US 2006/0040963 A1Published application

Piperidino pyrimidine dipeptidyl peptidase inhibitors for the treatment of diabetes

AssigneeMerck & Co., Inc.

InventorsRobert Mathvink, Scott Edmondson, Ann Weber

Life of this patent

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Abstract

The present invention is directed to compounds which are inhibitors of the dipeptidyl peptidase-IV enzyme (“DP-IV inhibitors”) and which are useful in the treatment or prevention of diseases in which the dipeptidyl peptidase-IV enzyme is involved, such as diabetes and particularly Type 2 diabetes. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which the dipeptidyl peptidase-IV enzyme is involved.

Claims39

Dependent claims

A compound of the formula I:

wherein:
Ar is phenyl which is unsubstituted or substituted with 1-5 of R3, wherein R3 is independently selected from the group consisting of:
(1) halogen,
(2) C1-6alkyl, which is linear or branched and is unsubstituted or substituted with 1-5 halogens,
(3) OC1-6alkyl, which is linear or branched and is unsubstituted or substituted with 1-5 halogens,
(4) CN, and
(5) OH;
R1 and R2 are independently selected from the group consisting of:
(1) hydrogen,
(2) CN,
(3) C1-10alkyl, which is linear or branched and which is unsubstituted or substituted with:
(a) halogen, or
(b) phenyl, which is unsubstituted or substituted with 1-5 substituents independently selected from halogen, CN, OH, R4, OR4, NHSO2R4, N(C1-6alkyl)SO2R4, SO2R4, SO2NR7R8, NR7R8, CONR7R8, CO2H, and CO2C1-6alkyl, wherein the C1-6alkyl is linear or branched,
(4) phenyl which is unsubstituted or substituted with 1-5 substituents independently selected from halogen, CN, OH, R4, OR4, NHSO2R4, N(C1-6alkyl)SO2R4, SO2R4, SO2NR7R8, NR7R8, CONR7R8, CO2H, and CO2C1-6alkyl, wherein the C1-6alkyl is linear or branched,
(5) a 5- or 6-membered heterocycle which may be saturated or unsaturated comprising 14 heteroatoms independently selected from N, S and O, the heterocycle being unsubstituted or substituted with 1-3 substituents independently selected from oxo, halogen, NO2, CN, OH, R4, OR4, NHSO2R4, N(C1-6alkyl)SO2R4, SO2R4, SO2NR7R8, NR7R8, CONR7R8, CO2H, and CO2C1-6alkyl, wherein the C1-6alkyl is linear or branched,
(6) C3-6cycloalkyl, which is optionally substituted with 1-5 substituents independently selected from halogen, OH, C1-6alkyl, and OC1-6alkyl, wherein the C1-6alkyl and OC1-6alkyl are linear or branched and optionally substituted with 1-5 halogens,
(7) OH,
(8) OR4, and
(9) NR7R8;
R4 is C1-6alkyl, which is linear or branched and which is unsubstituted or substituted with 1-5 groups independently selected from halogen, CO2H, and CO2C1-6alkyl, wherein the C1-6alkyl is linear or branched;
R5, R6 and R9 are independently selected from the group consisting of:
(1) hydrogen,
(2) C1-10alkyl, which is linear or branched and which is unsubstituted or substituted with one or more substituents selected from:
(a) halogen,
(b) hydroxy,
(c) phenyl, which is unsubstituted or substituted with 1-5 substituents independently selected from halogen, OH, C1-6alkyl, and OC1-6alkyl, wherein the C1-6alkyl is linear or branched and optionally substituted with 1-5 halogens,
(d) naphthyl, wherein the naphthyl is optionally substituted with 1-5 substituents independently selected from halogen, OH, C1-6alkyl, and OC1-6alkyl, wherein the C1-6alkyl is linear or branched and optionally substituted with 1-5 halogens,
(e) CO2H,
(f) CO2C1-6alkyl,
(g) CONR7R8,
(3) CN,
(4) phenyl which is unsubstituted or substituted with 1-5 substituents independently selected from C1-6alkyl, OC1-6alkyl, hydroxy and halogen, wherein the C1-6alkyl is linear or branched and optionally substituted with 1-5 halogens,
(5) naphthyl which is unsubstituted or substituted with 1-5 substituents independently selected from C1-6alkyl, OC1-6alkyl, hydroxy and halogen, wherein the C1-6alkyl is linear or branched and optionally substituted with 1-5 halogens,
(6) CO2H,
(7) CO2C1-6alkyl,
(8) CONR7R8, and
(9) C3-6cycloalkyl, which is unsubstituted or substituted with 1-5 substituents independently selected from halogen, OH, C1-6alkyl, and OC1-6alkyl, wherein the C1-6alkyl is linear or branched and optionally substituted with 1-5 halogens;
R7 and R8 are independently selected from the group consisting of:
(1) hydrogen,
(2) phenyl, which is unsubstituted or substituted with substituents independently selected from halogen, OH, C1-6alkyl, and OC1-6alkyl, wherein the C1-6alkyl is linear or branched and optionally substituted with 1-5 halogens,
(3) C3-6cycloalkyl, which is unsubstituted or substituted with substituents independently selected from halogen, OH, C1-6alkyl, and OC1-6alkyl, wherein the C1-6alkyl is linear or branched and optionally substituted with 1-5 halogens, and
(4) C1-6alkyl, which is linear or branched and which is unsubstituted or substituted with:
(a) halogen, or
(b) phenyl, which is unsubstituted or substituted with 1-5 substituents independently selected from halogen, OH, C1-6alkyl, and OC1-6alkyl, wherein the C1-6alkyl is linear or branched and optionally substituted with 1-5 halogens,
or wherein R7 and R8 together with the nitrogen atom to which they are attached form a heterocyclic ring selected from azetidine, pyrrolidine, piperidine, piperazine, and morpholine wherein said heterocyclic ring is unsubstituted or substituted with one to five substituents independently selected from halogen, hydroxy, C1-6 alkyl, and C1-6 alkoxy, wherein alkyl and alkoxy are unsubstituted or substituted with one to five halogens;
or a pharmaceutically acceptable salt thereof or an individual diastereomer thereof.

43 more elements

Dependencies are inferred from the claim text.

Facts

Application: 10/520,839Filed 11 Jul 2003
Priority: 15 Jul 2002
Published: 23 Feb 2006
Term ends: Not estimatedThe source records don’t support an estimate.

Classification24 codes

C07D 471/04
In which the condensed system contains two hetero rings: ortho-condensed systems
A61P 1/00
Drugs for disorders of the alimentary tract or the digestive system
A61P 1/02
Drugs for disorders of the alimentary tract or the digestive system: stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
A61P 1/18
Drugs for disorders of the alimentary tract or the digestive system: for pancreatic disorders, e.g. pancreatic enzymes

Family

Application60/395,846Us provisional application · filed 15 Jul 2002
US 7,208,498 B2Related patent
US 2006/0040963 A1This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

A compound of the formula I:

wherein:
Ar is phenyl which is unsubstituted or substituted with 1-5 of R3, wherein R3 is independently selected from the group consisting of:
(1) halogen,
(2) C1-6alkyl, which is linear or branched and is unsubstituted or substituted with 1-5 halogens,
(3) OC1-6alkyl, which is linear or branched and is unsubstituted or substituted with 1-5 halogens,
(4) CN, and
(5) OH;
R1 and R2 are independently selected from the group consisting of:
(1) hydrogen,
(2) CN,
(3) C1-10alkyl, which is linear or branched and which is unsubstituted or substituted with:
(a) halogen, or
(b) phenyl, which is unsubstituted or substituted with 1-5 substituents independently selected from halogen, CN, OH, R4, OR4, NHSO2R4, N(C1-6alkyl)SO2R4, SO2R4, SO2NR7R8, NR7R8, CONR7R8, CO2H, and CO2C1-6alkyl, wherein the C1-6alkyl is linear or branched,
(4) phenyl which is unsubstituted or substituted with 1-5 substituents independently selected from halogen, CN, OH, R4, OR4, NHSO2R4, N(C1-6alkyl)SO2R4, SO2R4, SO2NR7R8, NR7R8, CONR7R8, CO2H, and CO2C1-6alkyl, wherein the C1-6alkyl is linear or branched,
(5) a 5- or 6-membered heterocycle which may be saturated or unsaturated comprising 14 heteroatoms independently selected from N, S and O, the heterocycle being unsubstituted or substituted with 1-3 substituents independently selected from oxo, halogen, NO2, CN, OH, R4, OR4, NHSO2R4, N(C1-6alkyl)SO2R4, SO2R4, SO2NR7R8, NR7R8, CONR7R8, CO2H, and CO2C1-6alkyl, wherein the C1-6alkyl is linear or branched,
(6) C3-6cycloalkyl, which is optionally substituted with 1-5 substituents independently selected from halogen, OH, C1-6alkyl, and OC1-6alkyl, wherein the C1-6alkyl and OC1-6alkyl are linear or branched and optionally substituted with 1-5 halogens,
(7) OH,
(8) OR4, and
(9) NR7R8;
R4 is C1-6alkyl, which is linear or branched and which is unsubstituted or substituted with 1-5 groups independently selected from halogen, CO2H, and CO2C1-6alkyl, wherein the C1-6alkyl is linear or branched;
R5, R6 and R9 are independently selected from the group consisting of:
(1) hydrogen,
(2) C1-10alkyl, which is linear or branched and which is unsubstituted or substituted with one or more substituents selected from:
(a) halogen,
(b) hydroxy,
(c) phenyl, which is unsubstituted or substituted with 1-5 substituents independently selected from halogen, OH, C1-6alkyl, and OC1-6alkyl, wherein the C1-6alkyl is linear or branched and optionally substituted with 1-5 halogens,
(d) naphthyl, wherein the naphthyl is optionally substituted with 1-5 substituents independently selected from halogen, OH, C1-6alkyl, and OC1-6alkyl, wherein the C1-6alkyl is linear or branched and optionally substituted with 1-5 halogens,
(e) CO2H,
(f) CO2C1-6alkyl,
(g) CONR7R8,
(3) CN,
(4) phenyl which is unsubstituted or substituted with 1-5 substituents independently selected from C1-6alkyl, OC1-6alkyl, hydroxy and halogen, wherein the C1-6alkyl is linear or branched and optionally substituted with 1-5 halogens,
(5) naphthyl which is unsubstituted or substituted with 1-5 substituents independently selected from C1-6alkyl, OC1-6alkyl, hydroxy and halogen, wherein the C1-6alkyl is linear or branched and optionally substituted with 1-5 halogens,
(6) CO2H,
(7) CO2C1-6alkyl,
(8) CONR7R8, and
(9) C3-6cycloalkyl, which is unsubstituted or substituted with 1-5 substituents independently selected from halogen, OH, C1-6alkyl, and OC1-6alkyl, wherein the C1-6alkyl is linear or branched and optionally substituted with 1-5 halogens;
R7 and R8 are independently selected from the group consisting of:
(1) hydrogen,
(2) phenyl, which is unsubstituted or substituted with substituents independently selected from halogen, OH, C1-6alkyl, and OC1-6alkyl, wherein the C1-6alkyl is linear or branched and optionally substituted with 1-5 halogens,
(3) C3-6cycloalkyl, which is unsubstituted or substituted with substituents independently selected from halogen, OH, C1-6alkyl, and OC1-6alkyl, wherein the C1-6alkyl is linear or branched and optionally substituted with 1-5 halogens, and
(4) C1-6alkyl, which is linear or branched and which is unsubstituted or substituted with:
(a) halogen, or
(b) phenyl, which is unsubstituted or substituted with 1-5 substituents independently selected from halogen, OH, C1-6alkyl, and OC1-6alkyl, wherein the C1-6alkyl is linear or branched and optionally substituted with 1-5 halogens,
or wherein R7 and R8 together with the nitrogen atom to which they are attached form a heterocyclic ring selected from azetidine, pyrrolidine, piperidine, piperazine, and morpholine wherein said heterocyclic ring is unsubstituted or substituted with one to five substituents independently selected from halogen, hydroxy, C1-6 alkyl, and C1-6 alkoxy, wherein alkyl and alkoxy are unsubstituted or substituted with one to five halogens;
or a pharmaceutically acceptable salt thereof or an individual diastereomer thereof.

43 more elements

Facts

Application

10/520,839Filed 11 Jul 2003

Priority

15 Jul 2002

Published

23 Feb 2006

Term ends

Not estimatedThe source records don’t support an estimate.

Classification24 codes

C07D 471/04
In which the condensed system contains two hetero rings: ortho-condensed systems
A61P 1/00
Drugs for disorders of the alimentary tract or the digestive system
A61P 1/02
Drugs for disorders of the alimentary tract or the digestive system: stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
A61P 1/18
Drugs for disorders of the alimentary tract or the digestive system: for pancreatic disorders, e.g. pancreatic enzymes