IE913991A1 - Substituted azoles, process for their preparation, agents¹containing them and their use - Google Patents
Substituted azoles, process for their preparation, agents¹containing them and their useInfo
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- IE913991A1 IE913991A1 IE399191A IE399191A IE913991A1 IE 913991 A1 IE913991 A1 IE 913991A1 IE 399191 A IE399191 A IE 399191A IE 399191 A IE399191 A IE 399191A IE 913991 A1 IE913991 A1 IE 913991A1
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Abstract
Azoles of the formula in which X, Y and Z represent N or CR<2>, L denotes alkylene, A denotes an aromatic or heterocyclic radical and T denotes a bond or a bivalent radical and R<1>, R<2> and E are as defined in the description. A process for their preparation, compositions containing these compounds and their application as medicines are also described.
Description
HOECHST AKTIENGESELLSCHAFT HOE 90/F 346 Dr.JA/AP
Description
Substituted azoles, process for their preparation, agents containing them and their use
EP-A-324,377, EP-A-253,310, EP-A-28,834 and EP-A 323,841 disclose derivatives of imidazole, pyrrole, pyrazole and triazole and their use as antagonists of angiotensin II receptors.
Novel compounds of the azole type have now been found which are surprisingly highly active antagonists of angiotensin II receptors both in vitro and in vivo.
The invention relates to compounds of the formula I in which
a) X, Y and Z are identical or different and are N or
b) R1 is (C2-Clo)-alkyl
2. (C3-Clo)-alkenyl,
3· (C,-C10) -alkynyl,
4. OR3,
. (C3-Ce)-cycloalkyl,
6. (C4-C10)-cycloalkylalkyl, . (C5-C10) -cycloalkylalkenyl,
8. (C5-C10)-cycloalkylalkynyl,
9. -(CH2)B-B-(CH2)n-R*,
. benzyl,
11. a radical as defined under b) 1., 2., 3. or
9., which is monosubstituted by CO2R3,
12. a radical defined as under b) 1., 2., 3. or
9., in which 1 to all of the hydrogen atoms are substituted by fluorine, or
13. the radical defined under b) 10., which is substituted on the phenyl by 1 or 2 identical or different radicals from the series comprising halogen, (Ci-C*)-alkoxy and nitro;
c) R2 is 1.
2.
3.
4.
.
6.
7.
8. 9.
. 11. 12 .
13.
14.
.
16.
17.
18. 19.
.
21.
22.
23.
24.
.
26.
27.
hydrogen, halogen, nitro, sf5, pentafluorophenyl, cyano, (Cx—CA) -alkoxy, benzyloxy, phenyl, phenyl- (C1-C3) -alkyl, (C1-Cxo) -alkyl, (C3-Cw)-alkenyl, phenyl- (C2-C6) -alkenyl,
-imidazolyl- (CH2 )o-,
1,2,3-triazolyl-(CH2) n-, tetrazolyl-(CH2) B—,
- (CH2) 0_1-CHR7-OR5,
- (CH2) o-0-C0-R3,
- (CH2)O-S-R6,
-S(O)r-R6,
-CH=CH- (CH2) „-CHR3-OR6, -CH2=CH- (CH2) B-CO-R8, -CO-R8,
-CH-CH- (CH2) n-O-CO-R7, -(CH2)B-CH(CH3)-CO-R(
- (CH2) o-CO-R®,
-(CH2)o-0-C-NH-R8,
B
28.
29.
.
31.
32.
33.
34.
.
36.
37.
38.
-(CH2)0-NR7-C-OR8,
B
- (CH2) o-NR7-C0-NHRe,
-(CH2)o-NR7-S02R9,
-(CH2)o-NR7-C-R8,
B
-2)aF,
-(CH2)n-O-NO2,
-CH2-N3, ~ (CH2) n-NO2, -ch=n-nr5r7, phthalimido- (CH2) „-,
Rl°
39.
40.
41.
-(CH2)n-NQ\-£j> - {CH2) o. i- coOCH,
42.
phenyl-SO2-NH-N=CH-,
43.
44.
45.
46.
- (CH2) n-SO2-NR7-CO-NReR8,
-(CH2)o-SO2R9, a radical defined as under c) 9. or 10., which is substituted on the phenyl by or 2 identical or different radicals from the series comprising halogen, hydroxyl, methoxy, trifluoromethyl, CO2R3 and phenyl,
47. a radical defined as under c) 11., 12. or
., in which 1 to all of the hydrogen atoms are substituted by fluorine, or
48. the radical defined under c) 15., which is substituted by 1 or 2 identical or different radicals from the series comprising methoxycarbonyl and (Cj-C*)-alkyl;
d) R3 is 1.
2.
3.
4.
.
6.
e) R* is 1.
2.
3.
4.
.
f) R5 is 1.
2.
3.
4.
.
g) R6 is 1.
2.
3.
4.
.
hydrogen, (Ci-Ca)-alkyl, (C3-C8) -cycloalkyl, phenyl, benzyl or the radical defined under d) 2., in which 1 to all of the hydrogen atoms are substituted by fluorine;
hydrogen, (Ci-Cg)-alkyl, (C3-C8) -cycloalkyl, (C2—C4)—alkenyl or (C2-C4)-alkynyl;
hydrogen, (Ci-Cg)-alkyl, (C3-C8) -cycloalkyl, phenyl or benzyl;
hydrogen, (Ci-Ce)-alkyl, (C3-C8)-cycloalkyl, (C6-C12)-aryl, preferably phenyl, benzyl,
6. (Ci-Cg)-heteroaryl which can also be partially or completely hydrogenated, preferably 2-pyrimidinyl,
7. (Cj-CJ-alkanoyl,
8. (Cx-Cg)-heteroaryl-(Ci-Ca)-alkyl, where the heteroaryl moiety can also be partially or completely hydrogenated, or
9. a radical defined as under g) 4., 6. or 8., substituted by 1 or 2 identical or different radicals from the series comprising halogen, hydroxyl, methoxy, nitro, cyano, CO2R3, -NRX1R12 and tri fluoromethyl;
h) R7 is 1. hydrogen,
2. (Cx-Cg)-alkyl,
3. (C3-Ce)-cycloalkyl,
4. (C6-C12)-aryl-(Ci-Cg)-alkyl, preferably benzyl,
. phenyl or
6. (Ci-Cg) -heteroaryl;
i) Re is 1. hydrogen,
2. (Cx-Cg)-alkyl,
3. (C3-C8)-cycloalkyl,
4. phenyl-(CH2),-,
. OR5,
6. NRUR12 or r~ 2’«\ 7· Λ_Λ ’
j) R9 is 1. (Ci-Cg)-alkyl,
2. 1-adamantyl,
3. 1-naphthyl,
4. 1-naphthylethyl,
. phenyl- (CH2),- or
6. the radical defined under j) 1., in which 1 to all of the hydrogen atoms are substituted by fluorine;
or R6 and R8 together with the nitrogen atom carrying them are
k) R10 is cyano, nitro or CO2R7;
l) R11 and R12 are identical or different and are
1. hydrogen,
2. (CX-CJ-alkyl,
3. phenyl,
4. benzyl or
. a-methylbenzyl;
m) D is NR13, 0 or CH2;
n) R13 is hydrogen, (C2-C4)-alkyl or phenyl;
o) A is a) a (C6-C14)-aryl radical or
β) (Cx-Ce)-heteroaryl, which can either be aromatic, partially hydrogenated or completely hydrogenated, or
7) the radical of a fused heterocycle having 8 to 10 ring atoms, of which up to 9 are carbon atoms, it being possible to substitute A in each case by up to 3 identical or different radicals from the series comprising
1. halogen,
2. oxo,
3. nitroso,
4. nitro,
. cyano,
6. hydroxyl,
7. (Cx-Cg)-alkyl,
8. (Ci-CJ -alkanoyl,
9. (Ci-C*)-alkanoyloxy,
. CO2R3, 11. methanesuIfonylamino, 12. tri fluororaethanesulfonylamino 13. -CO-NH-OR9, 5 14. -SO2-NRbR7, 15. -ch2-or7, 16. (C6-C12)-aryl, 17. (C3-C8) -cycloalkyl, 18. (Cx-CJ-alkoxy, 10 19. (Cj-Ce) -heteroaryl, 20. CO2R3, 21. nr6r7 , 22. sulfo, 23. -SO3R3, 15 24. -so2-nr7-co-nr6r® , 25. -nr7-co-nr6-so2-ch2-r5 , 26. -C(CF3)2OH, 0 27. • 1 phosphonooxy, -O-P-OH , 28. -PO3H2, 0h 20 29. -NH-PO(OH)2, 30. -S(O)rR6, 31. -CO-R8 and 32. -CO-NReR9; P) τ 1. a single bond 25 2. -CO-, 3. -ch2-, 4. -0-, 5. -S-, 6. -NR21-, 30 7. -CO-NR21-, 8. -NRZ1-CO-, 9. -0-CH2-, 10. -ch2-o-, 11. -s-ch2-, 35 12. -ch2-s-, 13. -nh-cr20r22-, 14. -nr21-so2-, 15. so2-nr21- ,
16. -CR20R22-NH-,
17. -CH=CH-,
18. -CF-CF-,
19. -CH=CF-,
. -CF-CH-,
21. -CH2-CH2-,
22. -CF2-CF2-,
23. -CH(OR3)-,
24. -CH(OCOR5)-,
. -CNR23,
26. -Cr2*o z xor25
27. -Sq) E is a radical
B with the proviso that in the case where X=Y=CH, R1* is not COOH,
r) B is 0, NR7 or S;
s) L is (Ci-Ca)-alkanediyl;
t) R1* is -CO2R3, -CH2CO2R3, -PO3H2, -SO3H or tetrazolyl;
u) in is an integer from 0 to 5;
v) n is an integer from 1 to 5;
w) o is an integer from 1 to 10;
x) r is 0, 1 or 2, and
y) v is an integer from 1 to 6;
and their physiologically tolerable salts.
Alkyl, alkenyl and alkynyl can be straight-chain or branched. The same applies to radicals derived therefrom, such as alkanoyl or alkoxy.
Cycloalkyl is also understood as meaning alkyl-substituted rings.
(C6-C12)-aryl is, for example, phenyl, naphthyl or biphenylyl, preferably phenyl. The same applies to radicals derived therefrom, such as aroyl or aralkyl.
(0χ-0θ)-heteroaryl is in particular understood as meaning radicals which are derived from phenyl or naphthyl, in which one or more CH groups are replaced by nitrogen and/or in which at least two adjacent CH groups are replaced (with the formation of a five-membered aromatic ring) by S, NH or 0. In addition, one or two atoms of the condensation site of bicyclic radicals (such as in indolizinyl) can also be a nitrogen atom.
These are, for example, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, indazolyl, quinolyl, isoquinolyl, phthalazinyl, quinoxalinyl, quinazolinyl and cinnolinyl.
The fused heterobicyclic system is understood as meaning, in particular, a bicyclic ring system having 8 to 10 ring atoms, of which up to 9 are carbon atoms, in which two adjacent atoms are common components of both rings. One or both of these rings is/are formally derived from benzene in which one or more CH groups are replaced by N, O+ and S+ and/or in which two adjacent CH groups are replaced by S, NH or 0 (with the formation of a fivemembered aromatic ring).
These are, for example, a radical of benzothiophene, benzofuran, indole, isoindole, indazole, benzimidazole, quinoline, isoquinoline, phthalazine, quinoxaline, quinazoline, cinnoline, benzothiazole, benzothiazole1, 1-dioxide, coumarin, chroman, benzoxazole, benziso20 thiazole, benzodiazines, benzotriazole, benzotriazine, benzoxazine, imidazopyridine, imidazopyrimidine, imidazopyrazine, imidazopyridazine, imidazothiazole, pyrazolopyridine, thienopyridine and pyrrolopyrimidine. Said heterobicyclic system can also be partially or completely hydrogenated. However, one ring preferably remains aromatic, a benzo-fused heterobicyclic system being particularly preferred.
In the case of S-containing and/or partially saturated radicals, the bicyclic system can also, for example, be oxo-substituted, as is the case with the radical of the benzo-1,2,3-triazinone.
Physiologically tolerable salts of compounds of the formula I are understood as meaning both their organic and their inorganic salts, such as are described in
Remington's Pharmaceutical Sciences, (17th edition, page
1418 (1985). Owing to physical and chemical stability and solubility, sodium, potassium, calcium and ammonium salts, inter alia, are preferred for acid groups; salts with hydrochloric acid, sulfuric acid, phosphoric acid or with carboxylic acids or sulfonic acids, such as acetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid and p-toluenesulfonic acid, inter alia, for basic groups.
Preferred compounds of the formula I are those in which 10 a) X is N, Y is CR2 and Z is CR2;
b) X is CR2, Y is N and Z is CR2;
c) X is CR2, Y is CR2 and Z is N or
d) X, Y and Z are in each case N.
Compounds of the formula I are additionally preferred in which a) R1 is 1. (C3-C10)-alkyl, 2. (C3-C10)-alkenyl, 3. (C3-C10)-alkynyl, 20 4 . (C3-C8) -cycloalkyl, 5. benzyl or 6. benzyl which is substituted as defined above, or 7 . -(CH2)o-B-(CH3)n-R4; 25 b) R2 is 1. hydrogen, 2. halogen, 3. nitro, 4. 5. sf5, 30 6. pentafluorophenyl, 7. cyano, 8. (Ci-CJ-alkoxy, benzyloxy, 9. phenyl, 10. phenyl-(Cx-C3)-alkyl, 35 11. (Cx-Cm)-alkyl,
12. (C3-C10)-alkenyl,
13. phenyl-(C2-C6)-alkenyl,
14. l-imidazolyl-(CH2)B-,
. 1,2,3-triazolyl-(CH2)0-,
16. tetrazolyl-(CH2)B-,
17. -(CHJ^-CHR’-OR5,
18. -(CH2)o-O-COR3,
19. -COR8,
. - (CH2)o-CO-Re,
21. -S(O)tR6,
2 . -CH«CH- (CH2) B-CHR3-OR6 ,
3 . -CH2=CH- (CH2) B-CO-R8,
24. -(CH2)o-NH-C0-0R8,
. - (CH2)o-NH-S02-Rfl,
26. -(CH2)„F,
27. -(CH2)o-S03Rb,
8 . - (CH2) n-SO2-NH-CO-NR6R®, or
29. a radical defined as under b) 9., 10., 11.,
12. or 15., which is substituted as defined above under c) 46., 47. or 48. in each case as described for such a radical;
c) R8 is hydrogen, (Ci-Cs)-alkyl, OR5, NRUR12 or morpholino;
d) T is 1. a single bond 25 2. -CO-, 3. -CONR21-, 4. -ch2-ch2-, 5. -nr21-co- , 6. -o-ch2-, 30 7. -ch2-o-, 8. -s-ch2-, 9. -ch2-s-, 10. -nh-ch2-, 11. -ch2-nh- , 35 12. -CH=CH-, or
- 13 Ο ιι
13. -Sii ο
and the other radicals and variables are as defined above.
Particularly preferred compounds of the formula I are those in which
a) R1 is (C3—C7)—alkyl, (C3-C7)-alkenyl or (C3-C7)-alkynyl;
b) R2 is 1. hydrogen 10 2. chlorine, 3. bromine, 4. CvF2v+1 where v = 1, 2 or 3, 5. pentafluorophenyl, 6. (Ci-CJ-alkoxy, benzyloxy, 15 7. -S(O)rR6, 8. sf5, 9. (CH2)o.1-CHR7-0R5, 10 (CH2)o-0-C0-R3, 11. -COR8, 20 12. -(CH2)o-CO-R8, 13. -ch2-nh-co-r8, 14. -(CH2)o-NH-S02-R9, 15. -ch=ch-chr3-or®, 16. tetrazolyl- (CH2) B-, 25 17. - (CH2) nSO2-NH-CO-NR8R9, 18. -(CH2)o-S03Rb or 19. (Cj—Cg)—alkyl which is optionally sub- stituted by hydroxyl, preferably hydroxy- methyl ;
c) R3 is hydrogen or (Cj-CJ-alkyl;
d) R6 is hydrogen, (Ci-C*)-alkyl, (Cx-C4)-alkanoyl, phenyl which can optionally be substituted by 1 or 2 identical or different radicals from the series
- 14 comprising halogen, hydroxyl, methoxy, nitro, cyano, CO2R3 and tri fluoromethyl, or (Cx-CB)heteroaryl which can also be partially or completely hydrogenated, preferably
2-pyrimidyl; e) R7 is hydrogen, (Cx-C4)-alkyl, (Cx-Ce)-heteroaryl, or (C6-C12) -aryl- (Cx-C4) -alkyl; f) R8 is hydrogen, (Cx-C4)-alkyl, ORS or morpholino; g) R9 is CF3, (Cx-C6)-alkyl or phenyl; 10 h) A is q) a (C6-Cx0)-aryl radical or β) (Cx-C4)-heteroaryl which can either be
where
A aromatic, partially hydrogenated or completely hydrogenated, or the radical of a fused heterobicyclic system having 8 to 10 ring atoms, of which up to 9 are carbon atoms;
in each case can be substituted by up to 3 identical or different radicals from the series comprising halogen, nitro, cyano, hydroxyl, -NR6R7, phenyl, -S(O)rR6 and -CO2R3;
1) T is a single bond, -0-, -CO-, -NHCO-, -OCH2- or -S25 and the other radicals and variables are as defined above.
Very particularly preferred compounds of the formula I are those in which
a) R1 is (C3-C5)-alkyl,
b) Rz is hydrogen, chlorine, methoxy,
-S(O)rR6 or benzyloxy,
c) R3 is hydrogen or (Cj-CJ-alkyl, d) R4 and R5 are identical or different and are hydrogen or (Ci-C4)-alkyl, 5 e) R6 is hydrogen, (Ci-C4)-alkyl, phenyl or 4-tolyl, f) R14 is-COOH, -PO3H2, -SO3H or 5-tetrazolyl, 10 g) A is phenyl or the radical of a fused heterocyclic system having 8 to 10 ring atoms, of which up to 9 are carbon atoms, it being possible, however, for A to be substituted by up to 2 identical or different radicals from the series comprising halogen, nitro, cyano, phenyl, -S(O)rR6 and -CO2R3, h) B is 0, NH or S, 15 i) L is —CH2—, j) r is 0, 1 or 2, k) g is 0, 1) T is a single bond, m) m is 0, 1, 2 or 3 and 20 η) n is 1, 2 or 3
and X, Y and Z are as defined above.
The invention also relates to a process for the preparation of compounds of the formula I, which comprises alkylating compounds of the formula II
t
H (II) in which R1, X, Y and Z are as defined above, with com pounds of the formula III
U-L-A-T-E (HI) in which L, A, T and E are as defined above, and U is a 5 leaving group, if appropriate removing temporarily introduced protective groups and converting the compounds of the formula I obtained, if appropriate, into their physiologically tolerable salts.
Suitable leaving groups U are preferably a nucleofugic group (cf. Angew. Chem. 72 [1960] 71) such as halogen, o-toluenesulfonate, mesylate or triflate.
Processes for the preparation of the precursors of the formula (II) are known, inter alia, from US Patent No. 4,355,044, EP-A-324,377 and EP-A-323,841.
Other processes are described in G. L'abbe Chem. Rev. 69.
345 (1969); T. Srodsky in The Chemistry of the Azido Group, Wiley, New York, 1971, p. 331; H. Wamhoff in Comprehensive Heterocyclic Chemistry, S. Katritzky Ed., Pergamon Press, New York (1984).
To alkylate the azoles of the formula II, suitable alkylating agents are, for example, appropriate benzyl halides, tosylates, mesylates or triflates or appropriate alkyl halides, tosylates, mesylates or triflates.
The synthesis of derivatives such as benzofurans, benzo25 thiophenes and indoles having a benzylie -CH3 group was described, inter alia, by R.P. Dickson; et al. in J. Med. Chem. 2£, 1637 (1986), and ibid. 21, 1643 (1986). The preparation of benzimidazoles, benzothiazoles, benzodiazines, benzopyrones, benzothiazolones, benzotriazines, benzoxazines and benzoxazoles is outlined in the edition Comprehensive Heterocyclic Chemistry, S. Katritzky Ed. Pergamon Press, New York (1984) cited above.
The alkylation is carried out in an analogous manner to processes which are known in principle.
The azole derivative of the formula II is metalated, for example, in the presence of a base. Preferred bases are metal hydrides of the formula MH such as, for example, lithium hydride, sodium hydride or potassium hydride in, for example, DMF or DMSO as a solvent or metal alkoxides of the formula MOR, where R is methyl, ethyl or t-butyl, and the reaction is carried out in the corresponding alcohol, DMF or DMSO. The salts of the azoles thus formed are dissolved in an aprotic solvent such as DMF or DMSO and treated with a suitable amount of alkylating reagent.
An alternative possibility for the deprotonation of the azole derivatives is, for example, reaction with potas15 sium carbonate in DMF or DMSO.
The reactions are carried out at temperatures below room temperature up to the boiling point of the reaction mixture, preferably between +20 *C and the boiling point of the reaction mixture, for about 1 to 10 hours.
Fragments of the formula II
are synthesized via the addition of metalated isonitriles (Angew. Chem. 86, 878 (1974), 89, 351 (1977) to acid chlorides of the formula III
A - T - CO-CI (III) in inert solvents at -78 “C up to the boiling point of the solvent, preferably in diethyl ether or THF at -78°C to O’C.
- 18 IV)
The synthesis of fragments of the formulae IV and V
A - T (CH-,)
2'm
T
(V) is carried out by means of the alkylation, which is known in principle, of arylacetic acid derivatives or arylacetonitriles in an analogous manner, either in ethers such as diethyl ether, THF or dimethoxyethane with LDA at -78“C or with KOtBu at room temperature in t-butanol.
The compounds of the formula I according to the invention have antagonistic action on angiotensin II receptors and can therefore be used for the treatment of angiotensin Il-dependent hypertension. Possibilities of application furthermore exist in cardiac insufficiency, cardioprotection, myocardial infarct, cardiac hypertrophy, arteriosclerosis, nephropathy, kidney failure and vascular diseases of the brain such as transitory ischemic attacks and stroke.
Renin is a proteolytic enzyme of the aspartylprotease class, which is secreted into the blood circulation by the juxtaglomerular cells of the kidney as a consequence of various stimuli (volume depletion, sodium deficiency, £-receptor stimulation). In the blood, it cleaves the decapeptide angiotensin I from the angiotensinogen excreted from the liver. The former is converted into angiotensin II by the angiotensin-converting enzyme (ACE) . Angiotensin II plays an essential role in blood pressure regulation, as it directly increases the blood pressure by means of vascular contraction. It additionally stimulates the secretion of aldosterone from the adrenal gland and in this way increases the extracellular
- 19 fluid volume via the inhibition of sodium excretion, which for its part contributes to an increase in blood pressure.
Post-receptor actions are inter alia stimulation of 5 phosphoinositol conversion (Ca2+ release), activation of protein kinase C) and facilitation of cAMP-dependent hormone receptors.
The affinity of the compounds of the formula I for the angiotensin II receptor can be determined by measurement of 125I-angiotensin II or 3H-angiotensin II displacement from receptors on Zona glomerulosa membranes of bovine adrenal glands. For this purpose, the prepared membranes are suspended in buffer at pH 7.4. Aprotinin, a peptidase inhibitor, is added in order to prevent the degradation of the radioligand during the incubation. About 14000 cpm of a tracer having a specific activity of 74 TBq/mmol (available from Amersham Buehler) and a quantity of receptor protein which binds 50% of the tracer are additionally used. The reaction is begun by addition of
50 μΐ of membrane suspension to a mixture of 100 μΐ of buffer + aprotinin, 50 μΐ of buffer with or without angiotensin II or receptor antagonist and 50 μΐ of tracer. After an incubation time of 60 minutes at a temperature of 25’C, bound and free radioligand are separated on a Skatron* cell collector using Whatmann*
GFIC filters by means of a filtration assay.
Non-specific binding is prevented by treatment of the filter with 0.3% polyethyleneimine pH=10 (Sigma, No. 3143). The amount of displacement of the radioligand from the receptor is determined by measurement of the radioactivity in a gamma scintillation counter. The IC50 values, which denote the concentration of inhibitor for displacing 50% of the ligand, are determined according to Chem. et al. J. Theor. Biol. 59. 253 (1970). For the compounds of the formula (I) they are in the range from 1O'*-1O'9 M.
- 20 To determine the antagonistic action of the compounds of the formula (I), their effect on the angiotensin IIinduced blood pressure rise in anesthetized SpragueDawley rats can be measured. Na thiobarbital (Trapanal*,
Byk Gulden) is used as an anesthetic in the dose 100 mg/kg i.p. I.v. administration is carried out in the jugular vein. The blood pressure is measured in the carotid artery. The animals are first pretreated with pentolinium tartrate (10 mg/kg i.m.) so that a lower blood pressure level is achieved (ganglia blockade). ANG II (Hypertensin*, CIBA) is administered i.v. in the volume 0.1 ml/100 g at 10 minute intervals. The dose is 0.5 pg/kg. The compounds of the formula (I) are dissolved in distilled water and administered intravenously or intraduodenally in the doses 0.1? 1? 10 and 100 mg/kg.
The compounds of the formula (I) are effective in the range from 0.1-100 mg/kg.
The invention also relates to pharmaceutical compositions comprising a compound of the formula I and other active compounds, such as, for example, diuretics or non-steroidal anti-inflammatory active compounds. The compounds of the formula I can also be used as diagnostics for the renin-angiotensin system.
Pharmaceutical preparations contain an effective amount of the active compound of the formula I and if necessary other active compounds together with an inorganic or organic pharmaceutically utilizable excipient. Administration can be carried out intranasally, intravenously, subcutaneously or orally. The dosage of the active compound depends on the mammalian species, the body weight, the age and the manner of administration.
The pharmaceutical preparations of the present invention are prepared in a dissolving, mixing, granulating or coating process known per se.
- 21 For a form for oral administration, the active compounds are mixed with the additives customary therefor such as excipients, stabilizers or inert diluents and brought by means of customary methods into suitable administration forms, such as tablets, coated tablets, hard gelatin capsules, aqueous, alcoholic or oily suspensions or aqueous, alcoholic or oily solutions. Inert excipients which can be used are, for example, gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose, magnesium stearyl fumarate or starch, in particular maize starch. The preparation in this case can be both as dry and moist granules. Suitable oily excipients or solvents are, for example, vegetable or animal oils, such as sunflower oil and cod liver oil.
For subcutaneous or intravenous administration, the active compounds or their physiologically tolerable salts are brought into solutions, suspensions or emulsions, if appropriate with the substances customary therefor such as solubilizers, emulsifiers or other auxiliaries.
Suitable solvents are, for example, water, physiological saline solutions or alcohols, for example ethanol, propanediol or glycerol, in addition also sugar solutions such as glucose or mannitol solutions or alternatively a mixture of the different said solvents.
List of abbreviations:
DMF N,N-dimethylformamide NBS N-bromosuccinimide AIBN a,α-azobisisobutyronitrile El electron impact DC I desorption-chemical ionization RT room temperature EA ethyl acetate (EtOAc) DIP diisopropyl ether THF tetrahydrofuran M.p. melting point MTB methyl t-butyl ether
Β·Ρ·« boiling point at xx torr Et3N triethylamine MS mass spectrum FAB fast atom bombardment LDA lithium diisopropylamide
The following examples illustrate the invention without restricting the invention thereto:
Example 1
1- [ 4 - (1-Carboxy-l-cyclopentyl) benzyl ]-2-n-butyl-4-chloro10 5-formylimidazole
a) Ethyl 1-(p-tolylJcyclopentanecarboxylate g of 1-(p-tolyl)cyclopentanecarboxylic acid are suspended in 200 ml of ethanol, and the solution is slowly treated with 4.3 ml of SOCl2 and heated to reflux for 24 h. Excess SOC12 is removed in vacuo, and the residue is taken up with 100 ml of EA, washed twice with 50 ml of satd. aq. Na2SO3 solution and dried over Na2SO4. The solvent is then removed in vacuo and 11.3 g of the title compound are obtained as light brown crystals melting point: 47“C.
b) Ethyl l-(4-bromomethyl)phenylcyclopentanecarboxylate
2.5 g of ethyl 1-(p-tolylJcyclopentanecarboxylate, 1.94 g of NBS and 200 mg of benzoyl peroxide are heated to reflux in 50 ml of chlorobenzene for 3 h. The solvent is then removed in vacuo, and the residue is taken up in 300 ml of EA, washed once with 5% strength aq. Na2SO3 solution and twice with satd. aq. NaHCO3 solution and dried over Na2SOA. The solvent is finally removed in vacuo and 3.2 g of the title compound are obtained as an oil.
Rf (Si02; EA/heptane 1:4) = 0.50
MS (DCI) : 311 (M+l)
- 23 c) l-[4-( 1-ethoxycarbonyl-l-cyclopentyl) benzyl ]-2-n-butyl -4-chloro-5-formylimidazole
342 mg of ethyl l-(4-bromomethyl)phenylcyclopentanecarboxylate, 187 mg of 2-n-butyl-4-chloro-5-formyl5 imidazole and 138 mg of K2CO3 are stirred in 10 ml of DMF at RT for 22 h. The mixture is diluted with 100 ml of EA, washed once with 50 ml of H20 and once with 5% strength ag. NaCl solution and dried over Na2SO4, and the solvent is removed in vacuo. Chromatography on silica gel using
DIP yields 240 mg of the title compound as a colorless oil.
Rf (SiO2? DIP/MTB 1:1) = 0.68 MS (DCI) : 417 (M+l)
d) 1- [ 4- (1-carboxy-l-cyclopentyl) benzyl ] -2-n-butyl-4chloro-5-formylimidazole
115 mg of 1-[4-(1-ethoxycarbonyl-l-cyclopentyl)benzyl]2-n-butyl-4-chloro-5-formylimidazole and 415 μΐ of 1 N NaOH are heated to reflux in 8 ml of EtOH for 29 h. The ethanol is removed in vacuo, and the residue is diluted with 30 ml of H20 and washed with 10 ml of DIP. It is then adjusted to pH = 1-2 and extracted twice with 50 ml of EA each time. The extracts are dried over Na2SO4 and the solvent is removed in vacuo. Chromatography on silica gel using MTB yields 68 mg of the title compound as a light brown solid.
M.p: 134°C
Rf (SiO2? MTB) = 0.30 MS (DCI) : 389 (M+l)
The title compounds of Examples 2 and 3 are synthesized via the methyl ester analogously to Example 1:
Example 2
1-[4-(1-Carboxy-1-cyclohexyl)benzyl]-2-n-butyl-4-chloro5-formylimidazole
- 24 Example 3
1- [4- (1-carboxy-l-cyclohexyl) benzyl ] - 2-n-butyl-4-methoxy5-formylimidazole
670 mg of 1-(4-(1-methoxycarbonyl-1-cyclohexyl)benzyl]5 2-n-butyl-4-chloro-5-formylimidazole are reacted as described under Example Id). 300 mg of the title compound of
Example 2
Rf (SiO2? MTB/DIP 1:1) = 0.35 MS (DCI) : 403 (M + 1) melting point 147’C and 160 mg of the title compound of Example 3
Rf (SiO2? MTB/DIP 1:1) = 0.25 MS (DCI) : 399 (M + 1) melting point 167 °C are obtained, and can be separated by chromatography on silica gel using MTB/DIP 1:1.
Example 4
1-(4-( 1 -c arboxy-1-(4,4 -dimethyl) eye lohexyl ] benzyl) - 2 -nbutyl-4-chloro-5-formylimidazole
a) l-p-Tolyl-4,4-dimethylcyclohexanecarbonitrile
27.6 g of potassium t-butylate are taken up in 200 ml of t-butanol and the mixture is heated to reflux. A solution of 32 g of l,5-dibromo-3,3-dimethylpentane and 16.3 ml of
4-tolylacetonitrile in 100 ml of t-butanol is then added dropwise in the course of 1 h. The mixture is heated under reflux for 4 h, the solvent is removed in vacuo and the residue is taken up in 200 ml of satd. ag. NaHC03 and 200 ml of MTB. It is extracted twice with 200 ml of MTB each time and dried over Na2SO4, and the solvent is removed in vacuo. Distillation in a fine vacuum yields
9.7 g of a colorless oil.
- 25 B.p.o2 = 135-140’C MS (DCI) ϊ 228 (M+l)
b) l-p-Tolyl-4,4-dimethylcyclohexanecarboxylic acid
4.0 g of l-p-tolyl-4,4-dimethylcyclohexanecarbonitrile and 3.0 g of KOH are heated under reflux in 50 ml of diethylene glycol for 3 h. The mixture is allowed to cool, and is poured into 100 ml of 0.1 N NaOH and washed twice with 30 ml of DIP each time. It is then adjusted to pH = 1-2 with HCl and extracted 3 times with 100 ml of diethyl ether each time. The extracts are dried over
Na2SO4 and the solvent is removed in vacuo. 4.0 g of pale yellow crystals are obtained.
Melting point: 128eC MS (DCI) : 241 (M+)
c) Ethyl l-p-tolyl-4,4-dimethylcyclohexanecarboxylate
4.0 g of l-p-tolyl-4,4-dimethylcyclohexanecarboxylic acid 15 are dissolved in 50 ml of ethanol and treated with 1.5 ml of SOC12. The mixture is stirred at 50C for 3 h, then at reflux for 3.5 h. The solvent is removed in vacuo, and the residue is taken up in 200 ml of EA and washed 3 times with 50 ml of satd. ag. Na2C03 each time. The extracts are dried over Na2SO4 and the solvent is removed in vacuo. 5.0 g of a slightly contaminated brown oil are obtained, which is employed again without purification.
MS (DCI) : 275 (M+l)
d) Ethyl l-(4-bromomethyl)phenyl-4,4-dimethylcyclohexane25 carboxylate
.0 g of ethyl l-p-tolyl-4,4-dimethylcyclohexanecarboxylate, 2.9 g of NBS and 50 mg of benzoyl peroxide are heated to reflux in 50 ml of chlorobenzene for 1.5 h. The solvent is then removed in vacuo, and the residue is taken up in 200 ml of EA, and washed once with 100 ml of satd. ag. Na2SO3 and once with NaCI solution. The solution is dried over Na2SO4 and the solvent is removed in vacuo.
ΪΕ 9*1
.4 g of a brown oil are obtained.
Rf (SiO2; EA/heptane 1:8)-0-39 MS (DCI) s 353 (M+l)
Further reaction is carried out analogously to Examples lc and Id to give 1-(4-[1-carboxy-1-(4,4-dimethyl)cyclohexyl ] benzyl) -2-n-butyl-4-chloro-5-f ormylimidazole
R, 2; DIR) = 0.16 MS (DCI) : 431 (M+l)
Example 5
1-(4-(1-(5-tetrazolyl) cyclohexyl] benzyl)-2-n-butyl4-chloro- 5-hydr oxymethylimidazole
a) 1-(4-Tolyl)cyclohexanecarbonitrile
The compound was synthesized analogously to Example 3a)
S. p.ol - 95-100aC MS (DCI) : 200 (M+l)
b) 1-(4-3romomethylphenyl)cyclohexanecarbonitrile
The compound was synthesized analogously to Example 3 d) Rf (SiO2; EE/Hep 1:4) = 0,46 MS (DCI) : 278 (M+l)
c) 1-[4-(1-Cyano-1-cyclohexyl)benzyl]-2-n-butyl-4-chloro5-formylimidazole
The compound was synthesized analogously to Example lc),
Ri (SiO2? DIP) = 0.33 MS (DCI) : 384 (M+l) t
d) 1-(4- (1-Cyano- 1-cyclohexyl) benzyl ] -2 -n-butyl-4 -chloro5 - hy dr o xyroe t hy 1 imid a z ο 1 e
1.0 g of 1-(4-( 1-cyano-1-cyclohexyl)benzyl]-2-n-butyl-435 chloro-5-formylimidazole and 400 mg of NaBH4 are dissolved in 25 ml of ethanol and the solution is stirred at RT for
h. 5¾ aq, NaHSO* solution is then slowly added to pH = 2, the ethanol is removed in vacuo and the residue is extracted 3 times with 50 ml of EA. . The extracts are dried over Na2S04 and the solvent is removed in vacuo. 1.0 g of a colorless Oil is obtained.
- 27 Rt (SiO2; MTB) - 0.54 MS (DCI J 386 (M+l)
e) 1-(4-(1-(2-Trimethylstannyl-5-tetrazolyl)-1cyclohexyl ] benzyl-2-n-butyl-4-chloro-5-hydroxymethylimidazole
1.1 g of 1-(4-( 1-cyano-1-cyclohexyl) benzyl j-2-n-butyl4-chloro-5-hydroxymethylimidazole and 1.1 g of trimethyltin azide are heated to reflux in 25 ml of toluene for 48 h. The solvent is removed in vacuo and the residue is employed again without purification.
f) l-(4-[ l-(l-Triphenylmethyl-5-tetrazolyl)-1-cyclohexyl ] benzyl-2-n-butyl-4-chloro-5-hydroxymethyl imidazole
The unpurified title compound of Example 5e) is dissolved in 7 ml of CH2C12 and 1.5 ml of THF, treated with 0.35 ml of 10 N NaOH and stirred at RT for 5 min. The mixture is then treated with 900 mg of trityl chloride and stirred at RT for 3 days. It is diluted with 100 ml of BA, washed twice with 10 ml of 0.1 N NaOH each time and twice with 10 ml of satd. aq. NaCl each time and dried over Na2SO4, and the solvent is removed in vacuo. Chromatography on silica gel using MTB/DIP 1:1 yields 400 mg of the title compound as white foam.
R£ (SiO2; DIP/MTB 1:1) - 0.32 MS (FAB) : 677 (M+Li)
g) 1-(4-(1-( 5-Tetrazolyl)-1-cyclohexyl ] benzyl) -2-n-butyl25 4-chloro-5-hydroxymethylimidazole
400 mg of 1-( 4-(1-.( l-Tripheny lmethyl-5-tetrazolyl)l-cyclohexyl ] benzyl) -2-n-butyl-4-ehloro-5-hydroxymethylimidazole and 300 μΐ of 4 N aq. HCl are dissolved in 4 ml of methanol and the mixture is stirred at RT for 2 h. It is then diluted with 10 ml of H2O, the methanol is removed in vacuo and the residue is adjusted to pH = 13 with 2 N NaOH. It is washed 3 times with 5 ml of toluene each
- 28 time, then adjusted to pH = 4 with 10% KH2PO4 solution and extracted 3 times with 50 ml of EA each time. The extracts are dried over Na2SO* and the solvent ie removed in vacuo. The residue is then digested with 20 ml of EA in an ultrasonic bath, filtered off and washed twice with ml of EA each time. The residue is dried in a fine vacuum and 170 mg of the title compound are obtained as colorless crystals.
Melting point? 179*C/dec, <
Rf (Si02j EA/MeOH 10?l) = 0.44 MS (FAB) ? 429 (M+l)
Example 6
1-[ 4 - (4-Carboxy-5-oxazolyl) benzyl ]-2-n-butyl-4-chloro5-£ormy1imidazo1e
a) Methyl 4-bromomethylbenzoate
50 g of methyl p-tolylcarboxylate, 60 g of NBS and 200 mg of benzoyl peroxide are suspended in 300 ml of chlorobenzene and the mixture is cautiously heated to reflux. The reaction starts vigorously. The mixture is directly allowed to cool again, the chlorobenzene is removed in vacuo and the residue is distilled. 6Θ g of the title compound are obtained as colorless crystals.
B.p.9 = 145*C
Rf (SiO2; EA/heptane 1:4) = 0.50 MS (DCI) s 299 (M+l)
b) 4-Bromomethylbenzoic acid
.0 g of methyl 4-bromomethylbenzoate are suspended in ml of 48% aq. HBr and heated to reflux for 30 min. The mixture is adjusted to pH = 8 with NaHC03 and washed twice with DIP. The aqueous phase is then adjusted to pH = 2 with NaHSO* and extracted 3 times with 150 »i ox ax. The extracts are dried over Na2SO4 and the solvent is removed in vacuo. 3.8 g of the title compound are obtained as
- 29 colorless hygroscopic crystals.
Melting point! 45*C
Rf (SiO2; EA) = 0.43 MS (DCI) i 215 (M+l)
c) 4-Bromomethylbenzoyl chloride
3.8 g of 4-bromomethylbenzoic acid are suspended in 10 ml of SOC12 and the mixture is heated to reflux for 1 h. Excess SOC12 is removed in vacuo, and the residue is dried in a fine vacuum and employed again in crude form.
d) 5-(4-Bromomethyl)benzyl-4-methoxycarbonyloxazole
The crude product from Example 5c) is dissolved in 50 ml of anhydrous THF together with 5.4 ml of Et3N. 1.8 ml of methyl isocyanoacetate are added dropwise at 5’C and the mixture is stirred at R.T. for 3 days. It is then diluted with 300 ml of EA, washed 3 times with 100 ml of 0.7 M
KH2P04 each time, 3 times with 100 ml of satd. aq. NaHC03 and once with 100 ml of NaCl solution and dried over Na2SO4, and the solvent is removed in vacuo. Chromatography on silica gel using MTB yields 2.0 g of yellow crystals .
Melting point: 79°C Rf (SiO2; MTB) = 0.36
e) 1-(4-(4-Methoxycarbonyl-5-oxazolyl)benzyl]-2-n-butyl4-chloro-5-formylimidazole
296 mg of 5-(4-bromomethyl)benzyl-4-methoxycarbonyl25 oxazole, 187 mg of 2-n-butyl-4-chloro-5-formylimidazole and 139 mg of K2CO3 are stirred in 10 ml of DMF at RT for 21 h. The mixture is then diluted with 150 ml of EA, washed twice with 50 ml of satd. aq. NaHCO3 solution each time and once with 50 ml of aq. NaCl solution and dried over Na2SO4, and the solvent is removed in vacuo. Chromatography on silica gel using MTB/DIP 1:1 yields 250 mg of
- 30 IE 913991 a colorless oil.
Rf (SiO2; MTB/DIP 1:1) - 0.35 MS (DCI) : 402 (M+l)
f) 1-(4-( 4-Carboxy-5-oxazolyl) benzyl ] -2-n-butyl-4-chloro5-formylimidazole
240 mg of 1-(4-(4-methoxycarbonyl-5-oxazolyl)benzyl]-2n-butyl-4-chloro-5-formylimidazole are dissolved in 15 ml of methanol, treated with 2.5 ml of 1 N ag. NaOH and stirred at RT for 20 h. The methanol is removed in vacuo, and the residue is diluted with 20 ml of H20 and washed twice with 10 ml of DIP each time. It is then adjusted to pH = 2, extracted 3 times with 50 ml of EA each time, the extracts are dried over Na2SO4 and the solvent is removed in vacuo. Chromatography on silica gel using EA/glacial acetic acid 10:1 yields 90 mg of a light yellow foam.
Rf (SiO2; EA/glacial acetic acid 10:1) = 0.16 MS (DCI): 388(M+l)
Claims (14)
1. hydrogen
2. chlorine,
3. bromine,
4. CyF^i where v - 1, 2 or 3,
5. pentafluorophenyl,
6. (Cx-C*)-alkoxy, benzyloxy,
7. -S(O) r R 6 , 8. SF 5 , 9. (CH 2 ) e -x-CHR 7 -OR 5 , 10. (CH 2 ) o -0-C0-R 3 , 11. -COR®, 12. -(CH 2 ) o -CO-R®, 13. -CH 2 -NH-CO-R®, 14. -(CH 2 ) o -NH-SO 2 -R 8 , 15 . -CH=CH-CHR 3 -OR 6 , 16. tetrazolyl-(CH 2 ) B -, 17 . - (CH 2 ) n SO 2 -NH-CO-NR 6 R 8 , 18. -(CH 2 ) o -SO 3 R 8 or 19. (Cx-C 6 )-alkyl which is optionally substituted by hydroxyl, preferably hydroxymethyl ; c) R 3 is hydrogen or (Cx-CJ-alkyl; d) R 6 is hydrogen, (Cx-C 4 )-alkyl, (Cx-CJ-alkanoyl, phenyl, which can be optionally substituted by 1 or 2 25 identical or different radicals from the series comprising halogen, hydroxyl, methoxy, nitro, cyano, CO 2 R 3 and trifluoromethyl, or (Cx-C 9 )heteroaryl, which can also be partially or c omp1etely hydrogenated; e) R 7 is hydrogen, (Οχ-ϋ 4 )-alkyl, (Οχ-ϋ β )-heteroaryl, or (C 6 -Ci 2 ) -aryl- (Οχ-C*) -alkyl; f) R 8 is hydrogen, (Cx-C 4 )-alkyl, OR 5 or morpholino; g) R 8 is CF 3 , (Cx-C 6 )-alkyl or phenyl; - 42 h) A is a) a (C 6 -C 10 )-aryl radical or β) (Οχ-CJ-heteroaryl which can either be aromatic, partially hydrogenated or completely hydrogenated, or 5 7) the radical of a fused heterobicyclic system having 8 to 10 ring atoms, of which up to 9 are carbon atoms; where A in each case can be substituted by up to 3 10 identical or different radicals from the series comprising halogen, nitro, cyano, hydroxyl, -NR e R 7 , phenyl, -S(O)rR 6 and -CO2R 3 ; 1) T is a single bond, -0-, -CO-, -NHCO-, -OCH 2 - or |I 15 -SII and the other radicals and variables are as defined in the preceding claims, and its physiologically tolerable salts . 20 5. A compound of the formula I as claimed in one of claims 1-4, in which a) R 1 is (C 3 -C 5 )-alkyl, b) R 2 is hydrogen, chlorine, methoxy, benzyloxy, or S(O) r R e 25 c) R 3 is hydrogen or (Cj-CJ-alkyl, d) R* and R 5 are identical or different and are hydrogen or (Cj-C 4 )-alkyl, e) R 6 is hydrogen, (Cx-C 4 )-alkyl, phenyl or 4-tolyl, f) R 1 * is-COOH, -PO 3 H 2 , -SO 3 H or 5-tetrazolyl, - 43 g) A is phenyl or the radical of a fused heterocyclic system having 8 to 10 ring atoms, of which up to 9 are carbon atoms, it being possible, however, for A to be substituted by up to 2 5 identical or different radicals from the series comprising halogen, nitro, cyano, phenyl, -S(O) r R 6 and -CO 2 R 3 , h) B is 0, NH or S, i) L is -ch 2 -, j) r is 0, 1 or 2, k) q is 0, 1) T is a single bond, m) m is 0, 1, 2 or 3 and n) n is 1, 2 or 3 15 and X, Y and Z are as defined in the preceding claims, and its physiologically tolerable salts. 6. A process for the preparation of a compound of the formula I as claimed in one of claims 1-5, which comprises alkylating a compound of the formula II I H in which R 1 , X, Y and Z are as defined above, with a compound of the formula III U-L-A-T-E (III) in which L, A, T and E are defined as above and U is a IE 913931 - 44 leaving group, if appropriate removing temporarily Introduced protective groups and converting the compound of the formula I obtained, if appropriate, into its physiologically tolerable salts. 5 7. A compound as claimed in one of claims 1-5 for use as a medicament.
8. A compound as claimed in claim 7 for use as a hypotensive agent.
9. A pharmaceutical agent containing at least one 10 compound as claimed in one of claims 1-5, 7 and 8.
10. A process for the production of an agent as claimed in claim 9, which comprises bringing one or more compounds of the formula 1 or their physiologically tolerable salts into a suitable administration form together 15 with a physiologically acceptable excipient and, if appropriate, other additives and auxiliaries.
11. A compound as claimed in claim 1, substantially as hereinbefore described and exemplified.
12. A process for the preparation of a compound as claimed in claim 1, substantially as hereinbefore described and exemplified.
13. A compound as claimed in claim 1, whenever prepared by a process claimed in claim 6 or 12.
14. A pharmaceutical agent as claimed in claim 9, substan tially as hereinbefore described.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4036645A DE4036645A1 (en) | 1990-11-16 | 1990-11-16 | SUBSTITUTED AZOLE, METHOD FOR THE PRODUCTION THEREOF, THE AGENT, AND THEIR USE THEREOF |
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| Publication Number | Publication Date |
|---|---|
| IE913991A1 true IE913991A1 (en) | 1992-05-20 |
Family
ID=6418438
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE399191A IE913991A1 (en) | 1990-11-16 | 1991-11-15 | Substituted azoles, process for their preparation, agents¹containing them and their use |
Country Status (17)
| Country | Link |
|---|---|
| EP (1) | EP0485929A1 (en) |
| JP (1) | JPH04283569A (en) |
| KR (1) | KR920009802A (en) |
| CN (1) | CN1061410A (en) |
| AU (1) | AU8785591A (en) |
| BR (1) | BR9104948A (en) |
| CA (1) | CA2055636A1 (en) |
| CS (1) | CS347091A3 (en) |
| DE (1) | DE4036645A1 (en) |
| FI (1) | FI915381A (en) |
| HU (1) | HUT59673A (en) |
| IE (1) | IE913991A1 (en) |
| IL (1) | IL100058A0 (en) |
| MX (1) | MX9102098A (en) |
| NO (1) | NO914481L (en) |
| PT (1) | PT99521A (en) |
| ZA (1) | ZA919059B (en) |
Families Citing this family (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE4036706A1 (en) * | 1990-11-17 | 1992-05-21 | Hoechst Ag | METHOD FOR THE TREATMENT OF CARDIALS AND VASCULAR HYPERTROPHY AND HYPERPLASIA |
| US5616599A (en) * | 1991-02-21 | 1997-04-01 | Sankyo Company, Limited | Angiotensin II antagosist 1-biphenylmethylimidazole compounds and their therapeutic use |
| DE4200954A1 (en) * | 1991-04-26 | 1992-10-29 | Bayer Ag | New heterocycle-substd. phenylacetic acid derivs. - are angiotensin II antagonists for treating arterial hypertonia, atherosclerosis, coronary insufficiency, ischaemic cerebral disorders, respiratory disorders, etc. |
| DE4309968A1 (en) * | 1993-03-26 | 1994-09-29 | Bayer Ag | Phenylglycinamides of heterocyclic substituted phenylacetic acid derivatives |
| JP3501484B2 (en) * | 1992-12-17 | 2004-03-02 | 三共株式会社 | Biphenyl derivative |
| US5300668A (en) * | 1993-03-10 | 1994-04-05 | Pfizer Inc. | Certain esters of 1-(4-X-methylphenyl)cyclopent-3-ene-1-carboxylic acid, wherein X is a trialkylsilyloxy, bromo or hydroxy group, as intermediates |
| DE19645313A1 (en) | 1996-11-04 | 1998-05-07 | Basf Ag | Substituted 3-benzylpyrazoles |
| SE9903028D0 (en) | 1999-08-27 | 1999-08-27 | Astra Ab | New use |
| PE20070404A1 (en) | 2005-07-29 | 2007-05-10 | Wyeth Corp | COMPOUNDS DERIVED FROM CYANOPYRROL-SULFONAMIDE AS MODULATORS OF THE PROGESTERONE RECEPTOR |
| PE20070182A1 (en) | 2005-07-29 | 2007-03-06 | Wyeth Corp | CYANOPYRROL-PHENYL AMIDE DERIVATIVES AS PROGESTERONE RECEPTOR MODULATORS |
| EP2998314B1 (en) | 2007-06-04 | 2020-01-22 | Bausch Health Ireland Limited | Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders |
| US8969514B2 (en) | 2007-06-04 | 2015-03-03 | Synergy Pharmaceuticals, Inc. | Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia, atherosclerosis, coronary heart disease, gallstone, obesity and other cardiovascular diseases |
| US8034782B2 (en) | 2008-07-16 | 2011-10-11 | Synergy Pharmaceuticals, Inc. | Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders |
| ES2627848T3 (en) | 2008-06-04 | 2017-07-31 | Synergy Pharmaceuticals Inc. | Guanylate cyclase agonists useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders |
| US9616097B2 (en) | 2010-09-15 | 2017-04-11 | Synergy Pharmaceuticals, Inc. | Formulations of guanylate cyclase C agonists and methods of use |
| CA2905435A1 (en) | 2013-03-15 | 2014-09-25 | Synergy Pharmaceuticals Inc. | Compositions useful for the treatment of gastrointestinal disorders |
| US9708367B2 (en) | 2013-03-15 | 2017-07-18 | Synergy Pharmaceuticals, Inc. | Agonists of guanylate cyclase and their uses |
| PL3004138T3 (en) | 2013-06-05 | 2024-07-29 | Bausch Health Ireland Limited | Ultra-pure agonists of guanylate cyclase c, method of making and using same |
| CN115557898B (en) * | 2021-07-01 | 2024-08-20 | 诸葛国琴 | Imidazole compound, intermediate and application thereof |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL86134A (en) * | 1987-05-02 | 1993-06-10 | Basf Ag | N-substituted azoles, their manufacture and their use as pesticides and compositions containing them |
| CA1338238C (en) * | 1988-01-07 | 1996-04-09 | David John Carini | Angiotensin ii receptor blocking imidazoles and combinations thereof with diuretics and nsaids |
-
1990
- 1990-11-16 DE DE4036645A patent/DE4036645A1/en not_active Withdrawn
-
1991
- 1991-11-11 EP EP91119186A patent/EP0485929A1/en not_active Withdrawn
- 1991-11-14 FI FI915381A patent/FI915381A/en unknown
- 1991-11-14 BR BR919104948A patent/BR9104948A/en unknown
- 1991-11-14 IL IL100058A patent/IL100058A0/en unknown
- 1991-11-15 AU AU87855/91A patent/AU8785591A/en not_active Abandoned
- 1991-11-15 NO NO91914481A patent/NO914481L/en unknown
- 1991-11-15 JP JP3326662A patent/JPH04283569A/en active Pending
- 1991-11-15 CA CA002055636A patent/CA2055636A1/en not_active Abandoned
- 1991-11-15 ZA ZA919059A patent/ZA919059B/en unknown
- 1991-11-15 HU HU913583A patent/HUT59673A/en unknown
- 1991-11-15 CS CS913470A patent/CS347091A3/en unknown
- 1991-11-15 KR KR1019910020341A patent/KR920009802A/en not_active Application Discontinuation
- 1991-11-15 IE IE399191A patent/IE913991A1/en not_active Application Discontinuation
- 1991-11-15 CN CN91110736A patent/CN1061410A/en active Pending
- 1991-11-15 MX MX9102098A patent/MX9102098A/en unknown
- 1991-11-15 PT PT99521A patent/PT99521A/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| HUT59673A (en) | 1992-06-29 |
| CS347091A3 (en) | 1992-06-17 |
| FI915381A (en) | 1992-05-17 |
| CA2055636A1 (en) | 1992-05-17 |
| HU913583D0 (en) | 1992-01-28 |
| NO914481L (en) | 1992-05-18 |
| KR920009802A (en) | 1992-06-25 |
| BR9104948A (en) | 1992-06-23 |
| NO914481D0 (en) | 1991-11-15 |
| EP0485929A1 (en) | 1992-05-20 |
| PT99521A (en) | 1992-09-30 |
| FI915381A0 (en) | 1991-11-14 |
| DE4036645A1 (en) | 1992-05-21 |
| MX9102098A (en) | 1992-07-08 |
| CN1061410A (en) | 1992-05-27 |
| IL100058A0 (en) | 1992-08-18 |
| ZA919059B (en) | 1992-07-29 |
| JPH04283569A (en) | 1992-10-08 |
| AU8785591A (en) | 1992-05-21 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FC9A | Application refused sect. 31(1) |