EP1463715A1 - Nouveaux antagonistes de glucagon - Google Patents

Nouveaux antagonistes de glucagon

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Publication number
EP1463715A1
EP1463715A1 EP02804158A EP02804158A EP1463715A1 EP 1463715 A1 EP1463715 A1 EP 1463715A1 EP 02804158 A EP02804158 A EP 02804158A EP 02804158 A EP02804158 A EP 02804158A EP 1463715 A1 EP1463715 A1 EP 1463715A1
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EP
European Patent Office
Prior art keywords
alkyl
compound according
hydrogen
aryl
ocf
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Withdrawn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
EP02804158A
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German (de)
English (en)
Inventor
Janos Tibor Kodra
Peter Madsen
Jesper Lau
Anker Steen J Rgensen
Inge Th Ger Christensen
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Pfizer Inc
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Novo Nordisk AS
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Publication of EP1463715A1 publication Critical patent/EP1463715A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid, pantothenic acid
    • A61K31/198—Alpha-aminoacids, e.g. alanine, edetic acids [EDTA]
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones

Definitions

  • the present invention relates to agents that act to antagonize the action of the glucagon peptide hormone on the glucagon receptor. More particularly, it relates to glucagon antagonists or inverse agonists.
  • Glucagon is a key hormonal agent that, in co-operation with insulin, mediates ho- meostatic regulation of the amount of glucose in the blood. Glucagon primarily acts by stimulating certain cells (mostly liver cells) to release glucose when blood glucose levels fall. The action of glucagon is opposite to that of insulin, which stimulates cells to take up and store glucose whenever blood glucose levels rise. Both glucagon and insulin are peptide hormones.
  • Glucagon is produced in the alpha islet cells of the pancreas and insulin in the beta islet cells.
  • Diabetes mellitus is a common disorder of glucose metabolism.
  • the disease is characterized by hyperglycemia and may be classified as type 1 diabetes, the insulin- dependent form, or type 2 diabetes, which is non-insulin-dependent in character.
  • Subjects with type 1 diabetes are hyperglycemic and hypoinsulinemic, and the conventional treatment for this form of the disease is to provide insulin.
  • absolute or relative elevated glucagon levels have been shown to contribute to the hyperglycemic state.
  • glucagon suppression or an action that antagonizes glucagon could be a useful adjunct to conventional treatment of hyperglycemia in diabetic patients.
  • the action of glucagon can be suppressed by providing an antagonist or an inverse agonist, ie substances that inhibit or prevent gluca- gon-induced responses.
  • the antagonist can be peptidic or non-peptidic in nature.
  • Native glucagon is a 29 amino acid peptide having the sequence: His-Ser-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln-Asp- Phe-Val-Gln-Trp-Leu-Met-Asn-Thr-OH Glucagon exerts its action by binding to and activating its receptor, which is part of the Glucagon-Secretin branch of the 7-transmembrane G-protein coupled receptor family. The receptor functions by activating the adenylyl cyclase second messenger system and the result is an increase in cAMP levels.
  • Peptide antagonists of peptide hormones are often quite potent. However, they are generally known not to be orally available because of degradation by physiological enzymes, and poor distribution in vivo. Therefore, orally available non-peptide antagonists of peptide hormones are generally preferred.
  • non-peptide glucagon antagonists a quinoxa- line derivative, (2-styryl-3-[3-(dimethylamino)propylmethylamino]-6,7-dichloroquinoxaline was found to displace glucagon from the rat liver receptor (Collins, J.L. et al., Bioorganic and Medicinal Chem. Lett. 2(9):915-918 (1992)).
  • WO 94/14426 (The Wellcome Foundation Limited) discloses use of skyrin, a natural product comprising a pair of linked 9,10-anthracenedione groups, and its synthetic analogues, as glucagon antagonists.
  • US 4,359,474 (Sandoz) discloses the glucagon inhibiting properties of 1 -phenyl pyrazole derivatives.
  • US 4,374,130 (Sandoz) discloses substituted disilacyclohexanes as glucagon inhibiting agents.
  • WO 98/04528 (Bayer Corporation) discloses substituted pyridines and biphenyls as glucagon antagonists.
  • US 5,776,954 discloses substituted pyridyl pyrroles as gluca- gon antagonists and WO 98/21957, WO 98/22108, WO 98/22109 and US 5,880,139 (Merck & Co., Inc.) disclose 2,4-diaryl-5-pyridylirriidazoles as glucagon antagonists. Furthermore, WO 97/16442 and US 5,837,719 (Merck & Co., Inc.) disclose 2,5-substituted aryl pyrroles as glucagon antagonists.
  • WO 98/24780, WO 98/24782, WO 99/24404 and WO 99/32448 disclose substituted pyrimidinone and pyridone compounds and substituted pyrimidine compounds, respectively, which are stated to possess glucagon antagonistic activity.
  • Madsen et al. J. Med. Chem. 1998 (41) 5151-7) discloses a series of 2-(benzimidazol- 2-ylthio)-1-(3,4-dihydroxyphenyl)-1-ethanones as competitive human glucagon receptor antagonists.
  • WO 99/01423 and WO 00/39088 disclose different series of alkylidene hydrazides as glucagon antagonists/inverse agonists.
  • WO 00/69810, WO 02/00612, WO 02/40444, WO 02/40445 and WO 02/40446 disclose further classes of glucagon antagonists.
  • Halogen designates an atom selected from the group consisting of F, Cl, Br and I.
  • C ⁇ -alkyl represents a saturated, branched or straight hydrocarbon group having from 1 to 6 carbon atoms. Representative examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, terf-butyl, n-pentyl, isopentyl, ⁇ eopentyl, ferf-pentyl, n-hexyl, isohexyl and the like.
  • C 2 ⁇ -alkenyl represents a branched or straight hydrocar- bon group having from 2 to 6 carbon atoms and at least one double bond.
  • groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, iso-propenyl, 1,3-buta- dienyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1-pentenyl, 2-pentenyl, 3-pent- enyl, 4-pentenyl, 3-methyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 2,4-hexadienyl, 5- hexenyl and the like.
  • C 2 -6-alkynyl represents a branched or straight hydrocarbon group having from 2 to 6 carbon atom's and at least one triple bond.
  • groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4- hexynyl, 5-hexynyl, 2,4-hexadiynyl and the like.
  • C ⁇ -alkoxy refers to the radical -0-C 1-6 -alkyl wherein d ⁇ -alkyl is as defined above. Representative examples are methoxy, ethoxy, n-propoxy, iso- propoxy, butoxy, sec-butoxy, te/f-butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy and the like.
  • C M -cycloalkyl represents a saturated, carbocyclic group having from 3 to 8 carbon atoms. Representative examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
  • C 4 ⁇ -cycloalkenyl represents a non-aromatic, carbocyclic group having from 4 to 8 carbon atoms containing one or two double bonds.
  • Representative examples are 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopente ⁇ yI, 1-cyclohexenyl, 2-cyclo- hexenyl, 3-cyclohexenyl, 2-cycloheptenyl, 3-cycloheptenyl, 2-cyclooctenyl, 1 ,4-cycloocta- dienyl and the like.
  • heterocyclyl represents a non-aromatic 3 to 10 membered ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur and optionally containing one or two double bonds. Representative examples are pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, aziridinyl, tetrahydrofuranyl and the like.
  • aryl as used herein is intended to include carbocyclic, aromatic ring systems such as 6 membered monocyclic and 9 to 14 membered bi- and tricyclic, carbocyclic, aromatic ring systems.
  • Aryl is also intended to include the partially hydrogenated derivatives of the ring systems enumerated above.
  • Non-limiting examples of such partially hydrogenated derivatives are 1 ,2,3,4-tetrahydronaphthyl, 1 ,4- dihydronaphthyl, indanyl and the like.
  • arylene as used herein is intended to include divalent, carbocyclic, aromatic ring systems such as 6 membered monocyclic and 9 to 14 membered bi- and tricyclic, divalent, carbocyclic, aromatic ring systems. Representative examples are phenylene, bi- phenylene, naphthylene, anthracenylene, phenanthrenylene, fluorenylene, indenylene, az- ulenylene and the like. Arylene is also intended to include the partially hydrogenated derivatives of the ring systems enumerated above.
  • Non-limiting examples of such partially hydrogenated derivatives are 1 ,2,3,4-tetrahydronaphthylene, 1 ,4-dihydronaphthylene and the like.
  • aryloxy as used herein denotes a group -O-aryl, wherein aryl is as defined above.
  • aroyl denotes a group -C(0)-aryl, wherein aryl is as defined above.
  • C ⁇ -alkanoyl denotes a group -C(0)-C 1-6 -alkyl, wherein C L 6 -alkyl is as defined above.
  • heteroaryl as used herein is intended to include aromatic, heterocyclic ring systems containing one or more heteroatoms selected from nitrogen, oxygen and sulfur such as 5 to 7 membered monocyclic and 8 to 14 membered bi- and tricyclic aromatic, heterocyclic ring systems containing one or more heteroatoms selected from nitrogen, oxygen and sulfur.
  • furyl thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, 1 ,2,3-triazolyl, 1 ,2,4-triazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1 ,2,3-triazinyl, 1 ,2,4-triazinyl, 1 ,3,5- triazinyl, 1 ,2,3-oxadiazolyl, 1 ,2,4-oxadiazolyl, 1 ,2,5-oxadiazolyl, 1 ,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1 ,3,4-thiadiazolyl, tetrazolyl, thiadiazinyl, ind
  • Heteroaryl is also intended to include the partially hydrogenated derivatives of the ring systems enumerated above.
  • Non-limiting examples of such partially hydrogenated derivatives are 2,3-dihydrobenzofuranyl, pyrrolinyl, pyrazolinyl, indolinyl, oxazolidinyl, oxazolinyl, oxazepinyl and the like.
  • heteroarylene as used herein is intended to include divalent, aromatic, heterocyclic ring systems containing one or more heteroatoms selected from nitrogen, oxygen and sulfur such as 5 to 7 membered monocyclic and 8 to 14 membered bi- and tricyclic aromatic, heterocyclic ring systems containing one or more heteroatoms selected from nitro- gen, oxygen and sulfur.
  • Heteroaryl is also in- tended to include the partially hydrogenated derivatives of the ring systems enumerated above.
  • Non-limiting examples of such partially hydrogenated derivatives are 2,3-dihydro- benzofuranylene, pyrrolinylene, pyrazolinyle ⁇ e, indolinylene, oxazolidinylene, oxazolinylene, oxazepinylene and the like.
  • Aryl-C ⁇ -alkyl means C 1-6 -alkyl or C 2 ⁇ - alkenyl as defined above, substituted by an aryl or heteroaryl as defined above, for example:
  • treatment means the management and care of a patient for the purpose of combating a disease, disorder or condition.
  • the term is intended to include the delaying of the progression of the disease, disorder or condition, the alleviation or relief of symptoms and complications, and/or the cure or elimination of the disease, disorder or condition.
  • the patient to be treated is preferably a mammal, in particular a human being.
  • the present invention relates to a compound of the general formula (I):
  • n 0 or 1
  • n 0, 1, 2 or 3
  • R 4 is hydrogen, halogen or -(CH 2 ) 0 -OR 5 ,
  • o 0 or 1
  • R 5 is hydrogen, C 1-6 -alkyl, C . ⁇ -alkanoyl , aryl or aryl-C ⁇ -alkyl,
  • R and R 2 independently are hydrogen, halogen or C 1-6 -alkyl, or R 1 and R 2 are combined to form a double bond
  • R 3 is hydrogen, C 1-6 -alkyl or halogen, or R 3 and R 2 are combined to form a double bond to oxygen
  • X is arylene or heteroaryiene, which may optionally be substituted with one or two groups R 6 and R 7 selected from halogen, -CN, -CF 3 , -OCF 3 , -OCHF 2 , -N0 2 , -OR 8 , -NR 8 R 9 and C 1-6 -alkyl,
  • R 8 and R 9 independently are hydrogen or d-e-alkyl
  • Y is -C(O)-, -0-, -NR 10 -, -S-, -S(O)-, -S(0) 2 - or -CR 11 R 12 -,
  • R 10 is hydrogen or C ⁇ -alkyl
  • R 11 and R 2 independently are hydrogen, d-e-alkyl or hydroxy, or R 11 is combined with R 1 to form a double bond, and R 12 is hydrogen, C ⁇ . 6 -alkyl or hydroxy,
  • Z is -C(0)-(CR 13 R 1 ) p -, -0-(CR 13 R 14 ) p -, -S-(CR 13 R 14 ) P -, -S(0)-(CR 13 R 14 ) p -, -S(0) 2 -(CR 13 R 14 ) p -, -NR 15 -(CR 13 R 1 ) P - or -(CR 13 R 14 ) P -,
  • p 0, 1 or 2
  • R 13 and R 14 independently are selected from hydrogen, -CF 3 , -OCF 3 and C ⁇ -B -alkyl,
  • R 15 is hydrogen or C 1-6 -alkyl
  • D is aryl or heteroaryl, which may optionally be substituted with one or more substituents R 16 , R 17 , R 18 , R 19 , R 20 and R 21 , wherein
  • R 16 , R 17 , R 18 and R 19 independently are
  • aromatic and non-aromatic ring systems optionally may be substituted with one or more substituents selected from halogen, -dOJOR 22 , -CN, -CF 3 , -OCF 3 , -OCHF 2 , -N0 2 , -OR 22 , -NR 22 R 23 and C 1-6 -alkyl,
  • R 22 and R 23 independently are hydrogen, d- ⁇ -alkyl, a ⁇ /l-C ⁇ -alky! or aryl, or R 22 and R 23 when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds,
  • a 0, 1 or 2
  • c 1 or 2
  • R 24 , R 25 , R 26 and R 27 independently are hydrogen, C 1-6 -alkyl or fluoro,
  • R 20 and R 21 independently are hydrogen, C 1-5 -alkyl, C 3-8 -cycloalkyl or C 3-8 -cyclo- alkyl-C ⁇ -alkyl, E is
  • heteroaryl and aryl groups optionally may be substituted with one or more substituents selected from halogen, -CN, -CF 3 , -OCF 3 , -OCHF 2 , -N0 2 , -OR 33 , - NR R 34 and C ⁇ . 6 -alkyl,
  • R and R independently are hydrogen or d-e-alkyl
  • R 33 and R 34 when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds,
  • R 28 and R 29 are as defined above, and R 30 , R 31 and R 32 are independently selected from
  • aromatic and non-aromatic ring systems optionally may be substituted with one or more substituents selected from halogen, -CN, -CF 3 , -OCF 3 , -OCHF 2 , - N0 2 , -OR 35 , -NR 35 R 36 and C 1-6 -alkyl,
  • R 35 and R 36 independently are hydrogen, d. 6 -alkyl or aryl
  • R 35 and R 36 when attached to the same nitrogen atom together with the said nitro- gen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds,
  • t and I independently are 0, 1 , 2, 3, 4 or 5,
  • R 37 and R 38 independently are hydrogen or Ci-e-alkyl
  • A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
  • A is O
  • A is
  • A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
  • X is monocyclic arylene or heteroaryiene, which may optionally be substituted as defined for formula (I).
  • R 6 and R 7 are as defined for formula (I).
  • R 6 and R 7 are as defined for formula (I). In another embodiment, R s and R 7 are both hydrogen.
  • E is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
  • R ⁇ a , R , R* R J1 and R 32 are as defined for formula (I).
  • E is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
  • R 4B , R 29 , R J ⁇ , R 31 and R J2 are as defined for formula (I).
  • E is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
  • R , R J1 and R J4 are as defined for formula (I).
  • E is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
  • R 30 , R 31 and R 32 are as defined for formula (I).
  • E is
  • R ⁇ , Rf, R dU , R J1 and R J2 are as defined for formula (I).
  • R , R 1 and R 32 are independently
  • CL ⁇ -alk l which may optionally be substituted with one or more substituents selected from fluoro, -CN, -CF 3 , -OCF 3 , -OR 35 and -NR 35 R 36 , • or d-s-cycloalkenyl, which may optionally be substituted with one or more substituents selected from fluoro, -CN, -CF 3 , -OCF 3 , -OR 35 , -NR 35 R 36 and C 1-6 -alkyl,
  • aryl, aryloxy or of which the aryl moieties may optionally be substituted with one or more substituents selected from halogen, -CN, -CF 3 , -OCF 3 , -N0 2 , -R 35 , -NR 35 R 36 and C 1-6 -alkyl,
  • R 35 and R 36 independently are hydrogen, d_s-alkyl or aryl
  • R 35 and R 36 when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds.
  • R 30 , R 31 and R 32 are independently
  • d-g-alkyl which may optionally be substituted with one or more substituents selected from fluoro, -CN, -CF 3 , -OCF 3 , -OR 35 and -NR 35 R 36 ,
  • cyclohexyl or cyclohex-1-enyl which may optionally be substituted with one or more substituents selected from fluoro, -CN, -CF 3 , -OCF 3 , -OR 35 , -NR 35 R 36 and d. 6 -alkyl,
  • phenyl which may optionally be substituted with one or more substitutents selected from halogen, -CN, -CF 3 , -OCF 3 , -N0 2 , -OR 35 , -NR 35 R 36 and d. 6 -alkyl,
  • phenoxy or benzyloxy of which the phenyl moieties may optionally be substituted with one or more substituents selected from halogen, -CN, -CF 3 , -OCF 3 , -N0 2 , -OR 35 , -NR 35 R 36 and C 1-6 -alkyl, R and R 3 independently are hydrogen or
  • R M and R" are both hydrogen, and R J1 is different from hydrogen
  • E is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
  • E is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
  • E is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
  • R 30 is as defined for formula (I).
  • R 30 is
  • halogen or • heteroaryl which may optionally be substituted with one or more substituents selected from halogen, -CN, -CF 3) -N0 2 , -OR 35 , -NR 35 R 36 and C ⁇ -alkyl,
  • R 35 and R 36 independently are hydrogen or d ⁇ -alkyl
  • R 35 and R 36 when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds.
  • R 30 is
  • thienyl which may optionally be substituted with one or more substituents selected from halogen, -CN, -CF 3 , -N0 2 , -OR 35 , -NR 35 R 36 and C ⁇ -alkyl,
  • R 35 and R 36 independently are hydrogen or C 1-5 -alkyl
  • R 35 and R 36 when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds.
  • E is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
  • Y is -C(O)-, -0-, -S(0) 2 -, -NH- or -CH 2 -.
  • Y is -CHR 11 -, wherein R 11 is combined with R 1 to form a double bond. In another embodiment, Y is -C(O)-.
  • R 1 and R 2 are both hydrogen.
  • R 1 and R 2 are combined to form a double bond.
  • R 3 is hydrogen
  • Z is -C(0)-(CR 13 R 1 ) p -, -0-(CR 13 R 1 ) p -, -NR 15 -(CR 13 R 14 ) p or -S(0) 2 - (CR 13 R 14 )p-, wherein p, R 13 , R 14 and R 15 are as defined for formula (I).
  • Z is -NR 15 -(CR 13 R 14 ) p or -C(0)-(CR 3 R 14 ) p -, wherein p is as defined for formula (I), and R 3 and R 14 independently are selected from hydrogen, -CF 3 , -OCF 3 and C 1-6 -alkyl and R 15 is hydrogen.
  • Z is -NH(CH 2 ) P or-C(0)-(CH 2 ) p -, wherein p is as defined for formula (I).
  • Z is NH or -C(O)-.
  • Z is -C(O)-.
  • D is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • R 16 , R 17 , R 18 , R 19 , R 20 and R 21 are as defined for formula (I).
  • D is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • R 16 , R 17 and R 18 are as defined for formula (I).
  • R 15 , R 17 and R 18 are independently
  • • d- ⁇ -alkyl which may optionally be substituted with one or more substituents selected from fluoro, -CN, -CF 3 , -OCF 3 , -OR 22 and -NR 22 R 23 , • d-8-cycloalkyl, which may optionally be substituted with one or more substituents selected from fluoro, -C(0)OR 24 , -CN, -CF 3 , -OCF 3 , -OR 22 , -NR 22 R 23 and C ⁇ -alkyl,
  • aryl or aryloxy which may optionally be substituted with one or more substituents se- lected from halogen, -C(0)OR 22 , -CN, -CF 3 , -OCF 3 , -N0 2 , -OR 22 , -NR 22 R 23 and
  • R 22 and R 23 independently are hydrogen, C 1-6 -alkyl, aryl-C ⁇ -alkyl or aryl, or R 22 and R 23 when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds,
  • a 0, 1 or 2
  • c 1 or 2
  • R 24 , R 25 , R 26 and R 27 independently are hydrogen, d- ⁇ -alkyl or fluoro.
  • R 16 , R 17 and R 18 are independently
  • R 18 is hydrogen, and R 17 and R 18 are different from hydrogen.
  • R 16 and R 17 are hydrogen, and R 18 is different from hydrogen.
  • the invention relates to a compound of the general formula (l 4 ):
  • R 6 , R 7 , E and D are as defined for formula (I) or in any one of the above embodiments, as well as any diastereomer or enantiomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound of the general formula (l 5 ):
  • R 6 , R 7 , E and D are as defined for formula (I) or in any one of the above embodiments, as well as any diastereomer or enantiomer or tautomeric form thereof including mix- tures of these or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound of the general formula (l a):
  • R ⁇ , R 7 , E and D are as defined for formula (I), as well as a ' ny diastereomer or enanti- omer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound of the general formula (l 5 b):
  • R 6 , R 7 , E and D are as defined for formula (I), as well as any diastereomer or enantiomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound of the general formula (1 6 ):
  • R 6 , R 7 , E and D are as defined for formula (I) or in any one of the above embodiments, as well as any diastereomer or enantiomer or tautomeric form thereof including mix- tures of these or a pharmaceutically acceptable salt thereof.
  • the compounds of the present invention may be chiral, and it is intended that any enantiomers, as separated, pure or partially purified enantiomers or racemic mixtures thereof are included within the scope of the invention.
  • diastereomers when a double bond or a fully or partially saturated ring system or more than one center of asymmetry or a bond with restricted rotability is present in the molecule diastereomers may be formed. It is intended that any diastereomers, as separated, pure or partially purified diastereomers or mixtures thereof are included within the scope of the invention.
  • the present invention also encompasses pharmaceutically acceptable salts of the present compounds.
  • Such salts include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable metal salts, ammonium and alkylated ammonium salts.
  • Acid addition salts include salts of inorganic acids as well as organic acids. Representative examples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, nitric acids and the like.
  • suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, lactic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methanesulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-amino- benzoic, glutamic, benzenesulfonic, p-toluenesulfonic acids and the like.
  • compositions include the pharma- ceutically acceptable salts listed in J. Pharm. Sci. 1977, 66, 2, which is incorporated herein by reference.
  • metal salts include lithium, sodium, potassium, magnesium salts and the like.
  • ammonium and alkylated ammonium salts include ammonium, methyl-, dimethyl-, trimethyl-, ethyl-, hydroxyethyl-, diethyl-, n-butyl-, sec-butyl-, fe/ -butyl-, tetramethylammonium salts and the like.
  • pharmaceutically acceptable acid addition salts are the hydrates, which the present compounds, are able to form.
  • the pharmaceutically acceptable salts comprise basic amino acid salts such as lysine, arginine and ornithine.
  • the acid addition salts may be obtained as the direct products of compound synthe- sis.
  • the free base may be dissolved in a suitable solvent containing the appropriate acid, and the salt isolated by evaporating the solvent or otherwise separating the salt and solvent.
  • the compounds of the present invention may form solvates with standard low molecular weight solvents using methods well known to the person skilled in the art. Such sol- vates are also contemplated as being within the scope of the present invention.
  • the invention also encompasses prodrugs of the present compounds, which on administration undergo chemical conversion by metabolic processes before becoming pharmacologically active substances.
  • prodrugs will be functional derivatives of the compounds of the general formula (I), which are readily convertible in vivo into the required compound of the formula (I).
  • Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
  • the invention also encompasses active metabolites of the present compounds.
  • the compounds according to the present invention act to antagonize the action of glucagon and are accordingly useful for the treatment of disorders and diseases in which such an antagonism is beneficial.
  • the compounds according to the present invention preferably have an IC 50 value of no greater than 5 ⁇ M, more preferably of less than 1 ⁇ M, even more preferred of less than 500 nM, such as of less than 100 nM as determined by the Glucagon Binding Assay (I) or Glucagon Binding Assay (II) disclosed herein.
  • the present compounds may be applicable for the treatment of hyperglycemia, IGT (impaired glucose tolerance), insulin resistance syndromes, syndrome X, type 1 diabetes, type 2 diabetes, hyperlipidemia, dyslipidemia, hypertriglyceridemia, hyperlipo- proteinemia, hypercholesterolemia, arteriosclerosis including atherosclerosis, glucagonomas, acute pancreatitis, cardiovascular diseases, hypertension, cardiac hypertrophy, gastrointestinal disorders, obesity, diabetes as a consequence of obesity, diabetic dyslipidemia, etc.
  • glucagon receptors may be applicable as diagnostic agents for identifying patients having a defect in the glucagon receptor, as a therapy to increase gastric acid secretions and to reverse intestinal hypomobility due to glucagon administration. They may also be useful as tool or reference molecules in labelled form eg radio- labelled in binding assays to identify new glucagon antagonists.
  • the invention relates to a compound according to the invention for use as a medicament.
  • the invention also relates to pharmaceutical compositions comprising, as an active ingredient, at least one compound according to the invention together with one or more pharmaceutically acceptable carriers or excipients.
  • the pharmaceutical composition is preferably in unit dosage form comprising from about 0.05 mg to about 1000 mg, preferably from about 0.1 mg to about 500 mg and especially preferred from about 0.5 mg to about 200 mg of the compound according to the inven- tion.
  • the invention relates to the use of a compound according to the invention for the preparation of a pharmaceutical composition for the treatment of a disorder or disease, wherein a glucagon antagonistic action is beneficial.
  • the invention also relates to a method for the treatment of disorders or diseases, wherein a glucagon antagonistic action is beneficial the method comprising administering to a subject in need thereof an effective amount of a compound according to the invention.
  • the present compounds are used for the preparation of a medicament for the treatment of any glucagon-mediated conditions and diseases.
  • the present compounds are used for the preparation of a medicament for the treatment of hyperglycemia.
  • the present compounds are used for the preparation of a medicament for lowering blood glucose in a mammal.
  • the present compounds are effective in lowering the blood glucose, both in the fasting and the postprandial stage.
  • the present compounds are used for the preparation of a pharmaceutical composition for the treatment of IGT. In still another embodiment, the present compounds are used for the preparation of a pharmaceutical composition for the treatment of type 2 diabetes.
  • the present compounds are used for the preparation of a pharmaceutical composition for the delaying or prevention of the progression from IGT to type 2 diabetes.
  • the present compounds are used for the preparation of a pharmaceutical composition for the delaying or prevention of the progression from non- insulin requiring type 2 diabetes to insulin requiring type 2 diabetes.
  • the present compounds are used for the preparation of a pharmaceutical composition for the treatment of type 1 diabetes.
  • Such treatment is normally accompanied by insulin therapy.
  • the present compounds are used for the preparation of a pharmaceutical composition for the treatment of obesity.
  • the present compounds are used for the preparation of a pharmaceutical composition for the treatment of disorders of the lipid metabolism, such as dyslipidemia.
  • the present compounds are used for the preparation of a pharmaceutical composition for the treatment of an appetite regulation or energy expenditure disorder.
  • treatment of a patient with the present compounds is combined with diet and/or exercise.
  • the present compounds are administered in combination with one or more further active substances in any suitable ratio(s).
  • further active agents may be selected from antidiabetic agents, antihyperlipidemic agents, antiobe- sity agents, antihypertensive agents and agents for the treatment of complications resulting from or associated with diabetes.
  • Suitable antidiabetic agents include insulin, insulin analogues and derivatives such as those disclosed in EP 792 290 (Novo Nordisk A/S), eg N ⁇ B29 -tetradecanoyl des (B30) human insulin, EP 214 826 and EP 705 275 (Novo Nordisk A/S), eg Asp B28 human insulin, US 5,504,188 (Eli Lilly), eg Lys B28 Pro 829 human insulin, EP 368 187 (Aventis), eg Lantus®, all of which are incorporated herein by reference, GLP-1 and GLP-1 derivatives such as those disclosed in WO 98/08871 (Novo Nordisk A/S), which is incorporated herein by reference, as well as orally active hypoglycemic agents.
  • the orally active hypoglycemic agents include imidazolines, sulphonylureas, biguanides, meglitinides, oxadiazolidinediones, thiazolidinediones, ⁇ -glucosidase inhibitors, glucagon antagonists, GLP-1 agonists, agents acting on the ATP-dependent potassium channel of the ⁇ -cells, eg potassium channel openers such as those disclosed in WO 97/26265, WO 99/03861 and WO 00/37474 (Novo Nordisk A/S), all of which are incorporated herein by reference, or nateglinide or potassium channel blockers such as BTS-67582, insulin sensitizers, insulin secretagogues, DPP-IV (dipeptidyl peptidase-IV) inhibitors,
  • PTPase inhibitors inhibitors of hepatic enzymes involved in stimulation of gluconeogenesis and/or glycogenolysis, glucose uptake modulators, activators of glucokinase (GK) such as those disclosed in WO 00/58293, WO 01/44216, WO 01/83465, WO 01/83478.WO 01/85706, WO 01/85707 and WO 02/08209 (Hoffman-La Roche), which are incorporated herein by reference, GSK-3 (glycogen synthase kinase-3) inhibitors, compounds modifying the lipid metabolism such as antihyperlipidemic agents and antilipidemic agents, compounds lowering food intake, PPAR (peroxisome proliferator-activated receptor) and RXR (retinoid X receptor) agonists such as ALRT-268, LG-1268 or LG-1069.
  • GK glucokinase
  • PPAR peroxisome proliferator-activated receptor
  • RXR
  • the present compounds are administered in combination with insulin or an insulin analogue or derivative, such as N ⁇ B29 -tetradecanoyl des (B30) human insulin, Asp 828 human insulin, Lys B2a Pro 629 human insulin, Lys B29 -(N ⁇ ( ⁇ -glutamyl-N ⁇ litocholyl) des (B30) human insulin, Lantus, or a mix-preparation comprising one or more of these.
  • insulin or an insulin analogue or derivative such as N ⁇ B29 -tetradecanoyl des (B30) human insulin, Asp 828 human insulin, Lys B2a Pro 629 human insulin, Lys B29 -(N ⁇ ( ⁇ -glutamyl-N ⁇ litocholyl) des (B30) human insulin, Lantus, or a mix-preparation comprising one or more of these.
  • the present compounds are administered in combination with a sulphonylurea, eg tolbutamide, chlorpropamide, tolazamide, glibenclamide, glyburide, glipizide, glimepride or glicazide.
  • a sulphonylurea eg tolbutamide, chlorpropamide, tolazamide, glibenclamide, glyburide, glipizide, glimepride or glicazide.
  • the present compounds are administered in combination with a biguanide, eg metformin.
  • the present compounds are administered in combination with a meglitinide, eg repaglinide or nateglinide.
  • the present compounds are administered in combination with a thiazolidinedione insulin sen ⁇ itizer, eg troglitazone, ciglitazone, pioglitazone, rosiglitazone, isaglitazone, darglitazone, englitazone, CS-011/CI-1037 or T174 or the compounds disclosed in WO 97/41097, WO 97/41119, WO 97/41120, WO 00/41121 and WO 98/45292 (Dr. Reddy's Research Foundation).
  • the present compounds may be administered in combination with an insulin sensitizer such as Gl 262570, YM-440, MCC-555, JTT-501 , AR-H039242, KRP-297, GW-409544, CRE-16336, AR-H049020, LY510929, LY465608, MBX-102, CLX-0940, GW-501516, tesaglitazar (AZ 242) or the compounds disclosed in WO 99/19313, WO 00/50414, WO 00/63191, WO 00/63192, WO 00/63193 such as ragaglitazar (NN 622 or (-)DRF 2725) (Dr.
  • an insulin sensitizer such as Gl 262570, YM-440, MCC-555, JTT-501 , AR-H039242, KRP-297, GW-409544, CRE-16336, AR-H049020, LY510929, LY465608, MBX
  • the present compounds are administered in combination with an ⁇ -glucosidase inhibitor, eg voglibose, emiglitate, miglitol or acarbose.
  • an agent acting on the ATP-dependent potassium channel of the ⁇ -cells eg tolbutamide, chlorpropamide, tolazamide, glibenclamide, glyburide, glipizide, glicazide, BTS-67582, repaglinide or nateglinide.
  • the present compounds are administered in combina- tion with an antihyperlipidemic agent or antilipidemic agent, eg cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin, pravastatin, simva ⁇ tatin, probucol or dextrothyroxine.
  • an antihyperlipidemic agent or antilipidemic agent eg cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin, pravastatin, simva ⁇ tatin, probucol or dextrothyroxine.
  • the present compounds are administered in combination with more than one of the above-mentioned compounds, eg in combination with metformin and a sulphonylurea such as glibenclamide or glyburide; a sulphonylurea and acarbose; metformin and a meglitinide such as repaglinide; acarbose and metformin; a sul- fonylurea, metformin and troglitazone; a sulfonylurea, metformin and pioglitazone; a sulfony- lurea, metformin and an insulin sensitizer such as disclosed in WO 00/63189 or WO 97/41097; a meglitinide such as repaglinide, metformin and troglitazone; a meglitinide such as repaglinide, metformin and pioglitazone; a meglitinide such as
  • Such agents may be selected from the group consisting of CART (cocaine amphetamine regulated transcript) agonists, NPY (neuropeptide Y) antagonists, MC4 (melano- cortin 4) agonists, orexin antagonists, H3 histamine antagonists, TNF (tumor necrosis factor) modulators, CRF (corticotropin releasing factor) agonists, CRF BP (corticotropin releasing factor binding protein) antagonists, urocortin agonists, ⁇ 3 adrenergic agonists such as CL-316243, AJ-9677, GW-0604, LY362884, LY377267 or AZ-40140, MSH (melanocyte- stimulating hormone) agonists, MCH (melanocyte-concentrating hormone) antagonists, CCK (cholecystokinin) agonists, serotonin re-uptake inhibitors such as fluoxetine, seroxat or cita- lopram, serotonin
  • the antiobesity agent is fenfluramine or dexfenfluramine.
  • the antiobesity agent is sibutramine.
  • the antiobesity agent is orlistat.
  • the antiobesity agent is mazindol or phentermine.
  • the present compounds may be administered in combination with one or more antihypertensive agents.
  • antihypertensive agents are ⁇ -blockers such as alprenolol, atenolol, timolol, pindolol, propranolol and metoprolol, ACE (angiotensin converting enzyme) inhibitors such as benazepril, captopril, enalapril, fosinopril, lisinopril, quinapril and ramipril, calcium channel blockers such as nifedipine, felodipine, nicardipine, isradipine, nimodipine, diltiazem and verapamil, and ⁇ -blockers such as doxazosin, urapidil, prazosin and terazosin. Further reference can be made to Remington
  • the compounds of the invention may be administered alone or in combination with pharmaceutically acceptable carriers or excipients, in either single or multiple doses.
  • the phar- maceutical compositions according to the invention may be formulated with pharmaceutically acceptable carriers or diluents as well as any other known adjuvants and excipients in accordance with conventional techniques such as those disclosed in Remington: The Science and Practice of Pharmacy, 19 th Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995.
  • compositions may be specifically formulated for administration by any suitable route such as the oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, intracisternal, intraperitoneal, vaginal and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) route, the oral route be- ing preferred. It will be appreciated that the preferred route will depend on the general condition and age of the subject to be treated, the nature of the condition to be treated and the active ingredient chosen.
  • compositions for oral administration include solid dosage forms such as capsules, tablets, dragees, pills, lozenges, powders and granules. Where appropri- ate, they can be prepared with coatings such as enteric coatings or they can be formulated so as to provide controlled release of the active ingredient such as sustained or prolonged release according to methods well known in the art.
  • Liquid dosage forms for oral administration include solutions, emulsions, suspensions, syrups and elixirs.
  • Pharmaceutical compositions for parenteral administration include sterile aqueous and non-aqueous injectable solutions, dispersions, suspensions or emulsions as well as sterile powders to be reconstituted in sterile injectable solutions or dispersions prior to use. Depot injectable formulations are also contemplated as being within the scope of the present invention.
  • Other suitable administration forms include suppositories, sprays, ointments, cremes, gels, inhalants, dermal patches, implants etc.
  • a typical oral dosage is in the range of from about 0.001 to about 100 mg/kg body weight per day, preferably from about 0.01 to about 50 mg/kg body weight per day, and more preferred from about 0.05 to about 10 mg/kg body weight per day administered in one or more dosages such as 1 to 3 dosages.
  • the exact dosage will depend upon the frequency and mode of administration, the sex, age, weight and general condition of the subject treated, the nature and severity of the condition treated and any concomitant diseases to be treated and other factors evident to those skilled in the art.
  • a typical unit dosage form for oral administration one or more times per day such as 1 to 3 times per day may contain from 0.05 to about 1000 mg, preferably from about 0.1 to about 500 mg, and more preferred from about 0.5 mg to about 200 mg.
  • typically doses are in the order of about half the dose employed for oral administration.
  • the compounds of this invention are generally utilized as the free substance or as a pharmaceutically acceptable salt thereof.
  • One example is a base addition salt of a compound having the utility of a free acid.
  • a compound of the formula (I) contains a free acid such salts are prepared in a conventional manner by treating a solution or suspension of a free acid of the formula (I) with a chemical equivalent of a pharmaceutically acceptable base. Representative examples are mentioned above.
  • solutions of the novel compounds of the formula (I) in sterile aqueous solution, aqueous propylene glycol, aqueous vitamin E or sesame or peanut oil may be employed.
  • aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose.
  • the aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal admini- stration.
  • the sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art.
  • Suitable pharmaceutical earners include inert solid diluents or fillers, sterile aqueous solution and various organic solvents.
  • solid carriers are lactose, terra alba, sucrose, cyclodextrin, talc, gelatine, agar, pectin, acacia, magnesium stearate, stearic acid and lower alkyl ethers of cellulose.
  • liquid carriers are syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene and 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.
  • compositions formed by combining the novel compounds of the formula (I) and the pharmaceutically ac- ceptable carriers are then readily administered in a variety of dosage forms suitable for the disclosed routes of administration.
  • the formulations may conveniently be presented in unit dosage form by methods known in the art of pharmacy.
  • Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules or tablets, each containing a predetermined amount of the active ingredient, and which may include a suitable excipient.
  • the orally available formulations may be in the form of a powder or granules, a solution or suspension in an aqueous or non-aqueous liquid, or an oil-in-water or water-in-oil liquid emulsion.
  • the preparation may be tabletted, placed in a hard gelatine 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 gelatine capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.
  • a typical tablet that may be prepared by conventional tabletting techniques may con- tain:
  • Active compound (as free compound or salt thereof) 5.0 mg
  • the pharmaceutical composition of the invention may comprise the compound of the formula (I) in combination with further pharmacologically active substances such as those described in the foregoing.
  • DBU 1 ,8-diazabicyclo[5.4.0]undec-5-ene
  • DCM dichloromethane
  • DIPEA ⁇ /, ⁇ /-diisopropylethylamine
  • DMF ⁇ , ⁇ /-dimethyl formamide
  • NMP /V-methyl-2-pyrrolidinone
  • TFA trifluoroacetic acid
  • THF tetrahydrofuran
  • HOBt 1 -hydroxybenzotriazole
  • the instrument is controlled by HP Chemstation software.
  • the HPLC pump is connected to two eluent reservoirs containing:
  • HPLC conditions detector settings and mass spectrometer settings used are given in the following table.
  • HP LC/MSD ChemStation control software running on a HP Vectra computer is used for the instrument control and data acquisition.
  • the HPLC pump is connected to two eluent reservoirs containing: A: 0.01% TFA in water
  • the analysis is performed at room temperature by injecting 1 mL of the sample solution on the column which is eluted with a gradient of acetonitrile in 0.01% TFA.
  • HPLC conditions detector settings and mass spectrometer settings used are given in the following table.
  • the Sciex Sample control software running on a Macintosh PowerPC 7200 com- puter is used for the instrument control and data acquisition.
  • the HPLC pump is connected to four eluent reservoirs containing: A: Acetonitrile
  • the requirements for the samples are that they contain approximately 500 ⁇ g/mL of the compound to be analysed in an acceptable solvent such as methanol, ethanol, acetoni- trile, THF, water and mixtures thereof. (High concentrations of strongly eluting solvents will interfere with the chromatography at low acetonitrile concentrations.)
  • the analysis is performed at room temperature by injecting 20 ⁇ l of the sample solution on the column, which is eluted with a gradient of acetonitrile in either 0.05% TFA or 0.002 M ammonium acetate. Depending on the analysis method varying elution conditions are used.
  • the eluate from the column is passed through a flow splitting T-connector, which passed approximately 20 ⁇ l/min through approx. 1 m 75 ⁇ fused silica capillary to the API interface of API 100 spectrometer.
  • the remaining 1.48 mL/min is passed through the UV detector and to the ELS de- tector.
  • the detection data are acquired concurrently from the mass spectrometer, the UV detector and the ELS detector.
  • the instrument is controlled by HP Chemstation software.
  • the HPLC pump is connected to two eluent reservoirs containing:
  • the analysis is performed at 40 °C by injecting an appropriate volume of the sample (preferably 1 ⁇ l) onto the column which is eluted with a gradient of acetonitrile.
  • HPLC conditions detector settings and mass spectrometer settings used are given in the following table.
  • the title compound was prepared from indane and dichloromethyl methyl ether, using the same procedure as described above, providing a 1:2 mixture of indane-4-carbaldehyde and indane-5-carbaldehyde. The mixture was used for subsequent conversion to the chalcone
  • 3,5-Dichlorobe ⁇ zoic acid (19,10 g, 100 mmol) was dissolved in dry THF (165 mL) and cooled to 0 °C in an ice bath. With vigorous stirring, 138 mL (210 mmol) of methyl lithium (1.6 M in diethyl ether) was added dropwise over a period of 30 min via syringe. After 1 hour the mixture was poured into ice-water (500 mL). The aqueous phase was extracted with diethyl ether (4 x 50 mL). The combined organic phases were washed with saturated aqueous sodium hydrogen carbonate (2 x 50 mL) and saturated aqueous sodium chloride (2 x 50 L).
  • 6-Cyano-2,2,3,3-tetrafluoro-1.4-benzodioxene 35 g, 0.15 mol was dissolved in toluene (60 mL) and added to the reaction mixture. The mixture was heated to 80 °C for 1 hour without condenser to remove the diethyl ether. Additional 6- cyano-2,2,3,3-tetrafluoro-1.4-benzodioxene (25 g, 0.11 mol) was added and the mixture was heated at reflux temperature for 16 hours. The mixture was cooled with an ice bath and hydrochloric acid (6 M, 150 mL) was added carefully and the mixture was then heated to reflux for 1.5 hour.
  • Step 1
  • This reaction is known (Wang S.J., J. Am. Chem. Soc. 95, 1328, 1973) and is generally performed by stirring polystyrene resin loaded with a linker such as the Wang linker with a 4-10 molar excess of Fmoc-protected amino acid activated with a 2-5 molar excess of diisopropyl- carbodiimide, dicyclohexylcarbodiimide or 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride in the presence of a catalyst such as ⁇ /, ⁇ /-4-dimethylaminopyridine.
  • a linker such as the Wang linker with a 4-10 molar excess of Fmoc-protected amino acid activated with a 2-5 molar excess of diisopropyl- carbodiimide, dicyclohexylcarbodiimide or 1-[3-(dimethylamino)propyl
  • the ester- fication is carried out in solvent such as THF, dioxane, toluene, DCM, DMF, NMP or a mixture of two or more of these.
  • solvent such as THF, dioxane, toluene, DCM, DMF, NMP or a mixture of two or more of these.
  • the reactions are performed between 0 °C and 80 °C, prefera- bly between 20 °C to 40 °C.
  • excess of reagent is removed by filtration.
  • the resin is successively washed with the solvent used in the reaction, followed by washing with methanol.
  • the resin bound product can be further dried and analyzed.
  • Step 2 ⁇ /-Fluorenylmethylcarbonyl protecting group is removed by treating the resin bound derivative with a 20%-50% solution of a secondary amine such as piperidine in a polar solvent such as DMF or NMP (Carpino L, Han G., J. Org. Chem. 37, 3404, 1972).
  • the reaction is performed between 20 °C to 180 °C, preferably between 20 °C to 40 °C.
  • excess of reagent is removed by filtration.
  • the resin is successively washed with solvent used in the reaction.
  • the resulting resin bound intermediate is acylated with acid.
  • the acylation is known (The combinatorial index, Ed. Bunin B. A., 1998, Acedemic press, p.
  • acylation is carried out in a solvent such as THF, dioxane, toluene, DCM, DMF, NMP or a mixture of two or more of these.
  • aldehydes to activated double bonds is generally carried out by stirring the aldehyde with a compound that contains an activated dobbelt bond such as a substituted prope- none in the presence of a catalyst such as sodium or potassium cyanide or thiazolium salts such as 3,4-dimethyl-5-(2-hydroxyethyl)thiazolium iodide, 3-benzyl-5-(2-hydroxyethyl)-4- methyl-1 ,3-thiazolium chloride, 3-ethyl-5-(2-hydroxyethyl)-4-methyl-1 ,3-thiazolium bromide or vitamin Bi.
  • a catalyst such as sodium or potassium cyanide or thiazolium salts
  • a non-nucleophilic amine base such as triethyl amine, ⁇ , ⁇ /-diisopropylethylamine or DBU is added.
  • the addition is carried out in a solvent such as dioxane, DMSO, NMP or DMF or a mixture of two or more of these.
  • the reactions are performed between 50 °C to 120 °C, preferably between 50 °C to 80 °C.
  • excess of reagent is removed by filtration.
  • the resin is successively washed with the solvent used in the reaction, followed by washing with methanol.
  • the resin bound product can be further dried and analyzed.
  • the reaction is known (The combinatorial index, Ed. Bunin B. A., 1998, Acedemic press, p. 21) and is generally performed by stirring the resin bound intermediate obtained in step 3 with a 50-95 % solution of TFA.
  • the final cleavage is carried out in a solvent such as THF, DCM, 1 ,2 dichloroethane, 1 ,3-dichloropropane, toluene or a mixture or more of these.
  • the reactions are performed between 0 °C to 80 °C, preferably between 20 °C to 40 °C.
  • the reaction is complete the product is removed by filtration.
  • the resin is successively washed with DCM.
  • the product and washings are collected.
  • the solvent is removed and the product is dried in vacuo.
  • the procedure is illustrated in the following example.
  • Step 1 and Step 2 Resin bound 3-(4-formylbenzoylamino)propionic acid 3-(4-Formylbenzoylamino)propionic acid resin bound to a Wang resin (loading approximately 0.2 - 0.8 mmol/g) was synthesized according to the procedure described in WO 00/69810.
  • Step 3 and Step 4 Preparation of 3-(4-f2-biphenyl-4-yl-4-oxo-4-(4-trifluoromethoxyphenyl)- butyryllbenzoylamino)propionic acid
  • Step 1 - Step 3 Preparation of resin bound 3-(4-r2-f4-cvclohexylphenyl)-4-oxo-4-(4-trifluoro- methoxyphenvDbutyryllbenzoylaminolpropionic acid
  • the compound was synthesized according to general procedure (B).
  • Step 4 and Step 5 Preparation of 3-(4-r2-(4-cvclohexylphenyl)-4-oxo-4-(4-trifluoromethoxy- phenyl)but-2-enoyllbenzoylamino)propionic acid
  • Step 6 Preparation of (Z)-3-f4-r2-(4-cvclohexylphenyl)-4-oxo-4-(4-trifluoromethoxyphenyl)- but-2-enovnbenzoylamino)propionic acid
  • reaction mixture was filtered through a silica gel column eluted with DCM/methanol/acetic acid (90:9:1), and the solvent was removed by evaporation to yield an oil.
  • the oil was washed with boiling heptane (4 mL) to remove unreacted 3-biphenyl-4-yl-1- (3-trifluoromethyiphenyl)propenone, and remaining material was purified on silica gel column eluted with DCM/methanol/acetic acid (95:4:1) to yield the title compound (30 mg, 9%).
  • Step 1 wherein X, D, E, m, n and R 4 are as defined for formula (I), and Pg is a standard acid protecting group like methyl, ethyl, propyl, isopropyl, terf-butyl or benzyl.
  • Pg is a standard acid protecting group like methyl, ethyl, propyl, isopropyl, terf-butyl or benzyl.
  • the acylation of the amino group of of a protected amino acid is generally performed by activating the car- boxylic acid with diisopropyl-carbodiimide, dicyclohexylcarbodiimide or 1-[3-(dimethylamino)- propyl]-3-ethylcarbodiimide hydrochloride optionally in the presence of a side reaction inhibi- tor such as ⁇ /-hydroxybenzotriazole.
  • the protected amino acid (protected eg as methyl, ethyl, propyl, isopropyl, tert-butyl or benzyl ester) is then added to the activated carboxylic acid.
  • a non-nucleophilic base such as triethylamine or diispropylethyl amine is added.
  • the acylation is carried out in a solvent such as THF, dioxane, toluene, DCM, DMF, NMP or a mixture of two or more of these.
  • the reac- tion is generally performed between 0 °C to 80 °C, preferably between 20 °C to 40 °C.
  • the product can be obtained by work-up procedures known to those skilled in the art.
  • aldehydes to activated double bonds is generally carried out by stirring the alde- hyde with a compound that contains an activated dobbelt bond such as a substituted prope- none in the presence of a catalyst such as cyanid or thiazoliums salts such as 3,4-dimethyl- 5-(2-hydroxyethyl)thiazolium iodide, 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1 ,3-thiazolium chloride, 3-ethyl-5-(2-hydroxyethyl)-4-methyl-1 ,3-thiazolium bromide or vitamin B
  • a non-nucleophilic amine base such as triethyl amine or DBU is added.
  • the addition is carried out in a solvent such as ethanol, methanol, 1-propanol, 2-propa ⁇ ol, dioxane, DMSO, NMP or DMF or a mixture of two or more of these.
  • a solvent such as ethanol, methanol, 1-propanol, 2-propa ⁇ ol, dioxane, DMSO, NMP or DMF or a mixture of two or more of these.
  • the reactions are performed between 50 °C to 120 °C, preferably between 50 °C to 80 °C.
  • the product can be obtained by work-up procedures known to those skilled in the art.
  • Step 3 Removal of the standard acid protecting groups depends on the nature of the protecting groups but has in general been described. (Protective Groups in Organic Chemistry. Greene T. W., Wuts P. G. M. 1999, Wiley-lnterscience, p. 377) The procedure is illustrated in the following examples.
  • Step 1 3-(4-Formylbenzoylamino)-2r?-hvdroxypropionic acid methyl ester
  • 4-formylbenzoic acid 7.5 g, 50 mmol
  • DMF 80 mL
  • 1 -Hydroxybenzotriazole, hydrate 8.11 g, 60 mmol, 1.2 eq
  • ⁇ /'-(3- dimethylaminopropyl)- ⁇ /-ethylcarbodiimide hydrochloride (9.59 g, 50 mmol, 1 eq) were added.
  • Step 2 Preparation of 3-f4-r4-(4-fe/ -butylphenyl)-2-(4-cvclohexylphenyl)-4-oxobutyrvn- benzoylamino)-2H-hvdroxypropionic acid ethyl ester
  • Step 3 Pre p aration of 3- ⁇ 4-r4-(4-ten'-butylphenyl)-2-(4-cvclohexylphenyl)-4-oxobutyryll- benzoylamino)-2 ?-hvdroxypropionic acid
  • Step 1 - Step 3 Preparation of 3-(4-r4-(4-terf-butylphenyl)-2-(4-cvclohexylphenvn-4- oxobutyrvnbenzoylamino)-2R-hvdroxypropionic acid
  • Step 4 Preparation of 3- ⁇ 4-r4- ( 4-tert-Butylphenyl ) -2-(4-cvclohexylphenyl)-4-oxobut-2-enov ⁇ - benzoylamino ⁇ ft-hvdroxypropionic acid
  • Step 5 Preparation of (Z)- 3-(4-r4-(4-fe f-butylphenyl)-2R-(4-cvclohexylphenyl)-4-oxobut-2- enoyl1benzoylamino)-2R-hvdroxypropionic acid
  • Example 99 The compound of example 42 was also prepared according to the General procedure (F) as illustrated below: (Z)-3- ⁇ 4-[2-Biphenyl-4-yl-4-oxo-4-(4-trifluoromethoxyphenyl)but-2-enoyl]benzoylamino ⁇ -2 - hydroxypropionic acid
  • Example 102 (General procedure (G)).
  • the compound of example 65 was also prepared according to the General procedure (G) as illustrated below:
  • Step 1 and Step 2 4-r2-r4-(2,2-dimethyl ⁇ ropy0phenyl1-4-oxo-4-(4-trifluoromethoxyphenyl)- butyryllbenzoic acid
  • Step 4 and Step 5 Preparation of (Z)-3-(4-r2-f4-(2,2-Dimethyl-propyl)-phenvn-4-oxo-4-(4- trifluoromethoxy-phenyl)-but-2-enoyll-benzoylamino)propionic acid
  • the mixture was stirred at 40 °C for 2 hours.
  • the mixture was evaporated under reduced pressure and the residue was partitioned between water and ethyl acetate.
  • the organic phase was separated, washed with brine, dried (Na 2 S0 4 ) and evaporated.
  • the residue was dissolved in a mixture of methanol (80 mL) and THF (20 mL) and sodium hydroxide (1.69 g; 42.3 mmol) in 10 mL of water was added.
  • the mixture was stirred for 1.5 hours at room temperature.
  • the mixture was concentrated to about 30 mL under reduced pressure and 40 mL of water was added.
  • the pH was adjusted to 1.5 by addition of 1 M hydrochloric acid.
  • Step 1 4-r4-(4-fen'-Butylphenv ⁇ -4-oxo-2-(4-trifluoromethoxyphenyl)butyrvnbenzoic acid methyl ester

Abstract

Cette invention, qui a trait à de nouveaux composés agissant comme antagonistes de l'action de l'hormone peptidique glucagon sur le récepteur du glucagon, porte, plus précisément, sur des antagonistes ou des agonistes inverses du glucagon.
EP02804158A 2001-12-03 2002-11-28 Nouveaux antagonistes de glucagon Withdrawn EP1463715A1 (fr)

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