Pyrrolo[3,2-C] pyridine derivatives and processes for the preparation thereof

• US 8,148,529 B2
• Filed: 09/03/2005
• Issued: 04/03/2012
• Est. Priority Date: 09/03/2004
• Status: Expired due to Fees

• Current Assignee: Yuhan Corporation
• Original Assignee: Yuhan Corporation
• Inventors: Kim, Jae-Gyu, Ahn, Byung-Nak, Lee, Hyouk-Woo, Yoon, Suk-Won, Yoon, Young-Ae, Kim, Dong-Hoon, Keum, Se-Hoon, Kang, Heui Il, Shin, Young-Ah, Choi, Ryong
• Primary Examiner(s): Andres, Janet L.
• Assistant Examiner(s): Rahmani, Niloofar
• Application Number:
  US11/574,393
• Publication Number:
  US 20090005409A1
• Time in Patent Office: 2,404 Days
• Field of Search: 546/113
• US Class Current: 546/113
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

Abstract

The present invention provides novel pyrrolo[3,2-c]pyridine derivatives or pharmaceutically acceptable salts thereof, processes for the preparation thereof, and compositions comprising the same. The pyrrolo[3,2-c]pyridine derivatives or pharmaceutically acceptable salts thereof of the present invention have excellent proton pump inhibition effects and possess the ability to attain a reversible proton pump inhibitory effect.

Claims

1. A compound of the formula (I) or a pharmaceutically acceptable salt thereof:

2. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R₁ is hydrogen;

a straight or branched C₁-C₆ alkyl group;

a C₁-C₃ alkyl group substituted with one or more substituents selected from the group consisting of methoxy, ethoxy, hydroxy, cyclopropyl, cyclobutyl, cyclohexyl, methylthiazolyl, and 1,3-dioxolanyl;

a straight or branched C₂-C₆ alkenyl group;

a straight or branched C₂-C₆ alkynyl group;

cyclopropyl;

cyclopentyl;

or a benzyl group, optionally substituted with one or more substituents selected from the group consisting of halogen, methyl, and methoxy,

R₂ is a straight or branched C₁-C₃ alkyl group,

R₃ is hydrogen;

a straight or branched C₁-C₃ alkyl group;

a straight or branched C₂-C₅ alkenyl group;

or a benzyl group optionally one or more substituted with halogen, and

R₄ is a 1,2,3,4-tetrahydroisoquinolinyl group.

3. The compound or a pharmaceutically acceptable salt thereof according to claim 1, which is selected from the group consisting of:

2,3-dimethyl-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)-1H-pyrrolo[3,2-c]pyridine;

2,3-dimethyl-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)-1H-pyrrolo[3,2-c]pyridine hydrochloride;

2,3-dimethyl-1-(2-methoxyethyl)-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)-1H-pyrrolo[3,2-c]pyridine hydrochloride;

1-allyl-2,3-dimethyl-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)-1H-pyrrolo[3,2-c]pyridine hydrochloride;

1-benzyl-2,3-dimethyl-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)-1H-pyrrolo[3,2-c]pyridine hydrochloride;

1,2,3-trimethyl-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)-1H-pyrrolo[3,2-c]pyridine hydrochloride;

1-ethyl-2,3-dimethyl-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)-1H-pyrrolo[3,2-c]pyridine hydrochloride;

1-propyl-2,3-dimethyl-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)-1H-pyrrolo[3,2-c]pyridine hydrochloride;

1-butyl-2,3-dimethyl-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)-1H-pyrrolo[3,2-c]pyridine hydrochloride;

2,3-dimethyl-1-isopropyl-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)-1H-pyrrolo[3,2-c]pyridine hydrochloride;

2,3-dimethyl-1-isobutyl-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)-1H-pyrrolo[3,2-c]pyridine hydrochloride;

2,3-dimethyl-1-(3-methylbutyl)-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)-1H-pyrrolo[3,2-c]pyridine hydrochloride;

2,3-dimethyl-1-cyclopropyl-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)-1H-pyrrolo[3,2-c]pyridine hydrochloride;

2,3-dimethyl-1-cyclopentyl-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)-1H-pyrrolo[3,2-c]pyridine hydrochloride;

2,3-dimethyl-1-cyclopropylmethyl-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)-1H-pyrrolo[3,2-c]pyridine hydrochloride;

1-cyclobutylmethyl-2,3-dimethyl-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)-1H-pyrrolo[3,2-c]pyridine hydrochloride;

1-cyclohexylmethyl-2,3-dimethyl-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)-1H-pyrrolo[3,2-c]pyridine hydrochloride;

2,3-dimethyl-1-(pent-4-ynyl)-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)-1H-pyrrolo[3,2-c]pyridine hydrochloride;

2,3-dimethyl-1-(3-methylbut-2-enyl)-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)-1H-pyrrolo[3,2-c]pyridine hydrochloride;

2,3-dimethyl-1-(2-hydroxyethyl)-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)-1H-pyrrolo[3,2-c]pyridine hydrochloride;

2,3-dimethyl-1-methoxymethyl-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)-1H-pyrrolo[3,2-c]pyridine hydrochloride;

2,3-dimethyl-1-(2-ethoxyethyl)-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)-1H-pyrrolo[3,2-c]pyridine hydrochloride;

2,3-dimethyl-1-(2-methoxyethoxymethyl)-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)-1H-pyrrolo[3,2-c]pyridine hydrochloride;

2,3-dimethyl-1-([1,3]dioxolan-2-ylmethyl)-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)-1H-pyrrolo[3,2-c]pyridine hydrochloride;

2,3-dimethyl-1-(2-fluorobenzyl)-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)-1H-pyrrolo[3,2-c]pyridine hydrochloride;

2,3-dimethyl-1-(3-fluorobenzyl)-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)-1H-pyrrolo[3,2-c]pyridine hydrochloride;

2,3-dimethyl-1-(4-fluorobenzyl)-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)-1H-pyrrolo[3,2-c]pyridine hydrochloride;

2,3-dimethyl-1-(4-chlorobenzyl)-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)-1H-pyrrolo[3,2-c]pyridine hydrochloride;

2,3-dimethyl-1-(4-methylbenzyl)-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)-1H-pyrrolo[3,2-c]pyridine hydrochloride;

2,3-dimethyl-1-(4-methoxybenzyl)-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)-1H-pyrrolo[3,2-c]pyridine hydrochloride;

2,3-dimethyl-1-(2-methylthiazol-4-ylmethyl)-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)-1H-pyrrolo[3,2-c]pyridine hydrochloride;

3-benzyl-2-methyl-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)-1H-pyrrolo[3,2-c]pyridine;

3-benzyl-2-methyl-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)-1H-pyrrolo[3,2-c]pyridine hydrochloride;

3-benzyl-1,2-dimethyl-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)-1H-pyrrolo[3,2-c]pyridine hydrochloride;

3-benzyl-1-ethyl-2-methyl-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)-1H-pyrrolo[3,2-c]pyridine hydrochloride;

3-benzyl-1-propyl-2-methyl-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)-1H-pyrrolo[3,2-c]pyridine hydrochloride;

1-allyl-3-benzyl-2-methyl-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)-1H-pyrrolo[3,2-c]pyridine hydrochloride;

3-benzyl-1-isobutyl-2-methyl-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)-1H-pyrrolo[3,2-c]pyridine hydrochloride;

3-benzyl-1-cyclopropyl-2-methyl-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)-1H-pyrrolo[3,2-c]pyridine hydrochloride;

3-benzyl-1-cyclopropylmethyl-2-methyl-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)-1H-pyrrolo[3,2-c]pyridine hydrochloride;

3-benzyl-1-(2-methoxyethyl)-2-methyl-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)-1H-pyrrolo[3,2-c]pyridine hydrochloride;

3-benzyl-1-(2-hydroxyethyl)-2-methyl-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)-1H-pyrrolo[3,2-c]pyridine hydrochloride;

3-benzyl-1-([1,3]dioxolan-2-ylmethyl)-2-methyl-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)-1H-pyrrolo[3,2-c]pyridine hydrochloride;

1,3-dibenzyl-2-methyl-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)-1H-pyrrolo[3,2-c]pyridine hydrochloride;

3-benzyl-1-(2-fluorobenzyl)-2-methyl-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)-1H-pyrrolo[3,2-c]pyridine hydrochloride;

3-benzyl-1-(3-fluorobenzyl)-2-methyl-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)-1H-pyrrolo[3,2-c]pyridine hydrochloride;

3-benzyl-1-(4-fluorobenzyl)-2-methyl-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)-1H-pyrrolo[3,2-c]pyridine hydrochloride;

3-benzyl-2-methyl-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)-1H-pyrrolo[3,2-c]pyridine sodium;

3-(3-fluorobenzyl)-2-methyl-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)-1H-pyrrolo[3,2-c]pyridine hydrochloride;

3-(3-fluorobenzyl)-1,2-dimethyl-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)-1H-pyrrolo[3,2-c]pyridine hydrochloride;

3-allyl-2-methyl-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)-1H-pyrrolo[3,2-c]pyridine hydrochloride; and

3-allyl-1,2-dimethyl-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)-1H-pyrrolo[3,2-c]pyridine hydrochloride.

4. The compound or a pharmaceutically acceptable salt thereof according to claim 3, which is selected from the group consisting of:

2,3-dimethyl-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)-1H-pyrrolo[3,2-c]pyridine;

2,3-dimethyl-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)-1H-pyrrolo[3,2-c]pyridine hydrochloride;

2,3-dimethyl-1-(2-methoxyethyl)-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)-1H-pyrrolo[3,2-c]pyridine hydrochloride;

1,2,3-trimethyl-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)-1H-pyrrolo[3,2-c]pyridine hydrochloride;

1-ethyl-2,3-dimethyl-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)-1H-pyrrolo[3,2-c]pyridine hydrochloride;

2,3-dimethyl-1-(2-hydroxyethyl)-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)-1H-pyrrolo[3,2-c]pyridine hydrochloride;

3-benzyl-2-methyl-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)-1H-pyrrolo[3,2-c]pyridine hydrochloride;

3-benzyl-1,2-dimethyl-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)-1H-pyrrolo[3,2-c]pyridine hydrochloride;

3-benzyl-1-ethyl-2-methyl-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)-1H-pyrrolo[3,2-c]pyridine hydrochloride;

3-benzyl-1-cyclopropyl-2-methyl-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)-1H-pyrrolo[3,2-c]pyridine hydrochloride;

3-benzyl-1-(2-methoxyethyl)-2-methyl-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)-1H-pyrrolo[3,2-c]pyridine hydrochloride;

3-benzyl-1-([1,3]dioxolan-2-ylmethyl)-2-methyl-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)-1H-pyrrolo[3,2-c]pyridine hydrochloride;

1,3-dibenzyl-2-methyl-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)-1H-pyrrolo[3,2-c]pyridine hydrochloride; and

3-benzyl-2-methyl-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)-1H-pyrrolo[3,2-c]pyridine sodium, or

a pharmaceutically acceptable salt thereof.

5. The compound or a pharmaceutically acceptable salt thereof according to claim 4, which is 3-benzyl-2-methyl-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)-1H-pyrrolo[3,2-c]pyridine hydrochloride or 3-benzyl-1,2-dimethyl-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)-1H-pyrrolo[3,2-c]pyridine hydrochloride or a pharmaceutically acceptable salt.

6. A process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, which comprises:

(a) adding a sodium nitrite solution to a compound of formula (II), followed by reducing the resulting product with tin chloride, to obtain a compound of formula (III);

(b) reacting the compound of formula (III) with a compound of formula (IV) to obtain a compound of formula (V);

(c) performing a cyclization reaction of a compound of formula (V) to obtain a compound of formula (VI);

(d) halogenizing the compound of formula (VI) to obtain a compound of formula (VII);

(e) reacting the compound of formula (VII) with R₄—

H to obtain a compound of formula (Ia); and

(f) reacting the compound of formula (Ia) with R₁—

X to obtain a compound of formula (I);

7. A pharmaceutical composition comprising a therapeutically effective amount of any of the compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 and a pharmaceutically acceptable carrier.