USOO5243054A United States Patent (19) 11 Patent Number: 5,243,054 Naka et al. 45 Date of Patent: Sep. 7, 1993

(54) COMPOUND WHICH IS ANGIOTENSINI O3923.17 10/1990 European Pat. Off. . ANTAGONST O399732 11/1990 European Pat. Off. . O40O835 12/1990 European Pat. Off. . 75) Inventors: Takehiko Naka, Kobe, Yoshiyuki 040702 1/1991 European Pat. Off. . Inada, Kawanishi, both of Japan O411507 2/1991 European Pat. Off. . 4, 1766 2/1991 European Pat. Off. . 73) Assignee: Takeda Chemical Industries, Ltd., O420237 4/99 European Pat. Off. . Osaka, Japan O42592 5/1991 European Pat. Off. . O430300 6/1991 European Pat. Off. . (21) Appl. No.: 904,452 O432737 6/1991 European Pat. Off. . 22 Filed: Jun. 25, 1992 0434038 6/1991 European Pat, Off. . (30) Foreign Application Priority Data 5O1892 9/1992 European Pat. Off. . Primary Examiner-Bernard Dentz Jun. 27, 1991 JP Japan ...... 3-157194 Attorney, Agent, or Firm-Wegner, Cantor, Mueller & Jul. 29, 1991 JP Japan ...... 3-188882 Player Jul. 31, 1991 (JP) Japan ...... 3-92054 Aug. 12, 1991 JP Japan ...... 3-28827 Sep. 19, 1991 JP Japan ...... 3.239764 (57) ABSTRACT Dec. 24, 1991 JP Japan ...... 3-3410

51) Int. C...... CO7D 27/07 52) U.S. C...... 548/132; 548/129; 546/18 58) Field of Search ...... 548/32 (56) References Cited U.S. PATENT DOCUMENTS compounds shown by the above formula or salt thereof 4,880,804 11/1989 Carini et al...... 54.6/199 show a strong angiotensin II antagonistic activity and hypotensive action and CNS activity, and are useful as FOREIGN PATENT DOCUMENTS therapeutic agents of circulatory diseases such as hyper 0028833 5/1981 European Pat. Off. . tensive diseases and heart diseases (e.g. hypercardia, 0028834 5/1981 European Pat. Off. . heart failure, cardiac infarction), strokes, cerebral apo 149543 7/1985 European Pat. Off. . 0245637 / 1987 European Pat. Off. . plexy, nephritis, atherosclerosis, Alzheimer's disease, 0253310 1/1988 European Pat. Off. . senile dementia, etc. O291969 11/1988 European Pat. Off. . O32384 7/1989 European Pat. Off. . 1 Claim, No Drawings 5,243,054 1. 2 On the other hand, for solving the problems observed COMPOUND WHICH IS ANGIOTENSIN II in these peptide angiotensin II antagonists, studies on ANTAGONST non-peptide angiotensin II antagonists have been devel oped. In the earliest studies in this field, imidazole deriv FIELD OF THE INVENTION atives having angiotensin II antagonist activity have This invention relates to novel heterocyclic com been disclosed in JPA S56(1981)-71073, S56(1981)- pounds having excellent pharmacological actions and 71074, S57(1982)-98270 and S58(1983)-157768, U.S. Pat. intermediates for the synthesis thereof. No. 4,355,040 and 4,340,598, etc. Later, improved imid More specifically, the present invention relates to 10 azole derivatives are disclosed in EP-0253310, EP compounds of the general formula 0291969, EP-0324377, EP-403158, WO-900277, JPA S63(1988)-23868 and JPA H1(1989)-117876; pyrrole, pyrazole and triazole derivatives in EP-0323841, EP 04.09332 and JPA Hi(1989)-287071; benzimidazole de 15 rivatives in U.S. Pat. No. 4,880,804, EP-039237, EP 0399732, EP-0400835 and JPA H3(1991)-63264; azain (CH2) dene derivatives in EP-0399731; pyrimidone derivatives in EP-0407342; and quinazolinone derivatives in EP 04 1766; as angiotensin II antagonists. wherein R is an optionally substituted hydrocarbon 20 However, in order to become a therapeutically useful residue which is optionally bonded through a hetero drug, angiotensin II antagonists are required to have a atom; R2 is an optionally substituted 5-7 membered strong and long-lasting angiotensin II antagonistic ac heterocyclic residue having, as a group capable of con stituting the ring, a carbonyl group, a thioncarbonyl tion by oral administration. As shown in so far known group, an optionally oxidized sulfur atom or a group 25 literature references, the preferable angiotensin II an convertible into them; X is a direct bond or a spacer tagonist is considered to have an acid group, for exam having an atomic length of two or less between the ring ple, tetrazole group or carboxyl group on the biphenyl Y and the ring W; W and Y are independently an op side chain, especially tetrazole group as the most prefer tionally substituted aromatic hydrocarbon residue op able one. Clinical tests of compounds having the tet tionally containing a hetero-atom or an optionally sub 30 razole group for anti-hypertension agents are being stituted heterocyclic residue; n is an integer of 1 or 2; a conducted Y. Christen, B. Waeber, J. Nussberger, R. J. and b forming the heterocyclic residue are indepen Lee, P. B. M. W. M. Timmermans, and H. R. Brunner, dently one or two optionally substituted carbon or het Am. J. Hypertens., 4, 350S (1991). However, com ero atoms; c is an optionally substituted carbon or het pounds having tetrazole ring and azide compounds to ero atom; and, in the group of the formula 35 be used for synthesizing them have been known as in volving a danger of explosion, which becomes a serious problem to the large scale preparation and production. OBJECT OF THE INVENTION The present invention is to provide a novel com substituents on adjacent two atoms forming the ring are pound having a heterocyclic residue substitutable for optionally bonded to each other to form a 5-6 mem the tetrazole or carboxylic group which has strong bered ring together with the two atoms forming the angiotensin II antagonistic action and antihypertensive ring or a salt thereof. 45 action when administered orally and which becomes a therapeutically useful drug. BACKGROUND OF THE INVENTION The present inventors considered that compounds The renin-angiotensin system is involved in the ho blocking renin-angiotensin system as well as being clini meostatic function to control systemic blood pressure, cally useful for the treatment of circulatory diseases the volume of body fluid, balance among the electro 50 such as hypertensive diseases, heart diseases (hyper lytes, etc., associated with the aldosterone system. The cardia, heart failure, cardiac infarction, etc.), cerebral relationship between the renin-angiotensin system and apoplexy, nephritis, atherosclerosis, etc. are required to hypertension has been clarified by the development of have potent angiotensin II receptor antagonistic activ angiotensin II (AII) converting enzyme inhibitors ity and to show a strong and long-lasting angiotensin II (ACE inhibitor) which counteract angiotensin II with 55 antagonistic and hypotensive action by oral administra its strong vasoconstrictive action. Since angiotensin II constricts blood vessel to elevate blood pressure via the tion, and they have made extensive and intensive studies angiotensin II receptors on the cellular membranes, on a compound having angiotensin II antagonistic ac angiotensin II antagonists, like the ACE inhibitors, can tivity for years. be used for treating hypertension caused by angiotensin. As a result, the present inventors have found that It has been reported that a number of angiotensin II novel heterocyclic compounds (I) have a potent angio analogues such as saralasin, Sar, IleAII and the like tensin II receptor antagonistic activity as well as strong possess potent angiotensin II antagonist activity. It has, and long-lasting angiotensin II antagonistic and anti however, been reported that, when peptide antagonists hypertensive actions by oral administration. are administered non-orally, their actions are not pro 65 longed and, when administered orally, they are ineffec SUMMARY OF THE INVENTION tive M. A. Ondetti and D. W. Cushman, Annual Re More specifically, the present invention relates to (1) ports in Medicinal Chemistry, 13, 82-91 (1978)). a compound of the formula 5,243,054 4.

(I)

R l forming a ring) or a slat thereof, or (3) a compound represented of the formula wherein R is an optionally substituted hydrocarbon O (b) residue which is optionally bonded through a hetero atom; R2 is an optionally substituted 5-7 membered heterocyclic residue having, as a group capable of con stituting the ring, a carbonyl group, a thiocarbonyl 15 (CH2) group, an optionally oxidized sulfur atom or a group convertible into them; X is a direct bond or a spacer having an atomic length of two or less between the ring wherein R is an optionally substituted hydrocarbon Y and the ring W; W and Y are independently an op residue which is optionally bonded through a hetero tionally substituted aromatic hydrocarbon residue op 20 atom; R2 is an optionally substituted 5-7 membered tionally containing a hetero-atom or an optionally sub heterocyclic residue having, as a group capable of con stituted heterocyclic residue; n is an integer of 1 or 2; a stituting the ring, a carbonyl group, a thiocarbonyl group, an optionally oxidized sulfur atom or a group and b forming the heterocyclic residue are indepen convertible into them; X is a direct bond or a spacer dently one or two optionally substituted carbon or het 25 having an atomic length of two or less between the ring ero atoms; c is an optionally substituted carbon or het Y and the ring W; W and Y are independently an op ero atom; and, in the group of the formula tionally substituted aromatic hydrocarbon residue op tionally containing a hetero-atom or an optionally sub stituted heterocyclic residue; a and e forming the heter 30 ocyclic residue are independently one or two optionally substituted carbon or hetero atoms; d and f forming the heterocyclic residue are independently one optionally substituted carbon or hetero atom; b and c are indepen substituents on adjacent two atoms forming the ring are dently one optionally substituted carbon or nitrogen optionally bonded to each other to form a 5-6 mem 35 atom; in denotes an integer of 1 or 2; and, when a is an bered ring together with the two atoms forming the optionally substituted carbon atom, R and a may op tionally be bonded to each other to form a group of the ring or a salt thereof, more preferably, (2) a compound formula of the formula

(Ia) Rl l

45 forming a ring or a salt thereof. DETALED DESCRIPTION OF THE INVENTION wherein R is an optionally substituted hydrocarbon Referring to the general formula (I), examples of the residue which is optionally bonded through a hetero 50 hydrocarbon residue represented by R1 include alkyl, atom; R2 is an optionally substituted 5-7 membered alkenyl, alkynyl, cycloalkyl, aryl and aralkyl groups. heterocyclic residue having, as a group capable of con Among them, alkyl, alkenyl and cycloalkyl groups are stituting the ring, a carbonyl group, a thiocarbonyl preferable. The hydrocarbon residue may be bonded to the ring through a hetero atom or further substituted group, an optionally oxidized sulfur atom or a group 55 with, for example, an optionally substituted hydrocar convertible into them; X is a direct bond or a spacer bon residue which may be bonded through a hetero having an atomic length of two or less between the ring aton. Y and the ring W; W and Y are independently an op The alkyl group represented by R1 is a straight or tionally substituted aromatic hydrocarbon residue op branched lower alkyl group having 1 to about 8 carbon tionally containing a hetero-atom or an optionally sub atoms, as exemplified by methyl, ethyl, propyl, isopro pyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, i-pentyl, stituted heterocyclic residue; n is an integer of l or 2; a hexyl, hepty) or octyl. and b forming the heterocyclic residue are indepen The alkenyl group represented by R1 is straight or dently one or two optionally substituted carbon or het branched lower alkenyl group having 2 to about 8 car ero atoms; c is an optionally substituted carbon or het 65 bon atoms, as exemplified by vinyl, propenyl, 2-butenyl, ero aton; and, when a is an optionally substituted car 3-butenyl, isobutenyl or 2-octenyl. bon atom, R and a may optionally be bonded to each The alkynyl group represented by R is a straight or other to form a group of the formula branched lower alkynyl group having 2 to about 8 car 5,243,054 5 6 bon atoms, as exemplified by ethynyl, 2-propinyl, 2 butynyl, 2-pentynyl or 2-octynyl. The cycloalkyl group represented by R1 is a lower r a? cycloalkyl group having 3 to abo