine - Google Patents

Agonistes et antagonistes de la somatostatine

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Publication number
EP0912551A1
EP0912551A1 EP97921646A EP97921646A EP0912551A1 EP 0912551 A1 EP0912551 A1 EP 0912551A1 EP 97921646 A EP97921646 A EP 97921646A EP 97921646 A EP97921646 A EP 97921646A EP 0912551 A1 EP0912551 A1 EP 0912551A1
Authority
EP
European Patent Office
Prior art keywords
amino
propyl
thiourea
imidazol
pyridin
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Withdrawn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
EP97921646A
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German (de)
English (en)
Inventor
Michael Ankersen
Carsten Enggaard Stidsen
Henrik Sune Andersen
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Novo Nordisk AS
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Novo Nordisk AS
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Filing date
Publication date
Application filed by Novo Nordisk AS filed Critical Novo Nordisk AS
Publication of EP0912551A1 publication Critical patent/EP0912551A1/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/02—Drugs for disorders of the endocrine system of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • 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

Definitions

  • the present invention relates to compounds, compositions containing them, and their use for treating medical disorders related to binding to human somatostatin receptor subtypes.
  • Somatostatin somatotropin release inhibiting factor; SRIF
  • SRIF somatotropin release inhibiting factor
  • SRIF SRIF receptor-mediated by specific membrane receptors. Cur- rently, only agonists are available to study the pharmacology of SRIF receptors.
  • the present invention relates to a compound of general formula la or lb
  • n is 1 , 2 or 3, preferably 1
  • p is 1 , 2, 3, 4, 5 or 6, preferably 2, 3 or 4,
  • Rl and R2 are independently hydrogen or C-j_g-alkyl optionally substituted with halogen, amino, hydroxy, alkoxy or aryl,
  • A is aryl, preferably pyridinyl, quinolinyl, isoquinolinyl, pyrimidinyl, pyrazinyl, pyridazi- nyl or triazinyl optionally substituted with one or more, preferably one or two halogen, amino, hydroxy, nitro, C ⁇ _6-alkyl , C- ⁇ -alkoxy or aryl,
  • B is aryl, preferably phenyl, naphthyl, quinolinyl, isoquinolinyl, indolyl, thienyl, furanyl or pyridinyl optionally substituted with one or more, preferably one or two halogen, amino, hydroxy, C-
  • D is aryl, preferably imidazolyl, pyridinyl, pyrimidinyl, piperazinyl, triazolyl, tetrazolyl, thiadiazolyl, isoxazolyl or oxadiazolyl optionally substituted with one or more, pref ⁇ erably one or two halogen, amino, hydroxy, C-
  • the compounds of formula la or lb comprise any optical isomers thereof, in the form of separated, pure or partially purified optical isomers or racemic mixtures thereof.
  • A is pyridinyl, e.g. pyridin-2-yl, pyridin-3-yl, quinolinyl, e.g. quinol-2-yl, isoquinolinyl, pyrimidinyl, e.g. pyrimidin-2-yl, pyrazinyl, pyridazinyl, e.g. pyridazin-2-yl, or triazinyl optionally substi ⁇ tuted with one halogen, e.g. 5-bromo, amino, hydroxy, nitro, e.g. 5-nitro, C-j. ⁇ -alkyl , C-
  • halogen e.g. 5-bromo, amino, hydroxy, nitro, e.g. 5-nitro, C-j. ⁇ -alkyl , C-
  • A is pyridinyl or quinolinyl optionally substituted with halogen, amino, hy ⁇ droxy, nitro, C ⁇ _6-alkyl, C ⁇
  • B is phenyl, naphthyl, e.g. naphth-1-yl or naphth-2-yl , quinolinyl, isoquinolinyl, indolyl, thienyl, furanyl or pyridinyl optionally substituted with one or two halogen, e.g. 4-bromo or 3,4-dichloro, amino, hydroxy, C- ⁇ -alkyl, C-
  • halogen e.g. 4-bromo or 3,4-dichloro
  • B is phenyl or naphthyl optionally substituted with halogen, amino, hy- droxy, nitro, Ci_g-alkyl, C- ⁇ -alkoxy or aryl, preferably phenyl substituted with bromo or two chloro, or naphthyl, e.g naphth-1-yl.
  • D is amino, imida ⁇ zolyl, e.g. 1 H-imidazol-4-yl or imidazol-1-yl pyridinyl, e.g. pyridin-2-yl, pyrimidinyl, piperidinyl, pyrrolidinyl, e.g. pyrrolidin-1-yl, piperazinyl, pyridinylamino, pyrimidiny- lamino, piperidinylamino, pyrrolidinylamino, piperazinylamino, morpholinyl, e.g.
  • mor- pholin-4-yl triazolyl, tetrazolyl, thiadiazolyl, isoxazolyl or oxadiazolyl optionally sub ⁇ stituted with one or two halogen, amino, hydroxy, C ⁇ _6-alkyl, C-)_6-alkoxy or aryl.
  • D is imidazolyl, morpholinyl, pyrrolidinyl, amino or pyridinylamino option ⁇ ally substituted with one or two halogen, amino, hydroxy, C ⁇ .g-alkyl, C-j ⁇ -alkoxy or aryl, preferably imidazolyl, morpholinyl, dimethylamino, pyrrolidinyl, pyridinylamino, amino or pyridinyl.
  • and R2 are inde ⁇ pendently of each other hydrogen or C ⁇
  • the invention relates to somatostatin receptor ligands of nonpeptide origin which have affinity to the somatostatin receptor proteins selected from SST1 , SST2, SST3, SST4 and SST5.
  • said ligands have selective affinity to one or two of the somatostatin receptor proteins se ⁇ lected from SST1 , SST2, SST3, SST4 and SST5.
  • said ligands have selective affinity to SST1.
  • said ligands have selective affinity to SST2.
  • said ligands have selective affinity to SST3.
  • said ligands have selective affinity to SST4.
  • said ligands have selective affinity to SST5.
  • said ligands have selective affinity to SST1 and SST2, SST2 and SST3, SST3 and SST4, SST4 and SST5, SST1 and SST3, SST2 and SST4 or SST3 and SST5.
  • the compounds of the invention can be employed to mediate the biological effects of somatostatin agonists or antagonists. It is predicted that compounds of formula la or lb exhibit an improved bioavalability because they contain no amide bonds suscepti ⁇ ble to cleavage by proteolytic enzymes.
  • the increased resistance to proteolytic deg ⁇ radation combined with the reduced size of the compounds of the invention in com ⁇ parison with known somatostatin agonists and antagonists is expected to possess beneficial properties such as increased peroral absorption, increased biological half- life, lack of immunogenicity, and the ability to cross the blood-brain barrier compared to that of the compounds suggested in the prior literature.
  • the invention also provides methods for producing a prophylactic or therapeutic responce in a mammal by administering to the mammal a pharmaceutically effective amount of one or more compounds of the invention.
  • the present invention provides methods for producing such responses by modulating the activity of mammalian somatostatin receptors by administering an effective amount of one or more compounds of the invention.
  • the C-i. ⁇ -alkyl groups specified above are intended to include those alkyl groups of the designated length in either a linear or branched or cyclic configuration. Exam ⁇ ples of linear alkyl are methyl, ethyl, propyl, butyl, pentyl, and hexyl. Examples of branched alkyl are isopropyl, sec-butyl, tert-butyl, isopentyl, and isohexyl. Examples of cyclic alkyl are C3_6-cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • alkoxy groups preferably C ⁇ _ ⁇ -alkoxy groups specified above are intended to include those alkoxy groups of the designated length in either a linear or branched or cyclic configuration.
  • linear alkyloxy are methoxy, ethoxy, propoxy, bu- toxy, pentoxy, and hexoxy.
  • branched alkoxy are isopropoxy, sec- butoxy, tert-butoxy, isopentoxy, and isohexoxy.
  • cyclic alkoxy are C$_Q- cycloalkoxy such as cyclopropyloxy, cyclobutyloxy, cyclopentyloxy and cyclohexy- loxy.
  • aryl is intended to include aromatic rings, such as carbocyclic and heterocyclic aromatic rings selected from the group consisting of phenyl, naphthyl, thienyl, furyl, furanyl, pyridinyl, pyridyl, 1-H-tetrazol-5-yl, thiazolyl, imidazolyl, isoquinolinyl, indolyl, isoindolyl, piperidinyl, piperazinyl, pyridazinyl, pyrimidinyl, thiadiazolyl, pyrazolyl, oxadiazol, oxazolyl, isoxazolyl, thiopheneyl, quino- linyl, pyrazinyl, triazinyl, triazolyl, tetrazolyl or isothiazolyl, optionally substituted by one or more halogen, amino, hydroxy, carboxylic acid, carboxy
  • halogen is intended to include Chloro (Cl), Fluoro (F), Bromo (Br) and lodo (I).
  • the compounds of the present invention may have one or more asymmetric centres and stereoisomers in the form of separated, pure or partially purified stereoisomers or racemic mixtures thereof are intended to be included in the scope of the invention.
  • the intermediate 3 may be alkylated with an arylalkylhalogenide 4a after treatment with a base such as sodium hydrid under conditions known in the art to give a 1 ,1- disubstituted primary amine 5. Then 5 in a solvent like tetrahydrofuran or ethanol may be reacted with an isothiocyanate 6, prepared as shown in scheme 2, stirred overnight and concentrated in vacuo to afford a crude product 7a.
  • the isothiocy ⁇ anate may be protected and deprotected according to methods described in the art (e.g. T.W. Greene, Protective Groups in Organic Synthesis, 2nd. edition, John Wiley and Sons, New York, 1991).
  • the crude product 7a may be purified by methods known for those skilled in the art such as chromatography, to yield the final product 7a which is a compound of the general formula la. In the presence of a base such as sodium hydride, and an alkyl halide 4b the compound 7b which is a compound of the general formula lb may be obtained.
  • a base such as sodium hydride
  • an alkyl halide 4b the compound 7b which is a compound of the general formula lb may be obtained.
  • the isothiocyanate 6 as described in scheme I may be prepared from the appropri ⁇ ate protected primary amine 8 in a solvent like tetrahydrofuran and carbondisulfide in the presence of a reagent such as dicyclohexylcarbodiimide or other coupling rea- gents known in the literature under chilled conditions. The mixture may be stirred overnight and the solvent removed and the residue may be triturated with ether to remove dicyclohexylthiourea. The remaining product may be distilled under vacuum or chromatographed using technics known to those skilled in the art, to yield the iso ⁇ thiocyanate 6.
  • a reagent such as dicyclohexylcarbodiimide or other coupling rea- gents known in the literature under chilled conditions.
  • the mixture may be stirred overnight and the solvent removed and the residue may be triturated with ether to remove dicyclohexylthiourea.
  • the remaining product may be distilled under vacuum or
  • Compounds of formula la may be prepared as shown in reaction scheme III starting with an appropriate amine 5, prepared as described in reaction scheme I, and an ac ⁇ tivated imine 8 in which R3 may be benzoyl(-COPh) or nitrile (-CN) and R 4 may be thiomethoxy (-SCH3), phenoxy (-OPh) or cloride (-CI) in an appropriate solvent such as dimethylformamide or tetrahydrofuran at an appropriate temperature for an ap ⁇ intestinalte time to give the intermediate 9.
  • the intermediate 9 may further react with an amine 2 in an appropriate solvent such as pyridine with or without a catalyst e.g. silver salts (e.g.
  • reaction scheme III may be protected and deprotected accord ⁇ ing to methods described in the art (e.g. T.W. Greene, Protective Groups in Organic Synthesis, 2nd. edition, John Wiley and Sons, New York, 1991).
  • Compounds of the invention are preferred to the extent that they selectively and ef ⁇ fectively are bound by somatostatin receptor subtypes permanently expressed in eu- kariotic cell lines. It will be recognized that the degree to which a compound is bound by a receptor is known as its binding affinity. The affinity of a compound is commonly expressed as the inhibitory concentration at which the compound is able to displace 50% of another compound already bound to the receptor (IC 50 ). In the case of ligand- binding studies at somatostatin receptors, the compound that is displaced is a radio- active agonist, e.g. 125 l-Tyr 11 -SRIF-14, at the receptor.
  • a radio- active agonist e.g. 125 l-Tyr 11 -SRIF-14
  • a compound possess a clinically effective IC 50 in at least one mammal; that is, it should possess an IC 50 which is low enough to inhibit binding of radiolabelled agonist to somatostatin receptors while causing a minimum of unacceptable side effects in the mammal.
  • clinically effective concentrations vary depending on a number of factors, such as the pharmacokinetic characteristics and stability of the compound under study and thus must be deter ⁇ mined empirically for each compound and each factor. In general, it is desired that the potency of a compound of the invention be as great as possible, preferable greater than or equal to the native somatostatin.
  • somatostatin receptor an ⁇ tagonists Compounds displacing radiolabelled agonist at somatostatin receptors could belong to one of two classes, either agonists or antagonists. Simple ligand-binding studies will not distinguish between these two classes. All five somatostatin receptor subtypes (ie. SST1 , SST2, SST3, SST4 and SST5) have been shown to inhibit the activity of adenylyl cyclase via the G protein subunit G, (Patel, Y.C. et al. Biochem. Biophys.Res.Commun., 198:605-612, 1994). By direct activation of adenylyl cyclase by forskolin the inhibitory action of somato ⁇ statin agonists could be employed. Compounds specifically reversing the inhibitory action of SRIF on cyclic AMP accumulation will be termed somatostatin receptor an ⁇ tagonists.
  • prophylactic, diagnostic, and therapeutic treatments may be prepared from the compounds and compositions of this invention, due to agonism or antagonism at somatostatin receptors.
  • prophylactic or therapeu ⁇ tic responses can be produced in a human or some other type mammal.
  • Preferred responses are modulation of glucagon and insulin secretion to treat type I and type II diabetes; inhibition of cell proliferation and growth to treat various endocrine and exocrine tumours; modulation of growth hormone secretion to treat dwarfism, ac- romegaly, and other growth abnormalities; modulation of immune responses to treat autoimmune diseases, rheumatoid arthritis, and other inflammations; modulation of neuronal activity to treat diseases related to the central nervous system, i.e.
  • the present invention provides a variety of compounds which effec ⁇ tively and selectively are bound to somatostatin receptors.
  • the compounds are ca ⁇ pable of forming pharmaceutically acceptable salts with various inorganic and or ⁇ ganic acids, and such salts are also within the scope of this invention.
  • salts are acid addition salts including acetate, adipate, benzoate, benzene- sulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, ethanesul- fonate, fumarate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nitrate, oxalate, pamoate, persulfate, picrate, pivalate, propionate, succinate, sulfate, tar- trate, tosylate, and undecanoate.
  • acid addition salts including acetate, adipate, benzoate, benzene- sulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, e
  • the salts may be formed by conventional means, such as by reacting the free base form of the product with one or more equivalents of the appropriate acid in a solvent or medium in which the salt is insoluble, or in a sol ⁇ vent such as water, which is later removed in vacuo or by freeze drying.
  • the salts also may be formed by exchanging the anions of an existing salt for another anion on a suitable ion exchange resin.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising, as an active ingredient, a compound of the general formula la or formula lb or a pharmaceutically acceptable salt thereof together with a pharmaceutically ac ⁇ ceptable carrier or diluent.
  • Pharmaceutical compositions containing a compound of the present invention may be prepared by conventional techniques, e.g. as described in Remington's Pharma ⁇ ceutical Sciences. 1985. The compositions may appear in conventional forms, for example capsules, tablets, aerosols, solutions, suspensions or topical applications.
  • the pharmaceutical carrier or diluent employed may be a conventional solid or liquid carrier.
  • solid carriers are lactose, terra alba, sucrose, cyclodextrin, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid or lower alkyl ethers of cellulose.
  • liquid carriers are syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene or water.
  • the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
  • the preparation may be tabletted, placed in a hard gelatin capsule in powder or pellet form or it can be in the form of a troche or lozenge.
  • the amount of solid carrier will vary widely but will usually be from about 25 mg to about 1 g.
  • the preparation may be in the form of a syrup, emulsion, soft gelatin capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.
  • a typical tablet which may be prepared by conventional tabletting techniques may contain:
  • Active compound 100 mg Colloidal silicon dioxide (Aerosil) 1.5 mg
  • the preparation may contain a compound of formula la or formula lb dissolved or suspended in a liquid carrier, in particular an aqueous carrier, for aerosol application.
  • a liquid carrier in particular an aqueous carrier
  • the carrier may contain additives such as solubilizing agents, e.g. propylene glycol, surfactants, absorption enhancers such as lecithin (phosphatidylcholine) or cyclodextrin, or preservatives such as parabenes.
  • the compounds of the present invention are dispensed in unit dosage form comprising 50-200 mg of active ingredient together with a pharmaceutically ac ⁇ ceptable carrier per unit dosage.
  • the dosage of the compounds according to this invention is suitably 1-500 mg/day, e.g. about 100 mg per dose, when administered to patients, e.g. humans, as a drug.
  • the present invention relates to a pharmaceutical com ⁇ position for binding to somatostatin receptors, the composition comprising, as an ac ⁇ tive ingredient, a compound of the general formula la or formula lb or a pharmaceuti ⁇ cally acceptable salt therof together with a pharmaceutically acceptable carrier or di- luent.
  • the present invention relates to a method of binding to somato ⁇ statin receptors, the method comprising administering to a subject in need thereof an effective amount of a compound of the general formula la or formula lb or a pharma- ceutically acceptable salt thereof.
  • the present invention relates to the use of a compound of the general formula la or formula lb or a pharmaceutically acceptable thereof for the preparation of a medicament for binding to the somatostatin receptors.
  • a compound of the general formula la or formula lb or a pharmaceutically acceptable thereof for the preparation of a medicament for binding to the somatostatin receptors.
  • prophylactic, diagnostic, and therapeutic treatments may be prepared from the synthetic compounds and compositions of the invention, due in large part to the competition - that is, agonism or antagonism - of these moieties with the naturally- occuring SRIF or SRIF-28.
  • pro ⁇ phylactic or therapeutic responses can be produced in a human or some other type mammal.
  • Preferred responses are produced by modulating - that is, increasing, de ⁇ creasing or otherwise modifying - the activity of at least one somatostatin receptor subtype (ie. SST1 , SST2, SST3, SST4 and SST5).
  • SST1 , SST2, SST3, SST4 and SST5 somatostatin receptor subtype
  • the production of prophylactic or therapeutic responses includes the initiation or en ⁇ hancement of desirable responses, as well as the cessation or suppression of unde ⁇ sirable responses.
  • the compounds of formula la or formula lb may be used in the treatment of disorders with an aetiology comprising or associated with excess GH-secretion, gastro ⁇ intestinal disorders, malignant cell proliferative diseases, angiogenesis, or in preven ⁇ tion or combating graft vessel diseases, restenosis and vascular occlusion following vascular injury.
  • the compounds of formula la or formula lb may be administered in pharmaceutically acceptable acid addition salt form or, where appropriate, as a alkali metal or alkaline earth metal or lower alkylammonium salt.
  • Such salt forms are believed to exhibit ap ⁇ proximately the same order of activity as the free base forms.
  • the pharmaceutical composition of the invention may comprise a com ⁇ pound of formula la or formula lb combined with one or more compounds exhibiting a different activity, e.g., an antibiotic or other pharmacologically active material.
  • the route of administration may be any route which effectively transports the active compound to the appropriate or desired site of action, such as oral, nasal, pulmo ⁇ nary, transdermal or parenteral, the oral route being preferred.
  • the RP-HPLC analysis was performed using UV detection at 254nm and a Lichro- sorp RP-18 5mM column, which was eluted at 1 ml/minute.
  • the column was equili ⁇ brated with 20% acetonitrile in a buffer consiting of 0.1 M ammonium sulfate, which was adjusted to pH 2.5 with 4M sulfuric acid and eluted by a gradient of 20% to 80% acetonitrile in the same buffer over 30 minutes. The gradient was then extended to 100% acetonitrile over 5 minutes followed by isocratic elution with 100% acetonitrile for 6 minutes.
  • the affinity of somatostatin receptor ligands of nonpeptide origin according to the in ⁇ vention (including the compounds covered by formula la and lb) to the somatostatin receptor proteins selected from SST1 , SST2, SST3, SST4 and SST5, may be de ⁇ tected using the assays described below.
  • the skilled person will know which ad ⁇ justments/modifications to make in order to screen for specific ligands having affinity to one or more of the SST receptor subtypes 1-5.
  • conventional techniques see e.g. AmershamTM SPA Technology
  • AmershamTM SPA Technology known to the skilled person may be used to modify the assays.
  • One way of producing the present ligands is to provide a compound li ⁇ brary of nonpeptide origin using conventional techniques (see e.g. Combinatorial chemistry in the discovery and development of drugs. Doyle, P.M., Journal Of Che ⁇ mical Technology And Biotechnology (1995) Vol. 64, 317-24) well-known to the skil ⁇ led person, and screen for such ligands using the assays described below optionally with modifications, thereby providing somatostatin receptor ligands according to the invention.
  • Cell lines expressing SST receptor subtypes BHK cells (tk- ts13, ATCC CRL# 1632) and HEK 293 cells (ATCC CRL# 1573) were grown to 20-40% confluency in a tissue culture dish in Dulbeccos Modified Eagle Medium (DMEM) containing 1% penicillin / streptomycin , 10% foetal bovine serum, and 1% GlutamaxTM. Prior to transfection, the cells were washed twice with calcium- free PBS after which 20 ml of serum-free DMEM was added to the cells. Transfection was carried out as described previously (product description: Lipofec- tamin, Gibco BRL cat. no. 18324-012).
  • DMEM Dulbeccos Modified Eagle Medium
  • cDNA encoding a SST re ⁇ ceptor subtype inserted into the mammalian expression vector pcDNA3 (Invitrogen) was diluted in 300 ⁇ l of sterile water.
  • 30 ⁇ g of Lipofectamin was diluted in 300 ⁇ l of sterile water.
  • the cDNA and Lipofectamin solutions were mixed and left at room temperature for 15 minutes.
  • the Lipofectamin/cDNA mixture was added drop-wise to the cells (HEK 293 cells for SST 2 , BHK for the other receptor subtypes) while gently swirling the plates. The cells were then incubated for 16-24 hours, after which the medium was replaced with standard medium containing 1 mg/ml Geneticin (G-418 sulfate). Resistant colonies appearing after 1-2 weeks were isolated and propagated for further characterization.
  • Cells expressing individual SST receptor subtypes were resuspended in buffer (50 mM Tris-HCl (pH 7.4), 1 mM EGTA, 5 mM MgCI 2 ), and homogenised. Membranes were washed twice in buffer by homogenisation and centrifugation. Final membrane pellets were resuspended at a protein concentration of 125 ⁇ g/ml in buffer. Binding assays using 75 pM 125 l-Tyr 11 -SRIF (Amersham, IM-161) were done in duplicates in minisorb polypropylene tubes in a volume of 250 ⁇ l. The assays were incubated at 30-37 °C for 30-90 min depending on receptor subtype.
  • Binding was terminated by filtration through Whatman GF/B glass fiber filters pre-soaked for 4 hrs. in 0.5% poly ⁇ ethyleneimine and 0.1 % BSA. Filters were washed three times with 5 ml ice-cold 0.9% saline and counted in a Packard Cobra II Gamma Counter.
  • N-(4-bromobenzyl)-N-(3-isothiocyanatopropyl)-N-(pyridin-2-yl)amine(1 g, 2.76 mmol) and 3-(1-triphenylmethylimidazol-4- yl)propylamine (1.014 g, 2.76 mmol) were dissolved in chloroform (10 ml) and heated at reflux for 4 h.
  • reaction mixture was stirred for 4 days at room temperature poured on to ice water (800 ml) and extracted with ethyl acetate (5 x 150 ml). The combined organic extracts were washed with water (4 x 150 ml), dried (MgSO 4 ), filtered and the solvent evaporated in vacuo.
  • N-1-(5-bromopyrid-2-yl)-1- (3,4-dichlorobenzyl)ethane-1 ,2-diamine N-1-(pyrid-yl)propane-1 ,3-diamine (5.00 g, 33.1 mmol)
  • sodium hydride as a 60 % mineral oil dispersion (1.39 g, 34.8 mmol)
  • 4-bromobenzyl bromide (8.27 g, 33.1 mmol) in DMSO (50 mL) gave a yellow oil.
  • N-1-(5-bromopyrid-2-yl)-1-(3,4- dichlorobenzyl)ethane-1 ,2-diamine N-1-(5-bromopyrid-yl)propane-1 ,3-diamine (5.00 g, 21.7 mmol)
  • a 60% mineral oil suspension of of sodium hydride 0.14 g, 22.9 mmol
  • 3,4-dichlorobenzyl chloride (4.25 g, 21.7 mmol) in DMSO (45 mL) gave an oil.
  • N-1 -(5-bromopyrid-2-yl)ethane-1 ,2- diamine 2,5-dibromopyridine (4.40 g, 18.6 mmol), pyridine (1.86 g, 23.6 mmol), and 1 ,3-diaminopropane (25 mL) yielded an oil.
  • Vacuum distillation afforded 2.69 g (63%) of N-1 -(5-bromopyrid-yl)propane-1 , 3-diamine as an oil.
  • N-1-(5-bromopyrid-2-yl)-1-(3,4- dichlorobenzyl)ethane-1,2-diamine N-1-(5-bromopyrid-yl)propane-1 ,3-diamine (8.71 g, 37.9 mmol)
  • a 60 % mineral oil dispersion of sodium hydride (1.67 g, 41.6 mmol)
  • 1-(bromomethyl)naphthalene 9.21 g, 41.6 mmol) in DMSO (60 mL) gave an oil.
  • N-1-(5-bromopyrid-2-yl)ethane-1 ,2- diamine 2-bromopyridine (20.0 g, 126.7 mmol), 1,4-diaminobutane (56.3 g, 639 mmol), and pyridine (12.7 g, 160.8 mmol) gave 11.5 g (55%) of N-1-(pyrid-2- yl)butane-1 ,4-diamine as a light yellow oil.

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Abstract

L'invention porte sur les ligands (Ia) et (Ib) de la somatostatine servant au traitement de troubles médicaux liés aux sous-types de récepteurs humains de la somatostatine, de formules ci-jointes dans lesquelles: X est =S, =O, =NH, =NCOPh ou =N(CN); A est aryle facultativement substitué par halogène, amino, hydroxy, nitro, C1-6-alkyle, C1-6-alkoxy, ou aryle; B est aryle facultativement substitué par halogène, amino, hydroxy, C1-6-alkyle, C1-6-alkoxy, ou aryle; D est amino facultativement substitué par halogène, amino, hydroxy, C1-6-alkyle, C1-6-alkoxy, ou aryle, ou sur un de leurs sels pharmacocompatibles.
EP97921646A 1996-05-14 1997-05-14 Agonistes et antagonistes de la somatostatine Withdrawn EP0912551A1 (fr)

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US6159941A (en) * 1996-05-14 2000-12-12 Novo Nordisk A/S Use of somatostatin agonists and antagonists for treating diseases related to the eye
US6025372A (en) * 1997-04-04 2000-02-15 Merck & Co., Inc. Somatostatin agonists
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WO1998058646A1 (fr) * 1997-06-24 1998-12-30 Novo Nordisk A/S Utilisation d'agonistes et d'antagonistes de somatostatine pour le traitement de maladies associees a l'oeil
US6124256A (en) * 1998-03-27 2000-09-26 Haeyry; Pekka Method for the prevention of a patient's fibroproliferative vasculopathy
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CA2246791A1 (fr) * 1998-09-01 2000-03-01 Alison Buchan Traitement de l'endothelium avec des analogues de la somatostatine
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US6387932B1 (en) 1999-06-25 2002-05-14 Merck & Co., Inc. Somatostatin agonists
FR2796945B1 (fr) * 1999-07-30 2002-06-28 Sod Conseils Rech Applic Nouveaux derives d'hydantoines, de thiohydantoines, de pyrimidinediones et de thioxopyrimidinones, leurs procedes de preparation et leur application a titre de medicaments
GB0018891D0 (en) 2000-08-01 2000-09-20 Novartis Ag Organic compounds
ATE446758T1 (de) 2000-05-31 2009-11-15 Pfizer Prod Inc Verwendung von wachstumshormonsekretagoga zur förderung der beweglichkeit des verdauungstrakts
WO2002010140A2 (fr) 2000-08-01 2002-02-07 Societe De Conseils De Recherches Et D'applications Scientifiques (S.C.R.A.S.) Dérivés imidazolyles
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