EP0323841A2
Expired / Lapsed
EP
⏱️ 0.0 years remaining
Substituted pyrrole, pyrazole and triazole angiotensin II antagonists
Assignee: EIDP Inc
•
Filing: 1989-01-05
•
Granted: —
•
Expires: 2009-01-05
Abstract
Abstract Substituted pyrroles, pyrazoles and triazoles such as and their pharmaceutically suitable salts are useful as antihypertensive agents and for treatment of congestive heart failure.
Inventors
- 👤 David John Carini
- 👤 Gregory James Wells
- 👤 John Jonas Vytautas Duncia
Bibliographic Details
Application Number
—
Jurisdiction
EP
Data Source
google_patents
Last Synchronized
2026-10-27 18:41
CPC Classifications
C; C07; C07D; C07D231/00; C07D231/02; C07D231/10; C07D207/00; C07D207/02; C07D207/30; C07D207/32; C07D207/33; C07D207/333; A; A61; A61P; A61P9/00; A61P9/12; C07D207/325; C07D207/34; C07D231/12; C07D231/14; C07D233/00; C07D233/54; C07D233/56; C07D249/00; C07D249/02; C07D249/04; C07D249/08; C07D249/10; C07D403/00; C07D403/02; C07D403/10
Claims Analysis
Total Claims: 53
Claim 1
Independent Claim
451 words
An antihypertensive compound of the formula: or a pharmaceutically suitable salt thereof wherein X, Y and Z are independently N or CR 2 with the proviso that 1) when R 2 ≠ H, then only one of X, Y or Z can be CR 2 ; 2) when Z = N then Y and X # CR 2 ; or 3) when Y = N then Z and X ≠ CR 2 ; and 4) when X=Y=N, then Z # N; 5) when X=N, Y=Z=CR 2 , then with respect to Y, R z ≠ C 3-4 alkyl or C 4 alkenyl and with respect to Z, R 2 ≠ H or CI and R 1 ≠ (CH 2 ) n OR 4 where n = and R 4 =C 1 alkyl, A ≠ carbon carbon single bond, R 3 ≠ C0 2 H and R 5 ≠ H. A is a carbon carbon single bond, CO, 0, NHCO, OCH 2 ; R' is alkyl of 2 to 6 carbon atoms, alkenyl or alkynyl of 3 to 6 carbon atoms or (CH 2 ) n OR 4 provided that when R 1 is (CH 2 ) n OR 4 then R 2 is H, alkyl of 2 to 6 carbon atoms, alkenyl or alkynyl of 3 to 6 carbon atoms; R 2 is H, alkyl of 2 to 6 carbon atoms, alkenyl or alkynyl of 3 to 6 carbon atoms; R 3 is R 4 is H or alkyl of 1-4 carbon atoms; R 5 is H, halogen, N0 2 , methoxy, or alkyl of 1 to 4 carbon atoms; R 6 is H, alkyl of 1 to 6 carbon atoms; cycloalkyl of 3 to 6 carbon atoms, (CH 2 ) m C 6 H 5 , OR 7 or NR 8 R 9 ; R 7 is H, alkyl of 1 to 5 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl or benzyl; R 8 and R 9 independently are H, alkyl of 1 to 4 carbon atoms, phenyl, benzyl, or NR 8 R 9 taken together to form a ring of the formula Q is NR 10 , O or CH 2 ; R 10 is H, alkyl of 1 to 4 carbon atoms or phenyl; R 11 is alkyl of 1 to 6 carbon atoms or perfluoroalkyl of 1 to 6 carbon atoms, (CH 2 ) p C 6 H 5 ; R 12 is H, alkyl of 1 to 4 carbon atoms; or acyl of 1 to 4 carbon atoms; m is 0 to 6; n is 1 to 6; p is 0 to 3; r is 0 to 1; t is 0 to 2.
Claim 2
Dependent Claim
451 words
An antihypertensive compound of the formula: or a pharmaceutically suitable salt thereof wherein X, Y and Z are independently N or CR 2 with the proviso that 1) when R 2 ≠ H, then only one of X, Y or Z can be CR 2 ; 2) when Z = N then Y and X # CR 2 ; or 3) when Y = N then Z and X ≠ CR 2 ; and 4) when X=Y=N, then Z # N; 5) when X=N, Y=Z=CR 2 , then with respect to Y, R z ≠ C 3-4 alkyl or C 4 alkenyl and with respect to Z, R 2 ≠ H or CI and R 1 ≠ (CH 2 ) n OR 4 where n = and R 4 =C 1 alkyl, A ≠ carbon carbon single bond, R 3 ≠ C0 2 H and R 5 ≠ H. A is a carbon carbon single bond, CO, 0, NHCO, OCH 2 ; R' is alkyl of 2 to 6 carbon atoms, alkenyl or alkynyl of 3 to 6 carbon atoms or (CH 2 ) n OR 4 provided that when R 1 is (CH 2 ) n OR 4 then R 2 is H, alkyl of 2 to 6 carbon atoms, alkenyl or alkynyl of 3 to 6 carbon atoms; R 2 is H, alkyl of 2 to 6 carbon atoms, alkenyl or alkynyl of 3 to 6 carbon atoms; R 3 is R 4 is H or alkyl of 1-4 carbon atoms; R 5 is H, halogen, N0 2 , methoxy, or alkyl of 1 to 4 carbon atoms; R 6 is H, alkyl of 1 to 6 carbon atoms; cycloalkyl of 3 to 6 carbon atoms, (CH 2 ) m C 6 H 5 , OR 7 or NR 8 R 9 ; R 7 is H, alkyl of 1 to 5 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl or benzyl; R 8 and R 9 independently are H, alkyl of 1 to 4 carbon atoms, phenyl, benzyl, or NR 8 R 9 taken together to form a ring of the formula Q is NR 10 , O or CH 2 ; R 10 is H, alkyl of 1 to 4 carbon atoms or phenyl; R 11 is alkyl of 1 to 6 carbon atoms or perfluoroalkyl of 1 to 6 carbon atoms, (CH 2 ) p C 6 H 5 ; R 12 is H, alkyl of 1 to 4 carbon atoms; or acyl of 1 to 4 carbon atoms; m is 0 to 6; n is 1 to 6; p is 0 to 3; r is 0 to 1; t is 0 to 2.
Claim 3
Dependent Claim
140 words
2: A compound of claim 1 wherein A is a carbon-carbon single bond, or NHCO; R 1 is alkyl, alkenyl or alkynyl each of 3 to 5 carbon atoms; R 2 is H, alkyl, alkenyl or alkynyl each of 3 to 5 carbon atoms; R 3 is R 4 is H or CH 3 ; R S is H; R 6 is H, alkyl of 1 to 6 carbon atoms, OR 7 , or NR 8 R 9 ; R 7 is alkyl of 1 to 6 carbon atoms; R 8 and R 9 independently are H, alkyl of 1 to 4 carbon atoms, or taken together with the nitrogen form the ring R 11 is CF a , alkyl of 1 to 4 carbon atoms or phenyl; m is 0 to 3; nis1to3; or a pharmaceutically suitable salts thereof.
Claim 4
Dependent Claim
98 words
A compound of claim 1 wherein A is a carbon-carbon single bond R 1 is alkyl or alkenyl of 3 to 5 carbon atoms or CH 2 0R 4 ; provided that when R 1 is CH 2 0R 4 then R 2 is alkyl or alkenyl of 3 to 5 carbon atoms; R 2 is alkyl or alkenyl of 3 to 5 carbon atoms, CH 2 0R 4 , COR6, R 6 is H, OH, alkyl of 1 to 4 carbon atoms; R7 is alkyl of 1 to 4 carbon atoms; or a pharmaceutically suitable salt thereof.
Claim 5
Dependent Claim
13 words
Compound of claim 1 which is 3-methoxymethyl-5-propyl-4-[(2'-(1H-tetrazol-5-yl)-biphenyl-4-yl)-methyl]-1,2,4-triazole, or a pharmaceutically suitable salt thereof.
Claim 6
Dependent Claim
13 words
Compound of claim 1 which is 3-methoxymethyl-5-propyl-1-[(2'-carboxybiphenyl-4-yl)methyl]-pyrazole, or a pharmaceutically suitable salt thereof.
Claim 7
Dependent Claim
13 words
Compound of claim 1 which is 5-butyl-1-[(2'-carboxybiphenyl-4-yl)methyl]-1,2,3-triazole, or a pharmaceutically suitable salt thereof.
Claim 8
Dependent Claim
13 words
Compound of claim 1 which is 5-methoxymethyl-3-propyl-1-[(2'-carboxybiphenyl-4-yl)methyl]-pyrazole, or a pharmaceutically suitable salt thereof.
Claim 9
Dependent Claim
14 words
Compound of claim 1 which is 3-carboxy-5-n-propyl-1-[(2 -carboxybiphenyl-4-yl)methyl]pyrazole or a pharmaceutically suitable salt thereof.
Claim 10
Dependent Claim
9 words
Compound of claim 1 which is 5-n-propyl-1-[(2'-carboxybiphenyl-4-yl)methyl]pyrazole -2-caboxylic acid.
Claim 11
Dependent Claim
17 words
A pharmaceutical composition comprising a pharmaceutically suitable carrier and a compound of any one of claims 1-8.
Claim 12
Independent Claim
32 words
A method of treating hypertension in a warm-blooded animal comprising administering to the animal in an amount effective to lower the animal's blood pressure a compound of any one of claims 1-9.
Claim 13
Independent Claim
40 words
A method of treating congestive heart failure in a warm-blooded animal comprising administering to the animal a compound of any one of claims 1-9 in an amount effective to correct the hemodynamic burden on the heart to relieve the congestion.
Claim 14
Dependent Claim
31 words
A method of making a compound of claim 1 wherein the heterocyclic ring is a 1,2,3-triazole which comprises reacting an alkyne of formula (1)R -C=CH with a compound of formula (3)
Claim 15
Dependent Claim
43 words
A method of making a compound of claim 1 wherein the heterocyclic ring is a 1,2,3-triazole which comprises reacting a 1,2,3-triazole of formula (2) with a compound of formula (5): wherein A is a single bond, 0 or CO and X is halogen.
Claim 16
Dependent Claim
39 words
A method of making a compound of claim 1 wherein the heterocyclic ring is a 1,2,3-triazole and A is NHCO which comprises reacting a compound of formula (11) with a compound of formula (13) or other amide-bond forming reagent:
Claim 17
Dependent Claim
40 words
A method of making a compound of claim 1 wherein the heterocyclic ring is a 1,2,3-triazole, A is NHCO, and R 3 is C0 2 H which comprises reacting a compound of formula (11) with a compound of formula (12):
Claim 18
Dependent Claim
44 words
A method of making a compound of claim 1 wherein the heterocyclic ring is a 1,2,3-triazole and A is OCH 2 which comprises reacting a compound of formula (20) and reacting the resulting compound with a compound of formula (21): wherein X is halogen.
Claim 19
Dependent Claim
71 words
A method of making a compound of claim 1 wherein the heterocyclic ring is a 1,2,4-triazole and A is a single bond, 0 or CO, which comprises reacting a compound of formula (45) with a compound of formula (46) or reacting a compound of formula (51) with a compound of formula (52) R 1 CONHNH 2 (51) R 2 C(OR)a (52) then reacting the product with a compound of formula (47)
Claim 20
Dependent Claim
39 words
A method of making a compound of claim 1 wherein the heterocyclic ring is a 1,2,4-triazole and A is a single bond, 0 or CO, which comprises reacting a compound of formula (49) with a compound of formula (47):
Claim 21
Dependent Claim
34 words
A method of making a compound of claim 1 wherein the heterocyclic ring is a 1,2,4-triazole and A is a single bond, 0 or CO, which comprises cyclo-condensation of a compound of formula (50):
Claim 22
Dependent Claim
38 words
A method of making a compound of claim 1 wherein the heterocyclic ring is a 1,2,4-triazole and A is a single bond, 0 or CO, which comprises reacting a compound of formula (54) with a compound of formula
Claim 23
Dependent Claim
5 words
(5): wherein X is halogen.
Claim 24
Dependent Claim
5 words
(5): wherein X is halogen.
Claim 25
Dependent Claim
38 words
Method of making a compound of claim 1 wherein the heterocyclic ring is a 1,2,4-triazole and A is a single bond, 0 or CO, which comprises reacting a compound of formula (56) with a compound of formula (57):
Claim 26
Dependent Claim
33 words
Method of making a compound of claim 1 wherein the heterocyclic ring is a 1,2,4-triazole and A is NHCO which comprises reacting a compound of formula (61) with a compound of formula (13):
Claim 27
Dependent Claim
40 words
Method of making a compound of claim 1 wherein the heterocyclic ring is a 1,2,4-triazole and A is NHCO and R 3 is C0 2 H, which comprises reacting a compound of formula (61) with a compound of formula (12):
Claim 28
Dependent Claim
38 words
Method of making a compound of claim 1 wherein the heterocyclic ring is a 1,2,4-triazole and A is OCH 2 which comprises reacting a compound of formula (67) with a compound of formula (21): wherein X is halogen.
Claim 29
Dependent Claim
38 words
Method of making a compound of claim 1 wherein the heterocyclic ring is a pyrazole and A is a single bond, 0 or CO, which comprises reacting a compound of formula (78) with a compound of formula (57):
Claim 30
Dependent Claim
41 words
Method making a compound of claim 1 wherein the heterocyclic ring is a pyrazole and A is a single bond, 0 or CO, which comprises reacting a compound of formula (79) with a compound of formula (5): wherein X is halogen.
Claim 31
Dependent Claim
35 words
Method of making a compound of claim 1 wherein the heterocyclic ring is a pyrazole and A is NHCO which comprises reacting a compound of formula (82) with a compound of formula (12) or (13):
Claim 32
Dependent Claim
38 words
Method of making a compound of claim 1 wherein the heterocyclic ring is a pyrazole and A is OCH 2 which comprises reacting a compound of formula (86) with a compound of formula (21): wherein X is halogen.
Claim 33
Dependent Claim
42 words
Method of making a compound of claim 1 wherein the heterocyclic ring is a pyrazole and A is a single bond, O or CO, which comprises reacting a compound of formula (99a) with a compound of formula (5): wherein X is halogen.
Claim 34
Dependent Claim
38 words
Method of making a compound of claim 1 wherein the heterocyclic ring is a pyrazole and A is a single bond, 0 or CO, which comprises reacting a compound of formula (98) with a compound of formula (47):
Claim 35
Dependent Claim
38 words
Method of making a compound of claim 1 wherein the heterocyclic ring is a pyrazole and A is a single bond, 0 or CO, which comprises reacting a compound of formula (101) with a compound of formula (47):
Claim 36
Dependent Claim
38 words
Method of making a compound of claim 1 wherein the heterocyclic ring is a pyrazole and A is a single bond, O or CO, which comprises reacting a compound of formula (105) with a compound of formula (47):
Claim 37
Dependent Claim
59 words
Method of making a compound of claim 1 wherein the heterocyclic ring is a pyrazole and A is a single bond, O or CO, which comprises reacting a compound of formula (119) with a compound of formula (5) followed by elaboration of the carbonyl groups on the pyrrole ring to convert them to R 1 and R 2 :
Claim 38
Dependent Claim
34 words
Method of making a compound of claim 1 wherein R 2 is CH 2 CO 2 H (formula 128) which comprises hydrolyzing a corresponding compound wherein R 2 is CH 2 CN (formula 127).
Claim 39
Dependent Claim
39 words
Method of making a compound of claim 1 wherein R 2 is (CH 2 ) 2 0H (formula 130) which comprises reducing the corresponding compound of claim 1 wherein R 2 is CH 2 C0 2 H (formula 128).
Claim 40
Dependent Claim
46 words
Method of making a compound of claim 1 wherein R 2 is CH 2 C0 2 R 7 (formula 129) which comprises reacting the corresponding compound of claim 1 wherein R 2 is CH 2 C0 2 H (formula 128) with an alcohol R 7 0H.
Claim 41
Dependent Claim
66 words
Method of making a compound of claim 1 wherein R 2 is (CH 2 )OCOR 4 or (CH 2 ) 2 OCOR 4 (formula 131) which comprises reacting the corresponding compound of claim 1 wherein R 2 is CH 2 0H (formula 125) or (CH 2 ) 2 OH (formula 130) with an acid anhydride (R 4 CO) 2 O or acid chloride R 4 COCI.
Claim 42
Dependent Claim
49 words
Method of making a compound of claim 1 wherein R 2 is CH 2 0R 4 (formula 132) which comprises reacting the corresponding compound of claim 1 wherein R 2 is CH 2 0H (formula 125) with a compound R 4 L, where L is halogen, mesylate or tosylate.
Claim 43
Dependent Claim
45 words
Method of making a compound of claim 1 wherein R 2 is CH 2 0R 4 (formula 132) which comprises reacting a corresponding compound wherein R 2 is CH 2 CI (formula 126) with a compound R 4 OM, where M is sodium or potassium.
Claim 44
Dependent Claim
55 words
Method of making a compound of claim 1 wherein R 2 is -(CH 2 ) m CONR 8 R 9 (formula 133) which comprises reacting the corresponding compound of claim 1 wherein R 2 is (CH 2 ) m CO 2 H (formula 128) with a compound of the formula R 8 R 9 NH.
Claim 45
Dependent Claim
41 words
Method of making a compound of claim 1 wherein R 2 is -(CH2)nNHS02R" (formula 135) which comprises reacting a corresponding compound wherein R 2 is -(CH 2 ) n NH 2 (formula 134) with a compound R 11 SO 2 Cl.
Claim 46
Dependent Claim
52 words
Method of making a compound of claim 1 wherein R 2 is -(CH 2 ) n NHCO 2 R 11 (formula 136) which comprises reacting a corresponding compound wherein R 2 is -(CH 2 ) n NH 2 with a compound R 11 OCOCl or R 11 OCO 2 R 11 .
Claim 47
Dependent Claim
67 words
Method of making a compound of claim 1 wherein R 2 is -(CH 2 ) n S(O) t R 4 (formulae 137, 138) which comprises reacting a corresponding compound wherein R 2 is CH 2 CI (formula 126) with a compound R 4 Sm where M is sodium or potassium to produce the sulfide (formula 137) then optionally oxidizing to produce the sulfoxide or sulfone (formula 138).
Claim 48
Dependent Claim
43 words
Method of making a compound of claim 1 wherein R 2 is -(CH 2 ) n F (formula 140) which comprises reacting the corresponding compound of claim 1 wherein R 2 is -(CH 2 ) n OH (formula 139) with a fluorinating agent.
Claim 49
Dependent Claim
37 words
Method of making a compound of claim 1 wherein R 2 is -(CH 2 ) n SH (formula 140) which comprises hydrolyzing a corresponding compound wherein R 2 is -(CH 2 ) n SCOCH 3 (formula 141).
Claim 50
Dependent Claim
43 words
Method of making a compound of claim 1 wherein R 2 is tetrazolylmethyl (formula 143) which comprises reacting a corresponding compound wherein R 2 is cyanomethyl (formula 127) with sodium azide and ammonium chloride or by 2,3-dipolar cycloaddition of trialkyltin or triaryltin azide.
Claim 51
Dependent Claim
33 words
Method of making a compound of claim 1 wherein R 2 is -CHO (formula 144) which comprises oxidizing the corresponding compound of claim 1 wherein R 2 is -CH 2 0H (formula 125).
Claim 52
Dependent Claim
42 words
Method of making a compound of claim 1 wherein R 2 is alkenyl (formula 146) by chain-extension of the corresponding compound wherein R 2 is -CHO (formula 144) or by dehydration of a corresponding compound wherein R 2 is CHOHCHRR' (formula 145).
Claim 53
Dependent Claim
74 words
Method of making a compound of claim wherein R 1 is alkenyl (formula 149) which comprises contacting a corresponding compound wherein R 1 is bromoalkyl (formula 148) with a base. Method of making a compound of claim 1 wherein R 1 is alkenyl (formula 151) by chain extension of a corresponding compound wherein R1 is-CHO (formula 150) or by its reaction of the corresponding compound with a compound of the formula RCH = PPha.
References Cited (Backward Citations)
No citation records indexed.
USPTO Annuity & Maintenance Windows
Maintenance schedule is calculated for granted US utility patents.