HUMAN GLUCAGON-LIKE-PEPTIDE-1 MODULATORS AND THEIR USE IN THE TREATMENT OF DIABETES RELATED CONDITIONS

US 20070238669A1
Filed: 01/11/2007
Published: 10/11/2007
Est. Priority Date: 01/11/2006
Status: Abandoned Application

First Claim

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1. An isolated polypeptide comprising a sequence of Formula I
X_aa1-X_aa2-X_aa3-X_aa4-X_aa5-X_aa6-X_aa7-X_aa8-X_aa9-X_aa10-X_aa11

I wherein, X_aa1is a naturally or non-naturally occurring amino acid comprising an imidazole, such as histidine;

wherein any of the carbon atoms of said amino acid are optionally substituted with hydrogen, or with one or more alkyl groups, wherein the free amino group of said amino acid is optionally substituted with hydrogen, alkyl, acyl, benzoyl, L-lactyl, alkyloxycarbonyl, aryloxycarbonyl, arylalkyloxycarbonyl, heterocyclyloxycarbonyl, heteroarylalkyloxycarbonyl, alkylcarbamoyl, arylcarbamoyl, arylalkylcarbamoyl, heterocyclylsulfonyl, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, heteroarylalkylsulfonyl or heteroarylsulfonyl; and

wherein the amino group of X_aa1is optionally absent, such that X_aa1is the des-amino acid of histidine in which any of the carbon atoms are optionally substituted with hydrogen or one or more alkyl groups;

X_aa2is a naturally or non-naturally occurring amino acid selected from the group consisting of D-alanine, α

-amino-isobutyric acid (Aib), N-methyl-D-alanine, N-ethyl-D-alanine, 2-methyl-azetidine-2-carboxylic acid, alpha-methyl-(L)-proline, 2-methylpiperidine-2-carboxylic acid and isovaline;

X_aa3is a naturally or non-naturally occurring amino acid comprising an amino acid side chain which contains a carboxylic acid, for example aspartic acid or glutamic acid;

or wherein X_aa3is a naturally or non-naturally occurring amino acid containing an imidazole side chain, for example histidine, and wherein any of the carbon atoms of said amino acid are optionally substituted with one or more alkyl groups;

X_aa4is glycine;

X_aa5is a naturally or non-naturally occurring amino acid selected from the group consisting of (L)-threonine, and (L)-norvaline; and

wherein any of the carbon atoms of said amino acid are optionally substituted with one or more alkyl groups;

X_aa6is a naturally or non-naturally occurring amino acid comprising an alpha carbon which is di-substituted;

wherein one of the side chains of said amino acid contains an aromatic ring, for example alpha-methyl-phenylalanine, alpha-methyl-2-fluorophenylalanine, and alpha-methyl-2,6-difluorophenylalanine;

wherein any of the carbon atoms of said amino acid are optionally substituted with one or more alkyl groups or one or more halo groups;

X_aa7is a naturally or non-naturally occurring amino acid comprising an amino acid side chain which is substituted with a hydroxyl group, for example L-threonine;

wherein any of the carbon atoms of said amino acid are optionally substituted with one or more alkyl groups;

X_aa8is a naturally or non-naturally occurring amino acid selected from the group consisting of L-serine, and L-histidine;

wherein one or more of the carbon atoms of said amino acid is optionally substituted with one or more alkyl groups;

X_aa9is a naturally or non-naturally occurring amino acid comprising an amino acid side chain which contains a carboxylic acid, for example L-aspartic acid or L-glutamic acid;

wherein one or more of the carbon atoms of said amino acid is optionally substituted with one or more alkyl groups;

X_aa10is a naturally or non-naturally occurring amino acid of Formula II;

wherein R₁is selected from the group consisting of hydrogen, alkyl, and halo; and

R₂and R₃are each independently selected from the group consisting of hydrogen, halo, methyl, ethyl, alkyl, hydroxyl, methoxy, and alkoxy;

X_aa11is a naturally or non-naturally occurring amino acid of any of Formulae III, IV, V, or VI, wherein;

Formula III is;

wherein the C-terminal carbonyl carbon of said amino acid is attached to a nitrogen to form a carboxamide (NH₂);

wherein ring A is selected from the group consisting of aryl and heteroaryl;

wherein R₄and R₅are each independently selected from the group consisting of hydrogen, halo, methyl, ethyl, alkyl, hydroxyl, methoxy, alkoxy, aryl, heteroaryl; and

wherein X₁and X₂are each CH-alkyl, CH₂, NH, S or O; and

Formula III may further comprise at least one R₄or R₅groups, and, if more than one are present, may or may not be equivalent;

Formula IV is;

wherein the C-terminal carbonyl carbon of said amino acid is attached to a nitrogen to form a carboxamide (NH₂);

wherein R₄is selected from the group consisting of hydrogen, hydroxyl, methyl, ethyl, alkyl, methoxy, alkoxy, aryl, heteroaryl;

wherein R₅is selected from the group consisting of hydrogen, methyl, ethyl, alkyl, cycloalkyl, aryl, heteroaryl, alkylaryl, or heteroalkylaryl;

wherein X is selected from the group consisting of CH₂, CH₂CH₂, or CHCH₃;

wherein Y₁is selected from the group consisting of —

NH—

, —

O—

, and —

C═

O—

;

wherein Y₂is selected from the group consisting of —

C═

O—

, —

O═

C—

O— and

—

SO₂—

when Y₁is NH or O;

wherein Y₂is selected from the group consisting of —

NH—

, —

N—

, or —

O—

when Y₁is C═

O; and

wherein R₆is selected from the group consisting of hydrogen, methyl, ethyl, alkyl, cycloalkyl, aryl, heteroaryl, alkylaryl, or alkylheteroaryl; and

Formula IV further comprises at least one R₆group and, if more than one are present, may or may not, be equivalent;

Formula V is;

wherein the C-terminal carbonyl carbon of said amino acid is attached to a nitrogen to form a carboxamide (NH₂);

wherein R₄is selected from the group consisting of hydrogen, hydroxyl, methyl, ethyl, alkyl, methoxy, alkoxy, aryl, heteroaryl;

wherein R₅is selected from the group consisting of hydrogen, methyl, ethyl, alkyl, cycloalkyl, aryl, heteroaryl, alkylaryl, or heteroalkylaryl;

wherein X₁is either absent or consists of CH₂;

wherein X₂is selected from the group consisting of —

CO—

, CO—

N(−

)₂, —

CO—

O—

, —

SO—

, and —

SO₂—

;

wherein R₆and R₇are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, alkylaryl, or alkylheteroaryl; and

Formula V comprises at least one R₇group, and, if more than one are present, may or may not be equivalent. Formula VI is;

wherein the C-terminal carbonyl carbon of said amino acid is attached to a nitrogen to form a carboxamide (NH₂);

wherein R₄is selected from the group consisting of hydrogen, methyl, ethyl, alkyl, cycloalkyl, aryl, heteroaryl, alkylaryl, or heteroalkylaryl;

wherein R₅is selected from the group consisting of hydrogen, hydroxyl, methyl, ethyl, alkyl, methoxy, and alkoxy;

wherein R₆is selected from the group consisting of hydrogen, methyl, ethyl, alkyl, cycloalkyl, heterocycloalkyl, hydroxyl, methoxy, and alkoxy; and

Formula VI may further comprise at least one R₆group, and, if more than one are present, may or may not be equivalent and may further comprise R₅and R₆groups which together form a cycloalkyl, heterocycloalkyl, cycloalkylaryl, or cycloalkylheteroaryl group.

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Abstract

The present invention provides novel human glucagon-like peptide-1 (GLP-1)-receptor modulators that have biological activity similar or superior to native GLP-1 peptide and thus are useful for the treatment or prevention of diseases or disorders associated with GLP activity. Further, the present invention provides novel, chemically modified compounds that not only stimulate insulin secretion in type II diabetics, but also produce other beneficial insulinotropic responses. These synthetic peptide GLP-1 receptor modulators exhibit increased stability to proteolytic cleavage making them ideal therapeutic candidates for oral or parenteral administration. The compounds of this invention show desirable pharmacokinetic properties and desirable potency in efficacy models of diabetes.

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62 Claims

1. An isolated polypeptide comprising a sequence of Formula I
X_aa1-X_aa2-X_aa3-X_aa4-X_aa5-X_aa6-X_aa7-X_aa8-X_aa9-X_aa10-X_aa11
- I wherein, X_aa1is a naturally or non-naturally occurring amino acid comprising an imidazole, such as histidine;
  
  wherein any of the carbon atoms of said amino acid are optionally substituted with hydrogen, or with one or more alkyl groups, wherein the free amino group of said amino acid is optionally substituted with hydrogen, alkyl, acyl, benzoyl, L-lactyl, alkyloxycarbonyl, aryloxycarbonyl, arylalkyloxycarbonyl, heterocyclyloxycarbonyl, heteroarylalkyloxycarbonyl, alkylcarbamoyl, arylcarbamoyl, arylalkylcarbamoyl, heterocyclylsulfonyl, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, heteroarylalkylsulfonyl or heteroarylsulfonyl; and
  
  wherein the amino group of X_aa1is optionally absent, such that X_aa1is the des-amino acid of histidine in which any of the carbon atoms are optionally substituted with hydrogen or one or more alkyl groups;
  
  X_aa2is a naturally or non-naturally occurring amino acid selected from the group consisting of D-alanine, α
  
  -amino-isobutyric acid (Aib), N-methyl-D-alanine, N-ethyl-D-alanine, 2-methyl-azetidine-2-carboxylic acid, alpha-methyl-(L)-proline, 2-methylpiperidine-2-carboxylic acid and isovaline;
  
  X_aa3is a naturally or non-naturally occurring amino acid comprising an amino acid side chain which contains a carboxylic acid, for example aspartic acid or glutamic acid;
  
  or wherein X_aa3is a naturally or non-naturally occurring amino acid containing an imidazole side chain, for example histidine, and wherein any of the carbon atoms of said amino acid are optionally substituted with one or more alkyl groups;
  
  X_aa4is glycine;
  
  X_aa5is a naturally or non-naturally occurring amino acid selected from the group consisting of (L)-threonine, and (L)-norvaline; and
  
  wherein any of the carbon atoms of said amino acid are optionally substituted with one or more alkyl groups;
  
  X_aa6is a naturally or non-naturally occurring amino acid comprising an alpha carbon which is di-substituted;
  
  wherein one of the side chains of said amino acid contains an aromatic ring, for example alpha-methyl-phenylalanine, alpha-methyl-2-fluorophenylalanine, and alpha-methyl-2,6-difluorophenylalanine;
  
  wherein any of the carbon atoms of said amino acid are optionally substituted with one or more alkyl groups or one or more halo groups;
  
  X_aa7is a naturally or non-naturally occurring amino acid comprising an amino acid side chain which is substituted with a hydroxyl group, for example L-threonine;
  
  wherein any of the carbon atoms of said amino acid are optionally substituted with one or more alkyl groups;
  
  X_aa8is a naturally or non-naturally occurring amino acid selected from the group consisting of L-serine, and L-histidine;
  
  wherein one or more of the carbon atoms of said amino acid is optionally substituted with one or more alkyl groups;
  
  X_aa9is a naturally or non-naturally occurring amino acid comprising an amino acid side chain which contains a carboxylic acid, for example L-aspartic acid or L-glutamic acid;
  
  wherein one or more of the carbon atoms of said amino acid is optionally substituted with one or more alkyl groups;
  
  X_aa10is a naturally or non-naturally occurring amino acid of Formula II;
  
  wherein R₁is selected from the group consisting of hydrogen, alkyl, and halo; and
  
  R₂and R₃are each independently selected from the group consisting of hydrogen, halo, methyl, ethyl, alkyl, hydroxyl, methoxy, and alkoxy;
  
  X_aa11is a naturally or non-naturally occurring amino acid of any of Formulae III, IV, V, or VI, wherein;
  
  Formula III is;
  
  wherein the C-terminal carbonyl carbon of said amino acid is attached to a nitrogen to form a carboxamide (NH₂);
  
  wherein ring A is selected from the group consisting of aryl and heteroaryl;
  
  wherein R₄and R₅are each independently selected from the group consisting of hydrogen, halo, methyl, ethyl, alkyl, hydroxyl, methoxy, alkoxy, aryl, heteroaryl; and
  
  wherein X₁and X₂are each CH-alkyl, CH₂, NH, S or O; and
  
  Formula III may further comprise at least one R₄or R₅groups, and, if more than one are present, may or may not be equivalent;
  
  Formula IV is;
  
  wherein the C-terminal carbonyl carbon of said amino acid is attached to a nitrogen to form a carboxamide (NH₂);
  
  wherein R₄is selected from the group consisting of hydrogen, hydroxyl, methyl, ethyl, alkyl, methoxy, alkoxy, aryl, heteroaryl;
  
  wherein R₅is selected from the group consisting of hydrogen, methyl, ethyl, alkyl, cycloalkyl, aryl, heteroaryl, alkylaryl, or heteroalkylaryl;
  
  wherein X is selected from the group consisting of CH₂, CH₂CH₂, or CHCH₃;
  
  wherein Y₁is selected from the group consisting of —
  
  NH—
  
  , —
  
  O—
  
  , and —
  
  C═
  
  O—
  
  ;
  
  wherein Y₂is selected from the group consisting of —
  
  C═
  
  O—
  
  , —
  
  O═
  
  C—
  
  O— and
  
  —
  
  SO₂—
  
  when Y₁is NH or O;
  
  wherein Y₂is selected from the group consisting of —
  
  NH—
  
  , —
  
  N—
  
  , or —
  
  O—
  
  when Y₁is C═
  
  O; and
  
  wherein R₆is selected from the group consisting of hydrogen, methyl, ethyl, alkyl, cycloalkyl, aryl, heteroaryl, alkylaryl, or alkylheteroaryl; and
  
  Formula IV further comprises at least one R₆group and, if more than one are present, may or may not, be equivalent;
  
  Formula V is;
  
  wherein the C-terminal carbonyl carbon of said amino acid is attached to a nitrogen to form a carboxamide (NH₂);
  
  wherein R₄is selected from the group consisting of hydrogen, hydroxyl, methyl, ethyl, alkyl, methoxy, alkoxy, aryl, heteroaryl;
  
  wherein R₅is selected from the group consisting of hydrogen, methyl, ethyl, alkyl, cycloalkyl, aryl, heteroaryl, alkylaryl, or heteroalkylaryl;
  
  wherein X₁is either absent or consists of CH₂;
  
  wherein X₂is selected from the group consisting of —
  
  CO—
  
  , CO—
  
  N(−
  
  )₂, —
  
  CO—
  
  O—
  
  , —
  
  SO—
  
  , and —
  
  SO₂—
  
  ;
  
  wherein R₆and R₇are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, alkylaryl, or alkylheteroaryl; and
  
  Formula V comprises at least one R₇group, and, if more than one are present, may or may not be equivalent. Formula VI is;
  
  wherein the C-terminal carbonyl carbon of said amino acid is attached to a nitrogen to form a carboxamide (NH₂);
  
  wherein R₄is selected from the group consisting of hydrogen, methyl, ethyl, alkyl, cycloalkyl, aryl, heteroaryl, alkylaryl, or heteroalkylaryl;
  
  wherein R₅is selected from the group consisting of hydrogen, hydroxyl, methyl, ethyl, alkyl, methoxy, and alkoxy;
  
  wherein R₆is selected from the group consisting of hydrogen, methyl, ethyl, alkyl, cycloalkyl, heterocycloalkyl, hydroxyl, methoxy, and alkoxy; and
  
  Formula VI may further comprise at least one R₆group, and, if more than one are present, may or may not be equivalent and may further comprise R₅and R₆groups which together form a cycloalkyl, heterocycloalkyl, cycloalkylaryl, or cycloalkylheteroaryl group.
- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61)
- - 2. The isolated polypeptide of claim 1, wherein said X_aa1is L-Histidine and wherein the terminal amino group is optionally substituted with hydrogen, alkyl, dialkyl, acyl, benzoyl, L-lactyl, alkyloxycarbonyl, aryloxycarbonyl, arylalkyloxycarbonyl, heterocyclyloxycarbonyl, heteroarylalkyloxycarbonyl, alkylcarbamoyl, arylcarbamoyl, arylalkylcarbamoyl, heterocyclylsulfonyl, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, heteroarylalkylsulfonyl or heteroarylsulfonyl.
  - 3. The isolated polypeptide of claim 1, wherein said X_aa1is selected from the group consisting of L-His, L-N-methyl-His, L-α
    - -methyl-His, des-amino-His, 3-(1H-imidazol-4-yl)-2-methylpropanoyl, and (S)-3-(1H-imidazol-4-yl)-2-hydroxypropanoyl(L-β
      
      -imidazolelactyl).
  - 4. The isolated polypeptide of claim 1, wherein said X_aa2is selected from the group consisting of α
    - -amino-isobutyric acid (Aib), D-alanine, N-methyl-D-alanine, alpha-methyl-(L)-proline, 2-methyl-azetidine-2-carboxylic acid and 2-methylpiperidine-2-carboxylic acid.
  - 5. The isolated polypeptide of claim 1, wherein said X_aa3is selected from the group consisting of L-glutamic acid and L-aspartic acid.
  - 6. The isolated polypeptide of claim 1, wherein said X_aa4is Gly.
  - 7. The isolated polypeptide of claim 1, wherein said X_aa5is selected from the group consisting of L-Thr, and L-Nva.
  - 8. The isolated polypeptide of claim 1, wherein said X_aa6is selected from the group consisting of L-α
    - -Me-Phe, L-α
      
      -Me-2-fluoro-Phe, and L-α
      
      -Me-2,6-difluoro-Phe.
  - 9. The isolated polypeptide of claim 1, wherein said X_aa7is L-Thr.
  - 10. The isolated polypeptide of claim 1, wherein said X_aa8is selected from the group consisting of L-Ser, and L-His.
  - 11. The isolated polypeptide of claim 1, wherein said X_aa9is L-Asp.
  - 12. The isolated polypeptide of claim 1, wherein said X_aa10of Formula II is selected from the group consisting of 4-phenyl-phenylalanine, 4-[(4′
    - -methoxy-2′
      
      -ethyl)phenyl]phenylalanine, 4-[(4′
      
      -ethoxy-2′
      
      -ethyl)phenyl]phenylalanine, 4-[(4′
      
      -methoxy-2′
      
      -methyl)phenyl]phenylalanine, 4-[(4′
      
      -ethoxy-2′
      
      -methyl)phenyl]phenylalanine, 4-(2′
      
      -ethylphenyl)phenylalanine, 4-(2′
      
      -methylphenyl)phenylalanine, 4-[(3′
      
      ,5′
      
      -dimethyl)phenyl]phenylalanine and 4-[(3′
      
      ,4′
      
      -dimethoxy)phenyl]phenylalanine.
  - 13. The isolated polypeptide of claim 1, wherein said X_aa11is an amino acid of Formula III and selected from the group consisting of (S)-2-amino-5-phenylpentanoic acid, (S)-2-amino-4-phenoxybutanoic acid, (S)-2-amino-5-(4-chlorophenyl)pentanoic acid, (S)-2-amino-5-(quinolin-5-yl)pentanoic acid, and (S)-2-amino-4-(2-chlorophenoxy)butanoic acid;
    - (S)-2-amino-4-(2-methylphenoxy)butanoic acid; and
      
      (S)-2-amino-4-(2-methyl-4-chlorophenoxy)butanoic acid, wherein the C-terminal carbonyl carbon of said amino acid is attached to a nitrogen to form a carboxamide (NH₂).
  - 14. The isolated polypeptide of claim 1, wherein said X_aa11is an amino acid of Formula IV and selected from the group consisting of L-Asp(OBz)-OH, L-Glu(OBz)-OH, L-Ser(OBz)-OH, D-Ser(OBz)-OH, L-Thr(OBz)-OH, (S)-2-amino-5-(benzyl(methyl)amino)-5-oxopentanoic acid, (S)-3-((2-chlorobenzyloxy)carbonyl)-2-aminopropanoic acid, (S)-2-amino-5-benzyl(ethyl)amino-5-oxopentanoic acid, (S)-5-((3-methoxybenzyl)(methyl)amino)-2-amino-5-oxopentanoic acid, (S)-2-amino-4-(benzylamino)-4-oxobutanoic acid, (S)-2-amino-3-(3-methylbenzamido)propanoic acid, (S)-2-amino-3-(2-methylbenzamido)propanoic acid, (S)-2-amino-5-(isoindolin-2-yl)-5-oxopentanoic acid, (S)-2-amino-3-(benzyloxycarbonyl)propanoic acid, (S)-5-(2-methylbenzylamino)-2-amino-5-oxopentanoic acid, (S)-5-(2-fluorobenzylamino)-2-amino-5-oxopentanoic acid, (S)-2-amino-4-oxo-4-(piperidin-1-yl)butanoic acid, (S)-5-(4-(trifluoromethyl)benzylamino)-2-amino-5-oxopentanoic acid, (S)-2-amino-5-(dibenzylamino)-5-oxopentanoic acid, (S)-2-amino-3-(3-phenylureido)propanoic acid, (S)-2-amino-3-(3-benzylureido)propanoic acid, (S)-2-amino-3-(3-o-tolylureido)propanoic acid, (S)-2-amino-3-(2-o-tolylacetamido)propanoic acid, (S)-2-amino-5-(benzylamino)-5-oxopentanoic acid, (S)-5-(3-methoxybenzylamino)-2-amino-5-oxopentanoic acid, (S)-2-amino-3-(3-methylpicolinamido)propanoic acid, (S)-2-amino-3-(isonicotinamido)propanoic acid, (S)-2-amino-3-(2-phenylacetamido)propanoic acid, (S)-2-amino-5-(3,4-dihydroisoquinolin-2(1H)-yl)-5-oxopentanoic acid, (S)-2-amino-5-(butylamino)-5-oxopentanoic acid, (S)-2-amino-3-benzamidopropanoic acid, (S)-2-amino-5-oxo-5-(piperidin-1-yl)pentanoic acid, (S)-2-amino-5-(isobutylamino)-5-oxopentanoic acid, (S)-2-amino-4-oxo-4-(pyridin-2-ylmethylamino)butanoic acid, (S)-4-(2-methylbenzylamino)-2-amino-4-oxobutanoic acid, (S)-2-amino-4-(isobutylamino)-4-oxobutanoic acid, (S)-2-amino-3-(4-methylbenzamido)propanoic acid, (S)-2-amino-5-oxo-5-(2-(piperidin-1-yl)ethylamino)pentanoic acid, (S)-2-amino-5-oxo-5-(2-(pyridin-2-yl)ethylamino)pentanoic acid, (S)-2-amino-5-(2-(dimethylamino)ethylamino)-5-oxopentanoic acid, (S)-2-amino-5-oxo-5-(phenethylamino)pentanoic acid, and (S)-3-acetamido-2-aminopropanoic acid;
    - wherein the C-terminal carbonyl carbon of said amino acid is attached to a nitrogen to form a carboxamide (NH₂); and
      
      wherein R₆is selected from the group consisting of hydrogen and methyl.
  - 15. The isolated polypeptide of claim 1, wherein said X_aa11is an amino acid of Formula V selected from the group consisting of (S)-2-amino-3-(4-(benzamidomethyl)phenyl)propanoic acid, (S)-2-amino-3-(4-(phenylsulfonamidomethyl)phenyl)propanoic acid, (S)-2-amino-3-(4-(methylsulfonamidomethyl)phenyl)propanoic acid, (S)-2-amino-3-(4-((2,3-dimethoxybenzamido)methyl)phenyl)propanoic acid, (S)-2-amino-3-(4-((2,4-difluorobenzamido)methyl)phenyl)propanoic acid, (S)-2-amino-3-(4-((2,4-dimethoxybenzamido)methyl)phenyl)propanoic acid, (S)-2-amino-3-(4-((2,5-dimethoxybenzamido)methyl)phenyl)propanoic acid, (S)-2-amino-3-(4-((2,6-dichlorophenylsulfonamido)methyl)phenyl)propanoic acid, (S)-2-amino-3-(4-((2-chlorobenzamido)methyl)phenyl)propanoic acid, (S)-2-amino-3-(4-((2-methoxybenzamido)methyl)phenyl)propanoic acid, (S)-2-amino-3-(4-((2-methylbenzamido)methyl)phenyl)propanoic acid, (S)-2-amino-3-(4-((2-methylphenylsulfonamido)methyl)phenyl)propanoic acid, (S)-2-amino-3-(4-((3,4-dichlorophenylsulfonamido)methyl)phenyl)propanoic acid, (S)-2-amino-3-(4-((3,4-dimethoxybenzamido)methyl)phenyl)propanoic acid, (S)-2-amino-3-(4-((benzo[d][1,3]dioxole-5-carboxamido)methyl)phenyl)propanoic acid, (S)-2-amino-3-(4-((3,5-dichlorophenylsulfonamido)methyl)phenyl)propanoic acid, (S)-2-amino-3-(4-((3,5-dimethoxybenzamido)methyl)phenyl)propanoic acid, (S)-2-amino-3-(4-((3,5-dimethylisoxazole-4-sulfonamido)methyl)phenyl)propanoic acid, (S)-2-amino-3-(4-((3-(trifluoromethyl)benzamido)methyl)phenyl)propanoic acid, (S)-2-amino-3-(4-((3-chlorobenzamido)methyl)phenyl)propanoic acid, (S)-2-amino-3-(4-((3-chlorophenylsulfonamido)methyl)phenyl)propanoic acid, (S)-2-amino-3-(4-((3-cyanobenzamido)methyl)phenyl)propanoic acid, (S)-2-amino-3-(4-((3-ethoxybenzamido)methyl)phenyl)propanoic acid, (S)-2-amino-3-(4-((3-fluorobenzamido)methyl)phenyl)propanoic acid, (S)-2-amino-3-(4-((3-isopropylbenzamido)methyl)phenyl)propanoic acid, (S)-2-amino-3-(4-((3-methoxy-4-methylbenzamido)methyl)phenyl)propanoic acid, (S)-2-amino-3-(4-((3-methoxybenzamido)methyl)phenyl)propanoic acid, (S)-2-amino-3-(4-((3-methoxyphenylsulfonamido)methyl)phenyl)propanoic acid, (S)-2-amino-3-(4-((3-methylbenzamido)methyl)phenyl)propanoic acid, (S)-2-amino-3-(4-((3-(trifluoromethoxy)benzamido)methyl)phenyl)propanoic acid, (S)-2-amino-3-(4-((3-phenylbenzamido)methyl)phenyl)propanoic acid, (S)-2-amino-3-(4-(nicotinamidomethyl)phenyl)propanoic acid, (S)-2-amino-3-(4-((4-butylbenzamido)methyl)phenyl)propanoic acid, (S)-2-amino-3-(4-((4-chlorophenylsulfonamido)methyl)phenyl)propanoic acid, (S)-2-amino-3-(4-((4-cyclohexylbenzamido)methyl)phenyl)propanoic acid, (S)-2-amino-3-(4-((4-methoxybenzamido)methyl)phenyl)propanoic acid, (S)-2-amino-3-(4-((4-methylphenylsulfonamido)methyl)phenyl)propanoic acid, (S)-2-amino-3-(4-((4-methylbenzamido)methyl)phenyl)propanoic acid, (S)-2-amino-3-(4-((4-benzylbenzamido)methyl)phenyl)propanoic acid, (S)-2-amino-3-(4-((4-phenylphenylsulfonamido)methyl)phenyl)propanoic acid, (S)-2-amino-3-(4-((4-phenylphenylsulfonamido)methyl)phenyl)propanoic acid, (S)-3-(4-(acetamidomethyl)phenyl)-2-aminopropanoic acid, (S)-2-amino-3-(4-(cyclohexanecarboxamidomethyl)phenyl)propanoic acid, (S)-2-amino-3-(4-((3-methylbutanamido)methyl)phenyl)propanoic acid, (S)-2-amino-3-(4-(2,4-dimethoxybenzamido)phenyl)propanoic acid, (S)-2-amino-3-(4-(2,6-dichlorophenylsulfonamido)phenyl)propanoic acid, (S)-2-amino-3-(4-(2-chlorobenzamido)phenyl)propanoic acid, (S)-2-amino-3-(4-(2-methylbenzamido)phenyl)propanoic acid, (S)-2-amino-3-(4-(3,4-dichlorophenylsulfonamido)phenyl)propanoic acid, (S)-2-amino-3-(4-(3,4-dimethoxybenzamido)phenyl)propanoic acid, (S)-2-amino-3-(4-(3,5-dichlorophenylsulfonamido)phenyl)propanoic acid, (S)-2-amino-3-(4-(3,5-dimethylisoxazole-4-sulfonamido)phenyl)propanoic acid, (S)-2-amino-3-(4-(3-chlorophenylsulfonamido)phenyl)propanoic acid, (S)-2-amino-3-(4-(3-methylbenzamido)phenyl)propanoic acid, (S)-2-amino-3-(4-(nicotinamido)phenyl)propanoic acid, (S)-2-amino-3-(4-(4-methylphenylsulfonamido)phenyl)propanoic acid, (S)-2-amino-3-(4-(3-phenylbenzamido)phenyl)propanoic acid, (S)-2-amino-3-(4-(4-biphenylsulfonamido)phenyl)propanoic acid, (S)-2-amino-3-(4-(phenylsulfonamido)phenyl)propanoic acid, (S)-2-amino-3-(4-(methylsulfonamido)phenyl)propanoic acid, (S)-2-amino-3-(4-(2,4-difluorobenzamido)phenyl)propanoic acid, (S)-2-amino-3-(4-(2-chlorobenzamido)phenyl)propanoic acid, (S)-2-amino-3-(4-(2-methoxybenzamido)phenyl)propanoic acid, (S)-2-amino-3-(4-(2-methylphenylsulfonamido)phenyl)propanoic acid, (S)-2-amino-3-(4-(3-methoxybenzamido)phenyl)propanoic acid, (S)-2-amino-3-(4-(3-methoxyphenylsulfonamido)phenyl)propanoic acid, (S)-2-amino-3-(4-(4-chlorophenylsulfonamido)phenyl)propanoic acid, and (S)-2-amino-3-(4-(4-methoxyphenylsulfonamido)phenyl)propanoic acid;
    - wherein the C-terminal carbonyl carbon of said amino acid is attached to a nitrogen to form a carboxamide (NH₂); and
      
      wherein R₆is selected from the group consisting of hydrogen and methyl.
  - 16. The isolated polypeptide of claim 1, wherein said X_aa11is an amino acid of Formula VI selected from the group consisting of (2S,3S)-2-amino-3-methylpentanoic acid, (R)-2-amino-3-cyclohexylpropanoic acid, (R)-2-aminooctanoic acid, (R)-2-aminopentanoic acid, (S)-2-amino-3-(2-methoxyethoxy)propanoic acid, (S)-2-amino-3-butoxypropanoic acid, (S)-2-amino-3-cyclohexylpropanoic acid, (S)-2-amino-4-cyclohexylbutanoic acid, (S)-2-amino-4-methoxybutanoic acid, (S)-2-amino-4-methylpent-4-enoic acid, (S)-2-amino-5-methylhexanoic acid, (S)-2-aminodecanoic acid, (S)-2-aminohexanoic acid, (S)-2-aminooctanoic acid, (S)-2-aminopentanoic acid, and 1-aminocyclopentanecarboxylic acid;
    - wherein the C-terminal carbonyl carbon of said amino acid is attached to a nitrogen to form a carboxamide (NH₂); and
      
      wherein R₅is chosen from the group consisting of hydrogen and methyl.
  - 17. An isolated polypeptide of claim 1 comprising the following structure:
  - 18. The isolated polypeptide of claim 14 wherein X_aa2is an amino acid selected from the group consisting of N-methyl-D-Ala, α
    - -methyl-L-Pro and α
      
      -aminoisobutyric (Aib);
      
      wherein X is fluoro;
      
      Y is hydrogen;
      
      Z is selected from the group consisting of CH₂and O;
      
      X_aa8is an amino acid selected from the group consisting of L-Ser and L-His;
      
      R₂is ethyl;
      
      R₃is methoxy;
      
      R₄is selected from the group consisting of hydrogen, methyl and ethyl;
      
      R₅is selected from the group consisting of hydrogen, methyl and ethyl; and
      
      R₇is hydrogen.
  - 20. An isolated polypeptide of claim 16 wherein R₇is selected from the group consisting of methyl, and
  - 21. An isolated polypeptide of claim 1 comprising the following structure:
  - 22. The isolated polypeptide of claim 21 wherein R₈is selected from the group consisting of hydrogen and methyl;
    - X_aa2is an amino acid selected from the group consisting of N-methyl-D-Ala, α
      
      -methyl-L-Pro, and α
      
      -aminoisobutyric acid (Aib);
      
      X is fluoro;
      
      Y is hydrogen;
      
      X_aa8is an amino acid selected from the group consisting of L-Ser and L-His;
      
      R₂is ethyl;
      
      R₃is methoxy;
      
      R₄is selected from the group consisting of methyl and ethyl;
      
      R₅is selected from the group consisting of halo and hydrogen; and
      
      R₆is selected from the group consisting of hydrogen and methyl.
  - 23. An isolated polypeptide of claim 1 comprising the following structure:
  - 24. An isolated polypeptide of claim 23 wherein:
    - X_aa2is an amino acid selected from the group consisting of N-methyl-D-Ala, α
      
      -methyl-L-Pro and α
      
      -aminoisobutyric (Aib);
      
      X is fluoro;
      
      Y is hydrogen;
      
      X_aa8is an amino acid selected from the group consisting of L-Ser and L-His;
      
      R₂is ethyl;
      
      R₃is methoxy;
      
      R₄is selected from the group consisting of methyl and ethyl, alkylaryl and alkylheteroaryl;
      
      R₅is selected from the group consisting of hydrogen, methyl, ethyl, alkylaryl, and alkylheteroaryl;
      
      R₄and R₅together comprise a cyclic moiety; and
      
      R₆is hydrogen.
  - 25. An isolated polypeptide of claim 1 comprising the following structure,
  - 26. An isolated polypeptide of claim 1 comprising the following structure:
  - 27. An isolated polypeptide of claim 26 wherein:
    - X_aa2is an amino acid selected from the group consisting of N-methyl-D-Ala, α
      
      -methyl-L-Pro, and α
      
      -aminoisobutyric acid (Aib);
      
      X is fluoro;
      
      Y is hydrogen;
      
      X_aa8is an amino acid selected from the group consisting of L-Ser and L-His;
      
      R₂is ethyl;
      
      R₃is methoxy;
      
      R₄is hydrogen or methyl; and
      
      R₅is hydrogen.
  - 28. An isolated polypeptide of claim 1 comprising the following structure:
  - 29. An isolated polypeptide of claim 1 comprising the following structure:
  - 30. An isolated polypeptide of claim 1 comprising the following structure:
  - 31. An isolated polypeptide of claim 30 wherein:
    - X_aa2is an amino acid selected from the group consisting of N-methyl-D-Ala, α
      
      -methyl-L-Pro and α
      
      -aminoisobutyric (Aib);
      
      X is fluoro;
      
      Y is hydrogen;
      
      X_aa8is an amino acid selected from the group consisting of L-Ser and L-His;
      
      R₂is ethyl;
      
      R₃is methoxy;
      
      R₄is selected from the group of hydrogen and methyl; and
      
      R₅is selected from the group of methyl, ethyl, propyl, butyl, hexyl, cyclohexyl, and methylcyclohexyl.
  - 32. An isolated polypeptide of claim 1 comprising the following structure:
  - 33. An isolated polypeptide of claim 1 comprising the following structure,
  - 34. An isolated polypeptide of claim 33 wherein:
    - X_aa2is an amino acid selected from the group consisting of N-methyl-D-Ala, α
      
      -methyl-L-Pro, and α
      
      -aminoisobutyric acid (Aib);
      
      X is fluoro;
      
      Y is hydrogen;
      
      X_aa8is an amino acid selected from the group consisting of L-Ser and L-His;
      
      R₂is ethyl;
      
      R₃is methoxy; and
      
      Ring A is cyclopentyl.
  - 35. An isolated polypeptide of claim 1, wherein said isolated polypeptide selected from the group consisting of:
  - 36. An isolated polypeptide of claim 1, wherein said isolated polypeptide is selected from the group consisting of:
  - 37. An isolated polypeptide of claim 1, wherein said isolated polypeptide is selected from the group consisting of:
  - 38. An isolated polypeptide of claim 1, wherein said isolated polypeptide is selected from the group consisting of:
  - 39. An isolated polypeptide of claim 1, wherein said isolated polypeptide is selected from the group consisting of:
  - 40. An isolated polypeptide of claim 1, wherein said isolated polypeptide is selected from the group consisting of:
  - 41. An isolated polypeptide of claim 1, wherein said isolated polypeptide is selected from the group consisting of:
  - 42. An isolated polypeptide of claim 1, wherein said isolated polypeptide is selected from the group consisting of:
  - 43. An isolated polypeptide of claim 1, wherein said isolated polypeptide is
  - 46. A pharmaceutical composition comprising an isolated polypeptide of claim 1 or 62 and a pharmaceutically acceptable carrier thereof.
  - 47. A pharmaceutical combination comprising an isolated polypeptide of claim 1 or 62, and at least one therapeutic agent selected from the group consisting of an antidiabetic agent, an anti-obesity agent, an anti-hypertensive agent, an anti-atherosclerotic agent and a lipid-lowering agent.
  - 48. The pharmaceutical combination of claim 47, wherein said antidiabetic agent is selected from the group consisting of a biguanide, a sulfonyl urea, a glucosidase inhibitor, a PPAR γ
    - agonist, a PPAR α
      
      /γ
      
      dual agonist, an aP2 inhibitor, a DPP4 inhibitor, an insulin sensitizer, a glucagon-like peptide-1 (GLP-1) analog, insulin, and a meglitinide.
  - 49. The pharmaceutical combination of claim 48, wherein said antidiabetic agent is selected from the group consisting of metformin, glyburide, glimepiride, glipyride, glipizide, chlorpropamide, gliclazide, acarbose, miglitol, pioglitazone, troglitazone, rosiglitazone, muraglitazar, insulin, Gl-262570, isaglitazone, JTT-501, N,N-2344, L895645, YM-440, R-119702, AJ9677, repaglinide, nateglinide, KAD1129, AR-HO39242, GW-409544, KRP297, AC2993, LY315902, and NVP-DPP-728A, saxagliptin.
  - 50. The pharmaceutical combination of claim 47, wherein said anti-obesity agent is selected from the group consisting of a beta 3 adrenergic agonist, a lipase inhibitor, a serotonin (and dopamine) reuptake inhibitor, a thyroid receptor beta compound, a CB-1 antagonist and an anorectic agent.
  - 51. The pharmaceutical combination of claim 50, wherein said anti-obesity agent is selected from the group consisting of orlistat, ATL-962, AJ9677, L750355, CP331648, sibutramine, topiramate, axokine, dexamphetamine, phentermine, phenylpropanolamine rimonabant (SR141716A) and mazindol.
  - 52. The pharmaceutical combination of claim 47, wherein said lipid lowering agent is selected from the group consisting of an MTP inhibitor, cholesterol ester transfer protein inhibitor, an HMG CoA reductase inhibitor, a squalene synthetase inhibitor, a fibric acid derivative, an upregulator of LDL receptor activity, a lipoxygenase inhibitor, and an ACAT inhibitor.
  - 53. The pharmaceutical combination of claim 52, wherein said lipid lowering agent is selected from the group consisting of pravastatin, lovastatin, simvastatin, atorvastatin, cerivastatin, fluvastatin, nisvastatin, visastatin, fenofibrate, gemfibrozil, clofibrate, avasimibe, TS-962, MD-700, CP-529414, and LY295427.
  - 54. A method for treating or delaying the progression or onset of diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, wound healing, insulin resistance, hyperglycemia, hyperinsulinemia, Syndrome X, diabetic complications, elevated blood levels of free fatty acids or glycerol, hyperlipidemia, obesity, hypertriglyceridemia, atherosclerosis or hypertension, which comprises administering to a mammalian species in need of treatment a therapeutically effective amount of an isolated polypeptide of claim 1 or 62.
  - 55. The method of claim 54, further comprising administering, concurrently or sequentially, a therapeutically effective amount of one or more therapeutic agents selected from the group consisting of an antidiabetic agent, an anti-obesity agent, a anti-hypertensive agent, and an anti-atherosclerotic agent and a lipid-lowering agent.
  - 56. A method for treating or delaying the progression or onset of diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, wound healing, insulin resistance, hyperglycemia, hyperinsulinemia, Syndrome X, diabetic complications, elevated blood levels of free fatty acids or glycerol, hyperlipidemia, obesity, hypertriglyceridemia, atherosclerosis or hypertension, which comprises administering to a mammalian species in need of treatment a therapeutically effective amount of a pharmaceutical combination of claim 47.
  - 57. A method of administering a peptide of claim 1 or 62 using a parenteral or non-parenteral formulation.
  - 58. The method of claim 57 wherein said formulation is administered as an immediate release or sustained release formulation.
  - 59. A method for administering a peptide of claim 1 or 62 using a parenteral or non-parenteral formulation, wherein said formulation comprises any one of said compounds as the active ingredient and a pharmaceutically acceptable excipient.
  - 60. A method for administering a peptide of claim 1 or 62 using a parenteral or non-parenteral formulation, wherein said formulation is comprised of said peptide active ingredient and an encapsulated delivery system.
  - 61. An isolated polypeptide of claim 1, wherein said isolated polypeptide is selected from the group consisting of:

19. An isolated polypeptide comprising the following structure:

44. A compound of Formula XX:

45. A compound of Formula XXI:

62. An isolated peptide comprising a core sequence selected from the group consisting of:
- Thr-Ser-Asp-Bip-Xaa, wherein Xaa is an amino acid comprising a 2-amino-pentamide;
  
  Thr-Ser-Asp-Bip-Xaa, wherein Xaa is an amino acid comprising a 2-amino-butanamide;
  
  Thr-His-Asp-Bip-Xaa, wherein Xaa is an amino acid comprising a 2-amino-butanamide;
  
  Thr-Ser-Asp-Bip-Xaa, wherein Xaa is an amino acid comprising urea;
  
  Thr-Ser-Asp-Bip-Xaa, wherein Xaa comprises Glu;
  
  Thr-Ser-Asp-Bip-Xaa, wherein Xaa is an amino acid comprising 2-amino-propanoic acid;
  
  Thr-Ser-Asp-Bip-Xaa, wherein Xaa is an amino acid comprising a 3-amino-succinamide;
  
  Thr-Ser-Asp-Bip-Xaa, wherein Xaa is an amino acid comprising a 2-amino-propanamide;
  
  Thr-Ser-Asp-Bip-Xaa, wherein Xaa is an amino acid comprising an ocopropylcarbamate;
  
  Thr-Ser-Asp-Bip-Xaa, wherein Xaa is an amino acid comprising an isonicotinamide;
  
  Thr-Ser-Asp-Bip-Xaa, wherein Xaa is an amino acid comprising a methylpicolinamide;
  
  Thr-Ser-Asp-Bip-Xaa, wherein Xaa is an amino acid further comprising a 1- or 2-amino hexanoic, carboxylic, octanoic, decanoic, butanoic, pentanoic, and enoic acid; and
  
  Thr-Ser-Asp-Bip-Xaa, wherein Xaa comprises at least one amino acid coupled to a benzyl group;
  
  wherein said isolated peptide comprising said core sequence binds and activates a GLP-1 receptor.

Specification

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Litigation Campaign Assessment

Current Assignee
Bristol-Myers Squibb Company
Original Assignee
Bristol-Myers Squibb Company
Inventors
Ruan, Zheming, Lee, Ving, Zhu, Yeheng, Mapelli, Claudio, Ewing, William, Riexinger, Douglas, Sulsky, Richard, Haque, Tasir, Martinez, Rogelio

Application Number

US11/622,142
Publication Number

US 20070238669A1
Time in Patent Office

Days
Field of Search
US Class Current

514/7.200
CPC Class Codes

A61K 2300/00   Mixtures or combinations of...

A61K 38/26   Glucagons

A61K 38/28   Insulins

A61P 13/12   of the kidneys

A61P 17/02   for treating wounds, ulcers...

A61P 25/00   Drugs for disorders of the ...

A61P 3/04   Anorexiants; Antiobesity ag...

A61P 3/06   Antihyperlipidemics

A61P 3/10   for hyperglycaemia, e.g. an...

A61P 43/00   Drugs for specific purposes...

A61P 5/00   Drugs for disorders of the ...

A61P 5/50   for increasing or potentiat...

A61P 9/10   for treating ischaemic or a...

A61P 9/12   Antihypertensives

C07C 2603/18   Fluorenes; Hydrogenated flu...

C07C 271/16   to carbon atoms of hydrocar...

C07K 14/605   Glucagons

HUMAN GLUCAGON-LIKE-PEPTIDE-1 MODULATORS AND THEIR USE IN THE TREATMENT OF DIABETES RELATED CONDITIONS

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Abstract

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62 Claims

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HUMAN GLUCAGON-LIKE-PEPTIDE-1 MODULATORS AND THEIR USE IN THE TREATMENT OF DIABETES RELATED CONDITIONS

First Claim

1 Assignment

Subscription Required

Subscription Required

0 Petitions

Subscription Required

Accused Products

Subscription Required

Abstract

56 Citations

62 Claims

Specification

Subscription Required

Use Cases

Quick Links

Others