# US 7,608,577 B2 · Peptidyl ketones as inhibitors of DPIV

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- Number: US 7,608,577 B2
- Document ID: US7608577B2
- Status: Granted
- Kind: B2
- Application number: 10/216,305
- Filed: 2002-08-09
- Published: 2003-08-07
- Granted: 2009-10-27
- Earliest claimed: 2001-10-12
- Assignees: OSI Pharmaceuticals, Inc.
- Inventors: Ulrich Heiser; André Johannes Niestroj; Torsten Hoffmann; Hans-Ulrich Demuth
- Web page: https://patentgrep.com/patent/US7608577B2

## CPC

- C07K 7/06: having 5 to 11 amino acids
- A61K 38/04: Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof ({enzyme inhibitors A61K38/005;} gastrins {A61K38/2207}, somatostatins A61K38/31, melanotropins A61K38/34 {; protease inhibitors A61K38/55})
- A61K 38/06: Tripeptides
- A61K 38/07: Tetrapeptides
- A61K 38/08: Peptides having 5 to 11 amino acids {(A61K38/043 - A61K38/046 take precedence)}
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 3/06: Antihyperlipidemics
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 13/12: of the kidneys
- A61P 17/00: Drugs for dermatological disorders
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/04: Centrally acting analgesics, e.g. opioids
- A61P 25/08: Antiepileptics; Anticonvulsants
- A61P 25/20: Hypnotics; Sedatives
- A61P 25/24: Antidepressants
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07K 5/0806: {the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala}
- C07K 5/0808: {the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu}
- C07K 5/081: {the side chain containing O or S as heteroatoms, e.g. Cys, Ser}
- C07K 5/0812: {and aromatic or cycloaliphatic}
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention relates to compounds of the general formula 1 and pharmaceutically acceptable salts thereof, to the use of the compounds for the treatment of impaired glucose tolerance, glucosuria, hyperlipidaemia, metabolic acidosis, diabetes mellitus, diabetic neuropathy and nephropathy and of sequelae caused by diabetes mellitus in mammals.

## Claims

### Claim 1

A compound formula 1:
or a pharmaceutically acceptable salts thereof, wherein:
A is selected from:
wherein
X1 is H or an amino acid residue, a N-protected amino acid residue, a peptide residue or a N-protected peptide residue,
X2 is H, —(CH)m—NH—C5H3N—Y with m=2-4, or —C5H3N—Y (a divalent pyridyl residue) and Y is selected from H, Br, Cl, I, NO2 and CN,
X3 is H or an alkyl-, alkoxy-, halogen-, nitro-, cyano- or carboxy-substituted phenyl or from an alkyl-, alkoxy-, halogen-, nitro-, cyano- or carboxy-substituted pyridyl residue,
X4 is H or an alkyl-, alkoxy-, halogen-, nitro-, cyano- or carboxy-substituted phenyl or an alkyl-, alkoxy-, halogen-, nitro-, cyano- or carboxy-substituted pyridyl residue,
X5 is H or an alkyl, alkoxy or phenyl residue,
X6 is H or an alkyl residue,
for n=1
X is selected from OR2 and SR2, wherein:
R2 is an acyl residues, optionally substituted with alkyl, cycloalkyl, aryl or heteroaryl residues, or an amino acid residue or peptidic residue, or alkyl residue, which are optionally substituted with alkyl, cycloalkyl, aryl or heteroaryl residues,
for n=0
X is selected from:
wherein
B is O, S or NR5, wherein R5 is H, alkyl or acyl,
C, D, E, F, G, Y, K, L, M, Q, T, U, V and W are independently selected from alkyl and substituted alkyl residues, oxyalkyl, thioalkyl, aminoalkyl, carbonylalkyl, acyl, carbamoyl, aryl and heteroaryl residues, and
Z is H, or a branched or straight chain alkyl residue from C1-C9, a branched or straight chain alkenyl residue from C2-C9, a cycloalkyl residue from C3-C8, a cycloalkenyl residue from C5-C7, an aryl or heteroaryl residue, or a side chain selected from all side chains of all natural amino acids or derivatives thereof.

### Claim 2

A compound selected from the group consisting of
2-methylcarbonyl-1-N-[(L)-Alanyl-(L)-Valinyl]-(2S)-pyrrolidine hydrobromide;
2-methylcarbonyl-1-N-[(L)-Valinyl-(L)-Prolyl-(L)-Valinyl]-(2S)-pyrrolidine hydrobromide;
2-[(acetyloxy-methyl)carbonyl]-1-N-[(L)-Alanyl-(L)-Valinyl]-(2S)-pyrrolidine hydrobromide;
2-[(benzoyloxy-methyl)carbonyl]-1-N-[{(L)-Alanyl}-(L)-Valinyl]-(2S) -pyrrolidine hydrobromide;
2-{[(2,6-dichlorobenzyl)thiomethyl]carbonyl}-1-N-[{(L)-Alanyl}-(L)-Valinyl]-(2S)-pyrrolidine;
2-[(benzoyloxy-methyl)carbonyl]-1-N-[Glycyl-(L)-Valinyl]-(2S)-pyrrolidine hydrobromide;
2-[([1,3]-thiazol-2-yl)carbonyl]-1-N-[{(L)-Alanyl}-(L)-Valinyl]-(2S)-pyrrolidine trifluoracetate;
2-[(benzothiazol-2-yl)carbonyl]-1-N-[{(L-Alanyl}-(L)-Valinyl]-(2S)-pyrrolidine trifluoracetate;
2-[(-benzothiazol-2-yl)carbonyl]-1-N-[{(L)-Alanyl}-Glycyl]-(2S)-pyrrolidine trifluoracetate; and
2-[(pyridin-2-yl)carbonyl]-1-N[{(L)-Alanyl}-(L)-Valinyl]-(2S)-pyrrolidine trifluoracetate.

### Claim 3 (depends on 1)

A pharmaceutical composition for parenteral, enteral or oral administration, characterised in that it contains at least one compound according to claim 1 optionally in combination with customary carriers or excipients.

### Claim 4 (depends on 1)

A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein A is:
wherein
X1 is H or an amino acid residue, an N-acylated amino acid residue, a peptide residue from di- to pentapeptides, or an N-protected peptide residue from di- to pentapaptides,
X2 is H, —(CH)m—NH—C5H3N—Y with m=2-4, or —C5H3N—Y (a divalent pyridyl residue) and Y is selected from H, Br, Cl, I, NO2 and CN,
for n=1
X is selected from OR2 and SR2, wherein:
R2 is an acyl residue, optionally substituted with alkyl, cycloalkyl, aryl or heteroaryl residues, or an amino acid residue or peptidic residue, or alkyl residue, optionally substituted with alkyl, cycloalkyl, aryl or heteroaryl residues,
for n=0
X is selected from:
wherein
B is O, S or NR5, wherein R5 is H, alkyl or acyl,
C, D, E, F, G, Y, K, L, M and Q are independently selected from alkyl and substituted alkyl residues, oxyalkyl, thioalkyl, aminoalkyl, carbonylalkyl, acyl, carbamoyl, aryl and heteroaryl residues; and
Z is H, or a branched or straight chain alkyl residue from C1-C9, a branched or straight chain alkenyl residue from C2-C9, a cycloalkyl residue from C3-C8, a cycloalkenyl residue from C5-C7, an aryl or heteroaryl residue, or a side chain selected from all side chains of all natural amino acids or derivatives thereof.

### Claim 5

A compound of formula 1:
or a pharmaceutically acceptable salt thereof, wherein A is:
wherein
n=0
X1 is H or an amino acid residue, an N-acylated amino acid residue, or a dipeptide residue containing a Pro or Ala in the penultimate position, or an N-protected dipeptide residue containing a Pro or Ala in the penultimate position,
X is selected from:
wherein
B is O, C, D, E, F, G, Y, K, L, M and Q are H,
Z is H, or a branched or straight chain alkyl residue from C3-C5, a branched or straight chain alkenyl residue from C2-C9, a cycloalkyl residue from C5-C7, a cycloalkenyl residue from C5-C7, an aryl or heteroaryl residue, or a side chain selected from all side chains of all natural amino acids or derivatives thereof.