JP2005511683A - Novel glucagon antagonist - Google Patents

Abstract

A novel compound that acts on the glucagon receptor to antagonize the action of glucagon peptide hormones. More particularly, it relates to a glucagon antagonist or inverse agonist.

Description

Field of Invention

  The present invention relates to a drug that acts on the glucagon receptor to antagonize the action of glucagon peptide hormones. More particularly, the present invention relates to glucagon antagonists or inverse agonists.

Background of the Invention

  Glucagon is an important hormonal substance that, in cooperation with insulin, mediates homeostasis regulation of blood glucose levels. Glucagon works primarily by stimulating certain cells (mostly hepatocytes) to release glucose when blood glucose levels fall. This glucagon action is opposite to that of insulin, which stimulates cells to ingest and accumulate glucose when blood glucose levels rise. Glucagon and insulin are both peptide hormones.

  Glucagon is produced by pancreatic alpha islet cells, and insulin is produced by beta islet cells. Diabetes is a common disorder in glucose metabolism. This disease is characterized by hyperglycemia and is classified as an insulin-dependent form of type 1 diabetes or a type 2 diabetes characterized by insulin independence. Patients with type 1 diabetes are hyperglycemic and hypoinsulinic, and the conventional treatment for this form of the disease is to give insulin. However, in some patients with type 1 or type 2 diabetes, absolute or relatively elevated glucagon levels have been shown to contribute to the hyperglycemic state. In both healthy control animals and model animals with type 1 and type 2 diabetes, removal of circulating glucagon using selective and specific antibodies resulted in decreased blood glucose levels. These studies suggest that glucagon suppression or glucagon antagonism can be a useful adjunct to conventional therapies for hyperglycemia in diabetic patients. The action of glucagon can be suppressed by providing antagonists or inverse agonists, ie substances that inhibit or prevent the response induced by glucagon. The antagonist can be peptidic or non-peptidic in nature.

Natural glucagon is a 29 amino acid peptide having the following 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 seven-transmembrane G protein-coupled receptor family. . The receptor functions by activating the adenyl cyclase second messenger system, the result being an increase in cAMP levels.

Several publications disclose peptides that are stated to act as glucagon antagonists. Perhaps the most fully characterized antagonist is DesHis ¹ [Glu ⁹ ] -glucagonamide (Unson et al., Peptides 10, 1171 (1989); Post et al., Proc. Natl. Acad. Sci. USA 90, 1662 (1993)). Other ^{antagonists, DesHis 1, Phe 6 [Glu} 9] - glucagon amide (Azizh et al, Bioorganic & Medicinal Chem.Lett.16,1849 (1995).) And NLeu ^9, Ala ^11,16 - is glucagon amide (Unson et al., J. Biol. Chem. 269 (17), 12548 (1994)).

  Peptide antagonists of peptide hormones are often very potent. However, they are generally known to be not orally available due to poor degradation by physiological enzymes and poor distribution in vivo. Accordingly, orally available non-peptide antagonists of peptide hormones are generally preferred. Of these non-peptide glucagon antagonists, the quinoxaline derivative 2-styryl-3- [3- (dimethylamino) propylmethylamino] -6,7-dichloroquinoxaline has been found to displace rat liver receptors. (Collins, JL et al., Bioorganic, and Medicinal Chemistry Letters 2 (9): 915-918 (1992)). WO 94/14426 (The Welcome Foundation Limited) discloses the use of skyrin, i.e. natural products containing a pair of linked 9,10-anthracenedione groups and their synthetic analogs as glucagon antagonists. ing. US Pat. No. 4,359,474 (Sandoz) discloses glucagon inhibitory properties of 1-phenylpyrazole derivatives. US Pat. No. 4,374,130 (Sandoz) discloses substituted disilacyclohexanes as glucagon inhibitors. WO 98/04528 (Bayer Corporation) discloses substituted pyridines and biphenyls as glucagon antagonists. U.S. Pat.No. 5,776,954 (Merck & Co., Inc.) discloses substituted pyridylpyrroles as glucagon antagonists and also WO 98/21957, WO 98/22108, WO 98/22109 and U.S. Pat.No. 5,880,139. (Merck & Co., Inc.) discloses 2,4-diaryl-5-pyridylimidazoles as glucagon antagonists. In addition, WO 97/16442 and US Pat. No. 5,837,719 (Merck & Co., Inc.) disclose 2,5-substituted arylpyrroles as glucagon antagonists. WO 98/24780, WO 98/24782, WO 99/24404 and WO 99/32448 (Amgen Inc.) disclose substituted pyrimidinone and pyridone compounds and substituted pyrimidine compounds, respectively, which have glucagon antagonist activity. It is stated that Madsen et al. (J. Med. Chem. 1998 (41) 5151-7) described a series of 2- (benz-imidazol-2-ylthio) -1- (3,4-dihydroxyphenyl) -1-ethanones. Disclosed as an antagonistic human glucagon receptor antagonist. WO 99/01423 and WO 00/39088 (Novo Nordisk A / S) disclose different series of alkylidene hydrazides as glucagon antagonists / inverse agonists. WO 00/69810, WO 02/00612, WO 02/4444, WO 02/40445, and WO 02/40446 (Novo Nordisk A / S) disclose further types of glucagon antagonists.

  These known glucagon antagonists are structurally different from the compounds of the present invention.

Definition

The following is a detailed definition of the terms used to describe the compounds of the invention:
“Halogen” means an atom selected from the group consisting of F, Cl, Br and I.

The term “C _1-6 -alkyl” as used herein represents a branched or straight chain saturated hydrocarbon group having from 1 to 6 carbon atoms. Representative examples include methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, isohexyl, and the like. However, it is not limited to these.

The term “C _2-6 -alkenyl” as used herein represents a branched or straight hydrocarbon group having from 2 to 6 carbon atoms and at least one double bond. Examples of such groups are vinyl, 1-propenyl, 2-propenyl, iso-propenyl, 1,3-butadienyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1 -Pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 2,4-hexadienyl, 5-hexenyl, etc. It is not limited to.

The term “C _2-6 -alkynyl” as used herein represents a branched or straight hydrocarbon group having from 2 to 6 carbon atoms and at least one triple bond. Examples of such groups include 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-hexazinyl, and the like.

The term “C _1-6 -alkoxy” as used herein refers to the group —OC _1-6 -alkyl, where C _1-6 -alkyl is as defined above.

Representative examples are methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy and the like.

The term “C _3-8 -cycloalkyl” as used herein represents a saturated carbocyclic group having from 3 to 8 carbon atoms. Representative examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.

The term “C _4-8 -cycloalkenyl” as used herein represents a non-aromatic carbocyclic group having from 4 to 8 carbon atoms and containing 1 or 2 double bonds. Representative examples are 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1 cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 2-cycloheptenyl, 3-cycloheptenyl, 2-cyclooctenyl, 1,4 -Cyclooctadienyl and the like.

  The term “heterocyclyl” as used herein is a 3 to 10 membered non-aromatic cyclic group containing one or more heteroatoms selected from nitrogen, oxygen and sulfur and optionally containing 1 or 2 double bonds. Represents. Representative examples are pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, aziridinyl, tetrahydrofuranyl and the like.

  As used herein, the term “aryl” is intended to include aromatic carbocyclic systems, such as 6-membered monocyclic systems, and 9-14-membered bicyclic and tricyclic aromatic carbocyclic systems. ing. Representative examples are phenyl, biphenylyl, naphthyl, anthracenylphenanthrenyl, fluorenyl, indenyl, azulenyl and the like. Aryl is also intended to include the partially hydrogenated derivatives of the ring systems listed above. Non-limiting examples of such partially hydrogenated derivatives are 1,2,3,4-tetrahydronaphthyl, 1,4-dihydronaphthyl, indanyl and the like.

  As used herein, the term “arylene” includes divalent aromatic carbocyclic ring systems, such as 6-membered monocyclic systems, and 9-14-membered bicyclic and tricyclic divalent aromatic carbocyclic systems. Is intended. Representative examples are phenylene, biphenylylene, naphthylene, anthracenylene, phenanthrenylene, fluorenylene, indenylene, azlenylene, and the like. Arylene is also intended to include the partially hydrogenated derivatives of the ring systems listed above. Non-limiting examples of such partially hydrogenated derivatives are 1,2,3,4-tetrahydronaphthylene, 1,4-dihydronaphthylene and the like.

  The term “aryloxy” as used herein means an —O-aryl group, where aryl is as defined above.

  The term “aroyl” as used herein means a —C (O) -aryl group, where aryl is as defined above.

The term C _1-6 -alkanoyl as used herein means a —C (O) —C _1-6 -alkyl group, wherein C _1-6 -alkyl is as defined above.

  As used herein, the term “heteroaryl” refers to an aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen and sulfur, for example one or more heterocycles selected from nitrogen, oxygen and sulfur. It is intended to include 5-7 membered monocycles containing atoms, as well as 8-14 membered bicyclic and tricyclic aromatic heterocycles. Representative examples are furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, pyranyl, pyridyl, pyridanidyl, 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, thiadiazinylindolyl, isoindolyl, benzofuryl, benzothienyl , Indazolylbenzimidazolyl, benzthiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, purinyl, quinazolinyl, quinolidinyl Quinolinyl, isoquinolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, azepinyl, diazepinyl, acridinyl and the like. Heteroaryl is also intended to include the hydrogenated derivatives of the ring systems listed above. Non-limiting examples of such partially hydrogenated derivatives are 2,3-dihydrobenzofuranyl, pyrrolinyl, pyrazolinyl, indolinyl, oxazolidinyl, oxazolinyl, oxazepinyl and the like.

  As used herein, the term “heteroarylene” refers to a divalent aromatic heterocyclic ring system containing one or more heteroatoms selected from nitrogen, oxygen and sulfur, such as one or more heterocycles selected from nitrogen, oxygen and sulfur. Including 5-7 membered monocyclic and 8-14 membered bicyclic and tricyclic aromatic hetero ring systems containing atoms, typical examples include furylene, thienylene, pyrrolylene, oxazolylene, thiazolylene, Imidazolylene, isoxazolylene, isothiazolylene, 1,2,3-triazolylene, 1,2,4-triazolylene, pyrazinylene, pyridylene, pyridazinylene, pyrimidinylene, pyrazinylene, 1,2,3-triazinylene, 1,2,4-triazinylene 1,3,5-triazinylene, 1,2,3-oxadiazolylene, 1,2,4-oxadiazolylene, 1,2,5-oxadiazolylene, 1,3,4-oxadiazolylene 1,2,3-thiadiazolylene, 1,2,4-thiadiazolylene, 1,2,5-thiadiazolylene, 1,3,4-thiadiazolylene, tetrazolylene, thiadiazinylene, indolylene, isoindolylene, benzofurylene, benzothienylene, imidazolylene, benzoimidazole Rylene, benzothiazolylene, benzoisothiazolylene, benzoxazolylene, benzoisoxazolylene, plinylene, quinazolinylene, quinolinidylene, quinolinylene, isoquinolinylene, quinoxalinylene, naphthyridinylene, pteridinylene, carbazolylene, azepinylene, diazepinylene, diazepinylene, diazepinylene, etc. . Heteroaryl is also intended to include the partially hydrogenated derivatives of the ring systems listed above. Non-limiting examples of such partially hydrogenated derivatives are 2,3-dihydro-benzofuranylene, pyrrolinylene, pyrazolinylene, indolinylene, oxazolidinylene, oxazolinylene, oxazepinylene and the like.

“Aryl C _1-6 -alkyl”, “heteroaryl C _1-6 -alkyl”, “aryl C _2-6 -alkenyl” and the like are defined above, substituted by aryl or heteroaryl as defined above C _1-6 -alkyl or C _2-4 -alkenyl, for example

Means.

  The term “optionally substituted” as used herein means that the group in question is unsubstituted or substituted with one or more specified substituents. When the group in question is substituted with two or more substituents, these substituents may be the same or different.

  Certain terms defined above may appear more than once in the structural formula, and in such cases, each term should be defined independently of the others.

  Further, when using the terms “independently is” and “independently selected from ...”, it should be understood that the groups in question may be the same or different.

  As used herein, the term “treatment” refers to the management and care of a patient intended to combat a disease, disorder or condition. This term includes the following: delaying the progression of the disease, disorder or condition, alleviating or reducing symptoms and complications, and / or curing or eliminating the disease, disorder or condition. The patient to be treated is preferably a mammal, especially a human.

Description of the invention

The present invention relates to a compound of the following general formula (I), and any diastereomer, enantiomer or tautomer thereof and a mixture containing them, or a pharmaceutically acceptable salt thereof:

here,
A is

And
m is 0 or 1,
n is 0, 1, 2 or 3 where m and n are not both 0;
R ⁴ is hydrogen, halogen or-(CH ₂ ) _o -OR ⁵ ;
o is 0 or 1,
R ⁵ is hydrogen, C _1-6 -alkyl, C _1-6 -alkanoyl, aryl or aryl-C _1-6 -alkyl;
R ¹ and R ² are independently hydrogen, halogen or C _1-6 -alkyl, or R ¹ and R ² together form a double bond;
R ³ is hydrogen, C _1-6 -alkyl or halogen, or R ³ and R ² together form a double bond to oxygen,
X is arylene or heteroarylene, which is optionally _{halogen, -CN, -CF 3, -OCF 3} , -OCHF 2, -NO 2, -OR 8, -NR 8 R 9 and C _1-6 - Optionally substituted by one or two groups R ⁶ and R ⁷ selected from alkyl,
R ⁸ and R ⁹ are independently hydrogen or C _1-6 -alkyl;
Y is, -C (O) -, - O -, - NR 10 -, - S -, - S (O) -, - S (O) 2 -, or -CR ¹¹ R ¹² - and is,
R ¹⁰ is hydrogen or C _1-6 -alkyl;
R ¹¹ and R ¹² are independently hydrogen, C _1-6 -alkyl, or hydroxy, or R ¹¹ together with R ¹ forms a double bond, and R ¹² is hydrogen, C _{1 -6} -alkyl or hydroxy,
Z is -C (O)-(CR ¹³ R ¹⁴ ) _p- , -O- (CR ¹³ R ¹⁴ ) _p- , -S- (CR ¹³ R ¹⁴ ) _p- , -S (O)-(CR _{^{13 R 14) p -, -}} S (O) 2 - (CR 13 R 14) p -, - NR 15 - (CR 13 R 14) p -, or _{^{- (CR 13 R 14) p}} - in and,
p is 0, 1 or 2;
R ¹³ and R ¹⁴ are independently selected from hydrogen, —CF ₃ , —OCF ₃ and C _1-6 -alkyl;
R ¹⁵ is hydrogen or C _1-6 -alkyl;
D is aryl or heteroaryl optionally substituted with one or more substituents R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²⁰ and R ²¹ , where
R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ are independently
Hydrogen, _{halogen, -CN, -CH 2 CN, -CHF} 2, -CF 3, -OCF 3, -OCHF 2, -OCH 2 CF 3,
-OCF ₂ CHF ₂ , -S (O) ₂ CF ₃ , -SCF ₃ , -NO ₂ , -OR ²² , -NR ²² R ²³ , -SR ²² ,
-NR ²² S (O) ₂ R ²³ , -S (O) ₂ NR ²² R ²³ , -S (O) NR ²² R ²³ , -S (O) R ²² , -S (O) ₂ R ²² ,
-C (O) NR ²² R ²³ , -OC (O) NR ²² R ²³ -NR ²² C (O) R ²³ , -CH ₂ C (O) NR ²² R ²³ ,
-OCH ₂ C (O) NR ²² R ²³ , -CH ₂ OR ²² , -CH ₂ NR ²² R ²³ , -OC (O) R ²² , -C (O) R ²² or
-C (O) OR ²² ,
C _1-6 -alkyl, C _2-6 -alkenyl or C _2-4 -alkynyl,
This is optionally halogen, -CN, -CF ₃ , -OCF ₃ , -OCHF ₂ , -NO ₂ , -OR ²² , -NR ²² R ²³
And may be substituted with one or more substituents selected from: C _3-8 -cycloalkyl, C _4-8 -cycloalkenyl, heterocyclyl, C _3-8 -cycloalkyl-C _1-6 - alkyl, C _3-8 - cycloalkyl -C _1-6 - alkoxy, C _3-8 - cycloalkyloxy, C _3-8 - cycloalkyl -C _1-6 - alkylthio, C _3-8 - cycloalkyl thio, C _3-8 -cycloalkyl-C _2-6 -alkenyl, C _3-8 -cycloalkyl-C _2-6 -alkynyl, C _4-8 -cycloalkenyl-C _1-6 -alkyl, C _4-8 -Cycloalkenyl-C _2-6 -alkenyl, C _4-8 -Cycloalkenyl-C _2-6 -alkynyl, heterocyclyl-C _1-6 -alkyl, heterocyclyl-C _2-4 -alkenyl, heterocyclyl-C _{2- 6-}
Alkynyl, aryl, aryloxy, aryloxycarbonyl,
Aroyl, aryl-C _1-6 -alkoxy, aryl-C _1-6 -alkyl,
Aryl-C _2-6 -alkenyl, aryl-C _2-6 -alkynyl, heteroaryl,
Heteroaryl-C _1-6 -alkyl, heteroaryl-C _2-6 -alkenyl, or heteroaryl-C _2-6 -alkynyl,
The aromatic or non-aromatic ring system is halogen, -C (O) OR ²² , -CN, -CF ₃ , -OCF ₃ ,
-OCHF ₂ , -NO ₂ , -OR ²² , -NR ²² R ²³ and C _1-6 alkyl may be optionally substituted with one or more substituents,
R ²² and R ²³ are independently hydrogen, C _1-6 -alkyl, aryl-C _1-6 -alkyl or aryl, or when R ²² and R ²³ are bonded to the same nitrogen atom, Together with the nitrogen atom, a 3 to 8 member optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur and optionally containing one or two double bonds Or two of the R ^{16 to} R ¹⁹ groups can form a bridge- (CR ²⁴ R ²⁵ ) _a- when they are placed together in adjacent positions. O- (CR ²⁶ R ²⁷ ) _c -0- may be formed,
a is 0, 1, or 2;
c is 1 or 2,
R ²⁴ , R ²⁵ , R ²⁶ and R ²⁷ are independently hydrogen, C _1-6 alkyl or fluoro;
R ²⁰ and R ²¹ are independently hydrogen, C _1-6 alkyl, C _3-8 -cycloalkyl, or C _3-8 -cycloalkyl-C _1-6 -alkyl,
E is C _3-8 -cycloalkyl or C _4-8 -cycloalkenyl optionally substituted with one or two substituents R ²⁸ and R ²⁹ (wherein the substituents are independently
Hydrogen, _{halogen, -CN, -CF 3, -OCF 3} , -OCHF 2, -OR 33, -NR 33 R 34, C 1-6 - alkyl Le, C _3-8 - cycloalkyl, C _3-8 -Cycloalkenyl, heteroaryl and aryl,
Here, the heteroaryl group and aryl notation are optionally halogen, -CN,
May be substituted with one or more substituents selected from -CF ₃ , -OCF ₃ , -OCHF ₂ , -NO ₂ , -OR ³³ , -NR ³³ R ³⁴ and C _1-6 -alkyl;
R ³³ and R ³⁴ are independently hydrogen or C _1-6 -alkyl,
Or R ³³ and R ³⁴ , when they are attached to the same nitrogen atom, together with the nitrogen atom optionally contain one or two additional heteroatoms selected from nitrogen, oxygen and sulfur. And optionally selected to form a 3- to 8-membered heterocycle containing one or two double bonds), aryl, heteroaryl, aryl-C _2-4 -alkenyl, or aryl- C _2-6 -alkynyl, the aryl or heteroaryl moiety of which may optionally be substituted with one or more of R ²⁸ , R ²⁹ , R ³⁰ , R ³¹ and R ^{32 as} defined above, wherein R ²⁸ and R ²⁹ are as defined above, and R ³⁰ , R ³¹ and R ³² are independently
- hydrogen, _{halogen, -CHF 2, -CF 3, -OCF} 3, -OCHF 2, -OCH 2 CF 3, -OCF 2 CHF 2, -SCF 3,
-OR ³⁵ , -NR ³⁵ R ³⁶ , -SR ³⁵ , -S (O) R ³⁵ , -S (O) ₂ R ³⁵ , -C (O) NR ³⁵ R ³⁶ ,
-OC (O) NR ³⁵ R ³⁶ , -NR ³⁵ C (O) R ³⁶ , -OCH ₂ C (O) NR ³⁵ R ³⁶ , -C (O) R ³⁵ and -C (O) OR ³⁵
C _1-6 -alkyl, C _2-6 alkenyl and C _2-4 -alkynyl,
They optionally _{halogen, -CN, -CF 3, -OCF 3} , -OCHF 2, -NO 2, -OR 35, -NR 35 R 36
And optionally substituted with one or more substituents selected from C _1-6 -alkyl,
C _3-8 -cycloalkyl, C _4-8 -cycloalkenyl, heterocyclyl, C _3-8 -cycloalkyl-C _1-6 -alkyl, C _3-8 -cycloalkyl-C _2-6 -alkenyl, C _3-8 -Cycloalkyl-C _2-6 -alkynyl, C _4-8 -Cycloalkenyl-C _1-6 -alkyl, C _4-8 -Cycloalkenyl-C _2-6 -alkenyl, C _4-8 -Cyclo Alkenyl-C _2-6 -alkynyl,
Heterocyclyl -C _1-6 - alkyl, heterocyclyl -C _2-6 - alkenyl, Heteroshi acrylic -C _2-6 - alkynyl, aryl, aryloxy, aroyl,
Aryl-C _1-6 -alkoxy, aryl-C _1-6 -alkyl, aryl-C _2-6 -alkenyl, aryl-C _2-6 -alkynyl, heteroaryl, heteroaryl-C _1-6 -alkyl , Heteroaryl-C _2-6 -alkenyl, and heteroaryl-C _2-4 -alkynyl,
The aromatic or non-aromatic ring is optionally halogen, —CN, —CF ₃ , —OCF ₃ ,
May be substituted with one or more substituents selected from -OCHF ₂ , -NO ₂ , -OR ³⁵ , -NR ³⁵ R ³⁶ and C _1-6 -alkyl;
here,
R ³⁵ and R ³⁶ are independently hydrogen, C _1-6 -alkyl or aryl,
Or when R ³⁵ and R ³⁶ are attached to the same nitrogen atom, they together with the nitrogen atom optionally contain one or two additional heteroatoms selected from nitrogen, oxygen and sulfur; And optionally may form a 3-8 membered heterocycle containing one or two double bonds,
Or when two of R ³⁰ , R ³¹ and R ³² are attached to the same or adjacent ring carbon atoms, they are taken together to form a bridge
^{_{-O- (CH 2) t -CR 37}} R 38 - (CH 2) l -O -, - (CH 2) t -CR 37 R 38 - (CH 2) l -, or
^{_{-S- (CH 2) t -CR 37}} R 38 - (CH 2) iS- is formed,
t and l are independently 0, 1, 2, 3, 4 or 5,
R ³⁷ and R ³⁸ are independently hydrogen or C _1-6 -alkyl.

In another embodiment, A is represented by the following formula:

Here, m, n, and R ⁴ are as defined in Formula (I).

In another embodiment A is

It is represented by

In another embodiment A is

It is represented by

In another embodiment A is

It is represented by

  In another embodiment, X is a monocyclic arylene or heteroarylene, which may be substituted as defined in formula (I).

In another embodiment, X is

Here, R ⁶ and R ⁷ are as defined in formula (I).

In another embodiment, X is represented by the following formula:

Here, R ⁶ and R ⁷ are as defined in formula (I).

In another embodiment, R ⁶ and R ⁷ are both hydrogen.

In another embodiment, E is represented by the following formula:

Here, R ²⁸ , R ²⁹ , R ³⁰ , R ³¹ and R ³² are as defined in formula (I).

In another embodiment, E is represented by the following formula:

Here, R ²⁸ , R ²⁹ , R ³⁰ , R ³¹ and R ³² are as defined in formula (I).

In another embodiment, E is represented by the following formula:

Wherein R ³⁰ , R ³¹ and R ³² are as defined in formula (I). In another embodiment, E is represented by the formula:

Wherein R ³⁰ , R ³¹ and R ³² are as defined in formula (I). In another embodiment, E is represented by the formula:

Here, R ²⁸ , R ²⁹ , R ³⁰ , R ³¹ and R ³² are as defined in formula (I).

In another embodiment, R ³⁰ , R ³¹ and R ³² are independently
·hydrogen,
・ Halogen, -OCF ₃ , -SCF ₃ , or -CF ₃ ,
C _1-6 -alkyl; these are optionally fluoro, —CN, —CF ₃ , —OCF ₃ , —OR ³⁵ and
May be substituted with one or more substituents selected from -NR ³⁵ R ³⁶ ,
C _3-8 -cycloalkyl or C _4-8 -cycloalkenyl; these are optionally fluoro,
One or more substituents selected from -CN, -CF ₃ , -OCF ₃ , -OR ³⁵ , -NR ³⁵ R ³⁶ and C _1-6 -alkyl,
• aryl, aryloxy, or aryl-C _1-6 -alkoxy; these aryl moieties are optionally halogen, —CN, —CF ₃ , —OCF ₃ , —NO ₂ , —R ³⁵ , —NR ³⁵ R ³⁶ and
Optionally substituted with one or more substituents selected from C _1-6 -alkyl,
And
R ³⁵ and R ³⁶ are independently hydrogen, C _1-6 -alkyl or aryl,
Or when R ³⁵ and R ³⁶ are attached to the same nitrogen atom, they together with the nitrogen atom optionally contain one or two additional heteroatoms selected from nitrogen, oxygen and sulfur; In addition, a 3- to 8-membered heterocycle optionally containing one or two double bonds may be formed.

In another embodiment, R ³⁰ , R ³¹ and R ³² are independently
·hydrogen,
Halogen, -OCF ₃ or -CF ₃ ,
C _1-6 -alkyl; these are optionally fluoro, —CN, —CF ₃ , —OCF ₃ , —OR ³⁵ and
May be substituted with one or more substituents selected from -NR ³⁵ R ³⁶ ,
Cyclohexyl or cyclohexyl-1-enyl; these are optionally fluoro,
One or more substituents selected from -CN, -CF ₃ , -OCF ₃ , -OR ³⁵ , -NR ³⁵ R ³⁶ and C _1-6 -alkyl,
Phenyl: this is optionally halogen, -CN, -CF ₃ , -OCF ₃ , -NO ₂ , -R ³⁵ ,
Optionally substituted with one or more substituents selected from —NR ³⁵ R ³⁶ and C _1-6 -alkyl; • phenoxy or benzyloxy; these phenyl moieties are optionally halogenated, —CN, —CF ₃ , —OCF ₃ , —NO ₂ , —R ³⁵ , —NR ³⁵ R ³⁶ and optionally substituted with one or more substituents selected from C _1-6 -alkyl.
And
A compound wherein R ³⁵ and R ³⁶ are independently hydrogen or C _1-6 -alkyl.

In another embodiment, R ³⁰ and R ³² are both hydrogen and R ³¹ is different from hydrogen.

In another embodiment, E is represented by the following formula:

In another embodiment, E is represented by the following formula:

In another embodiment, E is represented by the following formula:

In another embodiment, E is represented by the following formula:

Here, R ³⁰ is as defined in formula (I).

In another embodiment,
R ³⁰ is halogen, or heteroaryl: this is optionally halogen, —CN, —CF ₃ , —NO ₂ , —OR ³⁵ , —NR ³⁵ R ³⁶
And optionally substituted with one or more substituents selected from C _1-6 -alkyl,
R ³⁵ and R ³⁶ are independently hydrogen or C _1-6 -alkyl,
Or when R ³⁵ and R ³⁶ are attached to the same nitrogen atom, they together with the nitrogen atom optionally contain one or two additional heteroatoms selected from nitrogen, oxygen and sulfur; In addition, a 3- to 8-membered heterocycle optionally containing one or two double bonds may be formed.

In another embodiment,
R ³⁰ is
• halogen, or • thienyl: one or more optionally selected from halogen, —CN, —CF ₃ , —NO ₂ , —OR ³⁵ , —NR ³⁵ R ³⁶ , and C _1-6 -alkyl And may be substituted with
R ³⁵ and R ³⁶ are independently hydrogen or C _1-6 -alkyl,
Or when R ³⁵ and R ³⁶ are attached to the same nitrogen atom, they together with the nitrogen atom optionally contain one or two additional heteroatoms selected from nitrogen, oxygen and sulfur; In addition, a 3- to 8-membered heterocycle optionally containing one or two double bonds may be formed.

In another embodiment, E is represented by the following formula:

In another embodiment, Y is —C (O) —, —O—, —S (O) ₂ —, —NH—, or —CH ₂ —.

In another embodiment, Y is —CHR ¹¹ — and R ¹¹ forms a double bond with R ¹ .

  In another embodiment, Y is —C (O) —.

In another embodiment, R ¹ and R ² are both hydrogen.

In another embodiment, R ¹ and R ² are joined to form a double bond.

In another embodiment, R ³ is hydrogen.

In another embodiment, Z is -C (O)-(CR ¹³ R ¹⁴ ) _p- , -O- (CR ¹³ R ¹⁴ ) _p- ,
^{-NR 15 - (CR 13 R 14} ) p or _{-S (O) 2, - (} CR 13 R 14) p - a is, as p, R ^13, R ¹⁴ and R ¹⁵ are as defined in formula (I) It is.

In another embodiment, Z is —NR ¹⁵ — (CR ¹³ R ¹⁴ ) _p , or —C (O) — (CR ¹³ R ¹⁴ ) _p —, where p is as defined in formula (I) R ¹³ and R ¹⁴ are independently selected from hydrogen, —CF ₃ , —OCF ₃ and C _1-6 -alkyl, and R ¹⁵ is hydrogen.

In another embodiment, Z is —NH (CH ₂ ) _p or —C (O) — (CH ₂ ) _p —, and p is as defined in formula (I). In another embodiment , Z is NH or —C (O) —. In another embodiment, Z is —C (O) —. In another embodiment, D is represented by the formula:

Here, R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²⁰ and R ²¹ are as defined in formula (I).

In another embodiment, D is represented by the following formula:

Wherein R ¹⁶ , R ¹⁷ and R ¹⁸ are as defined in formula (I). In another embodiment, R ¹⁶ , R ¹⁷ and R ¹⁸ are independently hydrogen, halogen, —CN, -CH ₂ CN, -CHF ₂ , -CF ₃ , -OCF ₃ , -OCHF ₂ , -OCH ₂ CF ₃ ,
-OCF ₂ CHF ₂ , -S (O) ₂ CF ₃ , -SCF ₃ , -NO ₂ , -OR ²² , -NR ²² R ²³ , -SR ²² ,
-NR ²² S (O) ₂ R ²³ , -S (O) ₂ NR ²² R ²³ , -S (O) NR ²² R ²³ , -S (O) R ²² , -S (O) ₂ R ²² ,
-C (O) NR ²² R ²³ , -OC (O) NR ²² R ²³ , -NR ²² C (O) R ²³ , -CH ₂ C (O) NR ²² R ²³ ,
-OCH ₂ C (O) NR ²² R ²³ , -CH ₂ OR ²² , -CH ₂ NR ²² R ²³ , -OC (O) R ²² , -C (O) R ²² or
Optionally substituted with one or more substituents selected from —C (O) OR ²² • C _1-6 -alkyl: optionally, fluoro, —CN, —CF ₃ , —OCF ₃ , —OR ²² and
Optionally substituted with one or more substituents selected from —NR ²² R ²³ • C _3-8 -cycloalkyl: optionally, fluoro, —C (O) OR ²⁴ , —CN, —CF ₃ ,
Optionally substituted with one or more substituents selected from -OCF ₃ , -OR ²² , -NR ²² R ²³ and C _1-6 -alkyl. Aryl or aryloxy: these are optionally fluoro, -C (O) OR ²⁴ , -CN,
-CF ₃ , -OCF ₃ , -OR ²² , -NR ²² R ²³ and optionally substituted by one or more substituents selected from C _1-6 -alkyl In the above, R ²² and R ²³ are independently , Hydrogen, C _1-6 -alkyl, aryl-
C _1-6 -alkyl or aryl, or when R ²² and R ²³ are attached to the same nitrogen atom, they are taken together with the nitrogen atom and are optionally selected from nitrogen, oxygen and sulfur May form a 3-8 membered heterocycle containing one or two additional heteroatoms, and optionally one or two double bonds,
Or when two of the radicals R ^{16 to} R ¹⁸ are arranged in adjacent positions, they are taken together to form _a bridge- (CR ²⁴ R ²⁵ ) _a -O- (CR ²⁶ R ²⁷ ) _c -O- may be formed,
a is 0, 1 or 2;
c is 1 or 2,
R ²⁴ , R ²⁵ , R ²⁶ and R ²⁷ are independently hydrogen, C _1-6 alkyl or fluoro.

In another embodiment, R ¹⁶ , R ¹⁷ and R ¹⁸ are independently
Hydrogen, halogen, -CF ₃ , -OCF ₃ , -SCF ₃ , C _1-6 -alkyl, C _1-6 -alkoxy, phenyl, cyclopentyl, cyclohexyl or phenoxy,
Or when two of the radicals R ^{16 to} R ¹⁸ are arranged in adjacent positions, they are taken together to form a bridge —O— (CF ₂ ) ₂ —O—, —CF ₂ —O -CF ₂ -O- or -O-CH ₂ -O-
May be formed.

In another embodiment, R ¹⁶ is hydrogen and R ¹⁷ and R ¹⁸ are different from hydrogen.

In another embodiment, R ¹⁶ and R ¹⁷ are hydrogen and R ¹⁸ is different from hydrogen. In another embodiment, the invention provides a compound of general formula (I ₄ ) as well as any dia Stereomers, enantiomers or tautomers and mixtures containing these, or pharmaceutically acceptable salts thereof:

Here, R ⁶ , R ⁷ , E and D are as defined for formula (I) or in any one of the above embodiments.

In another embodiment, the present invention provides a compound of general formula (I ₅ ) and any diastereomers, enantiomers or tautomers thereof and mixtures thereof, or pharmaceutically acceptable salts thereof. About:

Here, R ⁶ , R ⁷ , E and D are as defined for formula (I) or in any one of the above embodiments.

In another embodiment, the present invention provides a compound of general formula (I _5a ), and any diastereomers, enantiomers or tautomers thereof and mixtures thereof, or pharmaceutically acceptable salts thereof About:

Here, R ⁶ , R ⁷ , E and D are as defined for formula (I).

In another embodiment, the present invention provides compounds of general formula (I _5b ), and any diastereomers, enantiomers or tautomers thereof and mixtures thereof, or pharmaceutically acceptable salts thereof About:

Here, R ⁶ , R ⁷ , E and D are as defined for formula (I).

In another embodiment, the present invention provides a compound of general formula (I ₆ ), and any diastereomers, enantiomers or tautomers thereof and mixtures thereof, or pharmaceutically acceptable salts thereof About:

Here, R ⁶ , R ⁷ , E and D are as defined for formula (I).

  The compounds of the present invention may be chiral and any enantiomers as separated, pure or partially produced enantiomers or racemic mixtures thereof are intended to be included within the scope of the present invention.

    Furthermore, diastereomers may be formed when there are double bonds, fully or partially saturated ring systems, two or more asymmetric centers, or rotationally restricted bonds in the molecule. is there. Any diastereomers, such as separated, pure or partially purified diastereomers, or mixtures thereof are intended to be included within the scope of the present invention.

  Furthermore, some of the compounds of the present invention may exist in different tautomeric forms. Any tautomeric form that the compound can form is included within the scope of the invention.

  The present invention also includes pharmaceutically acceptable salts of the compounds of the present invention. Such salts include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable metal salts, ammonium and alkylated ammonium salts. Acid addition salts include inorganic and organic acid salts. Representative examples of suitable inorganic acids include hydrochloric acid, bromic acid, iodic acid, phosphoric acid, sulfuric acid, nitric acid and the like. Examples of suitable organic acids include formic acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, propionic acid, benzoic acid, cinnamic acid, citric acid, fumaric acid, glycolic acid, lactic acid, maleic acid, malic acid, malonic acid, mandel Acid, succinic acid, picric acid, pyruvic acid, salicylic acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, tartaric acid, ascorbic acid, pamoic acid, bismethylenesalicylic acid, ethanedisulfonic acid, gluconic acid, citraconic acid, asparagine Acids, stearic acid, palmitic acid, EDTA, glycolic acid, p-aminobenzoic acid, glutamic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like are included. Additional examples of pharmaceutically acceptable inorganic or organic acid acid addition salts include those described in J. Pat. Pharmaceutically acceptable salts listed in Pharm. Sci. 1977, 66, 2 are included. Examples of the metal salt include lithium salt, sodium salt, potassium salt, magnesium salt and the like. Examples of ammonium and alkylated ammonium salts include ammonium, methylammonium, dimethylammonium, trimethylammonium, ethylammonium, hydroxyethylammonium, diethylammonium, n-butylammonium, sec-butylammonium Salts, tert-butylammonium salts, tetramethylammonium salts and the like.

  Hydrates that can be formed by the compounds of the present invention are also contemplated as pharmaceutically acceptable acid addition salts.

  Furthermore, pharmaceutically acceptable salts also include basic amino acid salts such as lysine, arginine and ornithine.

  These acid addition salts can be obtained as direct products of compound synthesis. Alternatively, the salt may be isolated by dissolving the free base in a suitable solvent containing a suitable acid, evaporating the solvent, or 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 solvates are also contemplated as being within the scope of the present invention.

  The present invention also encompasses prodrugs of the compounds of the present invention, which prodrugs undergo chemical transformation by metabolic processes when administered prior to becoming pharmacologically active substances. In general, such prodrugs are functional derivatives of compounds of general formula (I) and can be readily converted in vivo to the required compounds of formula (I). Conventional methods for selecting and preparing suitable prodrug derivatives are described in, for example, H. et al. Bundgaard, Elsevier, “Design of Prodrugs” (1985).

  The present invention also encompasses the active metabolites of the present invention.

  The compounds according to the invention act to antagonize the action of glucagon and are therefore useful for the treatment and / or prevention of disorders and diseases where such antagonism is beneficial.

The compounds according to the invention are preferably 5 μM or less, more preferably less than 1 M, even more preferably less than 500 nM, for example 100 nM, as measured by the glucagon binding assay (I) and glucagon binding assay (II) described herein. Has an IC ₅₀ value of less than nM.

  Therefore, the compound of the present invention contains hyperglycemia, IGT (glucose tolerance disorder), insulin resistance syndrome, syndrome X, type 1 diabetes, type 2 diabetes, hyperlipidemia, dyslipidemia, hypertriglyceridemia, Hyperlipoproteinemia, hypercholesterolemia, arteriosclerosis including atherosclerosis, glucagonoma, acute pancreatitis, cardiovascular disease, hypertension, cardiac hypertrophy, gastrointestinal disorders, obesity, diabetes as a result of obesity, diabetic It can be applied to treatment and / or prevention of dyslipidemia and the like.

  Furthermore, they can be applied as diagnostic agents for identifying patients who are deficient in glucagon receptors, as treatments for increasing gastric acid secretion and reversing intestinal hypomotility with glucagon administration.

  They can also be useful as tools or reference molecules in binding assays to identify new glucagon antagonists in labeled form.

  Thus, in a further aspect, the present invention relates to a compound according to the invention for use as a medicament.

  The invention also relates to pharmaceutical compositions containing at least one compound according to the invention as active ingredient together with one or more pharmaceutically acceptable carriers or excipients.

  The pharmaceutical composition is preferably in unit dosage form containing from about 0.05 mg to about 1000 mg, preferably from about 0.1 mg to about 500 mg, particularly preferably from about 0.5 mg to about 200 mg of the compound according to the invention.

  The invention further relates to the use of the compounds according to the invention for the treatment and / or prevention of disorders or diseases in which glucagon antagonism is beneficial.

  The invention also relates to a method for treating and / or preventing a disorder or disease in which glucagon antagonism is beneficial, which method comprises administering to a patient in need thereof an effective amount of a compound according to the invention. Including doing.

  In one embodiment, the compounds of the invention are used for the manufacture of a medicament to treat any glucagon-mediated condition and disease.

  In another embodiment, the compounds of the invention are used to manufacture a medicament for the treatment of hyperglycemia.

  In yet another embodiment, the compounds of the invention are used to manufacture a medicament for lowering blood glucose in a mammal. The compounds of the present invention are effective in lowering blood glucose both during fasting and after feeding.

  In yet another embodiment, the compounds of the invention are used to prepare a pharmaceutical composition for the treatment of IGT.

  In yet another embodiment, the compounds of the invention are used to prepare a pharmaceutical composition for the treatment of type 2 diabetes.

  In yet another embodiment, the compounds of the invention are used to prepare a pharmaceutical composition that retards or prevents the progression of IGT to type 2 diabetes.

  In yet another embodiment, the compounds of the invention are used to prepare a pharmaceutical composition that retards or prevents progression from non-insulin requiring type 2 diabetes to insulin requiring type 2 diabetes.

  In a further embodiment, the compounds of the invention are used to prepare a pharmaceutical composition for treating type 1 diabetes. Such treatment usually involves insulin therapy.

  In a further embodiment, the compounds of the invention are used to prepare a pharmaceutical composition for treating obesity.

  In a further embodiment, the compounds of the invention are used to produce a pharmaceutical composition for treating disorders of lipid metabolism such as dyslipidemia.

  In a further embodiment, the compounds of the invention are used to prepare a pharmaceutical composition for treating an appetite regulation disorder or an energy expenditure disorder.

  In a further aspect of the invention, treatment of a patient with a compound of the invention is combined with diet and / or exercise.

  In a further aspect of the invention, the compounds of the invention are administered in combination with one or more additional active agents in any suitable ratio. Such further active substances are selected, for example, from anti-diabetic agents, anti-hyperlipidemic agents, anti-obesity agents, anti-hypertensive agents, agents for treating complications derived from or associated with diabetes. It's okay.

Suitable anti-diabetic agents include insulin; insulin analogs and derivatives disclosed in the following references which are incorporated herein by reference, ie EP 792 290 (Novo Nordisk A / S), eg N ^εB29 -tetradeca Noil des (B30) human insulin; EP 214 826 and EP 705 275 (Novo Nordisk A / S), eg Asp ^B28 human insulin; US Pat. No. 5,504,188 (Eli Lilly), eg Lys ^B28 Pro ^B29 human insulin; EP 368 187 (Aventis), eg, Lantus; GLP-1 and GLP-1 derivatives as disclosed in WO 98/08871 (Novo Nordisk A / S), incorporated herein by reference, and orally active Contains hypoglycemic agents.

  Orally active hypoglycemic agents include imidazolines, sulfonylureas, biguanides, meglitinides, oxadiazolidinediones, thiazolidinediones, α-glycosidase inhibitors, glucagon antagonists, GLP-1 agonists, and β-cell ATP dependence Agents that act on potassium channels, for example potassium channel opening as disclosed in WO 97/26265, WO 99/03861 and WO 00/37474 (Novo Nordisk A / S), which are incorporated herein by reference. Or potassium channel blockers such as nateglinide or BTS-67582, insulin sensitizers, insulin secretagogues, DPP-IV (dipeptidyl peptidase-IV) inhibitors, PTPase inhibitors, gluconeogenesis and / or glycogenolysis Inhibitors of liver enzymes involved in stimulation, regulators of glucose uptake, Like 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 by reference. Glucokinase (GK) activator, GSK-3 (glycogen synthase kinase-3) inhibitor, antihyperlipidemic or antilipidemic compounds that alter lipid metabolism, reduce food intake PPAR (peroxisome proliferator-activated receptor) and RXR (retinoid X receptor) agonists such as ALRT-268, LG-1268 or LG-1069 are included.

In one embodiment, the compound of the present invention is insulin or N ^{< [epsilon] B29,} - tetradecanoyl des (B30) human insulin, Asp ^{Ipushironbi28} human insulin, Lys ^B28 Pro ^B29 human insulin, Lys ^B29 - (Nε (γ- glutamyl -Nα lithocholyl ) des (B30) administered in combination with an insulin analog or derivative such as human insulin (Lantus ^™ ), or a mixed preparation comprising one or more of these.

  In a further embodiment of the invention, the compounds of the invention comprise a sulfonylurea, such as tolbutamide, chloropropamide, tolazamide, glibenclamide, glyburide, glipizide, It is administered in combination with glimepiride or glicazide.

  In another embodiment of the invention, the compounds of the invention are administered in combination with a biguanide such as metformin.

  In yet another embodiment of the invention, the compounds of the invention are administered in combination with a meglitinide, such as repaglinide or nateglinide.

  In yet another embodiment of the present invention, the compound of the present invention is a thiazolidinedione insulin sensitizer such as troglitazone, ciglitazone, pioglitazone, rosiglitazone, isaglitazone, darglitazone ( darglitazone), englitazone, CS011 / CI-1037 or T174, or WO 97/41097, WO 97/41119, WO 97/41120, WO 00/41121, and WO 98, which are incorporated herein by reference. / 45292 (Dr. Reddy's Research Foundation).

  In yet another embodiment, the compound of the invention comprises GI 262570, YM-440, MCC-555, JTT-501, AR-H039242, KRP-297, GW-409544, CRE-16336, AR-H049020, LY510929, Insulin sensitizers such as LY465608, MBX-102, CLX-0940, GW-501516, tesaglitazar (tes 242), or ragaglitazar (ragaglitazar; NN622 or (-) DRF2725) WO 99/19313, WO 00/50414, WO 00/63191, WO 00/63192, WO 00/63193 (Dr. Reddy's Research Foundation) and WO00 / 23425, WO 00/23415, WO 00/23451, WO00 / 23445, WO 00/23417, WO 00/23416, WO00 / 63153, WO 00/63196, WO 00/63209, WO 00/63190 and WO00 / 63189 (Novo Nordisk A / S) They may be administered together.

    In a further embodiment of the invention, the compounds of the invention are administered in combination with an alpha glucosidase inhibitor such as voglibose, emiglitate, miglitol or acarbose.

  In another embodiment of the present invention, the compound of the present invention comprises an agent that acts on an ATP-dependent potassium channel of β cells, such as tolbutamide, chlorpropamide, tolazamide, glibenclamide, glyburide Glipizide, glicazide, BTS-67582, repaglinide or nateglinide are administered in combination.

  In yet another embodiment of the invention, the compound of the invention comprises an antihyperlipidemic or antilipidemic agent such as cholestyramine, colestipol, clofibrate, gemfibro It is administered in combination with gemfibrozil, lovastatin, pravastatin, simvastatin, probucol, or dextrothyroxine.

  In yet another embodiment, the compound of the present invention comprises an antihyperlipidemic or hyperlipidemic agent, such as cholestyramine, colestipol, clofibrate, gemfibrozil. ), Lovastatin, pravastatin, simvastatin, probucol, or dextrothyroxine.

  In another aspect of the invention, a compound of the invention is combined with one or more of the above compounds, for example, metformin and sulfonylurea (eg, glibenclamide or glyburide); sulfonylurea and acarbose; metformin and meglitinide (eg, repaglinide) Sulfonylureas, metformin and troglitazone; sulfonylureas, metformin and pioglitazone; sulfonylureas, metformin, and insulin sensitizers disclosed in WO 00/63189 or WO97 / 41097; meglitinides (eg repaglinide), metformin and Troglitazone; meglitinide (eg repaglinide), metformin and pioglitazone; meglitinide (eg repaglinide), metformin and W Insulin sensitizers disclosed in O 00/63189 or WO97 / 41097; insulin and sulfonylurea; insulin and metformin; insulin, metformin and meglitinide (eg repaglinide); insulin, metformin and sulfonylurea; insulin and troglitazone; insulin and pioglitazone Insulin and insulin sensitizers disclosed in WO 00/63189 or WO 97/41097; insulin and lovastatin; insulin analogues or derivatives, metformin and meglitinide (eg repaglinide); insulin analogues or derivatives, metformin and sulfonylurea; insulin Analogs or derivatives and troglitazone; insulin analogs or induced poly and pioglitazone; insulin analogs or inducers It is administered in combination with like; body and WO 00/63189 or insulin sensitizers disclosed in WO97 / 41097.

  Furthermore, the compounds according to the invention may be administered in combination with one or more antiobesity agents or appetite regulating agents.

  Such drugs include CART (cocaine amphetamine-regulated transcript) agonists, NPY (neuropeptide Y) agonists, MC4 (melanocortin 4) agonists, aurexin antagonists, H3 histamine antagonist TNF (tumor necrosis factor) modulators, CRF ( Corticotropin releasing factor) agonist, CRF BP (corticotropin releasing factor binding protein) antagonist, urocortin agonist, β3 adrenergic agonist (eg CL-316243, AJ-9677, GW-0604, LY362884, LY377267 or AZ-40140), MSH (Fura site stimulating hormone) agonists, MCH (melanocyte-concentrating hormone) antagonists, CCK (cholecystokinin) agonists, serotonin reuptake inhibitors (eg fluoxetine, seroxat, or citalopram), serotonin and nor Adrenaline reabsorption inhibitor, 5HT (serotonin) agonist, bombesin agonist, galanin antagonist, growth hormone, growth hormone releasing compound, THR (threotropin releasing hormone) agonist, UPC2 or UPC3 (uncoupled protein 2 or 3) modulator, leptin agonist , A DA (dopamine) agonist (eg, bromocriptine, doprexin), a lipase / amylase inhibitor, a PPAR modulator, an RXR modulator, and a TRβ agonist shell.

  In another embodiment, the antiobesity agent is dexamphetamine or amphetamine.

  In another embodiment, the antiobesity agent is fenfluramine or dexfenfluramine.

  In yet another embodiment, the antiobesity agent is sibutramine.

  In a further embodiment, the antiobesity agent is orlistat.

  In another embodiment, the antiobesity agent is mazindol or phentermine.

  Furthermore, the compounds according to the invention may be administered in combination with one or more antihypertensive agents. Examples of anti-antihypertensive agents include beta blockers (eg, alprenolol, atenolol, timolol, pindolol, propranolol and metoprolol), ACE (angiotensin converting enzyme) inhibitors (eg, benazepril, captopril, enalapril). (enalapril), fosinopril, lisinopril, quinapril and ramipril), calcium channel blockers such as nifedipine, felodipine, nicardipine, isradipine , Nimodipine, diltiazem and verapamil), and alpha blockers (eg, doxazosin, urapidil, prazosin and terazosin). Further reference may be made to Remington: The Science and Practice of Pharmacy, 19th Edi-tion, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995.

  It should be noted that any suitable combination of diet and / or exercise, one or more of the compounds described above, and optionally one or more other active substances, with a compound according to the present invention is within the scope of the present invention. It should be understood that it is deceived.

<Pharmaceutical composition>
The compounds of the present invention may be administered alone or in combination with a pharmaceutically acceptable carrier or excipient in single or multiple doses. The pharmaceutical compositions according to the present invention are prepared using Remington: The Science and Practice of Pharmacy, 19th Edition, Gennaro, Ed., Using pharmaceutically acceptable carriers or diluents and other known adjuvants and excipients. , Mack Publishing Co., Easton, PA, 1995.

  The pharmaceutical composition is oral, rectal, nasal, lung, topical (including buccal and sublingual), transdermal, intracisternal, intraperitoneal, vaginal, and parenteral (subcutaneous, intramuscular, subarachnoid) It may be specially formulated for administration by any suitable route, such as intracavitary, intravenous, and intradermal routes, with the oral route being preferred. It will be appreciated that the preferred route will depend on the general condition and age of the patient to be treated, and the active ingredient chosen.

  Pharmaceutical compositions for oral administration include solid dosage forms such as capsules, tablets, dragees, pills, troches, powders and granules. Where appropriate, they can be prepared with enteric coatings or formulated to provide controlled release of the active ingredient, such as sustained release or delayed release, according to methods known in the art. can do.

  Liquid dosage forms for oral administration include solutions, emulsions, suspensions, syrups and elixirs.

  Pharmaceutical compositions for parenteral administration are reconstituted into sterile aqueous and non-aqueous injectable solutions, dispersions, suspensions or emulsions, and sterile injectable solutions or dispersions before use. Sterilized powder. Depot injection formulations are also considered to be within the scope of the present invention.

  Other suitable dosage forms include suppositories, sprays, ointments, creams, gels, inhalants, skin patches, implants and the like.

  A typical oral dosage is about 0.001 to about 100 mg / kg body weight per day, preferably about 0.01 to about 50 mg / kg body weight per day administered in one or more doses, such as 1 to 3 doses, and more Preferably, it is about 0.05 to about 10 mg / kg body weight per day. The exact dosage will depend on the frequency and mode of administration, the gender of the patient to be treated, age, weight and general symptoms, the nature and severity of the symptoms to be treated, and the concomitant diseases to be treated and others apparent to those skilled in the art Will depend on other factors.

  The formulation is conveniently provided in unit dosage form by methods known to those skilled in the art. A typical unit dosage form for oral administration of one or more times per day, for example 1-3 times a day, is 0.05 to about 1000 mg, preferably about 0.1 to about 500 mg, more preferably 0.5 mg to about 200 mg. Can be contained.

  For parenteral routes such as intravenous, intrathecal, intramuscular and similar administration, typical dosages are at about half the dosage used for oral administration.

  The compounds of the present 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. When the compound of formula (I) contains a free acid, such a salt can be obtained by treating a solution or suspension of the free acid of formula (I) with a chemical equivalent of a pharmaceutically acceptable base. By conventional methods. Representative examples are as described above. Physiologically acceptable salts of compounds having a hydroxy group include the anion of the compound in combination with a suitable cation such as sodium or ammonium ion.

  For parenteral administration, sterile aqueous solutions, aqueous propylene glycol, aqueous vitamin E, or solutions of the novel compound (I) in sesame oil or peanut oil may be used. Such aqueous solutions are suitably buffered if necessary, and the diluent is first made isotonic with saline or glucose. This aqueous solution is particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. All sterile aqueous media used are readily available by standard techniques known to those skilled in the art.

  Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solution and various organic solvents. Examples of solid carriers are lactose, clay, sucrose, cyclodextrin, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid, and lower alkyl ethers of cellulose. Examples of liquid carriers are syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene, and water. Similarly, the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax. The pharmaceutical compositions formed by combining the novel compound of formula (I) and a pharmaceutically acceptable carrier are then readily administered in a variety of dosage forms suitable for the disclosed route of administration. This formulation can be conveniently provided in unit dosage form by methods known in the dispensing arts.

  Formulations of the present invention suitable for oral administration are provided as discrete units, such as capsules or tablets each containing a predetermined amount of active ingredient and may contain suitable excipients. be able to. Furthermore, orally available formulations may be in the form of powders or granules, solutions or suspensions in aqueous or non-aqueous liquids, or liquid emulsions of water-in-oil or oil-in-water.

  When a solid carrier is used for oral administration, the preparation may be tableted, placed in a hard gelatin capsule in the form of a powder or pellets, or in the form of a troche or lozenge Good. The amount of solid carrier can vary widely but will usually be from about 25 mg to about 1 g. When a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule, or sterile injectable solution such as an aqueous or non-aqueous liquid suspension or solution.

Typical tablets that can be prepared by conventional tableting techniques include:
<Core>:
Active compound (as free compound or its salt) 5.0mg
Lactosum Ph. Eur. 67.8mg
Microcrystalline cellulose (Avicel) 31.4mg
Amberlite ^TM IRP88 ^* 1.0mg
Magnesium stearate Ph. Eur. Qs
<Coating>:
Hydroxypropyl methylcellulose about 9mg
Mywacett 9-40 T ^** about 0.9mg
^* Polacrillin potassium NF,
Tablet disintegrant, manufactured by Rohm and Haas
^** Used as plasticizer for film coating
Acrylic monoglycerides If desired, the pharmaceutical compositions of the invention may contain a compound of formula (I) together with further pharmacologically active substances as described above.

  The following examples and general procedures refer to the intermediate compounds and final products identified herein and in the synthetic schemes. The preparation of the compounds of the invention is described in detail using the following examples, but the chemical reactions described are described in terms of their general application to the preparation of the glucagon antagonists of the invention. In general, only one representative example has been described, but the compounds of the invention can be prepared by different methods. As specific examples, several compounds were prepared by the same method. In some cases, the reaction may not be applied as described for each compound included in the disclosed scope of the invention. The compounds for which this occurs will be readily recognized by those skilled in the art. In these cases, the reaction is performed by conventional modifications known to those skilled in the art, i.e. by appropriate protection of interfering groups, changes to other conventional reagents, or certain modifications of the reaction conditions, Can be implemented successfully. Alternatively, otherwise conventional reactions other than those described herein may be applied to the preparation of the corresponding compounds of the invention. All starting materials are known in all preparation methods or may be readily prepared from known starting materials. Unless otherwise noted, all temperatures are in degrees Celsius, when expressing yields, all parts and percentages are expressed in weight, and when expressing solvent and eluent, all parts are in weight. be written.

Some NMR data shown in the following examples is only selected data. In the examples, the following terms are intended to have the following general meaning:
DBU: 1,8-diazabicyclo [5.4.0] undec-5-ene
DCM: Dichloromethane, methylene chloride
DIPEA: N, N-diisopropylethylamine
DMF: N, N-dimethylformamide
DMSO: dimethyl sulfoxide, methyl sulfoxide
EDAC: 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride
Fmoc: 9-fluorenylmethyloxycarbonyl
NMP: N-methyl-2-pyrrolidinone
TFA: trifluoroacetic acid
THF: tetrahydrofuran
HOBt: 1-hydroxybenzotriazole.

HPLC-MS (Method A)
Use the following equipment:
Hewlett Packard Series 1100 G1312A Bin Pump
Hewlett Packard series 1100 column compartment
Hewlett Packard Series 1100 G13 15A DAD Diode Array Detector
Hewlett Packard series 1100 MSD
The instrument is controlled by HP Chemstation software. The HPLC pump is connected to two eluent reservoirs containing:
A: 0.01% TFA in water
B: 0.01% TFA in acetonitrile.

The analysis is performed at 40 ° C. by injecting an appropriate volume (preferably 1 mL) of sample into the column. The column is eluted using a gradient of acetonitrile. The HPLC conditions, detector settings, and mass spectrum settings used are listed in the table below.

HPLC-MS (Method B)
Use the following equipment:
Hewlett Packard Series 1100 MSD G1946A Single Quadrupole Mass Spectrometer
Hewlett Packard Series 1100 MSD G1312A Bin Pump
Hewlett Packard Series 1100 MSD G1313A ALS Sampler
Hewlett Packard Series 1100 MSD G1315A Diode Array Detector (DAD)
HP LC / MSD ChemStation control software running on an HP Vectra computer is used for instrument control and data acquisition. The HPLC pump is connected to two eluent reservoirs containing:
A: 0.01% TFA in water,
B: 0.01% TFA in acetonitrile.

The analysis is performed at room temperature by injecting 1 mL of the sample solution onto a column eluting with a gradient of acetonitrile in 0.01% TFA. The HPLC conditions, detector settings and mass spectrometer settings are listed in the table below.

HPLC-MS (Method C)
Use the following equipment:
・ Sciex API 100 single quadrupole mass spectrometer ・ Perkin Elmer series 200 Quard pump ・ Perkin Elmer series 200 automatic sampler ・ Applied Biosystems 785A UV detector ・ Sedex 55 evaporative scattering detector
A Valco column switch with a Valco actuator controlled by timed events from the pump.

Sciex sample control software running on a Macintosh PowerPC 7200 computer was used for instrument control and data acquisition. The HPLC pump is connected to four eluent reservoirs containing:
A: Acetonitrile B: Water C: 0.5% TFA in water
D: 0.02M ammonium acetate.

  The sample requirement is that it contains approximately 500 μg / mL of the compound to be analyzed in an acceptable solvent such as methanol, ethanol, acetonitrile, THF, water, and mixtures thereof (strong elution). The high concentration of solvent that will cause interference with chromatography at low concentrations of acetonitrile). This analysis is performed at room temperature by injecting 20 μL of sample solution onto the column, which elutes with a gradient of acetonitrile in either 0.05% TFA or 0.002M ammonium acetate.

Various elution conditions are used depending on the analytical method. The eluate from the column passes through a flow splitting T-connector at approximately 20 μL / min and reaches the API interface of the API 100 spectrometer via a 1 m75 μ quartz glass capillary. The remaining 1.48 mL / min passes through the UV detector and ELS detector. During LC-analysis, detection data is acquired simultaneously from the mass spectrometer, UV detector and ELS detector. The LC conditions, detector settings and mass spectrometer settings used in the different methods are listed in the table below.

HPLC-MS (Method D)
Use the following measuring equipment:
・ Hewlett Packard series 1100 G1312A bottle pump ・ Hewlett Packard series 1100 Column compartment ・ Hewlett Packard series 1100 G1315A DAD diode array detector ・ Hewlett Packard series 1100
MSD Sedere 75 Evaporative Light Scattering Detector This instrument is controlled by HP Chemstation software. The HPLC pump is connected to two eluent reservoirs containing:
A: 0.01% TFA in water,
B: 0.01% TFA in acetonitrile.

  The analysis is performed at 40 ° C. by injecting an appropriate volume of sample (preferably 1 μL) into the column eluting with a gradient of acetonitrile. The HPLC conditions, detector settings and mass spectrometer settings used are listed in the table below.

Column Waters Xterra MS C-18 × 3mm id 5μm
Gradient 5% -100% acetonitrile, linear, 7.5min at 1.5mL / min
Detection 210nm (analog output from DAD)
ELS (analog output from ELS)
MS ionization mode API-ES, scanning 100-1000amu process 0.1amu
Split the flow after DAD and divert approximately 1 mL / min of the liquid stream to ELS and 0.5 mL / min to MS.

Building blocks The following sections describe the building blocks used to prepare intermediates of formula (II):

In the formula, E and D are as defined above.

Starting materials for building blocks used to prepare intermediates of formula (II)
4-cyclohexylbenzaldehyde

This compound was synthesized according to a modified procedure of the literature (J. Org. Chem., 37, No. 24, (1972), 3972-3973). Cyclohexylbenzene (112.5 g, 0.702 mol) and hexamethylenetetramine (99.3 g, 0.708 mol) were mixed in TFA (375 mL). The mixture was stirred at 90 ° C. for 3 days under nitrogen. After cooling to room temperature, the mixture was poured into ice water (3600 mL) and stirred for 1 hour. The solution was neutralized with Na ₂ CO ₃ (2M solution in water) and extracted with DCM (2.5 L). The organic phase was dried (Na ₂ SO ₄ ) and the solvent removed in vacuo. The remaining oil was purified by fractional distillation to give the title compound (51 g, 39%).

¹ H NMR (CDCl ₃ ): δ 9.96 (s, 1H), 7.80 (d, 2H), 7.35 (d, 2H), 2.58 (m, 1H), 1.94-1.70 (m, 5H), 1.51-1.17 (m, 5H).

Starting materials for building blocks used to prepare intermediates of formula (II)
4- (2,2-Dimethylpropyl) benzaldehyde

This compound was synthesized analogously to a modified procedure of the literature (J. Med. Chem., 36, 23, (1993), 3700-3704).

(2,2-Dimethylpropyl) benzene (9,33 g, 63 mmol) was dissolved in dichloromethane (50 mL) and cooled to 0 ° C. with an ice bath. SnCl ₄ (28.66 g, 110 mmol) was added in one portion via syringe with vigorous stirring followed by dropwise addition of dichloromethyl methyl ether (7.24 g, 63 mmol) over 10 minutes. After 20 minutes, the ice bath was removed and the reaction was quenched by adding ice water (100 mL) to the mixture. The aqueous phase was discarded and the organic phase was washed with water (3 × 25 mL), 3N hydrochloric acid (3 × 25 mL), and saturated aqueous sodium chloride (2 × 25 mL). The organic phase was then treated with activated carbon, dried (magnesium sulfate), filtered and concentrated in vacuo. This gave the title compound. Yield 7.49 g (62%).

¹ H NMR (CDCl ₃ ): δ 0.94 (s, 9H), 2.57 (s, 2H), 7.28 (d, 2H), 7.80 (d, 2H), 9.98 (s, 1H).

Starting materials for building blocks used to prepare intermediates of formula (II) Indan-5-carbaldehyde

The title compound was prepared from indan and dichloromethyl methyl ether using a procedure similar to that described above and providing a 1: 2 mixture of indan-4-carbaldehyde and indan-5-carbaldehyde. This mixture was used for subsequent conversion to chalcone without further purification (building block 7). Data obtained only for the title compound, (major isomer)
¹ H NMR (DMSO-d ₆ ): δ 2.05 (q, 2H), 2.90 (m, 4H), 7.41 (d, 1H), 7.67 (d, 1H), 7.70 (s, 1H), 9.95 (s , 1H). HPLC-MS (method D): m / z = 147 (M + 1); R t = 3.53min.

Starting materials for building blocks used to prepare intermediates of formula (II)
4-Cyclohexyl-1-enyl-benzaldehyde

Magnesium scrap (14.6 g, 600 mmol) was placed in a dry four-necked flask. Dry THF (50 mL) and iodine crystals were added. A mixture of 2- (4-bromophenyl)-[1,3] -dioxolane (Tetrahedron, 57, No. 28, (2001), 5991-6002) (135 g, 589 mmol) in dry THF (200 mL) was slowly added. The reaction was started by adding. After the reaction started, the addition of 2- (4-bromophenyl)-[1,3] -dioxolane was continued at a rate where the temperature was maintained between 35-40 ° C. After completion of the addition, the mixture was stirred for 2 hours and then cooled to 5 ° C. with an ice bath. Cyclohexane (57.8 g, 580 mmol) was added dropwise while maintaining the temperature below 10 ° C. The mixture was stirred for 18 hours at room temperature and 2/3 of the THF was removed under vacuum. The residue was poured into a mixture of ammonium chloride (65 g) in ice water (1 liter) and extracted with ethyl acetate. The organic phase was washed with water, dried (magnesium sulfate), filtered and evaporated under vacuum. The residual oil was slurried in petroleum ether to give 48 g of 1- (4- [1,3] dioxolan-2-yl-phenyl) cyclohexanol as a solid. HPLC-MS (Method A): m / z = 231 (M + 1); R _t = 3.27 min.

  1- (4- [1,3] Dioxolan-2-yl-phenyl) cyclohexanol (45 g) and p-toluenesulfonic acid (3.4 g) in 300 mL of toluene were refluxed under Dean-Stark conditions for 3 hours. It was. After cooling, ethyl acetate and saturated sodium bicarbonate solution were added. The organic layer was washed twice with water, dried (magnesium sulfate), filtered and concentrated in vacuo. The residual oil was dissolved in glacial acetic acid (250 mL), 1M hydrochloric acid (25 mL) was added and the mixture was stirred at 50 ° C. for 2 h, after cooling, the mixture was concentrated in vacuo. The residual oil was partitioned between ethyl acetate and water. The organic phase was washed 3 times with water, dried (magnesium sulfate), filtered and concentrated in vacuo. The residual oil was evaporated under vacuum and the fraction boiling at 120-130 ° C. (0.2 mmHg) was collected to give 4.7 g of the title compound.

¹ H NMR (CDCl ₃ ): δ1.72 (m, 4H), 2.25 (m, 2H), 2.43 (m, 2H), 6.30 (m, 1H), 7.53 (d, 2H), 7.82 (d, 2H ), 9.98 (s, 1H).

Starting materials for building blocks used to prepare intermediates of formula (II)

  1- (3,5-Dichlorophenyl) ethanone 3,5-Dichlorobenzoic acid (19,10 g, 100 mmol) was dissolved in dry THF (165 mL) and cooled at 0 ° C. in an ice bath. With vigorous stirring, 138 mL (210 mmol) of methyllithium (1.6 M in diethyl ether) was added dropwise via syringe over 30 minutes. After 1 hour, the mixture was poured into ice water (500 mL). The aqueous phase was extracted with diethyl ether (4 × 50 mL). The combined organic phases were washed with saturated aqueous sodium bicarbonate (2 × 50 mL) and saturated aqueous sodium chloride (2 × 50 mL). The organic phase was dried (magnesium sulfate), filtered and the solvent removed in vacuo. This gave 17.06 g of the title compound containing 18% by weight of 2- (3,5-dichlorophenyl) propan-2-ol. This compound was used in the next step without further purification.

¹ H NMR (CDCl ₃ ): δ 2.62 (s, 3H), 7.92 (s, 2H), 7.94 (s, 1H).

Starting materials for building blocks used to prepare intermediates of formula (II)
1- (2,2,3,3-Tetrafluoro-2,3-dihydrobenzo [1,4] dioxin-6-yl) ethanone

  All equipment was dried in an oven at 120 ° C. for several hours. Magnesium chips (7.31 g, 0.30 mol) and diethyl ether (20 mL) were added in a dry three-necked 500 mL round bottom flask attached to a separatory funnel and condenser under a nitrogen atmosphere. With magnetic stirring, iodomethane (4.7 mL, 75 mmol) was added dropwise to the Mg to initiate the reaction. Iodomethane (14 mL, 0.22 mol) in diethyl ether (30 mL) was added slowly while maintaining reflux. After the addition was complete, the mixture was stirred for 1.5 hours. 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 at 80 ° C. for 1 hour without a condenser to remove 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 for 16 hours. The mixture was cooled in an ice bath, hydrochloric acid (6M, 150 mL) was carefully added and the mixture was then heated to reflux for 1.5 hours. After cooling, the mixture was partitioned between ethyl acetate and water and washed with aqueous sodium bicarbonate. The combined organic phases were dried (magnesium sulfate) and concentrated under vacuum. The residual oil was purified by chromatography on silica gel eluting with a mixture of ethyl acetate and heptane (2: 8). This gave the title compound (22g, 34%).

¹ H NMR (CDCl ₃ ): δ 7.80 (dd, 1H), 7.77 (d, 1H), 7.23 (d, 1H), 2.69 (s, 3H); HPLC-MS (Method A): m / z = 251 (M + 1); R _t = 4.27 min.

General procedure (A)
General procedure (A) for the liquid phase synthesis of building block compounds of general formula (II):

  This procedure will be described under the building block 1.

Building block 1 (general procedure (A))
3- (4-cyclohexylphenyl) -1- (4-trifluoromethylsulfanylphenyl) propenone

  4- (Trifluoromethylsulfanyl) acetophenone (2.34 g, 10.6 mmol) and 4-cyclohexylbenzaldehyde (2 g, 10.6 mmol) were mixed in ethanol (3 mL). NaOH (0.425 g, 14: 6 mmol) was dissolved in water (2 mL) and added to the mixture. The mixture was stirred at room temperature and a precipitate was observed after 10 minutes and additional ethanol (5 mL) was added with stirring for an additional 30 minutes. This mixture was poured into water (100 mL). The precipitate was filtered and dried. This crude product was pure enough for subsequent use without further purification (2.64 g, 64%). Alternatively, it can be recrystallized from heptane to obtain a pure product.

HPLC-MS (method A): m / z = 391 (M + 1); R t = 6.68min.

Building block 2 (general procedure (A))

  3- (4-Cyclohexyl-1-enylphenyl) -1- (4-trifluoromethoxyphenyl) propenone 4- (trifluoromethyloxy) acetophenone (5.18 g, 24.9 mmol) and 4-cyclohexyl-1-enylbenzaldehyde ( 4.63 g, 24.9 mmol) was mixed in ethanol (7 mL). NaOH (1.0 g, 25 mmol) was dissolved in water (5 mL) and added to the mixture. The mixture was stirred at room temperature, a precipitate was observed after 10 minutes, additional ethanol (10 mL) was added, and the mixture was stirred for an additional 30 minutes. This mixture was poured into water (100 mL). The precipitate was filtered and dried. This crude product was sufficiently pure for subsequent use without further purification (9.18 g, 99%). Alternatively, it can be recrystallized from heptane to obtain a pure product.

¹ H NMR (DMSO-d ₆ ): δ 1.60-1.68 (m, 2H), 1.72-1.80 (m, 2H), 2.23 (m, 2H), 2.40 (m, 2H), 6.35 (t, 1H) 7.50 (d, 2H), 7.58 (d, 2H), 7.77 (d, 1H), 7.86 (d, 2H), 7.93 (d, 1H), 8.30 (d, 2H); HPLC-MS (Method C) : M / z = 373 (M + 1); R _t = 8.90 min.

Building block 3 (general procedure (A))
3- (4-Cyclohexylphenyl) -1- (3,5-dichlorophenyl) propenone

Building block 4 (general procedure (A))
3-biphenyl-4-yl-1- (4-chlorophenyl) propenone

Building block 5 (general procedure (A))
3-biphenyl-4-yl-1-naphthalen-2-ylpropenone

Building block 6 (general procedure (A))
1- (4-cyclohexylphenyl) -3- (4-isopropylphenyl) propenone

Building block 7 (general procedure (A))
3-Indan-5-yl-1- (4-trifluoromethoxyphenyl) propenone

Building block 8 (general procedure (A))
3- [4- (2,2-Dimethylpropyl) phenyl] -1- (4-trifluoromethoxyphenyl) propenone

Building block 9 (general procedure (A))
1-Benzo [1,3] dioxol-5-yl-3- (4-cyclohexylphenyl) propenone

Building block 10 (general procedure (A))
3- (4-Cyclohexylphenyl) -1- (4-isopropylphenyl) propenone

Building block 11 (general procedure (A))
1,3-bis- (4-cyclohexylphenyl) propenone

Building block 12 (general procedure (A))
1- (4-Isobutylphenyl) -3- (4-trifluoromethoxyphenyl) propenone

Building block 13 (general procedure (A))
1- (4-Cyclopentylphenyl) -3- (4-trifluoromethoxyphenyl) propenone

Building block 14 (general procedure (A))
1-phenyl-3- (4-trifluoromethoxyphenyl) propenone

Building block 15 (general procedure (A))
1-p-Tolyl-3- (4-trifluoromethoxyphenyl) propenone

Building block 16 (general procedure (A))
1- (4-Methoxyphenyl) -3- (4-trifluoromethoxyphenyl) propenone

Building block 17 (general procedure (A))
3- (4-Cyclohexylphenyl) -1- (4-trifluoromethoxyphenyl) propenone

Building block 18 (general procedure (A))
3-biphenyl-4-yl-1- (4-trifluoromethoxyphenyl) propenone

Building block 19 (general procedure (A))
3-biphenyl-4-yl-1- (4-trifluoromethylsulfanylphenyl) propenone

Building block 20 (general procedure (A))
3-Biphenyl-4-yl-1- (2,2,3,3-tetrafluoro-2,3-dihydrobenzo [1,4] dioxin-6-yl) propenone

Building block 21 (general procedure (A))
3- (4-Cyclohexylphenyl) -1- (2,2,3,3-tetrafluoro-2,3-dihydrobenzo [1,4] dioxin-6-yl) propenone

Building block 22 (general procedure (A))
3- (4-Cyclohexylphenyl) -1- (3-trifluoromethoxyphenyl) propenone

Building block 23 (general procedure (A))
3- (4-tert-Butylphenyl) -1- (4-trifluoromethylsulfanylphenyl) propenone

Building block 24 (general procedure (A))
3-biphenyl-4-yl-1- (3-bromophenyl) propenone

Building block 25 (general procedure (A))
3-Biphenyl-4-yl-1- (3-trifluoromethylphenyl) propenone

Building block 26 (general procedure (A))
3- (4-Bromothiophen-2-yl) -1- (4-trifluoromethoxyphenyl) propenone

Building block 27 (general procedure (A))
1,3-bis- (4-trifluoromethoxyphenyl) propenone

Building block 28 (general procedure (A))
3- (4-tert-Butylphenyl) -1- (4-trifluoromethoxyphenyl) propenone

Building block 29 (general procedure (A))
3- (4-Phenoxyphenyl) -1- (4-trifluoromethoxyphenyl) propenone

Building block 30 (general procedure (A))
3- (3-phenoxyphenyl) -1- (4-trifluoromethoxyphenyl) propenone

Building block 31 (general procedure (A))
3- (4-Benzyloxyphenyl) -1- (4-trifluoromethoxyphenyl) propenone

Building block 32 (general procedure (A))
3- (4-Cyclohexylphenyl) -1- (3,4-difluorophenyl) propenone

Building block 33 (general procedure (A))
1- (4-sec-butylphenyl) -3- (3-phenoxyphenyl) propenone

Building block 34 (general procedure (A))
3- [3- (4-Chlorophenoxy) phenyl] -1- (5,6,7,8-tetrahydronaphthalen-2-yl) propenone

Building block 35 (general procedure (A))
3- (4-Benzyloxyphenyl) -1- (3-bromophenyl) propenone

Building block 36 (general procedure (A))
1-biphenyl-4-yl-3- (4-cyclohexylphenyl) propenone

Building block 37 (general procedure (A))
1- (2-Chlorophenyl) -3- (4-cyclohexylphenyl) propenone

Building block 38 (general procedure (A))
3- (4-cyclohexylphenyl) -1- (2-trifluoromethylphenyl) propenone

Building block 39 (general procedure (A))
1- (4-tert-Butylphenyl) -3- (4-cyclohexylphenyl) propenone

Building block 40 (general procedure (A))
3- (4-Cyclohexylphenyl) -1- (4-phenoxyphenyl) propenone

Building block 41 (general procedure (A))
3- (4-Cyclohexylphenyl) -1- (4-piperidin-1-ylphenyl) propenone

Building block 42 (general procedure (A))
3- (4-Trifluoromethoxyphenyl) -1- (4-trifluoromethylsulfanylphenyl) propenone

Building block 43 (general procedure (A))
1- (3-trifluoromethoxyphenyl) -3- (4-trifluoromethoxyphenyl) propenone

Building block 44 (general procedure (A))
1-3- (biphenyl-4-yl) -1- (4-cyclohexylphenyl) propenone

Building block 45 (general procedure (A))
1- (4-tert-Butylphenyl) -3- (4-trifluoromethoxyphenyl) propenone

Building block 46 (general procedure (A))
1- (2,2,3,3-Tetrafluoro-2,3-dihydrobenzo [1,4] dioxin-6-yl) -3- (4-trifluoromethoxyphenyl) propenone

Building block 47 (general procedure (A))
1- (4-Chlorophenyl) -3- (4-cyclohexylphenyl) propenone

Building block 48 (general procedure (A))
3- (4-Cyclohexylphenyl) -1- (5,6,7,8-tetrahydronaphthalen-2-yl) propenone

Building block 49 (general procedure (A))
1- (5,6,7,8-tetrahydronaphthalen-2-yl) -3- (4-trifluoromethoxyphenyl) propenone

Building block 50 (general procedure (A))
3- (4-Chlorophenyl) -1- (4-cyclohexylphenyl) propenone

Building block 51 (general procedure (A))
1-biphenyl-4-yl-3- (4-cyclohexylphenyl) propenone

Building block 52 (general procedure (A))
1- (4-cyclohexylphenyl) -3- (4-trifluoromethoxyphenyl) propenone

Building block 53 (general procedure (A))
1-Biphenyl-4-yl-3- (4-trifluoromethoxyphenyl) propenone

Building block 54 (general procedure (A))
1- (4-cyclohexylphenyl) -3- (3,5-dichlorophenyl) propenone

Building block 55 (general procedure (A))
3- (3-Bromophenyl) -1- (4-cyclohexylphenyl) propenone

Building block 56 (general procedure (A))
3- (4-Methylphenyl) -1- (4-chlorophenyl) propenone

This compound is known (Tet Lett. 39 (16), 2235, (1998)).

Building block 57 (general procedure (A))
1,3-bis- (4-chlorophenyl) propenone

This compound is known (Chem. Ber. 42, 1813, (1909)).

Building block 58 (general procedure (A))
3- (4-Cyclohexylphenyl) -1-indan-5-ylpropenone

Building block 59 (general procedure (A))
3- (4-Cyclohexylphenyl) -1- (4-isobutylphenyl) propenone

Building block 60 (general procedure (A))
3- (4-Cyclohexylphenyl) -1- (4-cyclopentylphenyl) propenone

Building block 4 (general procedure (A))
3- (4-Cyclohexylphenyl) -1-phenylpropenone

Building block 5 (general procedure (A))
3- (4-Cyclohexylphenyl) -1- (4-methylphenyl) propenone

Building block 6 (general procedure (A))
3- (4-Cyclohexylphenyl) -1- (4-methoxyphenyl) propenone

Building block 61 (general procedure (A))
1- (4-tert-Butylphenyl) -3- (4-trifluoromethoxyphenyl) propenone

4- (Trifluoromethoxy) benzaldehyde (16,5 g, 87 mmol) and 4-tert-butylacetophenone (15.3 g, 87 mmol) were dissolved in 99% ethanol (25 mL). To this solution was added sodium hydroxide (8N, 16.2 mL). The reaction mixture was stirred for 1 hour, diluted with water (100 mL), filtered after 2 hours and washed with water. The product was dried under vacuum and then suspended in ethanol (80 mL) and stirred at 20 ° C. for 1.5 hours. The mixture is placed in the refrigerator for 16 hours, the precipitated product is filtered off, washed with ice-cold 99% ethanol and dried to 11.5 g (38%) 1- (4-tert-butylphenyl) -3- (4-Trifluoromethoxyphenyl) propenone was obtained. HPLC-MS (method C): m / z = 349 (M + 1); R t = 7.10min.

Building block 62
1- (3,5-bis-trifluoromethylphenyl) -3- (4-cyclohexylphenyl) propenone

3 ′, 5′-bis (trifluoromethyl) acetophenone (9.3 g, 36.3 mmol) and 4-cyclohexylbenzaldehyde (6.83 g, 36.3 mmol) were dissolved in NMP (18 mL). Zinc (II) acetate (398 mg, 1.8 mmol) and 2,2′-bipyridine (283 mg, 1.81 mmol) were added and the mixture was heated at 100 ° C. under nitrogen for 16 hours. After cooling, the mixture was partitioned between heptane (250 mL) and water (250 mL). The organic phase is dried (NaSO ₄ ) and evaporated to dryness to give the crude material, which is evaporated to dryness to give the crude material, which can be recrystallized from heptane, pure title The compound was obtained as a solid. Yield: 5.8 g (38%).

HPLC-MS (method D): m / z = 427 (M + 1); R t = 6.71min.

General procedure (B)
General procedure (B) for solid phase synthesis of compounds of general formula (I ₅ ):

Wherein X, D, E, M, n and R ⁴ are as defined in formula (I) and the resin is a polystyrene resin loaded with a Wang-linker.

Step 1:
This reaction is known (Wang SJ, J. Am. Chem. Soc. 95, 1328, 1973) and generally in the presence of a catalyst such as N, N-4-dimethylaminopyridine, 2 to Wang with 4-10 molar excess of Fmoc-protected amino acid activated with 5 molar excess of diisopropylcarbodiimide, dicyclohexylcarbodiimide or 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride This is done by stirring a polystyrene resin loaded with a linker, such as a linker. The esterification is carried out in a solvent such as THF, dioxane, toluene, DCM, DMF, NMP or a mixture of two or more thereof. The reaction is carried out between 0 ° C. and 80 ° C., preferably between 20 ° C. and 40 ° C. When esterification is complete, excess reagent is filtered off. The resin was washed sequentially with the solvent used during the reaction, followed by methanol. The resin bound product can be further dried and analyzed.

Step 2:
The N-fluorenylmethylcarbonyl protecting group is removed by treatment with a 20% to 50% solution of a secondary amine such as piperidine in a polar solvent such as DMF or NMP using a resin bound derivative. (Carpino L., Han G., J. Org. Chem. 37, 3404, 1972). The reaction is carried out between 20 ° C. and 180 ° C., preferably between 20 ° C. and 40 ° C. When the reaction is complete, excess reagent is filtered off. The resin is washed successively with the solvent used in the reaction. The resulting resin bound intermediate is acylated with an acid. This acylation is known (The combinatorial index, Ed. Bunin BA, 1998, Acedemic press, p. 78) and is commonly used for side reaction inhibitors such as N-hydroxybenzotriazole. 2-5 molar excess of acid activated with 2-5 molar excess of diisopropyl-carbodiimide, dicyclohexyl-carbodiimide or 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride in the presence At the same time, the resin-bound intermediate is stirred. This reaction is carried out between 0 ° C. and 80 ° C., preferably between 20 ° C. and 40 ° C. When esterification is complete, excess reagent is filtered off. The resin is washed successively with the solvent used in the reaction followed by methanol. The resin bound product can be further dried and analyzed.

Step 3:
This reaction has not been previously reported on solid supports, but is a modification of the solution-based method (Stetter H., Krasselt JJ Heterocyclic. Chem. 14,573, 1977). Addition of aldehydes to the activated double bond is generally accomplished by potassium or sodium cyanide, or 3,4-dimethyl-5- (2-hydroxyethyl) thiazolium iodide, 3-benzyl-5- (2 -Hydroxyethyl) -4-methyl-1,3-thiazolium, thiazolium salts such as 3-ethyl-5- (2-hydroxyethyl) -4-methyl-1,3-thiazolium bromide, or vitamin B ₁ In the presence of such a catalyst by stirring the aldehyde with a compound containing an activated double bond such as a substituted propenone. When a thiazolium salt is used as a catalyst, a non-nucleophilic amine base such as triethylamine, N, N-diisopropylethylamine or DBU is added. This addition is performed in a solvent such as dioxane, DMSO, NMP or DMF, or a mixture of two or more thereof. This reaction is carried out between 50 ° C. and 120 ° C., preferably between 50 ° C. and 80 ° C. When the reaction is complete, excess reagent is filtered off. The resin is washed successively with the solvent used in the reaction followed by methanol. The resin bound product can be further dried and analyzed.

Step 4:
This reaction is known (The combinatorial index, Ed. Bunin BA, 1998, Acedemic press, p. 21) and generally the resin bound intermediate obtained in step 3 is stirred with a 50-95% solution of TFA. Is done. The final cleavage is performed in a solvent such as THF, DCM, 1,2-dichloroethane, 1,3-dichloropropane, toluene or mixtures thereof. This reaction is carried out between 0 ° C. and 80 ° C., preferably between 20 ° C. and 40 ° C. When the reaction is complete, the product is filtered off. The resin is washed continuously with DCM. Collect product and wash liquor. The solvent is removed and the product is dried under vacuum.

  The above procedure is illustrated in the following example.

Example 1 (General Procedure (B)) 3- {4- [2-Biphenyl-4-yl-4-oxo-4- (4-trifluoromethoxyphenyl) butyryl] benzoylamino} propionic acid

Step 1 and Step 2:
Resin-bound 3- (4-formylbenzoylamino) propionic acid
A 3- (4-formylbenzoylamino) propionic acid resin linkage (loading approximately 0.2-0.8 mmol / g) to the Wang resin was synthesized according to the procedure described in WO 00/69810.

Step 3 and Step 4:
Preparation of 3- [4- {2-biphenyl-4-yl-4-oxo-4- (4-trifluoromethoxyphenyl) -butyryl] benzoylamino] propionic acid Above resin bound 3- (4-formylbenzoylamino) Propionic acid (496 mg resin) was suspended in NMP (10 mL). 3,4-Dimethyl-5- (2-hydroxyethyl) thiazolium iodide (432 mg, 1.5 mmol), 3-biphenyl-4-yl-1- (4-trifluoromethoxyphenyl) propenone (1.05 g, 2.7 mmol) And DBU (225 μL, 1.50 mmol) were added and the suspension was shaken at 70 ° C. for 16 hours. The resin was separated by filtration and washed with DMF (3 × 10 mL), ethanol (2 × 10 mL), DCM (10 × 10 mL). Resin-bound 3- {4- [2-biphenyl-4-yl-4-oxo-4- (4-trifluoromethoxyphenyl) -butyryl] benzoylamino} propionic acid with 50% TFA in DCM (10 mL) For 0.5 hour at 25 ° C. The mixture was filtered and the resin was washed with DCM (10 mL). The combined filtrates were concentrated in vacuo to give an oil that was purified on a silica gel column eluted with DCM / methanol / acetic acid (95: 4: 1) to give the title compound.

  The following examples were prepared as described above.

Example 2 (General Procedure (B)) 3- {4- [2-Biphenyl-4-yl-4-oxo-4- (3-trifluoromethylphenyl) butyryl] benzoylamino} propionic acid

Example 3 (general procedure (B)) 3- {4- [2- (4-cyclohexylphenyl) -4-oxo-4- (4-trifluoromethylsulfanylphenyl) butyryl] benzoylamino} propionic acid

Example 4 (General procedure (B)) 3- {4- [4- (3,5-bis-trifluoromethylphenyl) -2- (4-cyclohexylphenyl) -4-oxobutyryl] benzoylamino} propionic acid

Example 5 (General Procedure (B)) 3- {4- [2-Biphenyl-4-yl-4- (3-bromophenyl) -4-oxobutyryl] benzoylamino} propionic acid

Example 6 (General Procedure (B)) 3- {4- [2-Biphenyl-4-yl-4-oxo-4- (2,2,3,3-tetrafluoro-2,3-dihydrobenzo [1, 4] Dioxin-6-yl) butyryl] benzoylamino} propionic acid

Example 7 (general procedure (B)) 3- {4- [2- (4-cyclohexylphenyl) -4-oxo-4- (2,2,3,3-tetrafluoro-2,3-dihydrobenzo [1 , 4] Dioxin-6-yl) butyryl] benzoylamino} propionic acid

Example 8 (General Procedure (B)) 3- {4- [2-Biphenyl-4-yl-4- (3,5-bis-trifluoromethylphenyl) -4-oxobutyryl] benzoylamino} propionic acid

Example 9 (General Procedure (B)) 3- {4- [2- (4-tert-Butylphenyl) -4-oxo-4- (4-trifluoromethylsulfanylphenyl) butyryl] benzoylamino} propionic acid

Example 10 (General Procedure (B)) 3- {4- [2- (4-Bromothiophen-2-yl) -4- (3,4-dichlorophenyl) -4-oxobutyryl] benzoylamino} propionic acid

Example 11 (General Procedure (B)) 3- {4- [2- (4-Bromothiophen-2-yl) -4- (4-chloro-3-methylphenyl) -4-oxobutyryl] benzoylamino} propionic acid

Example 12 (General Procedure (B)) 3- {4- [2- (4-tert-Butylphenyl) -4-oxo-4- (3-trifluoromethylphenyl) butyryl] benzoylamino} propionic acid

Example 13 (General Procedure (B)) 3- (4- [2-Biphenyl-4-yl-4-oxo-4- (4-trifluoromethylsulfanylphenyl) butyryl] benzoylamino} propionic acid

Example 14 (General Procedure (B)) 3- {4- [2- (4-Benzyloxyphenyl) -4-oxo-4- (4-trifluoromethoxyphenyl) butyryl] benzoylamino} propionic acid

Example 15 (general procedure (B)) 3- {4- [4-oxo-2- (4-phenoxyphenyl) -4- (4-trifluoromethoxyphenyl) butyryl] benzoylamino} propionic acid

Example 16 (General Procedure (B)) 3- {4- [2- (4-tert-Butylphenyl) -4-oxo-4- (4-trifluoromethoxyphenyl) butyryl] benzoylamino} propionic acid

Example 17 (General Procedure (B)) 3- {4- [4-Oxo-2- (3-phenoxyphenyl) -4- (4-trifluoromethoxyphenyl) butyryl] benzoylamino} propionic acid

Example 18 (General Procedure (B)) 3- {4- [2-Biphenyl-4-yl-4- (4-chlorophenyl) -4-oxobutyryl] benzoylamino} propionic acid

Example 19 (General procedure (B)) 3- [4- (2-Biphenyl-4-yl-4-naphthalen-2-yl-4-oxobutyryl) benzoylamino] propionic acid

Example 20 (General Procedure (B)) 3- {4- [4- (4-sec-Butylphenyl) -4-oxo-2- (3-phenoxyphenyl) butyryl] benzoylamino} propionic acid

Example 21 (General procedure (B)) 3- {4- [2- [3- (4-Chlorophenoxy) phenyl] -4-oxo-4- (5,6,7,8-tetrahydronaphthalen-2-yl ) Butyryl] benzoylamino} propionic acid

Example 22 (General procedure (B)) 3- {4- [2- (4-Benzyloxyphenyl) -4- (3-bromophenyl) -4-oxobutyryl] benzoylamino} propionic acid

Example 23 (general procedure (B)) 3- {4- [4- (4-cyclohexylphenyl) -2- (4-isopropylphenyl) -4-oxobutyryl] benzoylamino} propionic acid

Example 24 (General Procedure (B)) 3- {4- [4-Biphenyl-4-yl-2- (4-cyclohexylphenyl) -4-oxobutyryl] benzoylamino} propionic acid

Example 25 (General Procedure (B)) 3- {4- [4- (2-Chlorophenyl) -2- (4-cyclohexylphenyl) -4-oxobutyryl] benzoylamino} propionic acid

Example 26 (General Procedure (B)) 3- {4- [2- (4-cyclohexylphenyl) -4-oxo-4- (2-trifluoromethylphenyl) butyryl] benzoylamino} propionic acid

Example 27 (General procedure (B)) 3- {4- [4- (4-tert-Butylphenyl) -2- (4-cyclohexylphenyl) -4-oxobutyryl] benzoylamino} propionic acid

Example 28 (General procedure (B)) 3- {4- [2- (4-cyclohexylphenyl) -4-oxo-4- (4-piperidin-1-ylphenyl) butyryl] benzoylamino} propionic acid

Example 29 (general procedure (B)) 3- {4- [2- (4-cyclohexylphenyl) -4-oxo-4- (4-phenoxyphenyl) butyryl] benzoylamino} propionic acid

Example 30 (General procedure (B)) 3- {4- [4- (4-cyclohexylphenyl) -4-oxo-2- (4-trifluoromethoxyphenyl) butyryl] benzoylamino} propionic acid

Example 31 (General Procedure (B)) 3- {4- [4-Biphenyl-4-yl-4-oxo-2- (4-trifluoromethoxyphenyl) butyryl] benzoylamino} propionic acid

Example 32 (General procedure (B)) 3- {4- [4- (4-cyclohexylphenyl) -2- (3,5-dichlorophenyl) -4-oxobutyryl] benzoylamino} propionic acid

Example 33 (General Procedure (B)) 3- {4- [2- (3-Bromophenyl) -4- (4-cyclohexylphenyl) -4-oxobutyryl] benzoylamino} propionic acid

Example 34 (General Procedure (B)) 3- {4- [4-Benzo [1,3] dioxol-5-yl-2- (4-cyclohexylphenyl) -4-oxobutyryl] benzoylamino} propionic acid

General procedure (C)
General procedure (C) for the solid phase synthesis of compounds of general formula (I ₄ ):

Where X, D, E, M, n and R ⁴ are as defined in formula (I) and the resin is a polystyrene resin loaded with a Wang-linker. This procedure is illustrated in the following example.

Example 35 (General Procedure (C)) (Z) -3- {4- [2- (4-cyclohexylphenyl) -4-oxo-4- (4-trifluoromethoxyphenyl) but-2-enoyl] benzoylamino } Propionic acid

Steps 1 to 3: Preparation of resin bound 3- {4- [2- (4-cyclohexylphenyl) -4-oxo-4- (4-trifluoromethoxyphenyl) butyryl] benzoylamino} propionic acid. Synthesized according to (B).

Step 4 and Step 5: Preparation of 3- {4- [2- (4-cyclohexylphenyl) -4-oxo-4- (4-trifluoromethoxyphenyl) but-2-enoyl] benzoylamino} propionic acid Bound 3- {4- [2- (4-cyclohexylphenyl) -4-oxo-4- (4-trifluoromethoxyphenyl) butyryl] benzoylamino} propionic acid (500 mg resin) suspended in THF (10 mL) And iodine crystals (344 mg, 1.35 mmol) and DBU (225 μL) were added. This suspension was shaken at room temperature for 3.5 hours. The resin was isolated by filtration and washed with THF (1 × 10 mL), sodium pyrosulfate solution (2% in water) (1 × 10 mL), THF (2 × 10 mL), DCM (10 × 10 mL). This resin-bound 3- {4- [2- (4-cyclohexylphenyl) -4-oxo-4- (4-trifluoromethoxyphenylbut-2-enoyl] benzoylamino} propionic acid was dissolved in DCM (10 mL). Treated with 50% TFA for 0.5 h at 25 ° C. Filtered the mixture and washed the resin with DCM (10 mL) Combined filtrates were concentrated in vacuo to give an oil that was DCM. Purify on a silica gel column eluting with methanol / methanol / acetic acid (95: 4: 1) to give 3- {4- [2- (4-cyclohexylphenyl) -4-oxo-4- (4-trifluoromethoxyphenyl) A mixture of E and Z of but-2-enoyl] benzoylamino} propionic acid was obtained.

¹ H-NMR (CDCl ₃ ): δ 8.03-7.92 (m, 3H), 7.88-7.77 (m, 3H), 7.58-7.47 (m, 1H), 7.15 (t, 3H), 7.01 (d, 1H ; 6.90-6.80 (m, 2H), 3.73 (q, 2H), 2.72 (t, 2H), 2.37 (m, 1H), 1.78-1.66 (m, 5H), 1.42-1.23 (m, 5H); HPLC-MS (method A): m / z = 594 (M + 1); R t = 5.44min.

Step 6: Preparation of (Z) -3- {4- [2- (4-cyclohexylphenyl) -4-oxo-4- (4-trifluoromethoxyphenyl) -but-2-enoyl] benzoylamino} propionic acid
Rearrangement of the E and Z mixture to the Z-isomer was performed by a modification of the literature procedure (J. Am. Chem. Soc., 75, 5997-6002,1953). 3- {4- [2- (4-Cyclohexylphenyl) -4-oxo-4- (4-trifluoromethoxyphenyl) but-2-enoyl] benzoylamino} propionic acid (155 mg, 0.26 mmol) E and Z The mixture was dissolved in toluene (15 mL), concentrated HCl (37%, 3 drops) was added and the mixture was heated to reflux for 1 hour. The solvent is removed by evaporation to give pure 3- {4- [2- (4-cyclohexylphenyl) -4-oxo-4- (4-trifluoromethoxyphenyl) but-2-enoyl] benzoylamino} propionic acid The Z isomer of was obtained.

¹ H-NMR (CDCl ₃ ): δ 8.03 (d, 4H), 7.79 (d, 2H), 7.57 (s, 1H), 7.48 (d, 2H), 7.30 (d, 2H); 7.24 (d, 2H), 6.84 (t, 1H), 3.71 (q, 2H), 2.70 (t, 2H), 2.52 (m, 1H), 1.90-1.70 (m, 5H), 1.45-1.17 (m, 5H); HPLC -MS (method A): m / z = 594 (M + 1); R t = 5.37min.

_{Microanalysis: C 33 H 30 F 3 NO} 6, calculated for _{0.25H 2 O: C, 66.27%} ; H, 5.14%; N, 2.34%. Found: C, 66.33%; H, 5.20%; N, 2.57%.

Example 36 (General procedure (C)) (Z) -3- {4- [2- (4-cyclohexylphenyl) -4-oxo-4- (2,2,3,3-tetrafluoro-2, 3-Dihydrobenzo [1,4] dioxin-6-yl) but-2-enoyl] benzoylamino} propionic acid

E and Z mixture data obtained from step 5 in general procedure (C):
¹ H-NMR (CDCl ₃ ): δ 8.01-7.92 (m, 2H), 7.83-7.45 (m, 6H), 7.26-7.00 (m, 3H), 6.84 (br t, 1H), 3.71 (q, 2H), 2.70 (q, 2H), 2.52 (m, 1H), 1.88-1.67 (m, 5H), 1.45-1.17 (m, 5H).

Title compound data:
¹ H NMR (CDCl ₃ ): δ 7.98 (brd, 2H), 7.88-7.70 (m, 4H), 7.50 (t, 3H), 7.18 (d, 1H), 6.84 (br s, 1H), 3.71 ( br s, 2H), 2.70 (br s, 2H), 2.52 (m, 1H), 1.90-1.70 (m, 5H), 1.45-1.15 (m, 5H).

Example 37 (General Procedure (C)) (Z) -3- {4- [4- (3,5-bis-trifluoromethylphenyl) -2- (4-cyclohexylphenyl) -4-oxobut-2-enoyl ] Benzoylamino} propionic acid

Example 38 (General Procedure (C)) (Z) -3- {4- [4- (3,5-bis (trifluoromethyl) phenyl) -2- [2,2 '] bithiophenyl-5-yl-4 -Oxobut-2-enoyl] benzoylamino} propionic acid

Example 39 (General Procedure (C)) (Z) -3- {4- [2- (4-Bromothiophen-2-yl) -4-oxo-4- (4-trifluoromethoxyphenyl) but-2- Enoyl] benzoylamino} propionic acid

Example 40 (General procedure (C)) (Z) -3- {4- [2- (4-cyclohexylphenyl) -4-oxo-4- (3-trifluoromethoxyphenyl) but-2-enoyl] benzoylamino } Propionic acid

Example 41 (General Procedure (C)) (Z) -3- {4- [2- (4-cyclohexylphenyl) -4-oxo-4- (4-trifluoromethylsulfanylphenyl) but-2-enoyl] benzoyl Amino} propionic acid

Example 42 (General Procedure (C)) (Z) -3- {4- [4-Biphenyl-4-yl-2- (4-cyclohexylphenyl) -4-oxobut-2-enoyl] benzoylamino} propionic acid

Example 43 (General Procedure (C)) (Z) -3- {4- [4- (2-Chlorophenyl) -2- (4-cyclohexylphenyl) -4-oxobut-2-enoyl] benzoylamino} propionic acid

Example 44 (General procedure (C)) (Z) -3- {4- [2- (4-cyclohexylphenyl) -4-oxo-4- (2-trifluoromethylphenyl) but-2-enoyl] benzoylamino } Propionic acid

Example 45 (General Procedure (C)) (Z) -3- {4- [4- (4-tert-Butylphenyl) -2- (4-cyclohexylphenyl) -4-oxobut-2-enoyl] benzoylamino} Propionic acid

Example 46 (General Procedure (C)) (Z) -3- {4- (2- (4-cyclohexylphenyl) -4-oxo-4- (4-phenoxyphenyl) but-2-enoyl] benzoylamino} propion acid

Example 47 (General Procedure (C)) (Z) -3- {4- [2- (4-tert-Butyl] phenyl) -4-oxo-4- (4-trifluoromethoxyphenyl) but-2-enoyl ] Benzoylamino} propionic acid

Example 48 (General Procedure (C)) (Z) -3- {4- [4-Oxo-2- (4-phenoxyphenyl) -4- (4-trifluoromethoxyphenyl) but-2-enoyl] benzoylamino } Propionic acid

Example 49 (General Procedure (C)) (Z) -3- {4- [4-Oxo-2- (3-phenoxyphenyl) -4- (4-trifluoromethoxyphenyl) but-2-enoyl] benzoylamino } Propionic acid

Example 50 (General Procedure (C)) (Z) -3- {4- [2- (4-Benzyloxyphenyl) -4-oxo-4- (4-trifluoromethoxyphenyl) but-2-enoyl] benzoyl Amino} propionic acid

Example 51 (General Procedure (C)) (Z) -3- {4- [4-Oxo-2,4-bis- (4-trifluoromethoxyphenyl) but-2-enoyl] benzoylamino} propionic acid

Example 52 (General Procedure (C)) (Z) -3- {4- [2- (4-cyclohexylphenyl) -4- (3,4-difluorophenyl) -4-oxobut-2-enoyl] benzoylamino} Propionic acid

Example 53 (General Procedure (C)) (Z) -3- {4- [2-Biphenyl-4-yl-4-oxo-4- (4-trifluoromethoxyphenyl) but-2-enoyl] benzoylamino} Propionic acid

Example 54 (General Procedure (C)) (Z) -3- {4- [2-Biphenyl-4-yl-4-oxo-4- (2,2,3,3-tetrafluoro-2,3-dihydro Benzo [1,4] dioxin-6-yl) but-2-enoyl] benzoylamino} propionic acid

Example 55 (General Procedure (C)) (Z) -3-4- [4- (4-cyclohexylphenyl) -4-oxo-2- (4-trifluoromethoxyphenyl) but-2-enoyl] benzoylamino} Propionic acid

Example 56 (General Procedure (C)) (Z) 3- {4- [4-Benzo [1,3] dioxol-5-yl-2- (4-cyclohexylphenyl) -4-oxobut-2-enoyl] benzoyl Amino} propionic acid

Example 57 (General Procedure (C)) (Z) -3- {4- [2- (4-Cyclohexylphenyl) -4- (4-isopropylphenyl) -4-oxobut-2-enoyl] benzoylamino} propionic acid

Example 58 (General Procedure (C)) (Z) -3- {4- [2,4-bis- (4-cyclohexylphenyl) -4-oxobut-2-enoyl] benzoylamino} propionic acid

Example 59 (General Procedure (C)) (Z) -3- {4- [2- (4-cyclohexylphenyl) -4- (4-dichlorophenyl) -4-oxobut-2-enoyl] benzoylamino} propionic acid

Example 60 (General Procedure (C)) (Z) -3- {4- [4- (4-Isobutylphenyl) -4-oxo-2- (4-trifluoromethoxyphenyl) but-2-enoyl] benzoylamino } Propionic acid

Example 61 (General Procedure (C)) (Z) -3- {4- [4- (4-Cyclopentylphenyl) -4-oxo-2- (4-trifluoromethoxyphenyl) but-2-enoyl] benzoylamino } Propionic acid

Example 62 (General Procedure (C)) (Z) -3- {4- [4-Oxo-4-phenyl-2- (4-trifluoromethoxyphenyl) but-2-enoyl] benzoylamino} propionic acid

Example 63 (General Procedure (C)) (Z) -3- {4- [4-Oxo-4-p-tolyl-2- (4-trifluoromethoxyphenyl) but-2-enoyl] benzoylamino} propionic acid

Example 64 (General Procedure (C)) (Z) -3- {4- [4- (4-Methoxyphenyl) -4-oxo-2- (4-trifluoromethoxyphenyl) but-2-enoyl] benzoylamino } Propionic acid

Example 65 (General Procedure (C)) (Z) -3- {4- [2- [4- (2,2-Dimethylpropyl) phenyl] -4-oxo-4- (4-trifluoromethoxyphenyl) but -2-enoyl] benzoylamino} propionic acid

Example 66 (General Procedure (C)) (Z) -3- {4- [2-Indan-5-yl-4-oxo-4- (4-trifluoromethoxyphenyl) but-2-enoyl] benzoylamino} Propionic acid

Example 67 (General Procedure (C)) (Z) -3- {4- [2,4-biphenyl-4-yl-4- (4-chlorophenyl) -4-oxobut-2-enoyl] benzoylamino} propionic acid

Example 68 (General Procedure (C)) (Z) -3- [4- (2-Biphenyl-4-yl-4-naphthalen-2-yl-4-oxobut-2-enoyl) benzoylamino] propionic acid

Example 69 (General Procedure (C)) (Z) -3- {4- [4- (4-cyclohexylphenyl) -2- (4-isopropylphenyl) -4-oxobut-2-enoyl] benzoylamino} propionic acid

Example 70 (General procedure (C)) (Z) -3- {4- [4-oxo-2- (4-trifluoromethoxyphenyl) -4- (4-trifluoromethylsulfanylphenyl) but-2-enoyl ] Benzoylamino} propionic acid

Example 71 (General Procedure (C)) (Z) -3- {4- [4-Oxo-2,4-bis-trifluoromethoxyphenyl) but-2-enoyl] benzoylamino} propionic acid

Example 72 (General Procedure (C)) (Z) -3- {4- [4-Oxo-4- (3-trifluoromethoxyphenyl) -2- (4-trifluoromethoxyphenyl) but-2-enoyl] Benzoylamino} propionic acid

Example 73 (General Procedure (C)) (Z) -3- {4- [2-Biphenyl-4-yl-4- (4-cyclohexylphenyl) -4-oxobut-2-enoyl] benzoylamino} propionic acid

Example 74 (General Procedure (C)) (Z) -3- {4- [2-Biphenyl-4-yl-4-oxo-4- (4-trifluoromethoxyphenyl) but-2-enoyl] benzoylamino} Propionic acid

Example 75 (General Procedure (C)) (Z)-(3- {4- [4-Biphenyl-4-yl-4-oxo-2- (4-trifluoromethoxyphenyl) but-2-enoyl] benzoylamino } Propionic acid

Example 76 (Z) -3- {4- [2- (4-Cyclohexyl-1-enylphenyl) -4-oxo-4- (4-trifluoromethoxyphenyl) but-2-enoyl] benzoylamino} propionic acid

This compound was prepared according to the general procedure (B) with a modification (step 3) that the resin was shaken at 70 ° C. for 3 days prior to cleavage. This gave an oxidation product.

¹ H-NMR (CDCl ₃ ): δ 1.60-1.74 (m, 2H), 1.75-1.83 (m, 2H), 2.18-2.27 (m, 2H), 2.37-2.43 (m, 2H), 2.68-2.75 (t, 2H), 3.68-3.78 (q, 2H); 6.24 (t, 1H), 6.83 (t, 1H), 7.30 (d, 2H), 7.42 (d, 2H); 7.50 (d, 2H), 7.61 (s, 1H); 7.80 (d, 2H), 8.01 (dd, 4H); HPLC-MS ( method C): m / z = 592 (M + 1); R t = 7.60min.

Example 77 (General Procedure (C)) (Z) -3- {4- [4- (4-tert-Butylphenyl) -4-oxo-2- (4-trifluoromethoxyphenyl) but-2-enoyl] Benzoylamino} propionic acid

Example 78 (General procedure (C)) (Z) -3- {4- [4-oxo-4- (2,2,3,3-tetrafluoro-2,3-dihydrobenzo [1,4] dioxin- 6-yl) -2- (4-trifluoromethoxy-phenyl) but-2-enoyl] benzoylamino} propionic acid

Example 79 (General Procedure (C)) (Z) -3- {4- [4- (4-Chlorophenyl) -2- (4-cyclohexylphenyl) -4-oxobut-2-enoyl] benzoylamino} propionic acid

Example 80 (General procedure (C)) (Z) -3- {4- [2- (4-cyclohexylphenyl) -4-oxo-4- (5,6,7,8-tetrahydronaphthalen-2-yl) But-2-enoyl] benzoylamino} propionic acid

Example 81 (General Procedure (C)) (Z) -3- {4- [4-Oxo-4- (5,6,7,8-tetrahydronaphthalen-2-yl) -2- (4-trifluoromethoxy) Phenyl) but-2-enoyl] benzoylamino} propionic acid

Example 82 (General Procedure (C)) (Z) -3- {4- [2- (4-Chlorophenyl) -4- (4-cyclohexylphenyl) -4-oxobut-2-enoyl] benzoylamino} propionic acid

Example 83 (General Procedure (C)) (Z) -3- {4- [4- (4-Chlorophenyl) -4-oxo-2-p-tolylbut-2-enoyl] benzoylamino} propionic acid

Example 84 (General Procedure (C)) (Z) -3- {4- [2,4-bis- (4-Chlorophenyl) -4-oxobut-2-enoyl] benzoylamino} propionic acid

Example 85 (General Procedure (C)) (Z) 3- {4- [2- (4-cyclohexylphenyl) -4-indan-5-yl-4-oxobut-2-enoyl] benzoylamino} propionic acid

Example 86 (General Procedure (C)) (Z) 3- {4- [2- (4-cyclohexylphenyl) -4- (4-isobutylphenyl) -4-oxobut-2-enoyl] benzoylamino} propionic acid

Example 87 (General Procedure (C)) (Z) 3- {4- [2- (4-cyclohexylphenyl) -4- (4-cyclopentylphenyl) -4-oxobut-2-enoyl] benzoylamino} propionic acid

Example 88 (General procedure (C)) (Z) 3- {4- [2- (4-cyclohexylphenyl) -4-oxo-4-phenylbut-2-enoyl] benzoylamino} propionic acid

Example 89 (General Procedure (C)) (Z) 3- {4- [2- (4-cyclohexylphenyl) -4-oxo-4-p-tolylbut-2-enoyl] benzoylamino} propionic acid

Example 90 (General Procedure (C)) (Z) 3- {4- [2- (4-cyclohexylphenyl) -4- (4-methoxyphenyl) -4-oxobut-2-enoyl] benzoylamino} propionic acid

Example 91 (E) -3- {4- [2- (4-cyclohexylphenyl) -4-oxo-4- (4-trifluoromethoxyphenyl) but-2-enoyl] benzoylamino} propionic acid

A mixture of E and Z of 3- {4- [2- (4-cyclohexylphenyl) -4-oxo-4- (4-trifluoromethoxyphenyl) but-2-enoyl] benzoylamino} propionic acid was prepared according to the general procedure Prepared as described in steps 1-5 of (C). The mixture was separated by HPLC (chiralcel OD, 25 × 2 cm, eluting with isopropanol: heptane: trifluoroacetic acid (20: 80: 0.1), 6 mL / min) to give the pure E-isomer.

¹ H-NMR (CDCl ₃ ): δ 1.66-2.05 (m, 5H), 2.41 (m, 1H), 2.51 (m, 2H), 3.47 (q, 2H), 7.12 (d, 4H), 7.44 ( d, 2H), 7.96-8.01 (m, 6H), 8.72 (t, 1H).

General procedure (D)
General procedure (D) for the liquid phase synthesis of compounds of general formula (I ₃ ):

This procedure is illustrated in the following example:
Example 92 (General Procedure (D))
4- [2-Biphenyl-4-yl-4-oxo-4- (3-trifluoromethylphenyl) butyryl] -N- (2H-tetrazol-5-yl) benzamide

  4-Formyl-N- (2H-tetrazol-5-yl) benzamide (128 mg) (synthesis difficult to follow the procedure described in WO / 00169810), 3-biphenyl-4-yl-1- (3-trifluoromethylphenyl) ) Propenone (223 mg) and 3,4-dimethyl-5- (2-hydroxyethyl) thiazolium iodide (89 mg) were dissolved in dry DMF (2.2 mL). Triethylamine (0.180 mL) was added and the mixture was stirred at 70 ° C. for 3 days under nitrogen. The reaction mixture was filtered through a silica gel column eluting with DCM / methanol / acetic acid (90: 9: 1) and the solvent was removed by evaporation to give an oil. The oil was washed with boiling heptane (4 mL) to remove unreacted 3-biphenyl-4-yl-1- (3-trifluoromethylphenyl) propenone and the remaining material was DCM. Purification on a column on silica gel eluting with / methanol / acetic acid (95: 4: 1) gave the title compound (30 mg, 9%).

¹ H-NMR (CDCl ₃ ): δ12.8 (br s, 1H), 8.38 (d, 2H), 8.30 (s, 1H), 8.26 (d, 2H), 8.18 (d, 1H), 7.83 (d , 1H), 7.67-7.30 (m, 11H); 5.41 (dd, 1H), 4.30 (dd, 1H), 3.42 (dd, 1H); HPLC-MS (Method A): m / z = 570 (M + 1), R _t = 5.12 min.

General procedure (E)
General procedure (E) for the solution phase synthesis of compounds of general formula (I ₅ ):

Wherein X, D, E, M, n and R ⁴ are as defined in formula (I) and Pg is a standard such as methyl, ethyl, propyl, isopropyl, tert-butyl or benzyl It is an acid protecting group. This procedure is illustrated in the following example.

Step 1:
This reaction is known and was previously described in WO 00/69810. Acylation of protected amino acids is generally done with diisopropyl-carbodiimide, dicyclohexylcarbodiimide or 1- [3- (dimethylamino) -propyl] -3-ethylcarbodiimide hydrochloride, optionally in the presence of side reaction inhibitors Undertaken by activating the carboxylic acid. The activated carboxylic acid is then added to the protected amino acid (protected, eg, methyl, ethyl, propyl, isopropyl, tert-butyl or benzyl ester). If the protected amino acid is an ammonium salt, a non-nucleophilic base such as triethylamine or diisopropylethylamine is added. Acylation is carried out in a solvent such as THF, dioxane, toluene, DCM, DMF, NMP or a mixture of two or more thereof. The reaction is generally carried out between 0 ° C. and 80 ° C., preferably 20 ° C. to 40 ° C. The product can be obtained by work-up procedures known to those skilled in the art.

Step 2:
This reaction is known (Stetter H., Krasselt JJ Heterocyclic. Chem. 14,573, 1977). Addition of aldehydes to the activated double bond is generally accomplished by cyanide or 3,4-dimethyl-5- (2-hydroxyethyl) thiazolium iodide, 3-benzyl-5- (2- Hydroxyethyl) -4-methyl-1,3-thiazolium, thiazolium salts such as 3-ethyl-5- (2-hydroxyethyl) -4-methyl-1,3-thiazolium bromide, or vitamin B ₁ By stirring with a compound containing an activated dobbelt bond, such as a substituted propenone, in the presence of a suitable catalyst. When thiazilium salt is used as the catalyst, a non-nucleophilic amine base such as triethylamine or DBU is used as the catalyst. The addition is performed in a solvent such as ethanol, methanol, 1-propanol, 2-propanol, dioxane, DMSO, NMP or DMF, or a mixture of two or more thereof. The reaction is carried out between 50 ° C. and 120 ° C., preferably between 50 ° C. and 80 ° C. The product can be obtained by work-up procedures known to those skilled in the art.

  Step 3: Removal of standard acid protecting groups depends on the nature of the protecting group, but is generally described (Protective Groups in Organic Chemistry. Greene T.W., Wuts P.G.M. 1999, Wiley-lnterscience, p. 377). This procedure is illustrated in the following example.

Example 93 (General Procedure (E)) 3- {4- [4- (4-tert-Butylphenyl)-(4-cyclohexylphenyl) -4-oxobutyryl] benzoylamino} -2R-hydroxypropionic acid

Step 1: 3- (4-Formylbenzoylamino) -2R-hydroxypropionic acid methyl ester
4-Formylbenzoic acid (7.5 g, 50 mmol) was dissolved in DMF (80 mL) in a 500 mL round bottom flask. 1-Hydroxybenzotriazole hydrate (8.11 g, 60 mmol, 1.2 eq) and N ′-(3-dimethylaminopropyl) -N-ethylcarbodiimide hydrochloride (9.59 g, 50 mmol, 1 eq) were added. The solution is stirred under N ₂ for 3/4 h, R-isoserine methyl ester hydrochloride (prepared as described in WO 02/00612, 11.67 g, 75 mmol, 1.5 eq) and DIPEA (13.6 mL, 80 mmol, 1.6 Eq) was added and the mixture was stirred overnight. The reaction mixture was evaporated to 80 mL and then partitioned between ethyl acetate (200 mL) and water (200 mL). The aqueous phase was extracted twice with ethyl acetate (100 mL and 80 mL). The combined organic phases were washed with 0.2N HCl (3 × 100 mL) and sodium chloride saturated: water (1: 1) (3 × 100 mL), dried over magnesium sulfate and evaporated to dryness. The compound was suspended in acetic acid ethyl ester (30 mL) and filtered. The solid was washed and the combined filtrates were evaporated under vacuum. The residue was purified by column chromatography. The eluent used was ethyl acetate: n-heptane (95: 5) and ethyl acetate: methanol (95: 5). 3- (4-Formylbenzoylamino) -2R-hydroxypropionic acid methyl ester (2.24 g, 10%) was isolated. ¹ H-NMR (CDCl ₃ ): δ 3.82 (3H, s), 3.80-3.94 (1H, m), 4.42-4.49 (1H, m), 4.69 (1H, br s), 6.78 (1H, br s ), 7.92 (4H, s).

Step 2: Preparation of 3-4- {4- (4-tert-butylphenyl) -2- (4-cyclohexylphenyl) -4-oxobutyryl] benzoylamino-2R-hydroxypropionic acid ethyl ester absolute ethanol (99%, To a mixture of 1- (4-tert-butylphenyl) -3- (4-cyclohexylphenyl) propenone (1.00 g, 2.91 mmol) in 10 mL) under nitrogen, 3,4-dimethyl-5-iodide. (2-Hydroxyethyl) thiazolium (165 mg, 0.58 mmol) and triethylamine (0.325 mL, 2.33 mmol) were added and the mixture was heated to reflux. (R) -3- (4-Formylbenzoylamino) -2-hydroxypropionic acid methyl ester (1.01 g, 3.78 mmol) was dissolved in absolute ethanol (99%, 10 mL) and 1% was added to the above refluxing mixture. Added dropwise over time. The reaction mixture was refluxed for 7 days, cooled to room temperature, and partitioned between DCM (50 mL) and aqueous HCl (1N, 50 mL). The aqueous phase was washed with DCM (50 mL). The combined organic phases were dried (Na ₂ SO ₄ ) and evaporated under vacuum. The residual oil was purified by silica gel column chromatography using ethyl acetate and heptane (1: 1) as eluent to give pure 3- {4- [4- (4-tert-butylphenyl) -2- ( 4-Cyclohexylphenyl) -4-oxobutyryl] benzoylamino} -2R-hydroxypropionic acid ethyl ester was obtained. HPLC-MS (method D): m / z = 612 (M + 1); R t = 6.07min.

Step 3: Preparation of 3- {4- [4- (4-tert-butylphenyl) -2- (4-cyclohexylphenyl) -4-oxobutyryl] benzoylamino} -2R-hydroxypropionic acid Ethanol (10 mL) was added to (4- (4-tert-butylphenyl) -2R- (4-cyclohexylphenyl) -4-oxobutyryl] benzoylamino} 2-hydroxypropionic acid ethyl ester NaOH (244 mg). Dissolved in water (1 mL) and added to the above mixture The mixture was stirred for 30 minutes, diluted with water (15 mL) and the pH adjusted to 2 with aqueous HCl (1N). Separation by filtration gave the title compound Yield: 430 mg (25%).

Example 94 (General Procedure (E)) 3- {4- [4-Biphenyl-4-yl-2- (4-cyclohexylphenyl) -4-oxobutyryl] benzoylamino} -2R-hydroxypropionic acid

Example 95 (General Procedure (E)) 3- {4- [2-Biphenyl-4-yl-4-oxo-4- (4-trifluoromethoxyphenyl) butyryl] benzoylamino} -2R-hydroxypropionic acid

Example 96 (General Procedure (E)) 3- {4- [4- (4-cyclohexylphenyl) -2- (4-isopropylphenyl) -4-oxo-butyryl] benzoylamino} -2- (R) -hydroxy Propionic acid

General procedure (F)
General procedure (F) for the liquid phase synthesis of compounds of general formula (I ₄ ):

Wherein X, D, E, M, n and R ⁴ are as defined in formula (I), and Pg is a standard carboxylic acid such as methyl, ethyl, propyl, isopropyl, tert-butyl or benzyl. It is an acid protecting group. This procedure is illustrated in the following example.

Example 97 (General Procedure (F)) (Z) -3- {4- [4- (4-tert-Butylphenyl) -2- (4-cyclohexylphenyl) -4-oxobut-2-enoyl] benzoylamino} -2R-hydroxypropionic acid

Steps 1 to 3: Preparation of 3- {4- [4- (4-tert-butylphenyl) -2- (4-cyclohexylphenyl) -4-oxobutyryl] benzoylamino-2R-hydroxypropionic acid (E) It is difficult to synthesize.

Step 4: Preparation of 3- {4- [4- (4-tert-butylphenyl) -2- (4-cyclohexylphenyl) -4-oxobut-2-enoyl] benzoylamino-2R-hydroxypropionic acid
3- {4- [4- (4-tert-Butylphenyl) -2- (4-cyclohexylphenyl) -4-oxobutyryl] benzoylamino} -2R-hydroxypropionic acid (350 mg, 0.599 mmol) in THF (5 mL) Dissolved in. DBU (0.323 mL, 2.16 mmol) and crystalline iodine (183 mg, 0.719 mmol) were added. The mixture was stirred at room temperature for 30 minutes, poured into DCM (100 mL) and washed with aqueous sodium sulfite (2%, 50 mL). The organic phase was washed with aqueous HCl (1N, 50 mL), dried (Na ₂ SO ₄ ) and evaporated to dryness to give 3- {4- [4- (4-tert-butylphenyl) -2 An E and Z mixture of-(4-cyclohexylphenyl) -4-oxobut-2-enoyl] benzoylamino} -2R-hydroxypropionic acid was obtained.

¹ H-NMR (CDCl ₃ ): δ 1.28 and 1.32 (9H, s, 2 peaks), 1.15-1.40 (5H, m), 1.60-1.85 (5H, m), 2.36 and 2.50 (1H, m, 2 peaks), 4.38 (1H, q), 6.88 and 7.62 (1H, s, 2 peaks), 7.01 (1H, d), 7.13-7.25 (2H, dd), 7.30-7.40 (2H, m), 7.45 (2H, dd), 7.73-8.00 (6H, m).

Step 5: (Z) -3- [4- [4- (4-tert-butylphenyl) -2R- (4-cyclohexylphenyl) -4-oxobut-2-enoyl] benzoylamino] -2R-hydroxypropionic acid Preparation of
E and Z mixture of 3- {4- [4- (4-tert-butylphenyl) -2- (4-cyclohexylphenyl) -4-oxobut-2-enoyl] benzoylamino} -2R-hydroxypropionic acid in toluene (25 mL). Concentrated HCl (37%, 900 μL) was added and the mixture was heated to reflux for 1 hour. After removing the solvent by evaporation and drying under vacuum overnight, (Z) -3- {4- [4- (4-tert-butylphenyl) -2- (4-cyclohexylphenyl) -4-oxobut- 2-Enoyl] benzoylamino} -2R-hydroxypropionic acid was obtained.

¹ H-NMR (CDCl ₃ ): δ1.32 (9H, s), 1.15-1.42 (5H, m), 1.60-1.90 (5H, m), 2.50 (1H, m), 3.78 (1H, m), 3.88 (1H, m), 4.38 (1H, m), 7.22 (2H, d), 7.46 (2H, d), 7.48 (2H, d), 7.61 (1H, s), 7.78 (2H, d), 7.88 (2H, d), 7.98 (2H, d). HPLC-MS (Method D): m / z = 582 (M + 1), R _t = 5.40 min.

Example 98 (General Procedure (F)) (Z) -3- {4- [4- (4-tert-Butylphenyl) -2- (4-cyclohexylphenyl) -4-oxobut-2-enoyl] benzoylamino} -2R-hydroxypropionic acid

Example 99 (General procedure (F))
The compound of Example 42 was also prepared according to the general procedure (F) illustrated below:
(Z) -3- {4- [2-Biphenyl-4-yl-4-oxo-4- (4-trifluoromethoxyphenyl) but-2-enoyl] benzoylamino} -2R-hydroxypropionic acid

Example 100 (General Procedure (F)) (Z) -3- {4- [4- (4-cyclohexylphenyl) -2- (4-isopropylphenyl) -4-oxobut-2-enoyl] benzoylamino} -2R -Hydroxypropionic acid

Example 101 (General Procedure (F)) (Z) -3- {4- [2- (4-cyclohexylphenyl) -4- (3,5-dichlorophenyl) -4-oxobut-2-enoyl] benzoylamino} propion acid

General procedure (G)
General procedure (G) for the liquid phase synthesis of compounds of general formula (I ₄ ):

In which X, D, E, M, n and R ⁴ are as defined in formula (I) and Pg is a standard carboxylic acid such as methyl, ethyl, propyl, isopropyl, tert-butyl or benzyl Protecting group.

Example 102 (General procedure (G))
The compound of Example 65 was also prepared according to the general procedure (G) illustrated below:
3- {4- [2- [4- (2,2-Dimethyl-propyl) -phenyl] -4-oxo-4- (4-trifluoromethoxyphenyl) -but-2-enoyl] benzoylamino] propionic acid

Step 1 and Step 2: 4- [2- [4- (2,2-Dimethylpropyl) phenyl] -4-oxo-4- (4-trifluoromethoxyphenyl) -butyryl] benzoic acid
3- [4- (2,2-dimethylpropyl) phenyl] -1- (4-trifluoromethoxyphenyl) propenone (10.51 g; 29 mmol) (building block 8), 3,4-dimethyl-5- (iodide iodide) A mixture of 2-hydroxyethyl) thiazolium (1.77 g, 6.2 mmol) and triethylamine (3.52 mL; 25.27 mmol) was stirred and refluxed in 100 mL absolute ethanol. To this mixture was added dropwise a solution of methyl 4-formylbenzoate (6.8 g, 41.4 mmol) in 50 mL of absolute ethanol. Stirring and heating were continued for 16 hours. The mixture was cooled and partitioned between 1N HCl (150 mL) and DCM (200 mL). The organic phase was separated and the aqueous phase was further extracted with DCM (200 mL). The combined DCM extract was washed with water, dried (Na ₂ SO ₄ ), clarified with Norite A, filtered and evaporated to 14 g (80%) of the intermediate ester compound Got. This material was dissolved in 80 mL of methanol and sodium hydroxide (2.68 g; 67.1 mmol) in 10 mL of water was added to the mixture. Stirring was continued until the ester starting material disappeared, and the pH was adjusted to 2 using dilute hydrochloric acid. The precipitate was filtered off and dried to give 10.3 g of 4- [2- [4- (2,2-dimethylpropyl) phenyl] -4-oxo-4- (4-trifluoromethoxyphenyl) butyryl] benzoic acid Got.

¹ H-NMR (CDCl ₃ ): δ8.12 (d, 2H), 8.09 (d, 2H), 8.02 (d, 2H), 7.28 (d, 2H), 7.21 (d, 2H), 7.08 (d, 2H), 5.25 (dd, 1H) 4.20 (m, 1H), 3.30 (dd, 1H), 2.43 (s, 2H), 0.88 (s, 9H).

Step 3: Preparation of (E / Z) -4- [2- [4- (2.2-dimethylpropyl) phenyl] -4-oxo-4- (4-trifluoromethoxyphenyl) but-2-enonyl] benzoic acid
4- [2- [4- (2,2-Dimethylpropyl) phenyl] -4-oxo-4- (4-trifluoromethoxyphenyl) butyryl] benzoic acid (9.3 g; 20.1 mmol) in THF (700 mL) Dissolved in. The mixture was stirred while iodine (6.34 g; 24.1 mmol) and DBU (11 g; 42.4 mmol) were added. The mixture was stirred for 2 hours and concentrated under reduced pressure to a volume of about 100 mL. A 2% solution of sodium sulfite (150 mL) and 1N hydrochloric acid (150 mL) were added. The mixture was extracted with DCM (2 × 300 mL) and washed with brine (400 mL). The organic phase was separated, dried (Na ₂ SO ₄ ), cleaned using Norite A, filtered and evaporated to 8.2 (88%) of (E, Z) -4- [2- [4- ( 2,2-Dimethylpropyl) phenyl] -4-oxo-4- (4-trifluoromethoxyphenyl) but-2-enonyl] benzoic acid was obtained. HPLC-MS (method A): m / z = 511 (M + 1); R t = 5.60min.

Step 4 and Step 5: (Z) -3- {4- [2- [4- (2,2-dimethyl-propyl) -phenyl] -4-oxo-4- (4-trifluoromethoxy-phenyl)- Preparation of But-2-enoyl] benzoylamino} propionic acid
(E, Z) -4- [2- [4- (2,2-dimethylpropyl) phenyl] -4-oxo-4- (4-trifluoromethoxyphenyl) but-2-enonyl] in 20 mL DMF A solution of benzoic acid (7.2 g; 14.1 mmol) was stirred while 1-hydroxybenzotriazole hydrate (2.29 g; 19.9 mmol) was added. The mixture was stirred for 1 hour at room temperature followed by the addition of EDAC (3.24 g; 16.92 mmol), methyl 3-aminopropionate hydrochloride (2.95 g; 21.16 mmol) and DIPEA (7.37 mL; 42.31 mmol), respectively. 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 SO 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 under reduced pressure to about 30 mL and 40 mL of water was added. The pH was adjusted to 1.5 by adding 1M hydrochloric acid. The precipitate was filtered off and dried to give 7.9 g of crude material. This material was boiled in a mixture of toluene (100 mL) and concentrated hydrochloric acid (2.7 mL) for 1 hour. The mixture was cooled to room temperature and the precipitate separated to give 5.6 g (68%) of the title compound.

¹ H-NMR (CDCl ₃ ): δ 8.02 (m, 4H), 7.80 (d, 2H), 7.60 (s, 1H), 7.48 (d, 2H), 7.30 (d, 2H); 7.18 (d, 2H), 6.84 (t, 1H), 3.63 (q, 2H), 2.72 (t, 2H), 2.50 (s, 2H), 0.90 (s, 9H); HPLC-MS (Method A): m / z = 583 (M + 1); R _t = 5.03 min.

Example 103 3- {4- [4- (4-tert-butylphenyl) -4-oxo-2- (4-trifluoromethoxyphenyl) butyryl] benzoylamino} propionic acid

Step 1: 4- [4- (4-tert-Butylphenyl) -4-oxo-2- (4-trifluoromethoxyphenyl) butyryl] benzoic acid methyl ester In a dry 3-neck 50 mL round bottom flask, 1- (4-tert-Butylphenyl) -3- (4-trifluoromethoxyphenyl) propenone (9.47 g, 27.18 mmol), 3,4-dimethyl-5- (2 hydroxyethyl) thiazolium iodide (7.75 g, 27.18 mmol) ) And triethylamine (13.26 mL, 95.13 mmol) were placed under nitrogen. This mixture was dissolved in refluxing ethanol (45 mL, 99%). A solution of 3- (4-formylbenzoylamino) propionic acid methyl ester (6.97 g, 40.77 mmol) in ethanol (50 mL, 99%) was added dropwise over approximately 2.5 hours. After the mixture was refluxed for 5 hours under nitrogen, the reaction was cooled and evaporated to dryness. The residual oil was dissolved in DCM (100 mL) and extracted with 1N HCl (150 mL), and the aqueous phase was extracted once more with DCM (50 mL). The combined organic phases are dried using magnesium sulfate, filtered and evaporated to dryness to give 4- [4- (4-tert-butylphenyl) -4-oxo-2- (4-trifluoromethoxyphenyl) Butyryl] benzoic acid methyl ester (16.9 g) was obtained.

HPLC-MS (method C): m / z = 513 (M + 1); R t = 7.33min.

Step 2: 4- [4- (4-tert-Butylphenyl) -4-oxo-2- (4-trifluoromethoxyphenyl) butyryl] benzoic acid
4- [4- (4-tert-Butylphenyl) -4-oxo-2- (4-trifluoromethoxyphenyl) butyryl] benzoic acid methyl ester (13.9 g, 27.2 mmol) in ethanol (120 mL, 96%) And sodium hydroxide (4N, 27, 2 mL) was added. After 4 and a half hours, the reaction was evaporated to dryness. Water (200 mL) and hydrochloric acid (4N, 30 mL) were added to the residue, and precipitation occurred at pH 1-2. The mixture was stirred for half an hour. The precipitate was filtered, carefully washed with water and dried overnight at 40 ° C. under vacuum. The residue was crystallized from methanol and water to give 4- [4- (4-tert-butylphenyl) -4-oxo-2- (4-trifluoromethoxyphenyl) butyryl] benzoic acid (10.4 g). . HPLC-MS (method D): m / z = 499 (M + 1); R t = 5.51min.

3-4- [4- (4-tert-Butylphenyl) -4-oxo-2- (4-trifluoromethoxyphenyl) butyryl] benzoylamino-propionic acid methyl ester
4- [4- (4-tert-Butylphenyl) -4-oxo-2- (4-trifluoromethoxyphenyl) butyryl] benzoic acid (10.4 g, 20.86 mmol) was dissolved in DMF (150 mL) and EDAC (5.60 g, 29.20) and HOBt (4.23 g, 31.29 mmol) were added. After 1 hour, a solution of β-alanine methyl ester hydrochloride (4.37 g, 31.29 mmol) and DIPEA (5.36 mL, 31.29 mmol) in DMF (20 mL) was added to the above mixture and the reaction mixture was stirred overnight. The reaction was concentrated to 100 mL, diluted with water (200 mL) and extracted with ethyl acetate (200 mL). The aqueous phase was extracted with additional ethyl acetate (75 mL). The combined organic phases were washed with hydrochloric acid (0.2N, 3 × 150 mL), aqueous sodium chloride (50% saturation, 3 × 150 mL) and dried over magnesium sulfate. The dried organic phase was filtered and evaporated to dryness to give 3- {4- [4- (4-tert-butylphenyl) -4-oxo-2- (4-trifluoromethoxyphenyl) butyryl] benzoylamino] Propionic acid methyl ester (12.76 g) was obtained. HPLC-MS (method D): m / z = 584 (M + 1); R t = 5.48min.

Step 4: 3-4- [4- (4-tert-butylphenyl) -4-oxo-2- (4-trifluoromethoxyphenyl) butyryl] benzoylamino} propionic acid
3- {4- [4- (4-tert-butylphenyl) -4-oxo-2- (4-trifluoromethoxyphenyl) butyryl] benzoylamino} propionic acid methyl ester (12 g, 21 mmol) was added to ethanol 96% ( 250N), 4N NaOH (31.2 mL, 125 mmol) was added and stirred for 2 h 45 min. The reaction mixture was concentrated under vacuum, water (150 mL) was suspended in the residue and hydrochloric acid (4N, 34 mL) was added to pH 1-2. After 1 hour, the precipitate was filtered, washed carefully with water and dried. The residue was purified by preparative HPLC using acetonitrile (gradient from 42% to 97.5%), water and TFA (2.5%) as eluent to give 4.7 g of the title compound.

¹ H-NMR (DMSO-d ₆ ) Selected data: δ 8.68 (t, 1H), 8.15 (d, 2H), 7.93 (m, 4H), 7.56 (m, 4H), 7.33 (d, 2H 5.51 (m, 1H), 4.10 (m, 1H), 3.45 (m, 4H), 1.31 (s, 9H); HPLC-MS (Method A): m / z = 570 (M + 1); R _t = 5.95 min.

Example 104 3- {4- [4- (4-tert-butylphenyl) -4-oxo-2- (4-trifluoromethoxyphenyl) butyryl] benzoylamino} -2R-hydroxypropionic acid

3- {4- [4- (4-tert-Butylphenyl) -4-oxo-2- (4-trifluoromethoxyphenyl) butyryl] benzoylamino} -2R-hydroxypropionic acid methyl ester
4- [4- (4-tert-butylphenyl) -4-oxo-2- (4-trifluoromethoxyphenyl) butyryl] benzoic acid (0.64 g, 1.28 mmol) was dissolved in DMF (10 mL) and EDAC (0.35 g, 1.8 mmol) and 0.26 g of HOBt were added. After half an hour, a solution of R-isoserine methyl ester hydrochloride (0.30 g, 1.92 mmol) and diisopropylethylamine (0.31 mL, 1.92 mmol) in DMF (6 mL) was added to the above mixture and added at room temperature for 16 hours. . The mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL). The aqueous phase was extracted once more with ethyl acetate (15 mL), and the combined organic phases were washed with hydrochloric acid (0.2N, 3 × 20 mL), 50% aqueous sodium chloride solution (3 × 20 mL). , Dried over magnesium sulfate, filtered and evaporated to dryness to give 0.79 g of 3- {4- [4- (4-tert-butylphenyl) (4-trifluoromethoxyphenyl) butyryl] benzoylamino}- 2R-hydroxypropionic acid methyl ester was obtained. HPLC-MS (method D) m / z = 600 ( M + 1); R t = 5.20min.

3- {4- [4- (4-tert-Butylphenyl) -4-oxo-2- (4-trifluoromethoxyphenyl) butyryl] benzoylamino} -2R-hydroxypropionic acid methyl ester (0.77 g, 1.28 mmol ) Was dissolved in ethanol (96%, 30 mL), sodium hydroxide (4N, 1.93 mL) was added and stirred for 2.5 hours. The reaction was concentrated in vacuo and the residue was suspended in water (30 mL) and hydrochloric acid (4N, 2 mL) was added to pH 1-2. After half an hour, the precipitate was filtered, washed carefully with water and dried under vacuum. The product was purified by preparative HPLC using acetonitrile (gradient from 55.5% to 97.5%), water and TFA (2.5%) as eluent to give 0.16 g of the title compound. ¹ H-NMR (DMSO-d ₆ ) Selected data: δ8.66 (t, 1H), 8.15 (d, 2H), 7.93 (m, 4H), 7.56 (m, 4H), 7.33 (d, 2H 5.53 (m, 1H), 4.07-4.20 (m, 2H), 3.48-3.63 (m, 2H), 1.31 (s, 9H); HPLC-MS (Method C): m / z = 586 (M + 1); R _t = 5.42 min.

Example 105 3- {4- [4- (4-tert-butylphenyl) -4-oxo-2- (4-trifluoromethoxyphenyl) but-2-enoyl] benzoylamino} -2R-hydroxypropionic acid

Step 3: 3- {4- [4- (4-tert-Butylphenyl) -4-oxo-2- (4-trifluoromethoxyphenyl) but-2-enoyl] benzoylamino} -2R-hydroxypropionic acid Example 3- {4- [4- (4-tert-butylphenyl) -4-oxo-2- (4-trifluoromethoxyphenyl) butyryl] benzoylamino} -2R-hydroxypropionic acid from 104 (0.15 g, 0.24 mmol) was dissolved in THF (3 mL), DBU (0.13 mL, 0.86 mmol) and iodine (0.11 g, 0.44 mmol) were added and stirred at room temperature. The solvent is removed by evaporation, the residue is dissolved in DCM (25 mL), sodium sulfite (2%, 10 mL), hydrogen chloride (1N, 10 mL), water and sodium chloride saturated (2 × 1: 1,10 mL) ), Dried over magnesium sulfate, filtered and evaporated to dryness to give 0.11 g of a mixture of E and Zformation. The residue was dissolved in toluene (5 mL), concentrated hydrogen chloride was added and refluxed at 130 ° C. for 1 hour in an oil bath. The reaction was allowed to cool and evaporated to dryness, which was repeated twice with DCM (2 × 5 mL). The product was purified by preparative HPLC using acetonitrile (57.5% -97.5%), water and TFA (2.5%) as eluent and evaporated to give 0.04 g of the title compound.

¹ H-NMR (DMSO-d ₆ ) Selected data: δ8.63 (t, 1H), 8.05 (m, 3H), 7.95 (d, 2H), 7.91 (d, 2H), 7.80 (d, 2H 7.58 (d, 2H), 7.48 (d, 2H), 5.48 (broad, 1H), 4.15 (m, 1H), 3.54 (m, 1H) 1.31 (s, 9H); HPLC-MS (Method C) : M / z = 585 (M + 1); R _t = 5.78 min.

General procedure (H)
General procedure (H) for the preparation of optical isomers of compounds of general formula (I ₁ ):

Example 106 (General procedure (H))
The compound of Example 4 is also prepared, and the optical isomers are separated according to the general procedure (H) described in Illustrated below:
3- {4- [4- (3,5-bis-trifluoromethylphenyl) -2- (4-cyclohexylphenyl) -4-oxo-butyryl] benzoylamino} propionic acid

  Step 1: 3- (4-Formylbenzoylamino) propionic acid methyl ester 3- (4-Formylbenzoylamino) propion methyl ester was synthesized according to the procedure described in WO 00/69810.

Step 2: 3-4- [4- (3,5-bis-trifluoromethylphenyl) -2- (4-cyclohexylphenyl) -4-oxo-butyryl] benzoylamino] propionic acid methyl ester absolute ethanol (99% , 25 mL) in a mixture of 1- (3,5-bis-trifluoromethylphenyl) -3- (4-cyclohexylphenyl) propenone (6.12 g, 14.35 mmol) under nitrogen. Dimethyl-5- (2-hydroxyethyl) thiazolium (819 mg, 2.87 mmol) and triethylamine (1.60 mL, 11.5 mmol) were added and the mixture was heated to reflux. 3- (4-Formylbenzoylamino) propionic acid methyl ester (4.39 g, 18.7 mmol) was dissolved in absolute ethanol (99%, 15 mL) and added dropwise to the above refluxing mixture over 2 hours. The reaction mixture was refluxed for 30 minutes and cooled to room temperature. After filtration, washing with ethanol and drying under vacuum, 3- {4- [4- (3,5-bis-trifluoromethyl-phenyl) -2- (4-cyclohexyl-phenyl) -4 -Oxo-butyryl] benzoylamino} propionic acid methyl ester could be isolated: 6.9 g (73%).

Step 3: 3- {4- [4- (3.5-bis-trifluoromethylphenyl) -2- (4-cyclohexylphenyl) -4-oxobutyryl] -benzoyl} propionic acid
3- {4- [4- (3,5-bis-trifluoromethylphenyl) -2- (4-cyclohexylphenyl) -4-oxobutyryl] benzoylamino} propionic acid methyl ester (6.20 g, 9.38 mmol) in THF (75 mL), HCl (6N, 25 mL) was added and the mixture was heated to reflux, after 2 hours the heating was stopped and the mixture was stirred at room temperature for 16 hours. The mixture was evaporated to dryness to give the title compound. Yield: quantitative.

¹ H-NMR (DMSO-d ₆ ): δ 8.72 (t, 1H), 8.60 (s, 2H), 8.42 (s, 1H), 8.14 (d, 2H), 7.90 (d, 2H); 7.34 ( d, 2H), 7.17 (d, 2H), 5.43 (dd, 1H), 4.29 (dd, 1H), 3.64 (dd, 1H and t 2H), 3.42 (t, 2H), 2.42 (m, 1H), 1.78-1.64 (m, 5H), 1.38-1.25 (m, 5H); HPLC-MS (Method D): m / z = 648 (M + 1); R _t = 5.58 min.

Step 4: Chiral HPLC
3- {4- [4- (3,5-bis-trifluoromethylphenyl) -2- (4-cyclohexylphenyl) -4-oxobutyryl] benzoylamino} propionic acid (500 mg, 0.77 mmol) was added to isopropanol: heptane Dissolved in 60:40 (20 mL). Trifluoroacetic acid (0.02 mL) was added. The racemic mixture was separated at an AD column 50 × 500 mm (from DAICEL) at a flow rate of 100 mL / min. Elution with an isopropanol: heptane mixture containing 0.01% trifluoroacetic acid. Two fractions containing the compound in the eluent were collected. Each fraction was kept separate or otherwise processed separately. The volume of each fraction was reduced to about 1/8 of the initial value under vacuum and partitioned between dichloromethane (1 L) and aqueous NaHCO 3 (10%, 500 mL). The organic phase was dried (NaSO ₄ ) and evaporated to give white crystals. The crystals were refluxed in acetonitrile and subsequently cooled to room temperature. Pure optical isomers could be separated by filtration followed by drying under vacuum.

Example 107 3- {4- [4- (3,5-bis-trifluoromethylphenyl) -2- (4-cyclohexylphenyl) -4-oxo-butyryl] benzoylamino} propionic acid The fastest eluting optical isomer : Chiralpak AD, 4.6 x 250 mm heptane, isopropanol, trifluoroacetic acid 60: 40: 0.1, 0.6 mL / min flow rate. Retention time = 8.2min.

Example 108 3- {4- [4- (3,5-bis-trifluoromethylphenyl) -2- (4-cyclohexylphenyl) -4-oxo-butyryl] benzoylamino} propionic acid The slowest eluting optical isomer : Chiralpak AD, 4.6 x 250 mm heptane, isopropanol, trifluoroacetic acid 60: 40: 0.1, 0.6 mL / min flow rate. Retention time = 12.1min.

Further preferred compounds of the invention include:

General procedure (I)
General procedure (I) for the liquid phase synthesis of compounds of general formula (I ₆ ):

In the formula, Pg, E, X, D and R ⁴ are as defined above. The Pg added in step 5 may be different from the Pg in the previous step.

Example 109 (General Procedure (I)) 3- {4- [2- (4-cyclohexylphenyl) -2- (4-trifluoromethoxyphenylcarbamoyl) ethyl] benzoylamino} propionic acid

Step 1: E, Z-4- [2-carboxy-2- (4-cyclohexylphenyl) vinyl] benzoic acid methyl ester
Methyl 4-formylbenzoate (5.75 g; 35 mmol), 4-cyclohexylphenylacetic acid (10.93 g, 50.05 mmol) (Chem. Ber., 76, (1943), 308), acetic anhydride (17.54 mL, 185.5 mmol) and A mixture of triethylamine (4.87 mL; 35 mmol) was stirred and heated at 155 ° C. for 15 minutes. The mixture was cooled to 90 ° C. and water (18 mL) was added dropwise at a rate such that the temperature was maintained between 90 ° C. and 100 ° C. The mixture was cooled to room temperature and 50% aqueous acetic acid (25 mL) was added. The precipitate was filtered off and washed with 25% aqueous acetic acid (100 mL) and finally with water (125 mL). The crude product is dried and recrystallized from heptane to give 10.89 g (85%) of an E / Z mixture of 4- [2-carboxy-2- (4-cyclohexylphenyl) vinyl] benzoic acid methyl ester. It was.

¹ H-NMR (DMSO-d ₆ ): δ 12.88 (br s, 1H), 8.98-7.05 (m, 9H), 3.87 and 3.83 (s, 3H) 2.54 (m, 1H), 1.68-1.78 (m , 5H), 1.48-1.20 (m, 5H).

Step 2: 4- [2-carboxy-2- (4-cyclohexylphenyl) ethyl] benzoic acid methyl ester
E, Z-4- [2-carboxy-2- (4-cyclohexylphenyl) vinyl] benzoic acid methyl ester (10.85 g, 28.77 mmol) and palladium on activated carbon (1.085 g, 10%) in 100 mL of methanol The mixture was hydrogenated at 56 psi for 7 hours. The catalyst was filtered off and the filtrate was evaporated to dryness to give 5.73 (53%) of 4- [2-carboxy-2- (4-cyclohexylphenyl) ethyl] benzoic acid methyl ester as a solid.

¹ H-NMR (CDCl ₃ ): δ 7.90 (d, 2H), 7.23-7.13 (m, 6H), 3.88 (s, 3H), 3.84 (t, 1H), 2.43 (dd, 1H), 3.07 ( dd, 1H), 2.48 (m, 1H), 1.90-1.70 (m, 5H), 1.45-1.18 (m, 5H). HPLC-MS (method D): m / z = 367 (M + 1); R t = 5.03min.

Step 3: 4- [2-Chlorocarbonyl-2- (4-cyclohexylphenyl) ethyl] benzoic acid methyl ester 4- [2-carboxy-2- (4-cyclohexylphenyl) ethyl] benzoic acid methyl ester in toluene ( A solution of 5,58 g, 15,2 mmol) was stirred and thionyl chloride (2.79 mL, 38.20 mmol) was added. The mixture was stirred and refluxed for 15 minutes and toluene was removed under reduced pressure. The residue was stripped twice with toluene to give 5.75 g (98%) of 4- [2-chlorocarbonyl-2- (4-cyclohexylphenyl) ethyl] benzoic acid methyl ester.

¹ H-NMR (CDCl ₃ ): δ 7.79 (d, 2H), 7.40-7.08 (m, 6H), 4.11 (m, 1H), 3.85 (s, 3H), 3.30 (m, 1H), 3.03 ( m, 1H), 2.45 (m, 1H), 1.83-1.65 (m, 5H), 1.42-1.15 (m, 5H).

Step 4: 4- [2- (4-Cyclohexylphenyl) -2- (4-trifluoromethoxyphenylcarbamoyl) ethyl] benzoic acid 4-trifluoromethoxyaniline (0.575 g, 3.25 mmol) in dry toluene (50 mL) Was stirred under a nitrogen atmosphere. Triethylamine (0.448 mL, 3.25 mmol) was added, followed by 4- [2-chlorocarbonyl-2- (4-cyclohexylphenyl) ethyl] benzoic acid methyl ester (1.25 g, 3.25 mmol) in dry toluene (25 mL). A solution of was added. The mixture was refluxed for 1 hour, cooled to room temperature and washed with water (2 × 100 mL) and saturated sodium chloride solution (2 × 100 mL). The organic phase was collected and evaporated under reduced pressure until dry, yielding 1.43 g of the crude intermediate ester compound. The ester was dissolved in a mixture of methanol (12.5 mL) and THF (5 mL) and 4M aqueous sodium hydroxide (2.43 mL, 9.75 mmol) was added. The mixture was stirred for 16 hours at room temperature. The mixture was filtered and the filtrate was acidified with concentrated hydrochloric acid (pH = 2). The mixture is stirred for 1 hour, the precipitate is filtered off, washed with water and dried to give 1.32 g (80%) of 4- [2- (4-cyclohexylphenyl) -2- (4-tri Fluoromethoxy-phenylcarbamoyl) ethyl] benzoic acid was obtained as a solid.

¹ H-NMR (DMSO-d ₆ ): δ 10.38 (s, 1H), 7.78 (d, 2H), 7.65 (d, 2H); 7.28 (m, 2H), 7.30 (d, 2H), 7.18 ( d, 2H), 4.03 (m, 1H), 3.45 (m, 1H), 2.42 (m, 1H), 1.85-1.13 (m, 10H).

Step 5 and Step 6: 3- {4- [2- (4-cyclohexylphenyl) -2- (4-trifluoromethoxyphenylcarbamoyl) ethyl] benzoylamino} propionic acid
A solution of 4- [2- (4-cyclohexylphenyl) -2- (4-trifluoromethoxyphenylcarbamoyl) ethyl] benzoic acid (1.44 g; 2.82 mmol) in DMF (45 mL) was added to 1-hydroxy-benzotriazole. The mixture was stirred while adding hydrate (0.456 g; 3.38 mmol). The mixture was stirred for 1 hour at room temperature, followed by the addition of EDAC (0.648 g; 3.38 mmol), methyl 3-aminopropionate hydrochloride (0.589 g; 4.22 mmol) and DIPEA (1.47 mL; 8.45 mmol). 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 washed with brine, dried (MgSO ₄ ) and evaporated to give 2.11 g of intermediate ester. This material (0.3 g, 0.5 mmol) was dissolved in a mixture of methanol (11 mL) and THF (4.4 mL) and 4M sodium hydroxide solution (0.37 mL; 1.50 mmol) was added. The mixture was stirred for 16 hours at room temperature. The mixture was concentrated under reduced pressure to about 1 mL and water (15 mL) was added. The pH was adjusted to 1.5 by adding 1M hydrochloric acid. The precipitate was filtered off, washed with water and dried to give 0.25 g (85%) of the title compound.

¹ H-NMR (DMSO-d ₆ ): δ12.20 (br s, 1H), 10.25 (s, 1H), 8.43 (t, 1H), 7.70 (d, 2H), 7.62 (d, 2H), 7.35 (d, 2H), 7.30 (d, 2H), 7.26 (d, 2H), 7.18 (d, 2H), 3.99 (m, 1H), 3.40 (m, 1H), 3.00 (dd, 1H), 2.48 ( m, 3H), 1.85-1.13 (m, 10H).

  The following compounds (Examples 110-110) were prepared analogously to the above method.

Example 110 (General Procedure (I)) 3- {4- (3,5-Dichlorophenylcarbamoyl) -2- (4-trifluoromethoxyphenyl) ethyl] benzoylamino} propionic acid

Example 111 (General Procedure (I)) 3- {4- [2- (3,5-Dichlorophenylcarbamoyl) -2- (4-trifluoromethoxyphenyl) ethyl] benzoylamino} -2R-hydroxypropionic acid

Example 112 (General Procedure (I)) 2R-Hydroxy-3- {4- [2- (4-trifluoromethoxyphenyl) -2- (4-trifluoromethoxyphenylcarbamoyl) ethyl] benzoylamino} propionic acid

Example 113 (General Procedure (I)) 3- {4- [2- (4-trifluoromethoxyphenyl) -2- (4-trifluoromethoxyphenylcarbamoyl) ethyl] benzoylamino} propionic acid

Example 114 (General Procedure (I)) 3- {4- [2- (4-cyclohexylphenyl) -2- (3,5-dichlorophenylcarbamoyl) ethyl] benzoylamino} propionic acid

Example 115 (General Procedure (I)) 3- {4- [2- (4-cyclohexylphenyl) -2- (4-trifluoromethylphenylcarbamoyl) ethyl] benzoylamino} propionic acid

  The next two compounds (Examples 116 and 117) were prepared according to General Procedure (I) except that the hydrogenation step (Step 2) was omitted.

Example 116 3- {4- [2- (4-tert-butylphenylcarbamoyl) -2- (4-trifluoromethoxyphenyl) vinyl] benzoylamino} propionic acid

Example 117 3- {4- [2- (4-tert-butylphenylcarbamoyl) -2- (4-trifluoromethoxyphenyl) vinyl] benzoylamino} -2R-hydroxypropionic acid

The following preferred compounds are within the scope of the present invention and may be prepared by the procedures disclosed herein:

Where

<Pharmacological method>
In the following sections, binding assays as well as functional assays useful for assessing the effectiveness of the compounds of the present invention are described.

  Binding to the glucagon receptor may be determined in a competitive binding assay using cloned human glucagon receptor.

  Antagonism may be determined as the ability of the compound to inhibit the amount of cAMP formed in the presence of 5 nM glucagon.

Glucagon binding assay (I):
Receptor binding is tested using cloned human receptors (Lok et al., Gene 140, 203209 (1994)). The receptor inserted into the pLJ6 ′ expression vector using the EcoRI / SSt1 restriction site (Lok et al.) Is expressed in a neonatal hamster kidney cell line (A3 BHK 570-25). Clones are selected in the presence of 0.5 mg / mL G-418 and are shown to be stable for over 40 passages. Kd represents 0.1 nM.

  Cells are grown to confluency, they are detached from the surface, and cells are chilled (10 mM tris / HCl, pH 7.4: 30 mM NaCl, 1 mM dithiothreitol, 5 mg / L leupeptin (containing: Sigma), 5 mg / L pepstatin (Sigma), 100 mg / L bacitracin (Sigma), and 15 mg / L recombinant aprotinin (Novo Nordisk A / S)) and Polytron PT 10-35 homogenizer (Kinematica) Use to homogenize twice in 10 second bursts and prepare the plasma membrane by centrifuging at 95.000 xg for 75 minutes on a 41 w / v% sucrose layer. The precipitate containing the plasma membrane is suspended in buffer and stored at −80 ° C. until use. The white band located between the two phases is diluted in buffer and centrifuged at 40.000 × g for 45 minutes. The precipitate containing the plasma membrane is suspended in buffer and stored at −80 ° C. until use.

  Glucagon is iodinated according to the Chloramine T method (Hunter and Greenwood, Nature 194, 495 (1962)) and purified using anion exchange chromatography (Jorgensen et al., Hormone and Metab. Res. 4, 223- 224 (1972)). The specific activity is 460 μCi / μg on the day of iodination. Tracers are stored in aliquots at -18 ° C and used immediately after thawing.

The binding assay is performed in triplicate in filter microtiter plates (MADV N65, Millipore). Buffer used for the assay, 50 mM HEPES, 5 mM EGTA , 5 mM MgCl 2, 0.005% Tween 20, pH 7.4. Glucagon was dissolved in 0.05M HCl and the same amount (w / w) of human serum albumin was added and lyophilized. On the day of use, it is dissolved in water and diluted to the desired concentration in buffer.

Test compounds are dissolved and diluted in DMSO. Add 140 μL buffer, 25 μL glucagon or buffer, and 10 μL DMSO or test compound to each well. Dilute the tracer (50.000 cpm) in buffer and add 25 μL to each well. 1-4 μg fresh thawed plasma membrane protein is diluted in buffer and then 25 μL aliquots are added to each well. Incubate the plate at 30 ° C. for 2 hours. Nonspecific binding is determined using 10 ⁻⁶ M glucagon. The bound and unbound tracers are then separated by vacuum filtration (Millipore vacuum manifold). The plate is washed with 2 × 100 μL / well buffer. The plate is dried for 2 hours, when the filter is separated from the plate using a Millipore Puncher. The filter is counted in a gamma counter.

Functional assay (I):
Functional assays are performed in 96 well microtiter plates (tissue culture plates, Nunc). The buffer concentrations obtained in this assay are 50 mM tris / HCl, 1 mM EGTA, 1.5 mM MgSO ₄ , 1.7 mM ATP, 20 μM GTP, 2 mM IBMX, 0.02% Tween 20, and 0.1% human serum albumin . The pH was 7.4. Glucagon and the proposed antagonist are added in 35 μL aliquots diluted in 50 mM tris / HCl, 1 mM EGTA, 1.85 mM MgSO ₄ , 0.0222% Tween-20, and 0.111% human serum albumin, pH 7.4. Add 20 μL of 50 mM tris / HCl, 1 mM EGTA, 1.5 mM magnesium sulfate, 11.8 mM ATP, 0.14 mM GTP, 14 mM IBMX, and 0.1% human serum albumin, pH 7.4. Dissolve GTP just before the assay.

  Add 50 μL containing 5 μg of plasma membrane protein in tris / HCl, EGTA, magnesium sulfate, human serum albumin buffer (actual concentration depends on protein concentration in the stored plasma membrane).

  The total assay volume is 140 μL. Incubate the plate for 2 hours at 37 ° C. with continuous shaking. The reaction is stopped by adding 25 μL of 0.5N HCl. CAMP is measured using a scintillation proximity kit (Amersham).

Glucagon binding assay (II):
BHK (neonatal hamster kidney cell line) cells are transfected with human glucagon receptor to prepare membrane preparations of the cells. Wheat germ agglutinin-induced SPA beads containing scintillant (WGA beads; Amersham) were bound to the membrane.

¹²⁵ I-glucagon bound to the human glucagon receptor in the membrane and excited the scintillant in the WGA beads to emit light. Glucagon or sample binding to the receptor competed with ¹²⁵ I-glucagon.

All steps in membrane preparation are kept on ice or performed at 4 ° C. BHK cells are collected and centrifuged. The pellet is resuspended in homogenization buffer (25 mM HEPES, pH = 7.4, 2.5 mM CaCl ₂ , 1.0 mM MgCl ₂ , 250 mg / L bacitracin, 0.1 mM Pefabloc) and polytron (Polytron ) Homogenize for 2 x 10 seconds using a 10-35 homogenizer (Kinematica) and add the same amount of homogenization buffer used for resuspension. After centrifugation (2000 × g for 15 minutes), the supernatant is transferred to a cold centrifuge tube and centrifuged at 40,000 × g for 45 minutes. Suspend the pellet in homogenization buffer, homogenize for 2 x 10 seconds (Polytron), and add additional homogenization buffer. The suspension is centrifuged at 40,000 xg for 45 minutes and the pellet is resuspended in resuspension buffer (25 mM HEPES, pH = 7.4,2.5 mM, CaCl ₂ , 1.0 mM MgCl ₂ ). Homogenize for 2 x 10 seconds (Polytron).

The protein concentration is usually approximately 1.75 mg / mL. Add stabilization buffer (25 mM HEPES, pH = 7.4, 2.5 mM CaCl ₂ , 1.0 mM MgCl ₂ , 1% bovine serum albumin, 500 mg / L bacitracin, 2.5 M sucrose), and store membrane preparation at –80 ° C To do.

The glucagon binding assay is performed on an Optiplate (polystyrene microplate, Packard). 50 μL assay buffer (25 mM HEPES, pH = 7.5, 2.5 mM CaCl ₂ , 1.0 mM MgCl ₂ , 0.003% Tween 20, 0.005% bacitracin, 0.05% sodium azide) and 5 μL glucagon or test compound (in DMSO) Add to each well. 50 μL tracer ( ¹²⁵ I-porcine glucagon, 50,000 cpm) and 50 μL membrane (7.5 μg) containing human glucagon receptor are then added to each well. Finally, 50 μL of WGA beads (containing 1 mg of beads) are transferred to each well. The plate is incubated on a shaker for 4 hours and then allowed to stand for 8-48 hours. The opti plates are counted in a top counter. Nonspecific binding is determined using 500 nM glucagon.

When tested in this glucagon binding assay (II), the compounds according to the previous examples showed IC ₅₀ values of less than 1000 nM.

GIP binding assay:
BHK (neonatal hamster kidney cell line) cells are transformed with the human GIP receptor to prepare membrane preparations of the cells. Wheat germ agglutinin-induced SPA beads containing scintillant (WGA beads; Amersham) were bound to the membrane. ¹²⁵ I-glucagon bound to the human glucagon receptor in the membrane and excited the scintillant in the WGA beads to emit light. Glucagon or sample binding to the receptor competed with ¹²⁵ I-glucagon.

All steps in membrane preparation are kept on ice or performed at 4 ° C. BHK cells are collected and centrifuged. The pellet is resuspended in homogenization buffer (25 mM HEPES, pH = 7.4, 2.5 mM CaCl ₂ , 1.0 mM MgCl ₂ , 250 mg / L bacitracin, 0.1 mM Pefabloc) and polytron (Polytron ) Homogenize for 2 x 10 seconds using a 10-35 homogenizer (Kinematica) and add the same amount of homogenization buffer used for resuspension. After centrifugation (2000 × g for 15 minutes), the supernatant is transferred to a cold centrifuge tube and centrifuged at 40,000 × g for 45 minutes. The pellet is resuspended in homogenization buffer, homogenized for 2 × 10 seconds (Polytron), and additional homogenization buffer is added. This suspension is centrifuged at 40,000 xg for 45 minutes and the pellet is resuspended in resuspension buffer (25 mM HEPES, pH = 7.4, 2.5 mM, CaCl ₂ , 1.0 mM MgCl ₂ ). Homogenize for 2 x 10 seconds (Polytron). The protein concentration is usually approximately 1.75 mg / mL. Add stabilization buffer (25 mM HEPES, pH = 7.4, 2.5 mM CaCl ₂ , 1.0 mM MgCl ₂ , 1% bovine serum albumin, 500 mg / L bacitracin, 2.5 M sucrose), and store membrane preparation at –80 ° C To do.

The GIP binding assay is performed on an Optiplate (polystyrene microplate, Packard). 50 μL assay buffer (25 mM HEPES, pH = 7.5, 2.5 mM CaCl ₂ , 1.0 mM MgCl ₂ , 0.003% Tween 20, 0.005% bacitracin, 0.05% sodium azide), and 5 μL GIP or test compound (in DMSO) each Add to wells. 50 μL of tracer ( ¹²⁵ I-porcine GIP, 50,000 cpm) and 50 μL of membrane (20 μg) containing human GIP receptor are then added to each well. Finally, 50 μL of WGA beads (containing 1 mg of beads) are transferred to each well. The plate is incubated for 3.5 hours on a shaker and then allowed to stand for 8-48 hours. The opti plates are counted in a top counter. Nonspecific binding is determined using 500 nM GIP.

  In general, the compounds according to the above-mentioned examples show a higher affinity for the glucagon receptor compared to the GIP receptor.

Claims (69)

A compound of the following general formula (I), and any diastereomer, enantiomer or tautomer thereof, and a mixture thereof, or a pharmaceutically acceptable salt thereof:

here,
A is

And
m is 0 or 1,
n is 0, 1, 2 or 3 where m and n are not both 0;
R ⁴ is hydrogen, halogen or-(CH ₂ ) _o -OR ⁵ ;
o is 0 or 1,
R ⁵ is hydrogen, C _1-6 -alkyl, C _1-6 -alkanoyl, aryl or aryl-C _1-6 -alkyl;
R ¹ and R ² are independently hydrogen, halogen or C _1-6 -alkyl, or R ¹ and R ² together form a double bond;
R ³ is hydrogen, C _1-6 -alkyl or halogen, or R ³ and R ² together form a double bond to oxygen,
X is arylene or heteroarylene, which is optionally _{halogen, -CN, -CF 3, -OCF 3} , -OCHF 2, -NO 2, -OR 8, -NR 8 R 9 and C _1-6 - Optionally substituted by one or two groups R ⁶ and R ⁷ selected from alkyl,
R ⁸ and R ⁹ are independently hydrogen or C _1-6 -alkyl;
Y is, -C (O) -, - O -, - NR 10 -, - S -, - S (O) -, - S (O) 2 -, or -CR ¹¹ R ¹² - and is,
R ¹⁰ is hydrogen or C _1-6 -alkyl;
R ¹¹ and R ¹² are independently hydrogen, C _1-6 -alkyl, or hydroxy, or R ¹¹ together with R ¹ forms a double bond, and R ¹² is hydrogen, C _{1 -6} -alkyl or hydroxy,
Z is -C (O)-(CR ¹³ R ¹⁴ ) _p- , -O- (CR ¹³ R ¹⁴ ) _p- , -S- (CR ¹³ R ¹⁴ ) _p- , -S (O)-(CR _{^{13 R 14) p -, -}} S (O) 2 - (CR 13 R 14) p -, - NR 15 - (CR 13 R 14) p -, or _{^{- (CR 13 R 14) p}} - in and,
p is 0, 1 or 2;
R ¹³ and R ¹⁴ are independently selected from hydrogen, —CF ₃ , —OCF ₃ and C _1-6 -alkyl;
R ¹⁵ is hydrogen or C _1-6 -alkyl;
D is aryl or heteroaryl optionally substituted with one or more substituents R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²⁰ and R ²¹ , where
R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ are independently
Hydrogen, _{halogen, -CN, -CH 2 CN, -CHF} 2, -CF 3, -OCF 3, -OCHF 2, -OCH 2 CF 3,
-OCF ₂ CHF ₂ , -S (O) ₂ CF ₃ , -SCF ₃ , -NO ₂ , -OR ²² , -NR ²² R ²³ , -SR ²² ,
-NR ²² S (O) ₂ R ²³ , -S (O) ₂ NR ²² R ²³ , -S (O) NR ²² R ²³ , -S (O) R ²² , -S (O) ₂ R ²² ,
-C (O) NR ²² R ²³ , -OC (O) NR ²² R ²³ -NR ²² C (O) R ²³ , -CH ₂ C (O) NR ²² R ²³ ,
-OCH ₂ C (O) NR ²² R ²³ , -CH ₂ OR ²² , -CH ₂ NR ²² R ²³ , -OC (O) R ²² , -C (O) R ²² or
-C (O) OR ²² ,
C _1-6 -alkyl, C _2-6 -alkenyl or C _2-4 -alkynyl,
This is optionally halogen, -CN, -CF ₃ , -OCF ₃ , -OCHF ₂ , -NO ₂ , -OR ²² , -NR ²² R ²³
And may be substituted with one or more substituents selected from C _1-6 -alkyl, C _3-8 -cycloalkyl, C _4-8 -cycloalkenyl, heterocyclyl, C _3-8 -cycloalkyl-C _1-6 -alkyl, C _3-8 -cycloalkyl-C _1-6 -alkoxy, C _3-8 -cycloalkyloxy, C _3-8 -cycloalkyl-C _1-6 -alkylthio, C _3-8- Cycloalkylthio, C _3-8 -cycloalkyl-C _2-6 -alkenyl, C _3-8 -cycloalkyl-C _2-6 -alkynyl, C _4-8 -cycloalkenyl-C _1-6 -alkyl, C _4-8- cycloalkenyl-C _2-6 -alkenyl, C _4-8 -cycloalkenyl-C _2-6 -alkynyl, heterocyclyl-C _1-6 -alkyl, heterocyclyl-C _2-4 -alkenyl, heterocyclyl- C _2-6-
Alkynyl, aryl, aryloxy, aryloxycarbonyl,
Aroyl, aryl-C _1-6 -alkoxy, aryl-C _1-6 -alkyl,
Aryl-C _2-6 -alkenyl, aryl-C _2-6 -alkynyl, heteroaryl,
Heteroaryl-C _1-6 -alkyl, heteroaryl-C _2-6 -alkenyl, or heteroaryl-C _2-6 -alkynyl,
The aromatic or non-aromatic ring system is halogen, -C (O) OR ²² , -CN, -CF ₃ , -OCF ₃ ,
-OCHF ₂ , -NO ₂ , -OR ²² , -NR ²² R ²³ and C _1-6 alkyl may be optionally substituted with one or more substituents,
R ²² and R ²³ are independently hydrogen, C _1-6 -alkyl, aryl-C _1-6 -alkyl or aryl, or when R ²² and R ²³ are bonded to the same nitrogen atom, Together with the nitrogen atom, a 3 to 8 member optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur and optionally containing one or two double bonds Or two of the R ^{16 to} R ¹⁹ groups can form a bridge- (CR ²⁴ R ²⁵ ) _a- when they are placed together in adjacent positions. O- (CR ²⁶ R ²⁷ ) _c -O- may be formed,
a is 0, 1, or 2;
c is 1 or 2,
R ²⁴ , R ²⁵ , R ²⁶ and R ²⁷ are independently hydrogen, C _1-6 alkyl or fluoro;
R ²⁰ and R ²¹ are independently hydrogen, C _1-6 alkyl, C _3-8 -cycloalkyl, or C _3-8 -cycloalkyl-C _1-6 -alkyl,
E is C _3-8 -cycloalkyl or C _4-8 -cycloalkenyl optionally substituted with one or two substituents R ²⁸ and R ²⁹ (wherein the substituents are independently
Hydrogen, _{halogen, -CN, -CF 3, -OCF 3} , -OCHF 2, -OR 33, -NR 33 R 34, C 1-6 - alkyl Le, C _3-8 - cycloalkyl, C _3-8 -Cycloalkenyl, heteroaryl and aryl,
Here, the heteroaryl group and aryl notation are optionally halogen, -CN,
May be substituted with one or more substituents selected from -CF ₃ , -OCF ₃ , -OCHF ₂ , -NO ₂ , -OR ³³ , -NR ³³ R ³⁴ and C _1-6 -alkyl;
R ³³ and R ³⁴ are independently hydrogen or C _1-6 -alkyl,
Or R ³³ and R ³⁴ , when they are attached to the same nitrogen atom, together with the nitrogen atom optionally contain one or two additional heteroatoms selected from nitrogen, oxygen and sulfur. And optionally selected to form a 3- to 8-membered heterocycle containing one or two double bonds), aryl, heteroaryl, aryl-C _2-4 -alkenyl, or aryl- C _2-6 -alkynyl, the aryl or heteroaryl moiety of which may optionally be substituted with one or more of R ²⁸ , R ²⁹ , R ³⁰ , R ³¹ and R ^{32 as} defined above, wherein R ²⁸ and R ²⁹ are as defined above, and R ³⁰ , R ³¹ and R ³² are independently
- hydrogen, _{halogen, -CHF 2, -CF 3, -OCF} 3, -OCHF 2, -OCH 2 CF 3, -OCF 2 CHF 2, -SCF 3,
-OR ³⁵ , -NR ³⁵ R ³⁶ , -SR ³⁵ , -S (O) R ³⁵ , -S (O) ₂ R ³⁵ , -C (O) NR ³⁵ R ³⁶ ,
-OC (O) NR ³⁵ R ³⁶ , -NR ³⁵ C (O) R ³⁶ , -OCH ₂ C (O) NR ³⁵ R ³⁶ , -C (O) R ³⁵ and -C (O) OR ³⁵
C _1-6 -alkyl, C _2-6 alkenyl and C _2-4 -alkynyl,
They optionally _{halogen, -CN, -CF 3, -OCF 3} , -OCHF 2, -NO 2, -OR 35, -NR 35 R 36
And optionally substituted with one or more substituents selected from C _1-6 -alkyl,
C _3-8 -cycloalkyl, C _4-8 -cycloalkenyl, heterocyclyl, C _3-8 -cycloalkyl-C _1-6 -alkyl, C _3-8 -cycloalkyl-C _2-6 -alkenyl, C _3-8 -Cycloalkyl-C _2-6 -alkynyl, C _4-8 -Cycloalkenyl-C _1-6 -alkyl, C _4-8 -Cycloalkenyl-C _2-6 -alkenyl, C _4-8 -Cyclo Alkenyl-C _2-6 -alkynyl,
Heterocyclyl -C _1-6 - alkyl, heterocyclyl -C _2-6 - alkenyl, Heteroshi acrylic -C _2-6 - alkynyl, aryl, aryloxy, aroyl,
Aryl-C _1-6 -alkoxy, aryl-C _1-6 -alkyl, aryl-C _2-6 -alkenyl, aryl-C _2-6 -alkynyl, heteroaryl, heteroaryl-C _1-6 -alkyl , Heteroaryl-C _2-6 -alkenyl, and heteroaryl-C _2-4 -alkynyl,
The aromatic or non-aromatic ring is optionally halogen, —CN, —CF ₃ , —OCF ₃ ,
May be substituted with one or more substituents selected from -OCHF ₂ , -NO ₂ , -OR ³⁵ , -NR ³⁵ R ³⁶ and C _1-6 -alkyl;
here,
R ³⁵ and R ³⁶ are independently hydrogen, C _1-6 -alkyl or aryl,
Or when R ³⁵ and R ³⁶ are attached to the same nitrogen atom, they together with the nitrogen atom optionally contain one or two additional heteroatoms selected from nitrogen, oxygen and sulfur; And optionally may form a 3-8 membered heterocycle containing one or two double bonds,
Or when two of R ³⁰ , R ³¹ and R ³² are attached to the same or adjacent ring carbon atoms, they are taken together to form a bridge —O— (CH ₂ ) _{t ^{-CR 37 R 38 - (CH 2}} ) l -O -, - (CH 2) t -CR 37 R 38 - (CH 2) l -, or ^{_{-S- (CH 2) t -CR 37}} R 38 - ( CH ₂ ) _l -S-
t and l are independently 0, 1, 2, 3, 4 or 5,
R ³⁷ and R ³⁸ are independently hydrogen or C _1-6 -alkyl. The compound of claim 1, wherein A is

here,
m, n and R ⁴ are as defined in claim 1;
A compound that is 3. A compound according to claim 2, wherein A is

A compound that is 3. A compound according to claim 2, wherein A is

A compound that is The compound of claim 1, wherein A is

A compound that is A compound according to any one of the preceding claims, wherein X is a monocyclic arylene or heteroarylene, optionally substituted as defined in claim 1. A compound according to any one of the preceding claims, wherein X is

Wherein R ⁶ and R ⁷ are as defined in claim 1. 8. The compound of claim 7, wherein X is

Wherein R ⁶ and R ⁷ are as defined in claim 1. 9. A compound according to claim 7 or 8, wherein R ⁶ and R ⁷ are both hydrogen. A compound according to any one of the preceding claims, wherein E is

Wherein R ²⁸ , R ²⁹ , R ³⁰ , R ³¹ and R ³² are as defined in claim 1. The compound of claim 10, wherein E is

Wherein R ²⁸ , R ²⁹ , R ³⁰ , R ³¹ and R ³² are as defined in claim 1. 12. A compound according to claim 11 wherein E is

Wherein R ³⁰ , R ³¹ and R ³² are as defined in claim 1. 13. A compound according to claim 12, wherein E is

Wherein R ³⁰ , R ³¹ and R ³² are as defined in claim 1. 12. A compound according to claim 11 wherein E is

Wherein R ²⁸ , R ²⁹ , R ³⁰ , R ³¹ and R ³² are as defined in claim 1. A compound according to any one of claims 10 to 14, R ^30, R ³¹ and R ³² are independently
·hydrogen,
・ Halogen, -OCF ₃ , -SCF ₃ , -OCHF ₂ or -CF ₃ ,
C _1-6 -alkyl; these are optionally fluoro, —CN, —CF ₃ , —OCF ₃ , —OR ³⁵ and
May be substituted with one or more substituents selected from -NR ³⁵ R ³⁶ ,
C _3-8 -cycloalkyl or C _4-8 -cycloalkenyl; these are optionally fluoro,
One or more substituents selected from -CN, -CF ₃ , -OCF ₃ , -OR ³⁵ , -NR ³⁵ R ³⁶ and C _1-6 -alkyl,
• aryl, aryloxy, or aryl-C _1-6 -alkoxy; these aryl moieties are optionally halogen, —CN, —CF ₃ , —OCF ₃ , —NO ₂ , —R ³⁵ , —NR ³⁵ R ³⁶ and
Optionally substituted with one or more substituents selected from C _1-6 -alkyl,
And
R ³⁵ and R ³⁶ are independently hydrogen, C _1-6 -alkyl or aryl,
Or when R ³⁵ and R ³⁶ are attached to the same nitrogen atom, they together with the nitrogen atom optionally contain one or two additional heteroatoms selected from nitrogen, oxygen and sulfur; And a compound which may form a 3- to 8-membered heterocycle optionally containing one or two double bonds. A compound according to claim 15, R ^30, R ³¹ and R ³² are independently
·hydrogen,
・ Halogen, -OCF ₃ , -OCHF ₂ or -CF ₃ ,
C _1-6 -alkyl; these are optionally fluoro, —CN, —CF ₃ , —OCF ₃ , —OR ³⁵ and
May be substituted with one or more substituents selected from -NR ³⁵ R ³⁶ ,
Cyclohexyl or cyclohexyl-1-enyl; these are optionally fluoro,
One or more substituents selected from -CN, -CF ₃ , -OCF ₃ , -OR ³⁵ , -NR ³⁵ R ³⁶ and C _1-6 -alkyl,
Phenyl: this is optionally halogen, -CN, -CF ₃ , -OCF ₃ , -NO ₂ , -R ³⁵ ,
Optionally substituted with one or more substituents selected from —NR ³⁵ R ³⁶ and C _1-6 -alkyl; • phenoxy or benzyloxy; these phenyl moieties are optionally halogenated, —CN, —CF ₃ , —OCF ₃ , —NO ₂ , —R ³⁵ , —NR ³⁵ R ³⁶ and optionally substituted with one or more substituents selected from C _1-6 -alkyl.
And
A compound wherein R ³⁵ and R ³⁶ are independently hydrogen or C _1-6 -alkyl. A compound according to any one of claims 10 to 16, R ³⁰ and R ³² are hydrogen Both, R ³¹ are different compounds with hydrogen. 11. A compound according to claim 10, wherein E is:

19. A compound according to claim 18, wherein E is:

19. A compound according to claim 18, wherein E is:

11. A compound according to claim 10, wherein E is:

Here, R ³⁰ is as defined in claim 1. A compound according to claim 21, comprising
R ³⁰ is halogen, or heteroaryl: this is optionally halogen, —CN, —CF ₃ , —NO ₂ , —OR ³⁵ , —NR ³⁵ R ³⁶
And optionally substituted with one or more substituents selected from C _1-6 -alkyl,
R ³⁵ and R ³⁶ are independently hydrogen or C _1-6 -alkyl,
Or when R ³⁵ and R ³⁶ are attached to the same nitrogen atom, they together with the nitrogen atom optionally contain one or two additional heteroatoms selected from nitrogen, oxygen and sulfur; And a compound which may form a 3- to 8-membered heterocycle optionally containing one or two double bonds. A compound according to claim 22
R ³⁰ is
• halogen, or • thienyl: one or more optionally selected from halogen, —CN, —CF ₃ , —NO ₂ , —OR ³⁵ , —NR ³⁵ R ³⁶ , and C _1-6 -alkyl And may be substituted with
R ³⁵ and R ³⁶ are independently hydrogen or C _1-6 -alkyl,
Or when R ³⁵ and R ³⁶ are attached to the same nitrogen atom, they together with the nitrogen atom optionally contain one or two additional heteroatoms selected from nitrogen, oxygen and sulfur; And a compound which may form a 3- to 8-membered heterocycle optionally containing one or two double bonds. 24. The compound of claim 23, wherein E is represented below:

A compound according to any one of the preceding claims, wherein Y is -C (O)-, -O-, -S (O) _2- , -NH-, or -CH _2-. A compound that is A compound according to any one of claims 1 to 24,
Y is -CHR ¹¹ - and is,
R ¹¹ is a compound that forms a double bond with R ¹ . 26. The compound according to claim 25, wherein Y is -C (O)-. A compound according to claim 25 or 27, compound R ¹ and R ² are hydrogen Both. A compound according to claim 25 or 27, the compounds are R ¹ and R ² are attached form a double bond. A compound according to any one of the preceding claims, wherein R ³ is hydrogen. A compound according to any one of the preceding claims, wherein Z is
^{-C (O) - (CR 13} R 14) p -, - O- (CR 13 R 14) p -, - NR 15 - (CR 13 R 14) p or _{-S (O) 2, - (} CR 13 A compound wherein R ¹⁴ ) _p − and p, R ¹³ , R ¹⁴ and R ¹⁵ are as defined in claim 1. 32. The compound of claim 31, wherein Z is —NR ¹⁵ — (CR ¹³ R ¹⁴ ) _p , or —C (O) — (CR ¹³ R ¹⁴ ) _p —, wherein p is A compound as defined above, wherein R ¹³ and R ¹⁴ are independently selected from hydrogen, —CF ₃ , —OCF ₃ and C _1-6 -alkyl, and R ¹⁵ is hydrogen. A compound according to claim 32, Z is -NH (CH _{2) p} or
_{-C (O) - (CH 2} ) p - in and, p is as defined in claim 1 compound. 34. The compound of claim 33, wherein Z is NH or -C (O)-. 35. The compound of claim 34, wherein Z is -C (O)-. A compound according to any one of the preceding claims, wherein D is represented by the following formula:

Here, R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²⁰ and R ²¹ are as defined in claim 1. 37. The compound of claim 36, wherein D is represented by the following formula:

Here, R ¹⁶ , R ¹⁷ and R ¹⁸ are as defined in claim 1. 38. The compound of claim 37, wherein
R ¹⁶ , R ¹⁷ and R ¹⁸ are independently
Hydrogen, _{halogen, -CN, -CH 2 CN, -CHF} 2, -CF 3, -OCF 3, -OCHF 2, -OCH 2 CF 3,
-OCF ₂ CHF ₂ , -S (O) ₂ CF ₃ , -SCF ₃ , -NO ₂ , -OR ²² , -NR ²² R ²³ , -SR ²² ,
-NR ²² S (O) ₂ R ²³ , -S (O) ₂ NR ²² R ²³ , -S (O) NR ²² R ²³ , -S (O) R ²² , -S (O) ₂ R ²² ,
-C (O) NR ²² R ²³ , -OC (O) NR ²² R ²³ , -NR ²² C (O) R ²³ , -CH ₂ C (O) NR ²² R ²³ ,
-OCH ₂ C (O) NR ²² R ²³ , -CH ₂ OR ²² , -CH ₂ NR ²² R ²³ , -OC (O) R ²² , -C (O) R ²² or
Optionally substituted with one or more substituents selected from —C (O) OR ²² • C _1-6 -alkyl: optionally, fluoro, —CN, —CF ₃ , —OCF ₃ , —OR ²² and
Optionally substituted with one or more substituents selected from —NR ²² R ²³ • C _3-8 -cycloalkyl: optionally, fluoro, —C (O) OR ²⁴ , —CN, —CF ₃ ,
Optionally substituted with one or more substituents selected from -OCF ₃ , -OR ²² , -NR ²² R ²³ and C _1-6 -alkyl. Aryl or aryloxy: these are optionally fluoro, -C (O) OR ²⁴ , -CN,
-CF ₃ , -OCF ₃ , -OR ²² , -NR ²² R ²³ and optionally substituted by one or more substituents selected from C _1-6 -alkyl In the above, R ²² and R ²³ are independently , Hydrogen, C _1-6 -alkyl, aryl-
C _1-6 -alkyl or aryl, or when R ²² and R ²³ are attached to the same nitrogen atom, they are taken together with the nitrogen atom and are optionally selected from nitrogen, oxygen and sulfur May form a 3-8 membered heterocycle containing one or two additional heteroatoms, and optionally one or two double bonds,
Or when two of the radicals R ^{16 to} R ¹⁸ are arranged in adjacent positions, they are taken together to form _a bridge- (CR ²⁴ R ²⁵ ) _a -O- (CR ²⁶ R ²⁷ ) _c -O- may be formed,
a is 0, 1 or 2;
c is 1 or 2,
A compound wherein R ²⁴ , R ²⁵ , R ²⁶ and R ²⁷ are independently hydrogen, C _1-6 alkyl or fluoro. 40. The compound of claim 38, wherein
R ¹⁶ , R ¹⁷ and R ¹⁸ are independently
Hydrogen, halogen, -CF ₃ , -OCF ₃ , -SCF ₃ , C _1-6 -alkyl, C _1-6 -alkoxy, phenyl, cyclopentyl, cyclohexyl or phenoxy,
Or when two of the radicals R ^{16 to} R ¹⁸ are arranged in adjacent positions, they are taken together to form a bridge —O— (CF ₂ ) ₂ —O—, —CF ₂ —O -CF ₂ -O- or -O-CH ₂ -O-
A compound that may form A compound according to any one of claims 36 to 39, an R ¹⁶ is hydrogen, R ¹⁷ and R ¹⁸ of the compound different from hydrogen. 40. A compound according to any one of claims 36 to 39, wherein R ¹⁶ and R ¹⁷ are hydrogen and R ¹⁸ is different from hydrogen. The compound according to claim 1 of the general formula (I ₄ ), and any diastereomer, enantiomer or tautomer thereof, and a mixture containing them, or a pharmaceutically acceptable salt thereof:

Here, R ⁶ , R ⁷ , E and D are as defined in any one of claims 1, 10 to 22 or 36 to 41. The compound according to claim 1 of the general formula (I ₅ ), and any diastereomer, enantiomer or tautomer thereof and a mixture containing them, or a pharmaceutically acceptable salt thereof:

Here, R ⁶ , R ⁷ , E and D are as defined in any one of claims 1, 10 to 24 or 36 to 39. 44. The compound of claim 43 of the following general formula, and any diastereomer, enantiomer or tautomer thereof, and mixtures thereof, or pharmaceutically acceptable salts thereof:

Here, R ⁶ , R ⁷ , E and D are as defined in any one of 1, 10 to 24 or 36 to 41. 44. The compound of claim 43 of the following general formula, and any diastereomer, enantiomer or tautomer thereof, and mixtures thereof, or pharmaceutically acceptable salts thereof:

Here, R ⁶ , R ⁷ , E and D are as defined in any one of 1, 10 to 24 or 36 to 41. The compound according to claim 1 of the general formula (I ₆ ), and any diastereomer, enantiomer or tautomer thereof and a mixture containing them, or a pharmaceutically acceptable salt thereof:

Here, R ⁶ , R ⁷ , E and D are as defined in any one of 1, 10 to 24 or 36 to 41. A compound according to any one of the preceding claims, having an IC ₅₀ value of 5 μM or less as measured by the glucagon binding assay (I) and glucagon binding assay (II) described in the specification. Compound. 48. The compound of claim 47, as measured by the glucagon binding assay (I) and glucagon binding assay (II) described in the specification, less than 1 M, preferably less than 500 nM, more preferably 100 nM. A compound having an IC ₅₀ value of less than A compound according to any one of the preceding claims, useful for the therapeutic stomach of an indication selected from the group consisting of hyperlipidemia, IGT, type 2 diabetes, type 1 diabetes and obesity Compound that is an important drug. 50. A compound according to any one of claims 1 to 49 for use as a medicament. 50. A pharmaceutical composition comprising as active ingredient at least one compound according to any one of claims 1 to 49 together with one or more pharmaceutically acceptable carriers or excipients. 52. A pharmaceutical composition according to claim 51 in unit dosage form, comprising from about 0.05 mg to about 1000 mg, preferably from about 0.1 mg to about 500 mg, especially from about 0.5 mg to about 200 mg. A pharmaceutical composition comprising the compound according to claim 1. 50. Use of a compound according to any one of claims 1 to 49 for the preparation of a medicament for treating a disorder or disease for which a glucagon antagonist activity is useful. 50. Use of a compound according to any one of claims 1 to 49 for the preparation of a medicament for treating disorders and diseases mediated by glucagon. 50. Use of a compound according to any one of claims 1 to 49 for the preparation of a medicament for treating hyperlipidemia. 50. Use of a compound according to any one of claims 1 to 49 for the preparation of a medicament for lowering blood glucose in an animal. 50. Use of a compound according to any one of claims 1 to 49 for the manufacture of a medicament for treating IGT. 50. Use of a compound according to any one of claims 1 to 49 for the manufacture of a medicament for treating type 2 diabetes. 59. Use according to claim 58, for the manufacture of a medicament for delaying or preventing the progression from IGT to type 2 diabetes. 59. Use according to claim 58, for the manufacture of a medicament for delaying or preventing the progression from non-insulin requiring type 2 diabetes to insulin requiring type 2 diabetes. 50. Use of a compound according to any one of claims 1 to 49 for the manufacture of a medicament for treating type 1 diabetes. 50. Use of a compound according to any one of claims 1 to 49 for the manufacture of a medicament for treating obesity. 50. Use of a compound according to any one of claims 1 to 49 for the manufacture of a medicament for treating dyslipidemia. 62. Use according to any one of claims 53 to 61, comprising a treatment with a further antidiabetic agent. 63. Use according to any one of claims 53 to 62, comprising a treatment with a further anti-obesity agent. 63. Use according to any one of claims 53 to 62, comprising a treatment with a further antihyperlipidemic agent. 63. Use according to any one of claims 53 to 62, comprising a treatment with a further antihypertensive drug. 51. A method of treating a disorder or disease in which glucagon antagonism is beneficial, in an effective amount for a patient in need thereof, or an effective amount of a compound of any one of claims 1-49, or claim 51 or 53. A method comprising administering the pharmaceutical composition according to 52. 69. The method of claim 68, wherein the effective amount of the compound is from about 0.05 mg to about 2000 mg, preferably from about 0.1 mg to about 1000 mg, particularly preferably from about 0.5 mg to about 500 mg per day.