Claims for Patent: 6,656,935

Summary for Patent: 6,656,935

Title:	Aromatic nitrogen-containing 6-membered cyclic compounds
Abstract:	An aromatic nitrogen-containing 6-membered cyclic compound of the formula (I): ##STR1## wherein Ring A is a substituted or unsubstituted nitrogen-containing heterocyclic group; R.sup.1 is a substituted or unsubstituted lower alkyl group, --NH--Q--R.sup.3 (R.sup.3 is a substituted or unsubstituted nitrogen containing heterocyclic group, and Q is a lower alkylene group or a single bond), or --NH--R.sup.4 (R.sup.4 is a substituted or unsubstituted cycloalkyl group); R.sup.2 is a substituted or unsubstituted aryl group; one of Y and Z is .dbd.CH--, and the other is .dbd.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.
Inventor(s):	Yamada; Koichiro (Saitama-ken, JP), Matsuki; Kenji (Saitama-ken, JP), Omori; Kenji (Saitama, JP), Kikkawa; Kohei (Kawaguchi, JP)
Assignee:	Tanabe Seiyaku Co., Ltd. (Osaka, JP)
Application Number:	09/925,892
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 6,656,935
Patent Claims:	1. An aromatic nitrogen-containing 6-membered cyclic compound of the formula (I): ##STR364## wherein Ring A is a substituted or unsubstituted nitrogen-containing heterocyclic group; R.sup.1 is a substituted or unsubstituted lower alkyl group, a group of the formula: --NH--Q--R.sup.3 (in which R.sup.3 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--R.sup.4 (in which R.sup.4 is a substituted or unsubstituted cycloalkyl group); R.sup.2 is a substituted or unsubstituted aryl group; Z is a group of the formula: .dbd.CH--, and Y is a group of the formula: .dbd.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, R.sup.1 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--R.sup.3, or a group of the formula: --NH--R.sup.4, the nitrogen-containing heterocyclic group of the "substituted or unsubstituted nitrogen-containing heterocyclic group" for R.sup.3 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, R.sup.4 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, R.sup.2 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: ##STR365## 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: ##STR366## and the nitrogen-containing heterocyclic group of the "substituted or unsubstituted nitrogen-containing heterocyclic group" for R.sup.3 is a nonaromatic nitrogen-containing heteromonocyclic group of the formula: ##STR367## or an aromatic nitrogen-containing heterocyclic group of the formula: ##STR368## 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, R.sup.1 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--R.sup.3, or a group of the formula: --NH--R.sup.4, the "substituted or unsubstituted nitrogen-containing heterocyclic group" for R.sup.3 is a 5- or 6-membered nitrogen-containing heteromonocyclic group which may optionally be substituted by a lower alkyl group, R.sup.4 is a cycloalkyl group being substituted by a group selected from the group consisting of hydroxy group and a lower alkoxy group, R.sup.2 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: ##STR369## 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: ##STR370## the nitrogen-containing heterocyclic group of the "substituted or unsubstituted nitrogen-containing heterocyclic group" for R.sup.3 is a non-aromatic nitrogen-containing heteromonocyclic group of the formula: ##STR371## or an aromatic nitrogen-containing heteromonocyclic group of the formula: ##STR372## 6. The compound according to claim 1, wherein Ring A is a group of the formula: ##STR373## R.sup.1 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--R.sup.3, or a group of the formula: --NH--R.sup.4, R.sup.3 is a group of the formula: ##STR374## R.sup.4 is a group of the formula: ##STR375## and R.sup.2 is a group of the formula: ##STR376## 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, R.sup.1 is a lower alkoxy-substituted lower alkyl group, a group of the formula: --NH--Q--R.sup.3, or a group of the formula: --NH--R.sup.4, the "substituted or unsubstituted nitrogen-containing heterocyclic group" for R.sup.3 is a 5- or 6-membered nitrogen-containing heteromonocyclic group which may optionally be substituted by a lower alkyl group, R.sup.4 is a hydroxy-substituted cycloalkyl group, and R.sup.2 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: ##STR377## a group of the formula: ##STR378## the nitrogen-containing heterocyclic group of the "substituted or unsubstituted nitrogen-containing heterocyclic group" for R.sup.3 is a non-aromatic nitrogen-containing heteromonocyclic group of the formula: ##STR379## or an aromatic nitrogen-containing heteromonocyclic group of the formula: ##STR380## 9. The compound according to claim 1, wherein Ring A is a group of the formula: ##STR381## R.sup.1 is a lower alkoxy-substituted lower alkyl group, a group of the formula: --NH--Q--R.sup.3, or a group of the formula: --NH--R.sup.4, R.sup.3 is a group of the formula: ##STR382## R.sup.4 is a group of the formula: ##STR383## and R.sup.2 is a group of the formula: ##STR384## 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, R.sup.1 is a group of the formula: --NH--Q--R.sup.3, the "substituted or unsubstituted nitrogen-containing heterocyclic group" for R.sup.3 is a 5- or 6-membered nitrogen-containing heteromonocyclic group which may optionally be substituted by a lower alkyl group, and R.sup.2 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: ##STR385## or a group of the formula: ##STR386## the nitrogen-containing heterocyclic group of the "substituted or unsubstituted nitrogen-containing heterocyclic group" for R.sup.3 is a non-aromatic nitrogen-containing heteromonocyclic group of the formula: ##STR387## or an aromatic nitrogen-containing heteromonocyclic group of the formula: ##STR388## 12. The compound according to claim 1, wherein Ring A is a group of the formula: ##STR389## R.sup.1 is a group of the formula: --NH--Q--R.sup.3, R.sup.3 is a group of the formula: ##STR390## and R.sup.2 is a group of the formula: ##STR391## 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-methoxybenzylami no)-5-[N-(2-pyrimidinylmethyl)carbamoyl]pyrimidine; 2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)-4-(3-chloro-4-methoxybenzy lamino)-5-[N-(trans-4-methoxycyclohexyl)carbamoyl]pyrimidine; 2-(6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-6-yl)-4-(3-cyano-4-methoxybenzylami no)-5-[N-(trans-4-hydroxycyclohexyl)carbamoyl]pyrimidine; 2-(6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-6-yl)-4-(3-cyano-4-methoxybenzylami no)-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-(t rans-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-methoxybenzy lamino)-5-[N-(trans-4-hydroxycyclohexyl)carbamoyl]pyrimidine; 2-[cis-2,5-bis(hydroxymethyl)-1-pyrrolidinyl]-4-(3-chloro-4-methoxybenzylam ino)-5-[N-(2-pyrimidinylmethyl)carbamoyl]pyrimidine, 2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)-4-(3-chloro-4-methoxy-benz ylamino)-5-[N-(2-pyrimidinylmethyl)carbamoyl]pyrimidine; 2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)-4-(3-chloro-4-methoxy-benz ylamino)-5-[N-(2-morpholinoethyl)carbamoyl]pyrimidine; 2-(5,6,7,8-tetrahydro-1,7-naphthyridin-7-yl)-4-(3-chloro-4-methoxybenzylami no)-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-benz ylamino)-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-(tr ans-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-benz ylamino)-5-[N-(2-pyrimidinylmethyl)carbamoyl]pyrimidine; 2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)-4-(3-chloro-4-methoxy-benz ylamino)-5-[N-(2-morpholinoethyl)carbamoyl]pyrimidine; 2-(5,6,7,8-tetrahydro-1,7-naphthyridin-7-yl)-4-(3-chloro-4-methoxybenzylami no)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-methoxybenzy lamino)-5-[N-(2-pyrimidinylmethyl)carbamoyl]pyrimidine; 2-(5,6,7,8-tetrahydro-1,7-naphthyridin-7-yl)-4-(3-chloro-4-methoxybenzylami no)-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-methoxybenzylam ino)-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.