A renin-angiotensin (RA) system is a hormone system which is important for maintaining electrolyte balance of blood pressure and within body, and plays an important role for development and progress of circulatory diseases such as hypertension, congestive heart failure, renal disorder.
Renin which is an important component of RA system is an aspartic protease which is secreted mainly from the kidney into the blood, and specifically breaks down angiotensinogen which is generated in the liver to produce angiotensin I. Angiotensin I is converted into angiotensin II by angiotensin converting enzyme (ACE) which exists in lung and vascular endothelial cells. Angiotensin II not only constricts a blood vessel, but also stimulates the adrenal gland to promote secretions of aldosterone. Aldosterone acts on the kidney to conserve sodium and eliminate potassium. These cascades cause increased blood pressure (Nonpatent Document 1).
Recently, it has been indicated that RA system components also exist in local sites including peripheral tissues or central tissues such as heart, blood vessel, kidney, adrenal gland, adipose, and (pro)renin receptor has the possibility to play an important role in activation of local RA system as an additional new component (Nonpatent Document 2), and the importance of local (tissue) RA system has been recognized. It has been indicated that circulating RA system involves in short-term circulation controls, while tissue RA system has the possibility to cause organ damages such as cardiomegaly, arteriosclerosis, renal disorder by inducing long-term various organ remodelings in heart, kidney, blood vessel, etc. (Nonpatent Document 3).
RA system inhibiting agents include ACE inhibitors and angiotensin II receptor antagonists (ARB). It has been shown that these agents (especially, the former) are useful as a therapeutic agent not only for hypertension, but also for cardiovascular diseases and renal diseases such as heart failure and diabetic nephropathy, and these agents have been applied in a wide clinical setting (Nonpatent Document 4, Nonpatent Document 5).
There are multiple RA system inhibiting steps, and among them, renin is located in upstream of RA system and limits the cascade. Thus, to inhibit renin is significantly attractive approach in theory (Nonpatent Document 6, Nonpatent Document 7). Actually, it has been shown that a renin inhibitor aliskiren which has been recently developed significantly inhibits plasma renin activity in clinical trial intended for hypertension patients, and shows excellent hypotensive effects comparable to other RA system inhibiting agents (Nonpatent Document 8, Nonpatent Document 9, Nonpatent Document 10).
As a compound group wherein nitrogen atom in the ring of cyclic amino is substituted, a compound group of the following formula:
wherein R1 is hydrogen atom, C1-6 alkyl, —C(A)D, C3-8 cycloalkyl, aryl, hetero, aryl-C1-4 alkyl, or hetero-C1-4 alkyl, R2 is aryl or heteroaryl, A is S or O, D is hydrogen atom, halogen atom, C1-6 alkyl, aryl, aryl-C1-4 alkyl, or hetero-C1-4 alkyl, n is 0 or 1, provided that if n is 1, m is 0 or 1, provided that if n is 2, m is 0, * is a chiral center, R3 is hydrogen atom, C1-6 alkyl, etc. has been known (Patent Document 1). However, this compound group is structurally different from the present compound in view of aryl or heteroaryl skeleton in “R2”.
As a renin inhibitor having cyclic amino, derivatives with a piperidine ring (Patent Documents 2 and 3), derivatives with a pyrrolidine ring (Patent Document 4) have been reported to be effective as a renin inhibitor. The compounds disclosed in these documents are structurally characterized in that they all have a partial structure wherein amino group binds to 3-position of piperidine ring and pyrrolidine ring via carbonyl group or methylene chain, and that nitrogen atom in the ring of piperidine ring and pyrrolidine ring is unsubstituted. It has been reported that a compound group having aminocarbonyl on 3-position of pyrrolidine ring or piperidine ring is effective as a renin inhibitor (Patent Documents 5 to 12). However, all these compound groups are structurally characterized in that nitrogen atom in the ring of cyclic amino (including pyrrolidine ring, piperidine ring) is unsubstituted. Hence, they are different from the present invention described hereinafter in that nitrogen atom in the ring of cyclic amino is unsubstituted or substituted by specific substituents.    [Patent Document 1] WO2006/064336 pamphlet    [Patent Document 2] WO2006/069788 pamphlet    [Patent Document 3] WO2006/094763 pamphlet    [Patent Document 4] WO2006/066896 pamphlet    [Patent Document 5] WO2008/093737 pamphlet    [Patent Document 6] WO2008/136457 pamphlet    [Patent Document 7] WO2008/153135 pamphlet    [Patent Document 8] WO2009/005002 pamphlet    [Patent Document 9] WO2009/014217 pamphlet    [Patent Document 10] WO2009/072649 pamphlet    [Patent Document 11] WO2009/078481 pamphlet    [Patent Document 12] WO2009/154300 pamphlet    [Nonpatent Document 1] Nat Rev Drug Discov. 1(8): p. 621-36 (2002)    [Nonpatent Document 2] Curr Hypertens Rep. 6(2): p. 129-32 (2004)    [Nonpatent Document 3] Physiol. Rev. 86: p. 747-803, (2006)    [Nonpatent Document 4] Curr Diab Rep. 6(1): p. 8-16, (2006)    [Nonpatent Document 5] J Hypertens Suppl. 23(1): S9-17, (2005)    [Nonpatent Document 6] J Exp Med. 106(3): p. 439-53, (1957)    [Nonpatent Document 7] J Am Soc Nephrol 16: p. 592-599 (2005)    [Nonpatent Document 8] Hypertension 42(6): p. 1137-43, (2003)    [Nonpatent Document 9] Circulation 111(8): p. 1012-8, (2005)    [Nonpatent Document 10] J Hypertens. 24(Suppl 4): S82. Abstract P4.269, (2006)
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USPTO Backgrounds