Aromatic nitrogen-containing 6-membered cyclic compounds

• US 6,656,935 B2
• Filed: 08/10/2001
• Issued: 12/02/2003
• Est. Priority Date: 09/16/1999
• Status: Active Grant

• Current Assignee: Mitsubishi Tanabe Pharma Corporation (Mitsubishi Chemical Group Corp.)
• Original Assignee: Tanabe Seiyaku Co Ltd (Mitsubishi Chemical Group Corp.)
• Inventors: Omori, Kenji, Yamada, Koichiro, Kikkawa, Kohei, Matsuki, Kenji
• Primary Examiner(s): Raymond, Richard L.
• Assistant Examiner(s): Balasubramanian, Venkataraman
• Application Number:
  US09/925,892
• Publication Number:
  US 20030032647A1
• Time in Patent Office: 844 Days
• Field of Search: 544/323, 544/325, 544/105, 544/114, 544/238, 514/275, 514/230.5, 514/231.5, 514/252.01
• US Class Current: 514/230.5
• 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 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 15/10 for impotence
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: C07D 239/48 Two nitrogen atoms
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 403/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 403/14 containing three or more hetero rings
• CPC Class Codes: C07D 413/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 413/14 containing three or more hetero rings
• CPC Class Codes: C07D 417/14 containing three or more hetero rings
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 487/04 Ortho-condensed systems
• CPC Class Codes: C07D 513/04 Ortho-condensed systems
• CPC Class Codes: C07F 9/6512 having the nitrogen atoms in positions 1 and 3
• CPC Class Codes: C07F 9/65583 each of the hetero rings containing nitrogen as ring hetero atom

Abstract

An aromatic nitrogen-containing 6-membered cyclic compound of the formula (I):

wherein Ring A is a substituted or unsubstituted nitrogen-containing heterocyclic group; R¹ is a substituted or unsubstituted lower alkyl group, —NH—Q—R³ (R³ is a substituted or unsubstituted nitrogen containing heterocyclic group, and Q is a lower alkylene group or a single bond), or —NH—R⁴ (R⁴ is a substituted or unsubstituted cycloalkyl group); R² is a substituted or unsubstituted aryl group; one of Y and Z is ═CH—, and the other is ═N—, or a pharmaceutically acceptable salt thereof, these compounds exhibiting excellent selective PDE V inhibitory activities, and hence, being useful in the prophylaxis or treatment of penile erectile dysfunction, etc.

Claims

1. An aromatic nitrogen-containing 6-membered cyclic compound of the formula (I):

wherein Ring A is a substituted or unsubstituted nitrogen-containing heterocyclic group;

R¹ is a substituted or unsubstituted lower alkyl group, a group of the formula;

—

NH—

Q—

R³ (in which R³ is a substituted or unsubstituted nitrogen containing heterocyclic group, and Q is a lower alkylene group or a single bond), or a group of the formula;

—

NH—

R⁴ (in which R⁴ is a substituted or unsubstituted cycloalkyl group);

R² is a substituted or unsubstituted aryl group;

Z is a group of the formula;

═

CH—

, and Y is a group of the formula;

═

N—

, or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, wherein the nitrogen-containing heterocyclic group of the “

substituted or unsubstituted nitrogen-containing heterocyclic group”

for Ring A is a 5- or 6-membered nitrogen-containing heteromonocyclic group or a 8- to 10-membered nitrogen-containing heterobicyclic group, and the substituent of the above “

substituted or unsubstituted nitrogen-containing heterocyclic group”

is selected from the group consisting of (1) a lower alkyl group, (2) a hydroxy-substituted lower alkyl group, (3) a formyl group, (4) an oxo group, (5) an amino group, (6) a hydroxy group, (7) a lower alkoxycarbonyl group, and (8) a pyrimidinyl group substituted by (i) a benzylamino group substituted by a halogen atom and a lower alkoxy group, and (ii) a cycloalkylcarbamoyl group substituted by a hydroxy group, R¹ is a lower alkyl group which may optionally be substituted by a group selected from the group consisting of a lower alkoxy group, a hydroxy group, a morpholinyl group, a lower alkylsulfonyl group, a di-(lower alkyl)phosphino group, a di-(lower alkyl)amino group, a pyrimidinyl-substituted lower alkylamino group, a pyridyl group, a pyridylamino group and a lower alkyl-substituted piperazinyl group, a group of the formula;

—

NH—

Q—

R³, or a group of the formula;

—

NH—

R⁴, the nitrogen-containing heterocyclic group of the “

substituted or unsubstituted nitrogen-containing heterocyclic group”

for R³ is a 5- or 6-membered nitrogen-containing heteromonocyclic group or a 8- to 10-membered nitrogen-containing heterobicyclic group, and the substituent of the above “

substituted or unsubstituted nitrogen-containing heterocyclic group”

is selected from the group consisting of a lower alkyl group, a hydroxy-substituted lower alkyl group, an oxo group, an amino group, a di-(lower alkyl)amino group, a lower alkanoyl group and a cyano-substituted lower alkyl group, R⁴ is a cycloalkyl group being substituted by a group selected from the group consisting of hydroxy group, a lower alkoxy group and a pyrimidinyloxy group, R² is a phenyl group being substituted by a group selected from the group consisting of a lower alkoxy group, a halogen atom, a cyano group, a nitro group, a hydroxy group and a lower alkyl group.

3. The compound according to claim 2, wherein the nitrogen-containing heterocyclic group of the “

substituted or unsubstituted nitrogen-containing heterocyclic group”

for Ring A is a 5- or 6-membered nitrogen-containing heteromonocyclic group of the formula;

or a nitrogen-containing heterobicyclic group of the following formula wherein the above-mentioned 5- or 6-membered nitrogen-containing heteromonocyclic group and a 5- or 6-membered cyclic group are fused;

and the nitrogen-containing heterocyclic group of the “

substituted or unsubstituted nitrogen-containing heterocyclic group”

for R³ is a nonaromatic nitrogen-containing heteromonocyclic group of the formula;

or an aromatic nitrogen-containing heterocyclic group of the formula;

or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 1, wherein the nitrogen-containing heterocyclic group of the “

substituted or unsubstituted nitrogen-containing heterocyclic group”

for Ring A is a 5- or 6-membered nitrogen-containing heteromonocyclic group or a 8- to 10-membered nitrogen-containing heterobicyclic group, and the substituent of the above “

substituted or unsubstituted nitrogen-containing heterocyclic group”

is selected from the group consisting of a lower alkyl group, a hydroxy-substituted lower alkyl group, a formyl group and an oxo group, R¹ is a lower alkyl group which may optionally be substituted by a group selected from the group consisting of a lower alkoxy group and a morpholinyl group, a group of the formula;

—

NH—

Q—

R³, or a group of the formula;

—

NH—

R⁴, the “

substituted or unsubstituted nitrogen-containing heterocyclic group”

for R³ is a 5- or 6-membered nitrogen-containing heteromonocyclic group which may optionally be substituted by a lower alkyl group, R⁴ is a cycloalkyl group being substituted by a group selected from the group consisting of hydroxy group and a lower alkoxy group, R² is a phenyl group being substituted by a group selected from the group consisting of a lower alkoxy group, a halogen atom and a cyano group.

5. The compound according to claim 4, wherein the nitrogen-containing heterocyclic group of the “

substituted or unsubstituted nitrogen-containing heterocyclic group”

for Ring A is a 5- or 6-membered non-aromatic nitrogen-containing heteromonocyclic group of the formula;

or a nitrogen-containing heterobicyclic group of the following formula wherein the above-mentioned 5- or 6-membered non-aromatic nitrogen-containing heteromonocyclic group and a 5- or 6-membered aromatic nitrogen-containing heteromonocyclic group are fused;

the nitrogen-containing heterocyclic group of the “

substituted or unsubstituted nitrogen-containing heterocyclic group”

for R³ is a non-aromatic nitrogen-containing heteromonocyclic group of the formula;

or an aromatic nitrogen-containing heteromonocyclic group of the formula;

6. The compound according to claim 1, wherein Ring A is a group of the formula:

R¹ is a lower alkyl group, a lower alkoxy-substituted lower alkyl group, a morpholinyl-substituted lower alkyl group, a group of the formula;

—

NH—

Q—

R³, or a group of the formula;

—

NH—

R⁴, R³ is a group of the formula;

R⁴ is a group of the formula;

and R² is a group of the formula;

7. The compound according to claim 1, wherein the nitrogen-containing heterocyclic group of the “

substituted or unsubstituted nitrogen-containing heterocyclic group”

for Ring A is a 5- or 6-membered nitrogen-containing heteromonocyclic group or a 8- to 10-membered nitrogen-containing heterobicyclic group, and the substituent of the above “

substituted or unsubstituted nitrogen-containing heterocyclic group”

is a group selected from the group consisting of a lower alkyl group, a hydroxy-substituted lower alkyl group, a formyl group and an oxo group, R¹ is a lower alkoxy-substituted lower alkyl group, a group of the formula;

—

NH—

Q—

R³, or a group of the formula;

—

NH—

R⁴, the “

substituted or unsubstituted nitrogen-containing heterocyclic group”

for R³ is a 5- or 6-membered nitrogen-containing heteromonocyclic group which may optionally be substituted by a lower alkyl group, R⁴ is a hydroxy-substituted cycloalkyl group, and R² is a phenyl group being substituted by a group selected from the group consisting of a lower alkoxy group and a halogen atom.

8. The compound according to claim 7, wherein the nitrogen-containing heterocyclic group of the “

substituted or unsubstituted nitrogen-containing heterocyclic group”

for Ring A is a 5- or 6-membered non-aromatic nitrogen-containing heteromonocyclic group of the formula;

a group of the formula;

the nitrogen-containing heterocyclic group of the “

substituted or unsubstituted nitrogen-containing heterocyclic group”

for R³ is a non-aromatic nitrogen-containing heteromonocyclic group of the formula;

or an aromatic nitrogen-containing heteromonocyclic group of the formula;

9. The compound according to claim 1, wherein Ring A is a group of the formula:

R¹ is a lower alkoxy-substituted lower alkyl group, a group of the formula;

—

NH—

Q—

R³, or a group of the formula;

—

NH—

R⁴, R³ is a group of the formula;

R⁴ is a group of the formula;

and R² is a group of the formula;

10. The compound according to claim 1, wherein the nitrogen-containing heterocyclic group of the “

substituted or unsubstituted nitrogen-containing heterocyclic group”

for Ring A is a 5- or 6-membered nitrogen-containing heteromonocyclic group or a 8- to 10-membered nitrogen-containing heterobicyclic group, and the substituent of the above “

substituted or unsubstituted nitrogen-containing heterocyclic group”

is a hydroxy-substituted lower alkyl group, R¹ is a group of the formula;

—

NH—

Q—

R³, the “

substituted or unsubstituted nitrogen-containing heterocyclic group”

for R³ is a 5- or 6-membered nitrogen-containing heteromonocyclic group which may optionally be substituted by a lower alkyl group, and R² is a phenyl group being substituted by a group selected from the group consisting of a lower alkoxy group and a halogen atom.

11. The compound according to claim 10, wherein the nitrogen-containing heterocyclic group of the “

substituted or unsubstituted nitrogen-containing heterocyclic group”

for Ring A is a 5- or 6-membered non-aromatic nitrogen-containing heteromonocyclic group of the formula;

or a group of the formula;

the nitrogen-containing heterocyclic group of the “

substituted or unsubstituted nitrogen-containing heterocyclic group”

for R³ is a non-aromatic nitrogen-containing heteromonocyclic group of the formula;

or an aromatic nitrogen-containing heteromonocyclic group of the formula;

12. The compound according to claim 1, wherein Ring A is a group of the formula:

R¹ is a group of the formula;

—

NH—

Q—

R³, R³ is a group of the formula;

and R² is a group of the formula;

13. The compound according to claim 1, wherein said compound is selected from the group consisting of:

(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(2-pyrimidinylmethyl)carbamoyl]pyrimidime;

2-(6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-6-yl)-4-(3-cyano-4-methoxybenzylamino)-5-[N-(2-pyrimidinylmethyl)carbamoyl]pyrimidine;

2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(trans-4-methoxycyclohexyl)carbamoyl]pyrimidine;

2-(6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-6-yl)-4-(3-cyano-4-methoxybenzylamino)-5-[N-(trans-4-hydroxycyclohexyl)carbamoyl]pyrimidine;

2-(6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-6-yl)-4-(3-cyano-4-methoxybenzylamino)-5-[N-(2-morpholinoethyl)carbamoyl]pyrimidine;

(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)4-(3-chloro-4-methoxy-benzylamino)-5-[N-(2-morpholinoethyl)carbamoyl]pyrimidine;

2-[(2S)-2-hydroxymethyl-1-pyrrolidinyl]-4-(3-chloro-4-methoxy-benzylamino)-5-[N-[[(2R)-4-methyl-2-morpholinyl]methyl]carbamoyl]pyrimidine;

2-[(2S)-2-hydroxymethyl-1-pyrrolidinyl]-4-(3-chloro-4-methoxy-benzylamino)-5-[N-[[(2S)-4-methyl-2-morpholinyl]methyl]carbamoyl]pyrimidine;

(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxy-benzylamino)-5-[N-(4-pyrimidinylmethyl)carbamoyl]pyrimidine;

2-(4-methyl-3-oxo-I-piperazinyl)-4-(3-chloro-4-methoxybenzyl-amino)-5-[N-(trans-4-hydroxycyclohexyl)carbamoyl]pyrimidine;

2-(4-formyl-1-piperazinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(trans-4-hydroxycyclohexyl)carbamoyl]pyrimidine;

2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(trans-4-hydroxycyclohexyl)carbamoyl]pyrimidine;

2-[cis-2,5-bis(hydroxymethyl)-1-pyrrolidinyl]-4-(3-chloro-4-methoxybenzylamino)-5-[N-(2-pyrimidinylmethyl)carbamoyl]pyrimidine,

2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)-4-(3-chloro-4-methoxy-benzylamino)-5-[N-(2-pyrimidinylmethyl)carbamoyl]pyrimidine;

2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)-4-(3-chloro-4-methoxy-benzylamino)-5-[N-(2-morpholinoethyl)carbamoyl]pyrimidine;

2-(5,6,7,8-tetrahydro-1,7-naphthyridin-7-yl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(2-morpholinoethyl)carbamoyl]pyrimidine;

(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-acethylpyrimidine;

(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(4-pyridazinylmethyl)carbamoyl]pyrimidine;

(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(5-pyridazinylmethyl)carbamoyl]pyrimidine;

(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(2-pyrimidinylmethyl)carbamoyl]pyrimidine;

(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(2-morpholinoethyl)carbamoyl]pyrimidine;

2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)-4-(3-chloro-4-methoxy-benzylamino)-5-[N-[(4-methyl-2-morpholinyl)methyl]carbamoyl]pyrimidine;

(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[(2-methoxyethyl)carbonyl]pyrimidine; and

(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(1,3,5-trimethyl-4-pyrazolyl)carbamoyl]pyrimidine,

or a pharmaceutically acceptable salt thereof.

14. The compound according to claim 13, wherein said compound is selected from the group consisting of:

(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(2-pyrimidinylmethyl)carbamoyl]pyrimidine;

(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)5-[N-(4-pyrimidinylmethyl)carbamoyl]pyrimidine;

2-(4-methyl-3-oxo-1-piperazinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(trans-4-hydroxycyclohexyl)carbamoyl]pyrimidine;

2-(4-formyl-1-piperazinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(trans-4-hydroxycyclohexyl)carbamoyl]pyrimidine;

2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)-4-(3-chloro-4-methoxy-benzylamino)-5-[N-(2-pyrimidinylmethyl)carbamoyl]pyrimidine;

2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)-4-(3-chloro-4-methoxy-benzylamino)-5-[N-(2-morpholinoethyl)carbamoyl]pyrimidine;

2-(5,6,7,8-tetrahydro-1,7-naphthyridin-7-yl)-4-(3-chloro-4-methoxybenzylamino)5-[N-(2-morpholinoethyl)carbamoyl]pyrimidine;

(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-pyrimidinylmethyl)carbamoyl]pyrimidine;

(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[(2-methoxyethyl)carbonyl]pyrimidine; and

(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxy-benzylamino)-5-[N-(1,3,5-trimethyl-4-pyrazolyl)carbamoyl]pyrimidine,

or a pharmaceutically acceptable salt thereof.

15. The compound according to claim 13, wherein said compound is selected from the group consisting of:

(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4methoxybenzylamino)-5-[N-(2-pyrimidinylmethyl)carbamoyl]pyrimidine;

(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(2-morpholinoethyl)carbamoyl]pyrimidine;

2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(2-pyrimidinylmethyl)carbamoyl]pyrimidine;

2-(5,6,7,8-tetrahydro-1,7-naphthyridin-7-yl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(2-morpholinoethyl)carbamoyl]pyrimidine;

(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5[N-(5-pyrimidinylmethyl)carbamoyl]pyrimidine; and

(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(1,3,5-trimethyl-4-pyrazolyl)carbamoyl]pyrimidine,

or a pharmaceutically acceptable salt thereof.

16. The compound of claim 13, wherein said compound is (S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(2-pyrimidinylmethyl)carbamoyl]pyrimidine, or a pharmaceutically acceptable salt thereof.

17. The compound of claim 13, wherein said compound is 2-(5,6,7,8-tetrahydro-1,7-naphthyridin-7-yl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(2-morpholinoethyl)carbamoyl]pyrimidine, or a pharmaceutically acceptable salt thereof.

18. The compound of claim 13, wherein said compound is (S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(1,3,5-trimethyl-4-pyrazolyl)carbamoyl]pyrimidine, or a pharmaceutically acceptable salt thereof.

19. A pharmaceutical composition, which contains as an active ingredient the compound as set forth in any one of claims 1-12 and 13-18, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier therefor.

20. A method for treatment of penile erectile dysfunction, which comprises administering to a patient in need thereof an effective amount of the compound as set forth in any one of claims 1-12 and 13-18, or a pharmaceutically acceptable salt thereof.

21. A method for treatment of pulmonary hypertension, which comprises administering to a patient in need thereof an effective amount of the compound as set forth in any one of claims 1-12 and 24-18, or a pharmaceutically acceptable salt thereof.

22. A method for treatment of diabetic gastroparesis, which comprises administering to a patient in need thereof an effective amount of the compound as set forth in any one of claims 1-12 and 13-18, or a pharmaceutically acceptable salt thereof.