WO1999022735A1 - Agonistes de la somatostatine - Google Patents

Agonistes de la somatostatine Download PDF

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Publication number
WO1999022735A1
WO1999022735A1 PCT/US1998/022917 US9822917W WO9922735A1 WO 1999022735 A1 WO1999022735 A1 WO 1999022735A1 US 9822917 W US9822917 W US 9822917W WO 9922735 A1 WO9922735 A1 WO 9922735A1
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Prior art keywords
alkyl
aryl
group
heteroaryl
mammal
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PCT/US1998/022917
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English (en)
Inventor
Liangquin Guo
Ralph T. Mosley
Alexander Pasternak
Arthur A. Patchett
Lihu Yang
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Merck & Co., Inc.
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Publication date
Priority claimed from GBGB9806697.0A external-priority patent/GB9806697D0/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to AU12854/99A priority Critical patent/AU1285499A/en
Publication of WO1999022735A1 publication Critical patent/WO1999022735A1/fr

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    • 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

  • Somatostatin is a widely distributed peptide occurring in two forms SST- 14 (with 14 amino acids) and SST-28 (with 28 amino acids). SST has multiple functions including modulation of secretion of growth hormone, insulin, glucagon, pancreatic enzymes and gastric acid, in addition to having potent anti-proliferative effects.
  • the mechanism of action of somatostatin is mediated via high affinity membrane associated receptors. Five somatostatin receptors (SSTR1-5) are known (Reisine, T.; Bell, G.I. Endocrine Reviews 1995, 16, 427-442). All five receptors are heterogeneously distributed and pharmacologically distinct.
  • Trp-Lys dipeptide of somatostatin is important for high-affinity binding.
  • the availability of these receptors now makes it possible to design selectively active ligands for the sub-types to determine their physiological functions and to guide potential clinical applications.
  • SSTR2 somatostatin subtype 2 receptors
  • SSTR5 selective agonists inhibit insulin release.
  • novel compounds described herein are useful in the therapy of a variety of conditions which include acromegaly, retinal neovascularization, neuropathic and visceral pain, irritable bowel syndrome, chronic atrophic gastritis, Crohn's disease, rheumatoid arthritis and sarcoidosis.
  • the instant compounds inhibit cell proliferation and cause the regression of certain tumors including breast cancer and they are useful in preventing restenosis after angioplasty and to inhibit gastric motility. Their central activities include the promotion of REM sleep and an increase in cognitive function.
  • the compounds of this invention are also remarkably reduced in size in comparison with the natural hormone and its peptide analogs such as octreotide and seglitide, which allows ease of formulation. Many of the instant compounds show activity following oral administration.
  • This invention relates to compounds which are agonists of somatostatin and selective toward somatostatin receptor subtype SSTR2.
  • the compounds have a number of clinical uses including in the treatment and prevention of diabetes, cancer, acromegaly, depression, chronic atrophic gastritis, Crohn's disease, ulcerative colitis, retinopathy, arthritis, pain both viseral and neuropathic and to prevent restenosis. Many- of the compounds are orally active.
  • It is a further object to describe the specific preferred stereoisomers of the somatostatin agonists.
  • a still further object is to describe processes for the preparation of such compounds.
  • Another object is to describe methods and compositions which use the compounds as the active ingredient thereof. Further objects will become apparent from reading the following description.
  • R 1 is selected from the group consisting of: Ci-C ⁇ alkyl, aryl, aryl
  • C(O)OR a and aryl and heteroaryl are defined within, and where the aryl and heteroaryl are unsubstituted or substituted with a substitutent selected from: 1 to 3 of Ci-C ⁇ alkyl, 1 to 3 of halogen, 1 to 2 of -OR 2 , methylenedioxy, - S(O) m R 2 , 1 to 2 of -CF3, -OCF3, nitro, -N(R 2 )C(O)(R 2 ), -
  • R 2 & R 5 are selected from hydrogen, C1-C8 alkyl, (CH2H aryl, and C3- C7 cycloalkyl, and where two Ci-C ⁇ alkyl groups are present on one atom, they optionally are joined to form a C3-C8 cyclic ring, optionally including oxygen, sulfur or NR3a ? where R ⁇ a is hydrogen, or Ci-C ⁇ alkyl, optionally substituted by hydroxyl; aryl is defined within
  • R* a is selected from the group consisting of hydrogen, and C1-C3 alkyl
  • R 2a is selected from the group consisting of hydrogen and C1-C3 alkyl, said alkyl optionally substituted by hydroxyl;
  • E is selected from the group consisting of -SO2-, -CO(C(R 2 )2) -, -
  • Z 1 is -NR 2a ;
  • R 3 is selected from the group consisting of H, C ⁇ .8 alkyl, (CH 2 ) t aryl and (CH 2 ) t heteroaryl;
  • R 4 is CH(CO 2 R 2 )(CH 2 ) n N(R 2 ) 2 , CH(R 2 )-(CH 2 ) n N(R 2 ) 2 , CH(CO 2 R 2 ), CHCON(R 2 ) 2 , CH(CO 2 R 2 )CH 2 W(CH 2 ) n N(R 2 ) 2 ,
  • R 6 is optionally substituted with 1 to 3 groups of R 2 , 1 to 3 of halogen, 1 to 2 of -OR 2 , methylenedioxy, -S(O) m R 2 , 1 to 2 of -CF3, -OCF3, N(R 2 )C(O)(R 2 ), -C(O)OR 2 , -C(O)N(R 2 )(R 2 ), -SO2N(R 2 )(R 2 ), -N(R )SO2 phenyl, or -N(R 2 )SO2R 2 ;
  • R R can be any organic radical
  • X is selected from the group consisting of CH 2 , CHCO 2 R 2 , C(O), CHCH 2 CO2R 2 ,
  • W is selected from the group consisting of O, S, CH 2 , N(R 2 )C(O) and C(O)N(R 2 );
  • n is an integer from 0 to 2;
  • n is an integer from 0-5;
  • t is an integer from 0 to 3.
  • the compounds and their pharmaceutically acceptable salts of the present invention are those of the general structural formula Ia or lb:
  • C(O)OR 2a and aryl and heteroaryl are defined within, and where the aryl and heteroaryl are unsubstituted or substituted with a substitutent selected from: 1 to 3 of C1-C6 alkyl, 1 to 3 of halogen, 1 to 2 of -OR 2 , methylenedioxy, -
  • R 2 & R 5 are selected from hydrogen, C1-C8 alkyl, (CH2)t aryl, and C3-
  • Ci-C ⁇ alkyl and where two Ci-C ⁇ alkyl groups are present on one atom, they optionally are joined to form a C3-C8 cyclic ring, optionally including oxygen, sulfur or NR ⁇ a , where R ⁇ a is hydrogen, or C1-C6 alkyl, optionally substituted by hydroxyl; aryl is defined within
  • R ⁇ a is selected from the group consisting of hydrogen, and C1-C3 alkyl
  • R 2a is selected from the group consisting of hydrogen and C1-C3 alkyl, said alkyl optionally substituted by hydroxyl;
  • E is selected from the group consisting of -SO2-, -CO(C(R 2 )2) -, -
  • Z 1 is -NR 2a ;
  • R 3 is selected from the group consisting of H, C ⁇ g alkyl, (CH 2 ) t aryl and (CH 2 ) t heteroaryl;
  • R 4 is CH(CO 2 R 2 )(CH 2 ) n N(R 2 ) 2 , CH(R 2 )-(CH 2 ) n N(R 2 ) 2 , CH(CO 2 R 2 ),
  • R 6 is selected from the group consisting of:
  • R 6 is optionally substituted with 1 to 3 groups of R 2 , 1 to 3 of halogen, 1 to 2 of -OR 2 , methylenedioxy, -S(O) m R 2 , 1 to 2 of -CF3, -OCF3, N(R 2 )C(O)(R 2 ), -C(O)OR 2 , -C(O)N(R )(R 2 ), -SO2N(R 2 )(R 2 ), -N(R 2 )SO2 phenyl, or -N(R )SO2R 2 ;
  • R R can be any organic radical
  • X is selected from the group consisting of CH 2 , CHCO 2 R 2 , C(O), CHCH 2 CO2R 2 , CHCON(R 2 ) 2 and NSO 2 R 2 ;
  • W is selected from the group consisting of O, S, CH 2 , N(R 2 )C(O) and C(O)N(R 2 );
  • n is an integer from 0 to 2;
  • n is an integer from 0-5, and
  • t is an integer from 0 to 3.
  • Preferred compounds of the instant invention include those of
  • Rl is selected from the group consisting of: aryl (C1-C6 alkyl), heteroaryl(C ⁇ -C6 alkyl), where aryl and heteroaryl is selected from: phenyl, indanyl, benzyloxy, benzothiazolyl, biphenyl, aza-indolyl, benzyl(with 1,4-butane diamine) naphthyl, quinolinyl, indolyl, pyridyl, benzothienyl, benzofuranyl, thiazolyl, and benzimidazolyl, and where the aryl and heteroaryl are unsubstituted or substituted with a substitutent selected from: 1 to 3 of Ci-C ⁇ alkyl, 1 to 3 of halogen, 1 to 2 of -OR 2 , 1 to 2 of -CF3, -OCF3, nitro, C(O)OR 2 , or -C(O)N(R
  • R 2 is selected from: hydrogen, C1 -C8 alkyl, and (CH2H aryl, where two Cl-C ⁇ alkyl groups are present on one atom, they optionally are joined to form a C3-C8 cyclic ring, optionally including oxygen, sulfur or NR3a ? where R ⁇ a is hydrogen, or
  • R3 is selected from the group consisting of hydrogen, Ci-Cs alkyl and (CH2)t aryl;
  • R4 is CH(CO 2 R 2 )(CH 2 ) n N(R 2 ) 2 , CH(R 2 )-(CH 2 ) n N(R 2 ) 2 ,
  • R 6 is optionally substituted with 1 to 3 groups of R 2 , 1 to 3 of halogen, 1 to 2 of -OR 2 , 1 to 2 of -CF3, -OCF3, nitro, - -C(O)OR 2 , or -
  • R R can be any organic radical
  • X is selected from the group consisting of CH 2 , and NSO 2 R 2 ;
  • More preferred compounds of Formula Ib-1 and Ib-2 are realized when: Rl iS
  • R 2 which may be substituted by 1 to 3 of R 2 , 1 to 3 of halogen, 1 to 2 of -OR 2 , 1 to 2 of -CF3, -OCF3, nitro, -C(O)OR 2 , -C(O)N(R 2 )(R 2 );
  • R 3 is selected from hydrogen or methyl
  • R 4 is CH(CO 2 But)(CH 2 ) 4 NH 2 , CH(R 2 )-(CH 2 ) 4 NH 2 , CH(CO 2 But)CH 2 WCH 2 CH 2 NH 2 , or R 6
  • X is selected from the group consisting of CH 2 , and NS0 2 CH 3 ;
  • composition which is comprised of a compound of formula I in combination with a pharmaceutically acceptable carrier.
  • the invention also includes a method of treating diabetes, cancer, acromegaly chronic atrophic gastritis, Crohn's disease, ulcerative colitis, retinopathy, arthritis, viseral and neuropathic pain and to prevent restenosis, which comprises administering to a person or animal a compound of formula I in an amount which is effective for treating said disease or condition.
  • alkyl refers to a monovalent alkane (hydrocarbon) derived radical containing from 1 to 15 carbon atoms unless otherwise defined and if two carbon atoms or more they may include a double or a triple bond. It may be straight, branched or cyclic. Preferred straight or branched alkyl groups include methyl, ethyl, propyl, isopropyl, butyl and t-butyl. Preferred cycloalkyl groups include cyclopentyl and cyclohexyl.
  • Alkyl also includes a straight or branched alkyl group which contains or is interrupted by a cycloalkylene portion. Examples include the following:
  • the alkylene and monovalent alkyl portion(s) of the alkyl group can be attached at any available point of attachment to the cycloalkylene portion.
  • alkenyl refers to a hydrocarbon radical straight, branched or cyclic containing from 2 to 15 carbon atoms and at least one carbon to carbon double bond.
  • Preferred alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl.
  • the straight, branched or cyclic portion of the alkenyl group may contain double bonds and may be substituted when a substituted alkenyl group is provided.
  • alkynyl refers to a hydrocarbon radical straight, branched or cyclic, containing from 2 to 15 carbon atoms and at least one carbon to carbon triple bond. Up to three carbon-carbon triple bonds may be present.
  • Preferred alkynyl groups include ethynyl, propynyl and butynyl. As described above with respect to alkyl, the straight, branched or cyclic portion of the alkynyl group may contain triple bonds and may be substituted when a substituted alkynyl group is provided.
  • alkoxy refers to those groups of the designated length in either a straight or branched configuration and if two or more carbon atoms in length, they may include a double or a triple bond.
  • alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy allyloxy, propargyloxy, and the like.
  • halogen is intended to include the halogen atom fluorine, chlorine, bromine and iodine.
  • Aryl refers to aromatic rings e.g., phenyl, substituted phenyl and like groups as well as rings which are fused, e.g., naphthyl, indaryl, biphenyl and the like.
  • Aryl thus contains at least one ring having at least 6 atoms, with up to two such rings being present, containing up to 10 atoms therein, with alternating (resonating) double bonds between adjacent carbon atoms.
  • the preferred aryl groups are phenyl and naphthyl.
  • Aryl groups may likewise be substituted with from 1 to 3 groups of Ci-Cl ⁇ alkyl, halogen, -OR 2 , methylenedioxy, -S(O) m R 2 , -CF3, - OCF3, nitro, -N(R )C(O)(R 2 ), -C(O)OR 2 , -C(O)N(R 2 )2, -lH-tetrazol-5-yl, - SO2N(R 2 )2, -N(R 2 )SO2 phenyl or -N(R 2 )SO2R 2 .
  • Preferred substituted aryls include phenyl and naphthyl substituted with one or two groups.
  • heteroaryl refers to a monocyclic aromatic hydrocarbon group having 5 or 6 ring atoms, or a bi cyclic aromatic group having 8 to 10 atoms, containing at least one heteroatom, O, S or N, in which a carbon or nitrogen atom is the point of attachment, and in which one additional carbon atom is optionally replaced by a heteroatom selected from O or S, and in which from 1 to 3 additional carbon atoms are optionally replaced by nitrogen heteroatoms.
  • the heteroaryl group is optionally substituted with up to three groups selected from 1 to 3 of Ci -Cs alkyl, halogen, -OR 2 , methylenedioxy, -S(O) m R 2 , -CF3, -OCF3, N(R 2 )2, nitro, -N(R 2 )C(O)(R 2 ), -C(O)OR 2 , -C(O)N(R 2 )2, -lH-tetrazol-5-yl, - SO2N(R 2 )2, -N(R 2 )SO2 phenyl or -N(R 2 )SO2R 2 .
  • Heteroaryl thus includes aromatic and partially aromatic groups which contain one or more heteroatoms.
  • Examples of this type are thiophene, oxadiazole, imidazopyridine, pyridine, oxazole, thiazole, pyrazole, tetrazole, imidazole, pyrimidine, pyrazine, benzothienyl, benzofuranyl, indolyl, azaindole, benzimidazolyl, quinolinyl, isoquinolinyl and triazine.
  • heterocycloalkyl and “heterocyclyl” refer to a cycloalkyl group (nonaromatic) in which one of the carbon atoms in the ring is replaced by a heteroatom selected from O, S, SO, SO2 or N, and in which up to three additional carbon atoms may be optionally replaced by heteroatoms.
  • Heterocyclyl is carbon or nitrogen linked; if carbon linked and contains a nitrogen, then the nitrogen may be substituted by R 2 ⁇ .
  • heterocyclyls are piperidinyl, morpholinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydroimidazo[4,5-c]pyridinyl, imidazolinyl, piperazinyl, pyrolidin-2-onyl, piperidin-2-onyl and the like.
  • salts encompassed within the term "pharmaceutically acceptable salts" refer to non-toxic salts of the compounds of this invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid.
  • Representative salts and esters include the following:
  • the compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic and optically active forms. All of these compounds are contemplated to be within the scope of the present invention. Therefore, where a compound is chiral, the separate enantiomers, substantially free of the other, are included within the scope of the invention; further included are all mixtures of the two enantiomers. Also included within the scope of the invention are polymorphs and hydrates of the compounds of the instant invention.
  • Asymmetric centers may be present in the compounds of the instant invention depending upon the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers and it is intended that all of the possible optical isomers and diastereomers in mixture and as pure or partially purified compounds are included within the ambit of this invention.
  • the asymmetric carbon atom represented by an asterisk in Formula Ia and lb it has been found that compounds are more active as somatostatin agonists and, therefore preferred, in which the nitrogen substituent is above and the R ⁇ a is below the plane of the structure.
  • This configuration corresponds to that present in a D-amino acid. In most cases, this is also designated an R-configuration, although this will vary according to the value of R* used in making R- or S- stereochemical assignments. In addition, configurations of some of the most preferred compounds of this invention are indicated.
  • the carbon atom in Formula Ia or lb bearing an asterisk is of a defined and usually a D- configuration, up to two times more diastereomers result with each additional stereo centers are present.
  • These diastereomers are arbitrarily referred to as diastereomer 1 (dl) and diastereomer 2. (d2) and so on as so forth in this invention and, if desired, their independent syntheses or chromatographic separations may be achieved as described herein.
  • Their absolute stereochemistry may be determined by the x-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration.
  • pharmaceutically effective amount shall mean that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by a researcher or clinician.
  • substituted shall be deemed to include multiple degrees of substitution by a named substitutent.
  • substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties, singlely or plurally.
  • the compounds of the present invention to act as somatostatin agonists makes them useful as pharmacologic agents for mammals, especially for humans, for the treatment and prevention of disorders wherein somatostatin itself or the hormones it regulates may be involved. Examples of such disorders have been noted earlier and include diabetes, acromegalym neuropathic pain, restenosis, retinopathy, depression, arthritis and cancer.
  • the instant compounds can also be used in combination with other therapeutic agents which are useful in treating these conditions.
  • these agents include metformin or other biguanides, acarbose, sulfonylureas, thiazolidinediones or other insulin sensitizers including, but not limited to, compounds which function as agonists on peroxisome proliferator- activated receptor gamma (PPAR-gamma), insulin, insulin-like-growth factor I, glucagon-like peptide I-glp-I and available satiety-promoting agents such as dexfenfluramine.
  • PPAR-gamma peroxisome proliferator- activated receptor gamma
  • I insulin-like-growth factor
  • I-glp-I glucagon-like peptide I-glp-I
  • available satiety-promoting agents such as dexfenfluramine.
  • the compounds of the present invention can be administered in such oral dosage forms as tablets, capsules (each including timed release and sustained release formulations), pills, powders, granules, elixers, tinctures, suspensions, syrups and emulsions. Likewise, they may also be administered in intravenous (both bolus and infusion), intraperitoneal, subcutaneous or intramuscular form, all using forms well known to those of ordinary skill in the pharmaceutical arts. An effective but non-toxic amount of the compound desired can be employed as a tocolytic agent.
  • the dosage regimen utilizing the compounds of the present invention is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed.
  • An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.
  • Intravenous dosages or oral dosages of the compounds of the present invention when used for the indicated effects, will range between about 0.001 to 5 mg/kg and 0.1 to 50 mg/kg, respectively.
  • compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily.
  • preferred compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art.
  • the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
  • the compounds herein described in detail can form the active ingredient, and are typically administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as "carrier” materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent ' with conventional pharmaceutical practices.
  • carrier suitable pharmaceutical diluents, excipients or carriers
  • suitable pharmaceutical diluents, excipients or carriers suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent ' with conventional pharmaceutical practices.
  • the active drug component can be combined with an oral, non- toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
  • suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture.
  • Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like.
  • Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, zanthan gum and the like.
  • the compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
  • the instant compounds can be effective to inhibit the secretion of various hormones and trophic factors in mammals. They may be used to suppress certain endocrine secretions, such as GH, insulin, glucagon and prolactin, in the treatment of disorders such as acromegaly; endocrine tumors such as carcinoids, vipomas, insulinomas and glucagonomas; or diabetes and diabetes-related pathologies, including retinopathy, neuropathy and nephropathy. The compounds may also be used to suppress exocrine secretions in the pancreas, stomach and intestines, for treatment of disorders such as pancreatitis, fistulas, bleeding ulcers and diarrhea associated with such diseases as AIDS or cholera.
  • endocrine secretions such as GH, insulin, glucagon and prolactin
  • endocrine tumors such as carcinoids, vipomas, insulinomas and glucagonomas
  • diabetes and diabetes-related pathologies including retin
  • disorders involving autocrine or paracrine secretions of trophic factors such as IGF-1 which may be treated by administration of the instant compounds include cancers of the breast, prostate, and lung (both small cell and non-small cell epidermoids), as well as hepatomas, neuroblastomas, colon and pancreatic adenocarcinomas (ductal type), chondrosarcomas, and melanomas, and also atherosclerosis associated with vascular grafts and restenosis following angioplasty.
  • Somastostatin in the brain inhibits the neuronal release of substance P(NK-l) and NK-1 antagonists have been shown to have a marked use as an antidepressant agent. Accordingly, the instant compounds are also useful in treating depression.
  • the compounds of the instant invention are further useful to suppress the mediators of neurogenic inflammation (e.g. substance P or the tachykinins), and may be used in the treatment of rheumatoid arthritis; psoriasis; topical inflammation such as is associated with sunburn, eczema, or other sources of itching; and allergies, including asthma.
  • the compounds can also function as neuromodulators in the central nervous system, with useful applications in the treatment of Alzheimer's disease and other forms of dementia, pain (as a spinal analgesic), and headaches.
  • the compounds of the invention can provide cytoprotection.
  • the preparation of compounds of Formula Ia or lb of the present invention may be carried out in sequential or convergent synthetic routes.
  • standard peptide coupling reaction conditions is used repeatedly here, and it means coupling a carboxylic acid with an amine using an acid activating agent such as EDC, DCC, and BOP in a inert solvent such as dichloromethane in the presence of a catalyst such as HOBT.
  • acid activating agent such as EDC, DCC, and BOP
  • a inert solvent such as dichloromethane
  • a catalyst such as HOBT.
  • mixed urea formation refers to conversion of two different amines to form their mixed urea by using phosgene or equivalents such as CDI, DSC, or p-nitrophenyl chloroformate.
  • the reaction involves reacting one amine first with the phosgene or equivalents in the presence of a base such as NMM, TEA or DIEA in a inert solvent such as dichloromethane, THF and DMF or mixtures thereof, followed by addition of the second amine and a base such as NMM, TEA or DIEA.
  • a base such as NMM, TEA or DIEA
  • a base such as NMM, TEA or DIEA
  • CBZ and BOC were used extensively and their removal conditions are known to those skilled in the art.
  • removal of CBZ groups can be achieved by a number of methods such as catalytic hydrogenation in the presence of a noble metal or its oxide such as palladium on activated carbon in a protic solvent such as ethanol.
  • a protic solvent such as ethanol.
  • removal of CBZ groups can also be achieved by treatment with a solution of hydrogen bromide in acetic acid, or by treatment with a mixture of TFA and dimethyl sulfide.
  • Removal of BOC protecting groups is carried out in a solvent such as methylene chloride, methanol or ethyl acetate, with a strong acid, such as trifluoroacetic acid, hydrochloric acid or hydrogen chloride gas.
  • a strong acid such as trifluoroacetic acid, hydrochloric acid or hydrogen chloride gas.
  • the protected amino acid derivatives required in the synthesis of compounds of Formula Ia or lb are, in many cases, commercially available, where the protecting group (Pi) is, for example, methyl, allyl or benzyl groups.
  • Other protected amino acid can be prepared by literature methods (Williams, R. M. Synthesis of Optically Active -Amino Acids, Pergamon Press: Oxford, 1989). Many of the piperidines of Formula 2 are either commercially available or known in the literature and others can be prepared following literature methods described for analogous compounds. Some of these methods are illustrated in the subsequent schemes. Purification procedures include crystallization, normal phase or reverse phase chromatography
  • the compounds of the present invention can be prepared readily according to the following Schemes or modifications thereof using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants which are themselves known to those of ordinary skill in this art, but are not mentioned in greater detail.
  • the definition for Rl, B ⁇ a , R 2 , R3, R4 ? R5 J Zl, W, E, etc., is described above unless otherwise stated.
  • Intermediates of Formula 4A can be synthesized as described in Scheme 1.
  • Mixed urea formation between the protected amino acid 1 and the piperidine of Formula 2 is conveniently carried out under usual urea formation reactions use phosgene or equivalents such as CDI, DSC, or p-nitrophenyl chloroformate.
  • Removal of the P protecting group can be achieved by saponification for most esters, or by catalytic hydrogenolysis when pi is benzyl, or by palladium (0) based homogeneous catalysis when pi is allyl.
  • Intermediate 4A can be used as a common intermediate for the synthesis of somatostatin agonists with variation of the rest of the molecule of Formula I as shown in Scheme 2.
  • amide intermediates of formula 4B can be achieved as shown in Scheme IA.
  • Standard peptide coupling reactions of protected amino acid 1 with 2-halo acids such as 2-bromoacetic acid gives intermediate IA, which when reacted with amine of formula 2 gives the compound as 3A in the presence of a non-nucleophilic base such as DIEA.
  • the Pi protecting group can be removed as described above.
  • Intermediates of Formula 4 can be coupled to intermediates of formula 5 which is a properly mono protected with P2(such as BOC,
  • compounds of Formula I can be prepared starting from compound 5.
  • the protected amino acid derivatives 8 are in many cases commercially available, where P3 is, for example, BOC, Cbz, Fmoc, and the like.
  • N-Protected amino acid 8 can be coupled to intermediates of formula 5, wherein Z 2 is oxygen or substituted nitrogen to afford compounds of Formula 9 under standard ester or peptide coupling reaction conditions.
  • the protecting group in compound 8 is selected with the criteria that its removal can be achieved without removing P 2 .
  • the P2 protecting group is removed to afford compound 10
  • this compound can be further converted to compounds of formula I-A according to the procedures described in Scheme 1 and Scheme IA.
  • Acid and amine coupling reaction to form amide To a stirred solution of carboxylic acid (such as Intermediate 1), HOBT (1 equiv.) and the primary or secondary amine (such as intermediate 6, 1.2 equiv.) in dichloromethane (final concentration at about 0.2 M) at 0°C was added EDC (1.5 equiv.). If the amine is in its hydrochloride form, 1.2 equiv. of DIEA was added. The reaction mixture was stirred at 0°C for 4 hours, and then poured in to 3 N HCI. The organic layer was subsequently washed with aquous sodium bicarbonate and brine, dried and evaporated. Purification with silica chromatography give the desired product.
  • carboxylic acid such as Intermediate 1
  • HOBT 1- equiv.
  • the primary or secondary amine such as intermediate 6, 1.2 equiv.
  • dichloromethane final concentration at about 0.2 M
  • EDC 1.5 equiv.
  • esters The ester was dissolved in THF, treated with LiOH (2.5 equiv.) in 1:1 EtOH/water and stirred for 4h at room temperature. The pH was adjusted to -2-3 by addition of 3N HCI and the resulting solution was extracted with ethyl acetate 3 times. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated to give the acid.
  • Boc protecting group The Boc protected amine is dissolved in ethyl acetate, and two which HCI in dioxane (4 N, 4-10 equiv.) was added.
  • the intermediate was prepared using the methyl ester according to General procedure 5.
  • N-Cbz-D-tryptophan (10.4 g, 30.6 mmol)
  • N- ⁇ -t-BOC-L-Lysine methyl ester hydrochloride 9.55 g, 32.2 mmol
  • HOBt (6.21 g, 46.0 mmol)
  • DIEA 5.61 mL, 32.2 mmol
  • EDC 8.81 g, 46.0 mmol
  • the reaction mixture was allowed to warm to room temperature and stirred for 16 hrs.
  • the reaction mixture was then poured into a saturated solution of NaHCO3 (100 mL), and the layers were separated.
  • the organic layer was then sequentially washed with 100 L portions of IN HCI, water and brine, dried over anhydrous MgSO4, filtered and concentrated to give 17.8 g (100% crude yield) a yellow/white solid.
  • N-BOC-D-Tryptophan 15.2 g, 50.0 mmol
  • N- ⁇ -Cbz-L-Lysine i-butyl ester hydrochloride 18.7 g, 50.0 mmol
  • HOBt 6.76 g, 50 mmol
  • DIEA 8.71 mL, 50.0 mmol
  • EDC 12.5 g, 65.0 mmol
  • Step A 4-(t-butyloxycarbonylaminomethyl)-pyridine N-oxide:
  • the reaction mixture was then evaporated and partition between 3N HCI and dichloromethane.
  • the inorganic layer was extracted with dichloromethane five times and the extracts was combined and washed with small volume of sodium bicarbonate solution.
  • the organic solution was dried and evaporated and purified by 5-10% methanol in dichloromethane to give the N-oxide (4.33 g).
  • Step C 2-aminomethyl-4-(t-butyloxycarbonylaminomethyl)-pyridine:
  • Step A 4-(t-butyloxycarbonylaminomethyl)-2-(benzyloxy- carbonylaminomethyD-pyridine:
  • Step B 4-aminomethyl-2-(benzyloxycarbonylaminomethyl)-pyridine
  • the 4-(t-butyloxycarbonylaminomethyl)-2-aminomethyl- pyridine 160 mg, 0.43 mmol was dissolved in TFA (10 ml) and stirred at room temperature for two hours. The solvent was removed in vacuo. 163 mg of the crude product was collected and brought to next step reaction without further purification.
  • N-carboethoxyphthalimide (21.9 g, 0.10 mol), trans-4- (aminomethyl)cyclohexane carboxylic acid (15.7 g, 0.10 mol) and triethylamine (14 mL) were stirred in 100 mL THF and the mixture refluxed 18 hours. The nearly clear solution was poured into 400 ml water containing 10 mL glac. HOAc with rapid stirring and the precipitated product collected by suction and dried in a vacuum oven at 80°C. mp 190-192°.
  • Step 3 N-(4-tertbutoxycarbonylamino)cyclohexylmethyl phthalimide
  • step 2 The crude product from example 1, step 2 was treated with a solution of lithium tert butoxide in THF for 2 hours at room temperature to give a dark solution which was diluted with aqueous acetic acid and ice to precipitate the crude product which is recrystallized from 1- chlorobutane to give beige needles of the title urethane. mp. 163-165°.
  • Step 4 N-(4-tertbutoxycarbonylamino)cyclohexylmethyl amine
  • the above urethane phthalimide was treated with 1 equivalent anhydrous hydrazine in isopropanol for 18 hours at room temperature followed by 4 hours reflux.
  • the mixture was concentrated, diluted with cold aqueous acetic acid and filtered to remove phthalazinedione.
  • the aqueous layer was basified with NaOH followed by extraction with ethyl acetate, drying, and evaporation to afford the desired product Intermediate as a solid.
  • INTERMEDIATE 10 N-(4-tertbutoxycarbonylamino)cyclohexylmethyl amine
  • Step A 2-(N-t-Butoxycarbonylaminomethyl)-5-hydroxymethyl tetrahydrofuran 2-Aminomethyl-5-hydroxymethyl tetrahydrofuran (2.4 g, 18 mmol) was dissolved in THF (40 mL) and treated with a solution of Boc2O (3.99 g, 18.3 mmol) in THF (20 mL) over about 10 min. The reaction mixture was stirred for 24 h and then concentrated to afford the BOC amino protected compound which was purified by MPLC (silica, 1% methanol/ethyl acetate).
  • Step B 2-(N-t-Butoxycarbonylaminomethyl)-5-azidomethyl tetrahydrofuran
  • Step C 2-(N-t-Butoxycarbonylaminomethyl)-5-aminom ethyl tetrahydrofuran NHBOC
  • N-Cbz-serinol (497 mg, 2.21 mmol), (prepared using standard procedures from commercially available serinol oxalate and Cbz-Cl), phthalimidoacetaldehyde diethyl acetal (Aldrich, 581 mg, 2.21 mmol) and TsOH (21 mg, 0.11 mmol) in toluene (10 mL) was heated to reflux for 6 h. The resulting solution was cooled and evaporated in vacuo.
  • N-Cbz-serinol (31.5 g, 0.140 mol) (prepared using standard procedures from commercially available serinol oxalate and Cbz-Cl), and triphenylphosphine (80.7 g, 0.308 mol) in THF (500 mL) was cooled to 0° C and treated with DEAD (48.5 mL, 53.6 g, 0.308 mol), followed by thiolacetic acid (22.0 L, 23.4 g, 0.308 mol). The reaction mixture was stirred at 0° C for two h then at rt overnight. Concentration of the reaction mixture was followed by flash chromatography (30-90% EtOAc/Hexanes gradient).
  • the reaction mixture was warmed to rt and stirred overnight. Concentrated NH 4 OH solution (7 mL) was added to quench any remaining alkyl halides and the mixture was stirred for an additional 4h. The reaction mixture was then diluted with ether and washed with 3N HCI solution (2X), saturated NaHCO 3 solution, and brine. The organic phase was dried over MgSO 4 , filtered and concentrated. The crude product was purified by flash chromatography (5-15% EtOAc/hexanes) to afford 20.1 g of a mixture of isomers (47% yield). The BOC group was removed by dissolving the protected intermediate mixture in ether (200 mL) and bubbling HCI gas through this solution for 20 min.
  • reaction mixture was then diluted with CH 2 C1 2 , washed with IN HCI, saturated NaHC0 3 solution and brine, dried over MgSO 4 , filtered and concentrated to afford 1.12 g of crude trifluoroacetamide product.
  • This product was dissolved in CH 2 C1 2 and treated with 1.0 M BBr 3 in CH 2 C1 2 (2.9 mL, 2.9 mmol).
  • the reaction mixture was stirred at rt under N 2 for 1.25 h then poured into saturated NaHCO 3 solution which, in turn, was washed with CH 2 C1 2 .
  • the organic layer was washed with brine, dried over MgSO 4 , filtered and concentrated.
  • the title compound was prepared in 4 steps from D-l- naphthylalanine methylester by urea coupling according to general procedure 2, saponification of the methyl ester according to general procedure 5 [ESI-MS calc for C27H26N2O3: 426; Found 427 (M+H)], EDC amide condensation with H-Lys(Boc)-OMe by general procedure 1 [ESI-MS calc for C39H48N4O6: 668; Found 669 (M+H)], and BOC deprotection using general procedure 6.
  • Mammalian expression vectors containing full length coding sequences for hSSTRl-5 were constructed as follows: Fragments of genomic DNA carrying the various human somatostatin receptors were inserted into the multiple cloning site of pcDNA3 (Invitrogen). The fragments used were a 1.5-kb Pstl-Xmnl fragment for hSSTRl, 1.7-kb Bam ⁇ l-Hindlll fragment for hSSTR2, 2.0-kb iVcoI-H dlll fragment for hSSTR3, a 1.4-kb Nhel-Ndel fragment for hSSTR4, and a 3.2-kb Xhol- EcoRl fragment for hSSTR ⁇ .
  • CHO-K1 cells were obtained from American Type Culture Collection (ATCC) and grown in alpha-MEM containing 10% fetal calf serum. Cells were stably transfected with DNA for all 5 hSSTRs using lipofectamine. Neomycin resistant clones were selected and maintained in medium containing G418 (400 ⁇ g ml).
  • Cells were harvested 72 hr after transfection to 50 mM Tris- HCI, pH 7.8, containing 1 mM EGTA, 5 mM MgCl 2 , 10 ⁇ g/ml leupeptin, 10 ⁇ g/ml pepstatin, 200 ⁇ g/ml bacitracin, and 0.5 ⁇ g/ml aprotinin (buffer 1) and were centrifuged at 24,000 x g for 7 min at 4°. The pellet was homogenized in buffer 1 using a Brinkman Polytron (setting 2.5, 30 sec). The homogenate was then centrifuged at 48,000 ⁇ g for 20 min at 4°C.
  • the pellet was homogenized in buffer 1 and the membranes were used in the radioligand binding assay.
  • Cell membranes (approximately 10 ⁇ g of protein) were incubated with 125 I-Tyr 1:L -somatostatin (0.2 nM; specific activity, 2000 Ci/mmol; NEN) in the presence or absence of competing peptides, in a final volume of 200 ⁇ l, for 30 min at 25°.
  • Nonspecific binding was defined as the radioactivity remaining bound in the presence of 100 nM somatastatin.
  • the binding reaction was terminated by the addition of ice-cold 50 nM Tris-HCl buffer, pH 7.8, and rapid filtration with 12 ml of ice-cold Tris HCI buffer, and the bound radioactivity was counted in a gamma scintillation spectrophotometer (80% efficiency). Data from radioligand binding studies were used to generate inhibition curves. IC5 0 values were obtained from curve-fitting performed with the mathematical modeling program FITCOMP, available through the National Institutes of Health-sponsored PROPHET System.
  • Cells used for cAMP accumulation studies were subcultured in 12-well culture plates. COS-7 cells were transfected 72 hr before the experiments. Culture medium was removed from the wells and replaced with 500 ⁇ l of fresh medium containing 0.5 mM isobutylmethylxanthine. Cells were incubated for 20 min at 37°- Medium was then removed and replaced with fresh medium containing 0.5 mM isobutylmethylxanthine, with or without 10 ⁇ M forskolin and various concentrations of test compound. Cells were incubated for 30 min at 37°. Medium was then removed, and cells were sonicated in the wells in 500 ⁇ L of 1 N HCI and frozen for subsequent determination of cAMP content by radioimmunassay. Samples were thawed and diluted in cAMP radioimmunassay buffer before analysis of cAMP content using the commercially available assay kit from NEW/DuPont (Wilmington, DE).
  • rat anterior pituitary cells Functional activity of the various compounds was evaluated by quantitating release of growth hormone secretion from primary cultures of rat anterior pituitary cells.
  • Cells were isolated from rat pituitaries by enzymatic digestion with 0.2% collagenase and 0.2% hyaluronidase in Hank's balanced salt solution. The cells were suspended in culture medium and adjusted to a concentration of 1.5 x 10 5 cells per milliliter, and 1.0 ml of this suspension was placed in each well of a 24-well tray. Cells were maintained in a humidified 5% CO2-95% air atmosphere at 37°C for 3 to 4 days.
  • the culture medium consisted of Dulbecco's modified Eagle's medium containing 0.37% NaHCO 3 , 10% horse serum, 2.5% fetal bovine serum, 1% nonessential amino acids, 1% glutamine, 1% nystatin, and 0.1% gentamycin.
  • the compounds of the insant invention were tested in quadruplicate by adding them in 1 ml of fresh medium to each well and incubating them at 37°C for 15 min. After incubation, the medium was removed and centrifuged at 2000g for 15 min to remove any cellular material. The supernatant fluid was removed and assayed for GH by radioimmunoassay.
  • the compounds of this invention were found to inhibit the binding of somatostatin to its receptor at an IC50 of about 30 pM to about 3 ⁇ M.

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Abstract

La présente invention concerne des composés agonistes de la somatostatine présentant un fort potentiel de haute sélectivité vis-à-vis du sous-type 2 du récepteur. Ces composés présentent un meilleur coefficient thérapeutique pour le traitement du diabète, du cancer, de l'acromégalie, et de la rétinopathie. Nombre de ces composés sont aussi oralement actifs. L'invention concerne donc, non seulement ces composés, mais également les stéréoïsomères spécifiques préférés des agonistes de la somatostatine, et aussi les procédés d'élaboration de tels composés. L'invention concerne enfin des procédés et des compositions utilisant ces composés comme principe actif. D'autres objets de l'invention sont aisément identifiables à la lecture du corps de l'invention.
PCT/US1998/022917 1997-10-30 1998-10-28 Agonistes de la somatostatine WO1999022735A1 (fr)

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EP1086947A1 (fr) * 1999-09-01 2001-03-28 Pfizer Products Inc. Antagonistes et agonistes de la somatostatin, qui agissent sur le recepteur SST subtype 2
US6696418B1 (en) 1999-09-01 2004-02-24 Pfizer Inc. Somatostatin antagonists and agonists that act at the SST subtype 2 receptor
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FR2802206A1 (fr) * 1999-12-14 2001-06-15 Sod Conseils Rech Applic Derives de 4-aminopiperidine et leur utilisation en tant que medicament
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US6316414B1 (en) 2000-07-31 2001-11-13 Dabur Research Foundation Somatostatin analogs for the treatment of cancer
US6720330B2 (en) 2000-11-17 2004-04-13 Pfizer Inc. Somatostatin antagonists and agonists that act at the SST subtype 2 receptor
EP1415986A1 (fr) * 2001-08-07 2004-05-06 Banyu Pharmaceutical Co., Ltd. Composes spiro
US7205417B2 (en) 2001-08-07 2007-04-17 Banyu Pharmaceutical Co., Ltd. Spiro compounds
EP1415986A4 (fr) * 2001-08-07 2005-11-02 Banyu Pharma Co Ltd Composes spiro
AU2002323787B2 (en) * 2001-08-07 2008-04-24 Banyu Pharmaceutical Co., Ltd. Spiro compounds
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EP2385032A1 (fr) 2002-11-08 2011-11-09 Takeda Pharmaceutical Company Limited Régulateur de fonction de récepteur GPR40
JP2006519200A (ja) * 2003-02-27 2006-08-24 サノフィ−アベンティス・ドイチュラント・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング シクロアルキル置換アルカン酸誘導体、その製造方法、及び医薬としてのその使用
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US8158791B2 (en) 2005-11-10 2012-04-17 Msd K.K. Aza-substituted spiro derivatives
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