CA2055636A1 - Substituted azoles, process for their preparation, agents containing them and their use - Google Patents
Substituted azoles, process for their preparation, agents containing them and their useInfo
- Publication number
- CA2055636A1 CA2055636A1 CA002055636A CA2055636A CA2055636A1 CA 2055636 A1 CA2055636 A1 CA 2055636A1 CA 002055636 A CA002055636 A CA 002055636A CA 2055636 A CA2055636 A CA 2055636A CA 2055636 A1 CA2055636 A1 CA 2055636A1
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- Prior art keywords
- alkyl
- phenyl
- hydrogen
- radical
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/68—Halogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/70—One oxygen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
Abstract
ABSTRACT OF THE DISCLOSURE:
Substituted azoles, process for their preparation, agents containing them and their use Azoles of the formula
Substituted azoles, process for their preparation, agents containing them and their use Azoles of the formula
Description
~55~;3~i HOECHST AKTIENG~SELLSCHAF~ HOE 90/F 346 Dr.~A/AP
De~cription Substituted azoles, process for ~heir preparation, agent~
cont~ining them and their use EP-A-324,377, EP-A-253,310, EP-A-2B,834 ~nd ~P-A 323,841 disclose deri~ative~ of imidazolls, pyrrola, pyrazole and triazole and their U8e ~8 antagoni~t~ of angiotensin II
receptors.
Novel compounds of the azole type have now been found which are surprisingly highly active antagonists of angioten6in II receptoxs both in vitro and in ViYo.
The invention relates to compounds of the formula I
Z~y R1 ~
--X
L-A-T-E
in which a) X, Y and Z are identical or di~ferent and are ~ or CR2, b) R1 is 1. (C2-C10)-alkyl, 2. ~ C3 Clo ) -alkenyl, 3. (C3-Clo )-alkynyl, 4. ~3, 5 . ( C3_CB )--CYC loalkyl, 6. (C~-Cl0)~cycloalkylalkyl, 7 ( Cs Clo ~ -cycloal~lalkenyl r 8. ~Cs-ClO~cycloalkylalkynyl, 9 . - ( C~Iz ) m~B~ ~ CH2 ~ n~R4 10. ben~yl, . ~ , -~55~i3~
De~cription Substituted azoles, process for ~heir preparation, agent~
cont~ining them and their use EP-A-324,377, EP-A-253,310, EP-A-2B,834 ~nd ~P-A 323,841 disclose deri~ative~ of imidazolls, pyrrola, pyrazole and triazole and their U8e ~8 antagoni~t~ of angiotensin II
receptors.
Novel compounds of the azole type have now been found which are surprisingly highly active antagonists of angioten6in II receptoxs both in vitro and in ViYo.
The invention relates to compounds of the formula I
Z~y R1 ~
--X
L-A-T-E
in which a) X, Y and Z are identical or di~ferent and are ~ or CR2, b) R1 is 1. (C2-C10)-alkyl, 2. ~ C3 Clo ) -alkenyl, 3. (C3-Clo )-alkynyl, 4. ~3, 5 . ( C3_CB )--CYC loalkyl, 6. (C~-Cl0)~cycloalkylalkyl, 7 ( Cs Clo ~ -cycloal~lalkenyl r 8. ~Cs-ClO~cycloalkylalkynyl, 9 . - ( C~Iz ) m~B~ ~ CH2 ~ n~R4 10. ben~yl, . ~ , -~55~i3~
11. a radical a~ defin~d under b) 1., 2., 3. or 9., which i~ mono~ub~tituted by CO2R3, 12. a radical defined a~ under b) 1., 2., 3. or 9., in which 1 to all of the hydrogen atoms are ~ub~tituted by ~luorine, o.r 13. the r~dical define~i undex b~ 10.~ which i~
substituted on the phenyl by 1 or 2 identi-cal or differen~ radicals from th~ 8erie6 compri~ing halogen, (Cl C4)-alkoxy a~d nitro;
c) R2 is 1. hydrogen, 2. halogen, 3. nitro, ~. CVF
5. SFs, 6. pentafluorophenyl, 7. cyano, 8. (Cl-C4)-alkoxy, benæyloxy, 9. phenyl, 10. phanyl-(cl-c3 )-alkyl, 11. (Cl-C~ alkyl, 12. (C3-C10)-alkenylO
13. phenyl-( C2 C~ ) -alkenyl, 14. l-imidaz~lY~ 2)~-~
substituted on the phenyl by 1 or 2 identi-cal or differen~ radicals from th~ 8erie6 compri~ing halogen, (Cl C4)-alkoxy a~d nitro;
c) R2 is 1. hydrogen, 2. halogen, 3. nitro, ~. CVF
5. SFs, 6. pentafluorophenyl, 7. cyano, 8. (Cl-C4)-alkoxy, benæyloxy, 9. phenyl, 10. phanyl-(cl-c3 )-alkyl, 11. (Cl-C~ alkyl, 12. (C3-C10)-alkenylO
13. phenyl-( C2 C~ ) -alkenyl, 14. l-imidaz~lY~ 2)~-~
15. 1,2,3 triaZolyl-(c~2)n-t 16. tetraZolyl-~cHz) m~
17. -(CHz)ol-C~R7 oR5 18. -(CH2)~ o-Co-R3, 19 . - ( t::H2 ) o~ R5 ~ ~
20. ~S() 21. -CH=CH-( CH2 ) ~CHR3-oR
22. C~2=CH-(CH~ Co-R3, 23. -CO-RB, 24. -C~-C~-(CH2)~ o-Co-R7, 25. -(C~2)~ CH~CH3)~CO R5, 26. -(C~2lo~CO~R
27. -(CHz)o-O-C-NH-Ra, ,:
- 3 ~ 36 2 8 . - ( CH2 ) o-NR7-C-oR9, 2 9 . - ( CH2 ) o -NR7-CC)-N}IR0 r 3 O ~ ~ ( CH2 ) o~NR -SO2R
31 . - ( CH2 ) o-NR7-C-R~
32 . ~ (CH23n 3 3 . - ( CH2 ) "--N2 3 4 . -CH2-N3 o 35 . ~ (cH2)n-N()2 36 . -CH=N-NRsR7 3 7 . phthali~lido- ( CH2 ~ "~
N\
3 t3 - ( CH2 ) n~~ NH
39. - (CH2)n~~ ~CF
H
1$ 40 (~H2)n~N/~
41 . ( C~2 ~ ~ ~ - 1- Co- N~
~C~3 42. phenyl-SO2-NH-N=CH-, ~N
4 3 . - CH~N~ /<
N
H
4 4 . - ( CHz ) D-So2-NR7-Co-NR8R~, 45. -(C~)O SO2~9, 46. a radical defined a~ under c) 9. or 10,, which is ~ubstituted on ~he phenyl by :
":, . .
.
~ , . . .
~ 4 - 2~ S~
1 or 2 identical or dif~Qrent radicals ~rom the series compri~ing halogen, hydroxyl, methoxy, trifluoromethyl, Co2R3 and phenyl, 47. a radical de~ined ,as under c) 11., 12. or 20., in which 1 ~o all of ~he ~ydrogen atoms are ~ub~tituted by ~luorine, or 48. the radic~l d~fined under c) 15., which i8 sub~tituted by 1 or 2 id~ntical or differ~
ent radicals from the ~erie~ ~omprising methoxycarbonyl ancl tC1~C4)-al~yl;
d) R3 is 1. hydrogen, 2. (Cl-C~)-alkyl, 3. (C3-C~)-cycloalkyl, . 4. phenyl, 5. benzyl or 6. the radical de~ined under d) 2., in which 1 to all o~ the hydrogen atom~ are ~ubskitu ted by fluorine;
e) R4 is 1. hydrogen, 2. (Cl-C6)-alkyl, 3. ( C3-C~ ) -CyC loalkyl, 4. (C2-C4)-alkenyl or 5. ( C2-C4 ) ~ CyTlyl;
f) Rs is 1. hydrogen, 2:5 2. (C1-C6~-alkyl, 3. (C3-Ca)-cycloalkyl, 4. phenyl or 5. benzyl;
: . g) R6 i~ 1. hydrogen, : ~ 30 2. (C1~C6)-alkyl, 3 ( C3-C0 )~ycloalkyl, 4. ~C6-Cl2)-aryl, p~efera~ly phenyl, 5. benzyl, :
- 5 - ~55~3~
6. (C1-C~)-heteroaryl which can al~o be partially or completely hydrogenated, preferably 2-pyrimidinyl, 7. (Cl-C~)-alkanoyl, 8. (C1-C~)-hateroaryl-(C1-C3)-alkyl, where the heteroaryl moiety can al80 be partially or comple~ely hydrogema~ed, or 9. a radical defi~ed a~ under g) 4., 6. or 8., substituted by 1 or 2 identical or diffar-ent radicals ~rom ~he ~eries comprising halogen, hydro~yl, methoxy, nitro, cyano, Co2R3, -NR11R12 and trifluoromethyl;
h) R7 is 1. hydrogen/
2. (Cl-C6)-alkyl, 3. (C3-C8)-cycloalkyl, 4- (co-cl2)-aryl-(cl-c~)-alkyl~ prefsrably benzyl, S. phenyl ox 6. (C1~Cg)-heteroaryl;
i) R8 is 1. hydrogen, 2. (Cl-C6)~alkyl, 3. (C3-Ca~-cycloalkyl, 4, phenyl-(CH2)q~~
5. oR5, 6. NRl1R12 or r 7.
:
;) R9 is 1. (C1-Ca) alkyl, 2. 1-adaman~yl, 3. l-naphthyl, 4. l-naphthylethyl, 5. phenyl-(CH2)~- or 6. the radical defined under ;) 1., in which 1 t,o all of the hydrogen atoms are sub~titu-ted by ~Iuorine;
:
:
, ~ '55~;3 ~ 6 -or R5 and R8 together wi~h the nitrogen akom carxying them are ~ R12;
k) R~ cyano, ni~ro or CoaR7;
l~ Rl1 and R12 are identi~l or differenk and are 1. hydrogen, 2. (C1-C4)-alkyl, ~. phenyl, 4. benzyl or 5. ~-methylbenzyl;
lO m) D is NR13, O or CH2;
n) Rl3 is hydrogen, ( Cl-C4 )-alkyl or phenyl;
o) A i~ ~) a (C6-C14)-aryl r~dical or ~) (cl-c9)-heteroaryll which can either be aromatic, partially hy~rogenated or comple~ely hydrog~natPd, or ~) the radical of a fused hete~ocycl2 having 8 to lO ring atoms, of which up to 9 are carbon atoms, it being po~sible to substituke A in each c~e by up 2G to 3 identical or different radical0 from the ~eries compri~ing : 1. halogen, ~ . oxo, 3. nitro~o, 4. nitro, 5. cyano, 6. hydroxyl, 7. I~Cl-C~ lkyl, : 8. C1-C4)-alkanoyl, 9 ( Cl-C4 ) -alkan . ~ . . .
- ... . . ~: ~
: : , - . ~ : . ; - . : .:
~ ' . ~ : ~ '', . :
- 7 ~ 3~i 10. Co2R3, 11 . methanesul f onylamino, 12. trifluoxome~hanesulfoTIylamino, 13 . -Co-NH-oR9, 14. -So2-NR6R7, 1 5 . -CH2-OR7, 16 . ( C6-C12 ) -aryl, 17 . t C3~C8 ) -cycloalkyl, 18. (Cl C4)v-alkoxy~
19. (cl-c9)~heteroa~
2 0 . Co2R3, 21. NR6R7, 22. aulfo, 2 3 ~ -So3R3 r 2 4 . -So2-NR7-Co-NR~R9, 2 5 . -NR7-Co-NR6-So2-CH2-R5, 26. -C~CF3)aOH, O
2 7 . pho~phonooxy, ~O-P-OH
2 8 . -PO3H2 r bH
29. -NX-PO(oH) 30. ~S(O)rR6, 31. -Co-R3 and 3 2 . -Co-NR6R3;
p ~ ~ 1. a single bond 2. -CO-, 3. -CH2-, 4 . -O-, 5 . -$-, 6 . -MR21-, 3 0 7 . ~ O-NR21-, ~ . -NR2~-co_, 9. -O-CH2-, :
1 0 . -CH2-C)-, S-CH2- ~
12. -CH2-S-, 13. -~I-CR20R22_, 14. -NR2l-SO2-, 15 . ~ SO2-NR21-, ,, . ;
.. ~ , :
~S~i~36 17 . -CH=CH-, 18. CF-CF-, l9 . -CH=CF-, 2 0 . -CF=CH-, 21. -CH2-C~z~ ~
2 2 . -CF2-CF2-, 23 . -C}I(OR33~, 24 . -C~(oCoR5) -, 25. ~C-~R23 ~
2 6 . -C- or R240 ' 'olR25 27. ~
q ) E is a xadical 1. ~ with ~he proviso that in the ca~e < 1l where x=~r=cH ~ Rl4 i~ not COOH, . 2. ~ B
< I
y~X
S ( CH~5< R4 (CH2 )m R~
, , . . - , , , ' ~. ~ i ;~; , , ~ C~S~ t~
r) B is 0, NR7 or S;
6) L is (C1-C3)-alkanediyl;
t) R14 i~ -Co2R3, -CH2Co2R3, -PO3H2, -SO3H or tetrazolyl, u) m is an integer from O tv 5;
v) n is ~n integer from 1 to 5;
w) o is an integer from l to 10;
x) r i5 0 r l or ~, and y) v is an integer from 1 to 6;
and their physiologically tolerable 8alt~.
Alkyl, alkenyl and alkynyl can be s~raigh~-chain or branched. The same applie6 to radicals derived therefrom, such as alkanoyl or alkoxy.
Cycloalkyl is also understosd as meaning alkyl-8ubstitu-ted rings.
(C6-Cl23-aryl is, for example, phenyl, naphthyl or bi-phenylyl, pre~erably phenyl. The same ~pplies to r~dical~
: derived therefrom, such ~ aroyl or aralkyl.
(Cl-Cg)-heteroaryl i8 in particular under~tood a~ meaning radical~ which ~re derived from phe~l or naphthyl, in which one or more CH groups are replaced ~y nitro~en and/or in which at lesst two ad~acent CH groups re replaoed (with the formation o~ a ~ive-me~bered aro~atic ring) by S, NH or 0. In addition, one or two atom~ of the condensation ~ite of bicyclic radicals ( ~u~h a6 in ~5 indolizinyl) can also be a nitrogen atom.
These are, for example, furanyl, thienyl, pyrrolyl, - , lo ~ 5~.s3~;
imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyxidyl, pyraxinyl, pyrimidinyl, pyridazinyl, indolyl, inda~olyl, quinolyl/
i~oquinolyl, phthalazinyl, guinoxalinyl, quinazolinyl and cinnolinyl.
The fused heterobicyclic ~ys~em iB understood as meaning, in particular, a bicyclic ring sy~tem having 8 to 10 rin~
atoms, of which up to 9 are carbon atoms, in which two adjacent atoms are common componenkR of both ring~ . One or both of these rings ls/are formally derived from benzene in which one or more CH groups are repl~ced by N, O+ and S~ and/or in which two ad;acent CH group are replaced by S, NH or O (with the formation of a five-membered aromatic ring).
These are, for e~ample, a radical of benzothiophene, benzo~uran, indole, isoindole, indazole, benzimidaxole, quinoline, isoquinoline, phthalazine, quinoxaline, quinazoline, cinnolinel benzothiazole, ben~othiazole-l,1-dioxide, coumarin, chroman, benzoxazole, benziso-thiazole, benzodiazines, benzotriazol~, benzotriazine,benzoxazine, imidazopyridine, imidazopyrimidine, imidazopyrazine, imidazopyridazine, imidazothiazole, pyrazolopyridine, thienopyridine and pyrrolopyrLmidine.
Said heterobicyclic ~ystem can also be partially or completely hydrogenated. However, one ring preferably remains aromatic, a benzo-fu~ed heterobicyclic aystem being particularly preferred.
In the ca~e of S-containin~ and/or partially saturated radicals, the bicyclic ~ystem ~an also, for e~ample, be oxo-substituted, a~ is the ca~ with the radical of the benzo-1,2,3-triazinone.
Physiologically tolerable ~alt~ of compounds of the formula I ~re understood a6 meaning both their organic and their ino:rgani~ salts, such a~ are described in Remington's Pharmaceutical Sciences, (17th editiont page , ~
:
'5~
1418 (1985). Owing to phy~ical and chemical ~tability and solubility, ~odium, potassi~m~ calcium and nmmonium salts, inter ~lia, are pre~erred for acid group ; ~alt~
with hydrochloric acid, sulfuric ~cid, pho6phoric acid or S with carboxylic acid~ or sulfoni.c acid~, such as 2cetic acid, citric acid, benzoic acidg maleic acid, fu~aric acid, tartaric acid and p-toluenesulfoni~ acid~ inter alial for basic groups.
Preferred compounds of the ~ormula I are tho~e in which a) X i~ N, Y is CR2 and Z i8 CR2~
b) X is CR2, Y i8 N and Z i CR2;
c) X is CR2, Y is CR2 and Z 1~ N
or d) X, Y and Z are in each case N.
Compounds of the formula I are additionally preferred in which a) Rl is 1. (~3-Clo)-alkyl, 2. ( C3 Clo ) -alkenyl, 3. ( C3 Clo )-al~ynyl, 4. (C3-C8)-cycloalkyl, 5. benzyl or 6. benzyl which i~ ~ubstituted as defined above, or 7. -(CH2)~-B-(CH3)n-R4;
~5 b) R2 is 1. hydrosen, 2. halogen, 3. nitro, 4. CvF2~l, 5~ SFs~
6. pen~afluorophenyl, 7. cyano, 8. (Cl-C4~-alkoxy, benzyloxy, 9. phenyl, 10. phenyl-(C1 C3 )-alkyl, 11. (C1-C,0)-alkyl, .
.~ .': ~ `. , -- 12 - 2C,~55~j3~D
12 . ( C3-Clo ) -alkenyl, 13 . phenyl- ( C2 C~ ) -alkenyl, 14 . l-imidazolyl- ( CH2 ) m-15 . 1, 2, 3~triazolylD ( CH2 ) O-16 . tetrazolyl ~ ~ CH2 ) m~
17 . --( CH2 ) o 1 -CHR7-oR5 18 . -(CH2)o-o-CoR3, 1g. -COR8, 20. -(CH2~ CO-Ra, 21. -S(O)rR6t .2 2 . -CH=CH- ( CH2 ) ,"-CHR3- OR6, X 3 . ~ CH2=CH- ( CH2 ) " Co-~8, 2 4 . - ( CH;I ) o~NH~CO~ORD, 2 5 . - ( CH2 ) O ~H-SO2-R, 26. -(CH2)n~, 2 7 . - ( C~z ) o-SO3R ~
2 8 . - ( CH2 ) n~ SO2-NH- CO-NR6R~ t or 29. a radical defined a~ under b) 9., 10., 11., 12. or 15., which is ~ub~ti~u~ed as defined above under c) 45., 47, or 4~. ln each case a~ described for ~uch a radical;
c ) R8 is hydrogen, ( Cl-C5 ) -alkyl, O~s, ~RllRl2 or morphollno;
d) T is 1. a ~ingle bond, 2 5 2 . -CO-, 3 . -CONR21-, 4. CH2-CH2-, 5 . -NR71-Co-6. t)-C:H2 3 0 7 . -CH2-O-8 . -S~C~a-9. -CH2-S-, 10. ~ CH2-, 1 1 . -C~2~
12 . -CH=C~I- t or .
.
- 13 ` ~ i5~
o 13 . _l _ O
and the other radica.ls and variable~ are a~
def ined abs:)v0 .
Particularly preferred compounc1s of the formula I a:re those in which a) R1 iS ~C3-C,)-alk~ (C3 C,)-alkenyl or (C3--C,) -alkynyl;
b ) R~ is l . hydrogen l 0 2 . chlorine, 3. bromine, 4. CVF2V~l where v = 1, 2 or 3, 5 . pentaf luorophenyl, 6 . ( Cl-C4 ) -al3coxy, berlzylc~
7, --S(O)r~
8. SF5, 9 . ( CH2 ) o l-CHR'-t)R5 ~
(CH2)o-O~CO R3, 11. C ORa, 2 0 l 2 . - ( C~I2 ) o-CO-Ra ~
l 3 . -CH2~ CO-R3, 14. -(CH2~ SO2-R , 15 . -CH--CII-CHR3-OR5 l 6 . tetrazolyl- ( CE~2 ) m'- ~
2 5 l 7 . - ~ CH~ ) I,SOa-NH-CO-NR8R~, 18 . - ( CEI2 ) o-SO3R or 19 . ( Cl-Cs) -alkyl which 16 optionally sub-stituted by hydroxyl, pref~rably hydroxy-m~3thyl;
30 c) R3 is hydrogen or ~Cl Cb)-alkyl;
d) R6 is hydrogen, (Cl-C4)-alkyl, (Cl-C:4~allcanoyl! phenyl which can op~ionally ba sub~tituted by l or 2 . .
iden~ical or di~ferent radicals from the s~rie~
- 14 ~ 5~
compri~ing halogen, hydxoxyl, metho~y, nitro, cyano, Co2R3 and trifluoromethy1, or tC1-C~)-heteroaryl which can al80 be partially or completely hydrogenated, preferably 2-pyrimidyl;
e) R7 is hydrogen, (Cl-C")-alkyl., (Cl-C~)-hetç!roaryl, or ( C6-Cl2 ) -aryl - ( Cl-C4 ) -allcyl;
f ) RB i8 hydrogen, ( Cl-c4 ) -allcyl ~ oR5 or ms:~rpholino;
g) R~ is CF3, (Cl-C6)-alkyl or phenyl;
h) A is ct) a (C6-C10~-aryl radical or ) ( Cl-C4 ) -heteroaryl which can aither ba aromatic, paxtially hydrogenated or com-plately hydrogenated, or ~ the radical of a fused heterobicyclic ~ystem having 8 to 10 ring a~oms, o~ which up to 9 are carbon atoms;
where A in each case can be 6ubs~ituted by up to 3 identical or different radical~ from the series comprising halogen, nitro, cyano, hydroxyl, -NR~R7, phenyl, -S(O) rR6 and -Co2R3;
1) T is a single bond, -O-, CO-, N~CO-, OCH2- or -S-11 ~.
and the other radioals and v~riable~ are as defined above.
Very particula:rly preferred compounds of the ~onmula I
are those ln which ~.
a) ~1 is (C3-~5)-b) R~ is hydrogen, chlorine, methoxy, -S(O)rR~ or $3 henzyloxy, c ) R3 i~ hydrogen or ( C~ 4 ) -alkyl, d) R4 and R5 axe idenkical or diff~erent and are hydrogen or ( Cl~ 4 ) -alkyl, e~ R5 is hydrogan, (cl-c4)-alkyll phenyl or 4-tolyl, f) R14 is-COOH, ~PO3Hz~ -S~3~ or S-tetrazolyl, g) A is phenyl or the radical o~ a fu~ed heterocyclic system having 8 to lO ring atom~, o~ which up to 9 are c~rbon atoms~ it being po~ible, however~ ~or A to be sub~tituted by up to 2 identical or di~ferenk radic~ rom the ~eries comprising halogen, nitro, cyano, phenyl, -S(O)rR~ and -CO2~ , h) B i8 0, NH or S, i) L is CH2-, ; ) r is 0, 1 or 2, k) q is 0, a ~ingle bond, m ) m is a, 1, 2 or 3 and n) n i8 1, 2 or 3 and X, Y and Z are as defined above.
Th~ invention al80 x~late~ to a process for the prepara-tion of compolmd~ of the formula I, which compri~es aIkylating ~Qmpound~ of the or~ula II
Y ~II) -~
X
H
.
. .
16 - 2~5~3~
in which R1, X, Y and Z ~ra a~ defined above, with com-pounds of the formula III
U-L-A~'r-E (II~) in which L, A, T and E are a~ de~fined above, and U i~ a leaving group, i~ appropriatel removing temporarily introduced protec~ive groups and converting the co~pound~
of the formula I ob~ained, i~ ,appropriate, into their physiologically tolerable alts.
Suitable leaving ~roups U ~re preferably a nucleofugic group (cf. Angew. Chem. 72 [1960] 713 such a~ halogen, o-toluenesulfonate, mesyl~te or triflate.
Processes for the preparation of the precur~ors of the formula (II) are known, inter alia, from ~S Patent No.
4,355,044, EP-A-324,377 snd EP-A-323,841.
lS Other processes are described in G. L'abbe Chem. Rev. 69, 345 (1969); T. Srodsky in ~The Chemis~ry of ~he Azido ~roup", Wiley, Nsw York, 1971, p. 331; H. W~mhof~ in "Comprehensive Heterocyclic Chemi~try", S. ~atxi~zky Ed., Pergamon Press, New York (1984).
To alkyla~s the azole~ o~ the ~ormula II, suitable alkylating agents are, for ex~mple, appropri~te benzyl halides, tosylate~, me~ylate~ or trifla~e~ or appropriate alkyl halides, to8ylat08~ mesylates or trlflate~
~ he synthesis of derivatives such a~ benzofuran~, benzo-thioph0ne and indole~ havlng a ben3yllc -CH3 group wa~
described, inter aIia, by R.P. Dick~on,o et al. in J. ~ed.
Chem. 29, 1637 (1986)~ and ibid. 29, 16~3 (1986). The preparation o~ benzimidazoles, benzothiazole~, b~nzo-diazines, benzopyrone~, benzothlazolones, benzotria~ines, b~nzoxazines and benzo~azoles i~ ou~lined in ~he edi~ion "Comprehensive Heterocyclic Chemistry~, S. Ratrit2ky Ed.
Pergamon Pres~ New York (1984) cited above.
:: : .
~ .
- -:
- 17 ~ 5~3~
The alkylation is carried out in an analogous manner to proce~ses which are known in principle.
The azole deri~ati~e of the formula II i~ metalated, for ex~mple, in ~he pre~ence of a ba~e. Preferred base~ ~re metal hydrides of the formula ~1 ~uch as, for example, lithium hydride, 80dlum hydride or pota~ium hydride in, for example, D~F or DM~O 88 a solvent or metal alkoxides of the formula MOR, where R i8 methyl, ethyl or ~butyl~
and ~he reaction i5 carried out in the corre~ponding alcohol, DMF or DNSO. The 8al~8 of the azoles thus formed are dissolved in an apro~ic ~olvent such as D~F or DMSO
and treated with a suitable amount of alkylating reagent.
An alternative pofi~ibility for the deprotonation of the a201e derivatives is, for example, r~action with potas-15 6ium carbonate in DM~I or DMSO.
The reaction~ are carried out at temperature~ below roomtemperature up to the boiling poin~ of the reaction mixture, preferably between ~20C and the boiling point of the reaction mix~urel for about 1 to 10 hour~.
Fragments of the fonmula II
A - T ~ (II) are synthe6ized via the addition of metalated ~sonitriles ~Angew. Chem. 86, 878 (1974), 89, 351 (1977) to acid chlorides of the formula III
A - ~ - CO-C:l (~II) in inert solvents at -78C up to the boiling point cf the solvent, preferably in diethyl ether or THF at 78C to OC.
18 - ~ ~ SS~ ~6 The synthe~i~ of ~ragment~ of the fo.rmulaa IV and V
R14 ~H2~ R4 A - T ~ m "' X R5 IV) R14 ~V) A - T ~ R
is carrisd out by means of tha ~l~ylation, which i~ known in principle, of arylacetic acid derivative~ or aryl-acetonitrile~ in an nnalogous m~nner, elkher in ethers such as diethyl ether, ~HF or dimethoxyethane with LDA at -78C or with ROtBu at room tempera~ure in t butanol.
The compounds of the formula I according to the invantion have antagonistic action on an~iot2nsin II receptor~ and can therefoxe ~e u~ed for the treatment of angiotensin II-dependent hypertension. Po~sibilities of application furthermore exist in cardiac in~ufficiency, cardioprotec-tion, myocardial infarct, cardiac hypertrophy, arterio-sclerosis, nephropathy, kid~ey failure ~nd v~culardiseases of the brain such as transitory ischemic attack~
and stroke.
Renin is a proteolytic enzyme o~ the aspartylprotease cla~s, which is ~ecr~t~d into the bl~d circulation ~y the juxtaglomerular cell~ of the kid~ey as a consequence of various stimuli tvolume depletion, 30dium deficiency, ~-receptor:~timulation). In ths blood, it clea~es the ; ~ decapeptide angiotenBin I from th~ an~ioten~inogen excreted from the liver. ~he former is conver~ed into angio~ensin II by the "an~iotensin convertin~ ~nzyme~
(ACE). Angiotensin~ plays an essential role in ~lood pressure regula~ion,~a~ it directly increases ~he ~lood : pre sure by ~ans~ of vascular contraction. It addi-~ioDally ~timulates the secretion of aldos~erone from ~he adrenal gland and in this w~y increa~es the extracellular : ~ : :
fluid volume via the inhibitlon of sodium excr~atio~, which for it_ part contribute~ to an increa~e in blood pressure.
Post-receptor actionq are inter alia 6timulation of pho~phoinositol conversion (CaZ+ release), activa~ion of protein kinase C) and facilitation of ~A~æ-dependenk hormone receptors.
The affinity of the compounds of the ~ormula I ~or the angiotensin II r~ceptor can be deater~ined by measurement of 125I-angiotensin II or 3H-angiotensin II displacement from receptor6 on Zona glomerulosa membranes o~ bovine adrenal glands. For this purpose, the prepared me~rane~
are su6pended in buffer at pH 7.4. Aprotinln, a p~ptidase inhibitor, i8 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 T~q/mmol (available from Amersham Buchler~ and a guantity of receptor protein which binds 50% of the tracer are additionally used. The reaction i8 begun by addition of 50 ~1 of membrane su6pension to a mixture of 100 ~1 of buffer + aprotinin, 50 ~1 of buffer with or without angiotensin II or r~ceptor antagonist and 50 ~1 of tracer. After an incubatio~ time of 60 minutes at a temperature of 25C, bound and free radioligand are ~eparated on a Skatron0 cell collector using ~hatmann GFIC filtars by means o~ a filtration as~ay.
Non-specific bindin~ is prevented by treatment of the filter with 0.3% polyethyleneimine pH=10 (Sigma, NoO
3143). The amount of displacement of the radioligand from 3~ the receptor i5 determined by measurement of the radio-activity in a gamma scintillation counter. ~he IC50 values, which denote the concentrativn of inhibitor for displacing 50% of the ligand, are de~ermin~d according to Chem. et al. .J. Theor. Biol. 59, 253 ~1970). For the compound~ of the formula (I) ~hey are in the range from 10-4-10~ M.
, 3~;
~ 20 -rro dete~nine the antagoni~tic ac~ion of the cumpound~ of the formula (I), their e~fect on the Angio^ten~in II-induced blood pre~ure ri~e in ane~the~ized Sprague-Dawley rats can be mea~ured. Na thiobarbital (Trapanal, Byk Gulden) i8 used a~ an ane~thetic in the dose 100 mg/kg i.p. I.~. administrakion i8 carried out in the jugular vein. The blood pre~sure i~ mea~ured in the carotid artery. The animals arle firat pretreated with pentolinium ~artrate (10 mg/kg i.m.) 80 that a lower blood pxessure level i8 achieved (ganglia blockada). ~N~
II (~yperten~in, CIBA) i~ a~mini3tered i.v. in the volume O.1 ml~100 g at 10 minute intervals. ~he do~e is 0.5 ~g/kg. The compounds of the formula (I) are di~solved in distilled water and administered intra~enously or intraduodenally in the doses 0.1; 1; 10 and 100 mg/kg.
The compounds o~ ths formula ~I) are ef~e~tive 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 acti~e compounds, ~uch as, ~or example, diuretics or non-~teroi-dal anti-inflammatory active compound~. The compounds of the formula I can al80 be u~ed as diagnostics for the renin-angioten~in Gystem.
Pharma~eutical preparation~ cont~in an effective amount o the active compound of the formula T and if nscessary other active compounds together with an inorganic or organic pharmaceutically utilizable e~cipient. A*minis-tration can be carried out intranasally, intravenously, subcutaneou~ly or orally. The do~age of the active compound depends on the mammalian 6pecies, the body weight, the age and the manner of administration.
The pharmaceut.ical preparations of the present invention are prepared in a dissolving, mixing, ~ranulating or coatin~ process known per ~e.
.
. .
For a form for oral at~minigtra~ion~ the active compounds are mixed with the addi~ives cu~tomary ~.herefor such a6 excipien~s, s~abilizers or iner~ diluen~i and brought by means of customary method~ into ~uitable admini~tration forms, such as tablets, coa~ed tableks, hard gelatin capsules, aqueous, alcoholic or oily ~uspension~ ox aqueousl alcoholic or oily solutions. ~nert excipients which can be used are, for examplle, gum ~rabic, magnesia, magnesium carbonate, pota~si~n phosphate, lactose, gluco~e, magnesium stearyl fumarate or ~tarch, in parti-cular maize ~tarch. The preparation in thiEt cas~ can be both a~ dry and moist granule~. 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 phy6iologically tolerable salts are brought into solutions, suspensions or emul~ions, if appropria~e with the substances customary therefor such as ~olubilizer~, emulsifiers or other auxiliaries.
Suitable solvents are, for example, water, physiological saline solu~ions or alcoholt~, for exa~ple ethanol, propanediol or glycerol, in addition al~o ~ugar solutions such as glucose or mannitol solutions or alternatively a mixture of the different ~aid solvents.
List of abbreviations:
DMF N,N-dimethylformamide NBS N-bromosuccinimide AIBN ~ azobi~isobutyronitrile EI electron impact DCI desorption-chemical ionization RT room temperakure EA ethyl atetate (EtOAc) DIP diisoprt?pyl ether THF tetrahydrofuran M.p. melting point ~TB methyl t-butyl ether :: .
~ ~2 ~
B.p.~ boiling point at xx torr Et3N triethylamine MS ma~s spectrum FAB fast atom bombardment LDA lithium diisopropylamide ~he following examples illu~trate the inven~ion withou~
restrictin~ ~he invention theretoo Example 1 1-[4~ Carboxy-1-cyclopentyl)benzyl] 2-n-butyl-4-chloro-5-formylLmidazole a) Ethyl 1-(p-tolyl)~yclopentanecarboxylate g of 1-(p-~olyl)cyclopentanecarboxylic acid are su~pended in 200 ml of ethanol, and the 301ution iQ
slowly treated with 4.3 ml of SOCl~ and heated to reflux for 24 h. ~xces~ SOc12 i8 remoYed in vacuo, and the residue is taken up with 100 ml of EA, wa~hed twice with 50 ml of ~atd. aq. Na2SO3 solution and dried over ~a2SO
The solvent is then removed in vacuo and 11.3 g of th~
title compound are obtained a~ light br~wn cry~tal~
melting point: 47C.
b) Ethyl 1-(4-bromomethyl)phenylcyclopentanecarboxylate : 2.5 g of ethyl l-~p-tolyl)cyclopentanecarboxyl~te, 1094 g of NBS and 200 mg of benzoyl peroxide are heated to reflux in 50 ml of ~hlorobenzene ~or 3 h. The solvant i8 then removed in vacuo, and the re~idue i~ t~ken up in 300 ml of EA, wa~hed once with S% strength ~q. Na2SO3 solu~ion and twice wi~h 5atd. aq~ NaHCO3 ~olution ~nd dried over Naa~O4~ ~he sol~ent iz finally remo~ed in vacuo and 3.2 g of the title compound are obtained as an oil.
30: R~ (SiO2; EA/heptane 1:4) - 0.50 M5 (DCI) : 311 (N~1) -. : , ~
.. ..
, : ' : .
..
., ~ . , - ~3 ~ r~
c) 1-[4~ ethoxycarbonyl-1-cyclopentyl)b~nzylJ-~-n-butyl -4-chloro-5-formylimidazole 342 my of ethyl 1-(4-bromomethyl)phenylcyclopentane-carboxylate, 187 mg of 2-n-butyl-4-chloro~5-~ormyl-Lmidazole and 138 mg of R2C03 are stirred in 10 ml of DNF
at RT for 22 h. The mixture is dilu~ed with 100 ~1 of ~, washed once with 50 ml of }120 and once with 5% strength aq. NaCl solution and dried over Na2SO4, and the ~olvent is removed in vacuo. Chromatogr~lphy on ~ilica gel ~sing DIP yields 240 mg of the title compound a~ a colorle~s oil.
R~ (SiO2; DIP/MTB 1~ 0.68 MS (DCI) : 417 ~M~
d) 1-[4~ carboxy-1-cyclopentyl3benzyl~-2-n-butyl-4-chloro-5-formylimidazole 115 mg of 1-[4-(1-etho~ycarbonyl-1-cyclopentyl)benæyl]~
2-n-butyl-4-chloro-5-~ormylimidazole snd 415 ~1 of 1 N
NaOH are heated to reflux in 8 ml of EtOH for 29 h~ ~he e~hanol is removed in vacuo, and the residue i~ dilu~ed with 30 ml Of ~2 and washed with 10 ml vf DXP. It i~ then adju~ted to pH = 1-2 and extracted twice with SO ml of EA
each tLme. The extracts are dried oYer Na2SO4 and the solvent is removed in vacuo. Chromatoqraphy on ~ilica gel using MT~ yields 68 mg of the title compound as a light brown solid.
M.p: 134~C
R~ (SiO2; N~B3 = 0.30 MS ~DCI) : 389 (M+13 The title compounds o Examples 2 and 3 axe synthesised ~ia the methyl e~ter analogously to Example 1: :
Example 2 30: 1-[4-(1-Carboxy-l-cyclohexyl)benzyl]-2-n-butyl-4 chloro-S-formylimida~ole ':
, : ' ~'5S~i3~
Ex~nple 3 1-~4~ carboxy~l-cyclohexyl)benzyl~-2-n-butyl 4-me~hoxy-5-formylimidazole 670 m~ of 1 [4~ methoxycar~onyl-1-cyclohexyl)benzyl]-2-n-butyl~4-chloro 5-formylimidazole are reacted a~ de~-cribed under ~xample ld). 300 m~ of the title compound of Example 2 R~ (SiO2; ~TB/DIP 1:1) = 0.35 MS (DCI) : 403 (M + 1) malting point 147C
and 160 mg of the title compound of Example 3 R~ (SiO2; M~B/DIP 1~ 0.25 MS (DCI) s 399 (M ~ 1) melting point 167 DC
are obtained, and can be ~eparated by chromatogr~phy on silica gel using MTB/DIP lsl.
Example 4 1-~4~ caxboxy~ 4~4-dimethyl)cyclohe~l]benzyl)-2-n-butyl-4~chloro-5-formylimidazole a) l-p-Tolyl-4,4-dimethylcyclohexanecarbonitrile 27.S g of potas~ium t-butylate are taken up in 200 ml of t-butanol and the mixture i~ heatad to reflux. A solution of 32 g of 195-dibromo-3,3-dimethylpentane and 16.3 ml of 4-tolylacetonitrile in 100 ml o~ t-butanol is then added dropwi~e in the course of 1 h. The miscture i~ heated under reflux for 4 h, the solvent i~ removed in ~acuo and the residue is taken up ln 200 ml of ~atd. a~. ~aHC03 and 200 ml of ~B. It is extr~cted twice with 200 ml o~ NTB
each time and dried over Na25O4, and the solvent is removed in vacuo. Di~tillation in a fine vacuum yields 9 . 7 g of a colorless oil .
:
:
- 25 - 2 ~ ~ S6 B.P.02 - 135-140C MS (DCI) 5 228 (M~1) b) l-p-Tolyl-4,4 dimethylcyclohexanscarbo~ylic acid 4.0 g ~f 1-p-tolyl~4,4-dLmethy:Lcyclohexanec~rbonitrile and 3.0 g of ROH are heated under reflux in 50 ml of diethyl~ne glycol ~or 3 h. The mixture is allowed to cool, and .is poured into 100 ml of 0.1 ~ NaOH and washed twice with 30 ml of DIP each time. It i8 then adju~ted to pH = 1-2 wi~h HCl and ex~rac~ed 3 times wi~h 100 ml of diethyl ethçr each time. The extrac~s ~re dried over Na2SO4 and the solvent i8 removed in vacuo. 4.0 g of pale yellow cxystals are obtained.
Melting point: 128C MS (DCI) : 241 (~) c) Ethyl l-p-tolyl-4,4-dLmethylcyclohexanecarboxylate 4.0 g o~ l~p-tolyl-4,4-dLmethylcyclohexanecarboxylic acid are dissolved in 50 ml of ethanol and trea~ed with l.S ml of SOCl2. The mixture i~ stirred at 50C for 3 h, then at reflux for 3~5 h. The ~olvent is removed in vacuo, and the residue is taken up in ~00 ml of EA and washed 3 tLmes with 50 ml of ~atd. aq. Na2CO3 ~ach time. The extracts are dried o~er Na2SOq and the solvent 1~ removed in vacuo. 5.0 g of a slightly con~aminated bxown oil are obtained, which is employed again without purification.
~S ~DCI) : 275 (M+l~
d) Ethyl 1-(4-bromomethyl)phenyl-4,4-dimethylcyclohaxane-~5 carboxylate 5.0 g of ethyl 1-p-tolyl-4,4-dLmethylryclohexane-carboxyla~e, 2.g g of NBS and 50 mg o~ benzoyl p~roxi~e are heated to reflux in 50 ml of chlorobenzene ~or 1.5 h.
The ~olvent is then removed in vacuo, and the residue is taken up in 200 ml of EA, and washed once with 100 ml of satd. aq. Na2SO3 and once wlth NaCl solution. The ~olution is dried over Na2SO4 and the solvent i~ removed in vacuo.
.
- 26 - HOE 90/F' ~
Z ~ ~4~>~6 5.4 g of a brown oil ar~ obtained.
R, (SiO2; EA/hep~ane 1:8) = 0.39 MS (DCI) : 353 (M~l) Further reaction is carried out analogously to Examples lc and ld to give 1-(4~ carboxy-1 (4,4-dimethyl)cyclo-hexyl]benæyl)-2-n-butyl-4-chloro--5-formyl~idazole R, (SiO2; DIP) = 0.16 ~S (DCI) : 431 (~+1) Example 5 1-(4-~1-(5-tetrazolyl)cyclohex~l]benzyl) 2-n-butyl-4-chloro-5-hydroxymethylLmidazole z) 1-(4-Tolyl)cyclohexanecarbonitrile mhs co~ound was sy~lthesized analogously to Example 3a) 3 ? ~3 = 9S-100C u~ (D~ 200 (Y~l) b) 1-(4-Bromo~ethylphenyl)cyclohexanecarbonitrlle The compound was synthesized analogously to Example 3 d) Rf (SiO2; EE/Hep 1:4) = 0,~6 MS (DCI) : 278 ~M~l) c) 1-[4-(1-Cyano-l-cyclohexyl)benzyl]-2-n-butyl-4-chloro-5-formylimi~azole ~he compound was synthesized analogously to Example lc).
R~ (SiO2; DIP) = 0.33 ~S ~DCI) : 384 (~+1) d) l-[4~ Cyano-l-cyclohexyl)benzyl~-2-n-butyl-4-chloro-5-hydroxymethylimidazole 1.0 g of l-[4-~1-cyano-1-cyclohexyl)benzyl]-2-n~butyl-4-chloro-5-formylLmidazole and 400 mg of NaBH~ arP dis~olved in 25 ml of ethanol and the solution is ~tiTred at R~ for 18 h. 5~ aq. NaHSO4 soluti2n is then slowly added to pH =
2, the ethanol is removed in vac~o and the resldue is extracted 3 tLmes with 5~ ml of EA. Th~ extracts are dried over Na2SO4 and the solvent is removed in vacuo. 1.0 g of a colorless oil is obtai~ed.
.
, , ~ ~
- ' .:
- : .
~S~4 R~SiO2; NT~) - 0.54 ~S (DCI s 386 ~
e) 1-(4~ (2-Trim~thyl~tanny;L-5-~e~razolyl)-1-cyclohexyl]benzyl-2-n-butyl-4 chloro-5-hydroxymethyl imidazole 1.1 g of 1-[4~ yano-1-cycloh~yl)ben~yl]-2-n-butyl-4chloro-5~hydxo~methylimidazol~ ~nd 1.1 ~ of trimethyl-tin azide are h~ated ~o re~lux in 25 ml o~ tolueno ~or 48 h. The solvent $ 8 removed in ~cuo ~nd th3 re~idue i~
employed again with~ut pur~icatio~.
f) 1-(4-[1-(1-Triph~nylm0thyl-5-tekr~olyl)-1-cyclo-hexyl~benzyl-~-n-butyl-4-chloro~S-hydroxy~ethyl-Lmidazole ~he unpurified title compound of Example Se) is dis~olved in 7 ml o~ CH2C12 and 1.5 ml o~ ~HF, ~reated wi~h 0.35 ~1 of 10 N NaOH and ~irred a~ RT ~or 5 min. The ~ixture is then treated with 9~0 ~g of trityl ~hloride and ~tirred at RT for 3 days. It is diluted with 100 ml of ~A, w~h~d twice with 10 ml of 0.1 N NaO~ e~ch time and tw~ce with 10 ml o satd. ~g. NaCl ea~h ti~e ~nd dried sver Ma2SO~, and the solvent i~ removed in vacuo. Chromato~raphy on ~ilica gel usin~ NTB/DIP 1:1 yield~ ~00 mg of tho t~tle compound a~ white fOamJ
Rf (SiO2~o DIP/NTB 1~ 0,32 ~S (F~) ~ 677 (~+Li) g) 1-(4-~1 (5-Tetrazolyl)-l-cyclohe~yl~benzyl)~2 n-~utyl-4-chloro-5 hydroxymethylimidazole 400 mg of 1-(4~ (1 Triph~nylmPthyl-5-tetrazolyl~-l-cyclohexyl~benzyl) 2-n-butyl 4-~hloro-5-hydro~y~*thyl-imidazole and 300 ~1 of 4 N ag. HCl are dissolved i~ 4 ml of methanol and the mixtur~ tirred ~t RT ~or 2 h~ It is then diluted with 10 ml Of ~2~ the methanol i~ r~mo~d in ~acuo and the xe~idu~ i~ ad~usted to pH ~ 13 with 2 N
NaOH. It i~ wa hed 3 times with 5 ml of So~u~ne each , .; ~ -' , , ~
., ,. .
:
i3~i time, then adjusted to pH - 4 with 10~ R~2PO~ ~olu~ion ~nd extracted 3 ~imeR with 50 ml o ~ each t.i~. The ex-tract~ are ~ried over NazSO4 and the ~olvent is r~movad in vacuo. The residue is then dige~ted ~ikh 20 ml of ~A ~n an ultrasoni~ ~ath~ erad off ~ld wa~hed ~wic~ with 2 ml of EA e~ch tim~. ~be residue i~ dried i~ ~ ~lne vacuum and 170 mg of the titlo compou~d ~re obt~ined a colorlea~ cry~tal~.
Melting point: 179C/dec.
R~ (SiO2; EA/M~OH 10~ 3.44 ~S (FAB) ~ 4~9 (~
Example 6 1-~4-(4-Carboxy-5-oxazolyl)benzyl]-2-n-butyl-4-chloro-5-formylLmidazole a) Methyl 4-bromQmethyl~enzoate 50 g of methyl p-tolylc~rboxylate, 60 g of N~S ~nd 200 mg of benzoyl peroxide are suspended in 300 ml of chloro-benzene and the mixture is cautiou~ly h~ted to r~lux.
The reaction ~tart~ vigorou~ly. The-~ixture i~ directly allowed to eool ~gain, the chlorobenzene is removed in vacuo and the re~idue is di~tilled. 6B g o~ the title compound are obtained as colorless cry~t 1 B.p.5 = 145C
R~ (SiO2; E~/heptane 1s4) ~ 0.50 ~S (DCI) ~ 299 (~+1) b~ 4-Bromomethylbenzoic ~id 5.0 g of methyl 4 br~momethylbenzo~t~ ~re su~pandad in 15 ml of 48% ~q. 8Br ~nd he~ted to reflu~ for 30 min, ~he mixture i~ ad~u~ted to pH ~ 8 with NaHCO3 and wa~hed twice with DIP. ~he agueous pha~e i~ then ad~u~ted to pH ~ 2 with NaHSO~ and extra~ted 3 time~ with 150 ml of ~4 The extra~s are driecl o~er ~a~SO~ and ~he ~olvent i~ r~movQd in vacuo. 3.8 g of the title compound ars obt~ine~ as 2~ 3~
colorless hygroscopic crystal~.
Meltin~ point- 45C
R~ (5iO2; EA) a 0.43 MS (DCI) : 215 (M~1) c) 4-Bromomethylb0nzoyl chloride 3.8 g o~ 4-bromomethylbenzoic acid are su~pended in 10 ~1 of SOCl2 and ~he mixture i~ hea~ted to reflux for 1 h.
Excess SOC12 i~ removed in vacuo, and the re3idue i~ dried in a fine vacuum and employed again in crude form.
d) 5-(4-Bromomethyl)benzyl-4-methoxycarbonyloxa201e The ~rude product from Example 5c) i~ di~solvad in 50 ml of anhyd~ous THF togsther with 5.4 ml of Et3N~ 1.8 ml of methyl .isocyanoacetate are adde~ dropwi~e at 5C and the mixture i~ stirred at R.T. for 3 days. It i~ then dill~ted with 300 ml of EA, washed 3 times with 100 ml of 0.7 M
KH2PO4 each time, 3 times with 100 ml of satd. aq. NaHC03 and once with 100 ml of NaCl ~olution and dried over Na2S04, and the solvent is removed in v~cuo. Chroma-tograph~ on silica ~el u~iny MTB yields 2.~ ~ of yellow crystals.
Meltin~ point: 79C
Rf (SiO2; ~TB) = 0.36 e) 1-~4-~4-~etho~ycarbonyl-5-ox~zolyl~banzyl]-2-n-butyl-4-chloro-5-fonnylimidazolQ
2~6 mg of 5-(4-bromomethyl)benzyl-4 metho~ycarbonyl-oxazole~ 187 mg of 2-n-butyl-4-chloro-5-fo~m~limidazole and 139 mg of R2CO3 are ~tirred i~ 10 ml o~ D~ at RT for 21 h. Th~ mixture i~ then dilu~ed with 150 ml of EA, wa~hed twice w.;th 50 ml of satd. aq. Na~CO3 ~olution eaoh time and once with 50 ml of aq. NaCl ~olution and dried over Na2SO4, ~nd th~ solvent is remo~ed in vacuo. Chroma-tography on ~ilica gel using MT~DIP 1:1 yields 250 mg of .
, ,, ~
a colorle~s oil. ~ 5~3~
R~ (SiO2; NTB/DIP 1:1) ~ 0.35 ~S (DCI) s 402 (~
f) 1-[4-(4-Carboxy-5-oxazolyl)benzyl]-2-n-hutyl 4-chloro-S-formylLmidazale 240 mg of 1-[4-(4 methoxycarbonyl-5-oxazolyl)benzyl]~2-n-butyl-4-chloro-5-~oxmylimidazole are dis~ol~ed in 15 ml of methanol, treated with 2.5 ml of 1 ~ a~. NaOH and stirred at RT for 20 h. The methanol i~ removed in ~cuo, and the residue iB diluted with 20 ml of H2O and wa~hed twice with 10 ml of DIP each time. It i8 then ad~u~ted to pH = 2, extract2d 3 times with 50 ml of EA each kime, the extracts are dried over Na2SO4 and khe solvent i~ removed in vacuo. Chromakography on silica gel using ~A/glacial acetic acid 10:1 yields 90 mg of a light yellow ~oam.
R~ (SiO2; EA/glacial acetic acid 10:1) = 0.16 MS (DCI): 38~(M~l) ::
, ': ' ' ~ .
, .
- 3 ~ 36 2 8 . - ( CH2 ) o-NR7-C-oR9, 2 9 . - ( CH2 ) o -NR7-CC)-N}IR0 r 3 O ~ ~ ( CH2 ) o~NR -SO2R
31 . - ( CH2 ) o-NR7-C-R~
32 . ~ (CH23n 3 3 . - ( CH2 ) "--N2 3 4 . -CH2-N3 o 35 . ~ (cH2)n-N()2 36 . -CH=N-NRsR7 3 7 . phthali~lido- ( CH2 ~ "~
N\
3 t3 - ( CH2 ) n~~ NH
39. - (CH2)n~~ ~CF
H
1$ 40 (~H2)n~N/~
41 . ( C~2 ~ ~ ~ - 1- Co- N~
~C~3 42. phenyl-SO2-NH-N=CH-, ~N
4 3 . - CH~N~ /<
N
H
4 4 . - ( CHz ) D-So2-NR7-Co-NR8R~, 45. -(C~)O SO2~9, 46. a radical defined a~ under c) 9. or 10,, which is ~ubstituted on ~he phenyl by :
":, . .
.
~ , . . .
~ 4 - 2~ S~
1 or 2 identical or dif~Qrent radicals ~rom the series compri~ing halogen, hydroxyl, methoxy, trifluoromethyl, Co2R3 and phenyl, 47. a radical de~ined ,as under c) 11., 12. or 20., in which 1 ~o all of ~he ~ydrogen atoms are ~ub~tituted by ~luorine, or 48. the radic~l d~fined under c) 15., which i8 sub~tituted by 1 or 2 id~ntical or differ~
ent radicals from the ~erie~ ~omprising methoxycarbonyl ancl tC1~C4)-al~yl;
d) R3 is 1. hydrogen, 2. (Cl-C~)-alkyl, 3. (C3-C~)-cycloalkyl, . 4. phenyl, 5. benzyl or 6. the radical de~ined under d) 2., in which 1 to all o~ the hydrogen atom~ are ~ubskitu ted by fluorine;
e) R4 is 1. hydrogen, 2. (Cl-C6)-alkyl, 3. ( C3-C~ ) -CyC loalkyl, 4. (C2-C4)-alkenyl or 5. ( C2-C4 ) ~ CyTlyl;
f) Rs is 1. hydrogen, 2:5 2. (C1-C6~-alkyl, 3. (C3-Ca)-cycloalkyl, 4. phenyl or 5. benzyl;
: . g) R6 i~ 1. hydrogen, : ~ 30 2. (C1~C6)-alkyl, 3 ( C3-C0 )~ycloalkyl, 4. ~C6-Cl2)-aryl, p~efera~ly phenyl, 5. benzyl, :
- 5 - ~55~3~
6. (C1-C~)-heteroaryl which can al~o be partially or completely hydrogenated, preferably 2-pyrimidinyl, 7. (Cl-C~)-alkanoyl, 8. (C1-C~)-hateroaryl-(C1-C3)-alkyl, where the heteroaryl moiety can al80 be partially or comple~ely hydrogema~ed, or 9. a radical defi~ed a~ under g) 4., 6. or 8., substituted by 1 or 2 identical or diffar-ent radicals ~rom ~he ~eries comprising halogen, hydro~yl, methoxy, nitro, cyano, Co2R3, -NR11R12 and trifluoromethyl;
h) R7 is 1. hydrogen/
2. (Cl-C6)-alkyl, 3. (C3-C8)-cycloalkyl, 4- (co-cl2)-aryl-(cl-c~)-alkyl~ prefsrably benzyl, S. phenyl ox 6. (C1~Cg)-heteroaryl;
i) R8 is 1. hydrogen, 2. (Cl-C6)~alkyl, 3. (C3-Ca~-cycloalkyl, 4, phenyl-(CH2)q~~
5. oR5, 6. NRl1R12 or r 7.
:
;) R9 is 1. (C1-Ca) alkyl, 2. 1-adaman~yl, 3. l-naphthyl, 4. l-naphthylethyl, 5. phenyl-(CH2)~- or 6. the radical defined under ;) 1., in which 1 t,o all of the hydrogen atoms are sub~titu-ted by ~Iuorine;
:
:
, ~ '55~;3 ~ 6 -or R5 and R8 together wi~h the nitrogen akom carxying them are ~ R12;
k) R~ cyano, ni~ro or CoaR7;
l~ Rl1 and R12 are identi~l or differenk and are 1. hydrogen, 2. (C1-C4)-alkyl, ~. phenyl, 4. benzyl or 5. ~-methylbenzyl;
lO m) D is NR13, O or CH2;
n) Rl3 is hydrogen, ( Cl-C4 )-alkyl or phenyl;
o) A i~ ~) a (C6-C14)-aryl r~dical or ~) (cl-c9)-heteroaryll which can either be aromatic, partially hy~rogenated or comple~ely hydrog~natPd, or ~) the radical of a fused hete~ocycl2 having 8 to lO ring atoms, of which up to 9 are carbon atoms, it being po~sible to substituke A in each c~e by up 2G to 3 identical or different radical0 from the ~eries compri~ing : 1. halogen, ~ . oxo, 3. nitro~o, 4. nitro, 5. cyano, 6. hydroxyl, 7. I~Cl-C~ lkyl, : 8. C1-C4)-alkanoyl, 9 ( Cl-C4 ) -alkan . ~ . . .
- ... . . ~: ~
: : , - . ~ : . ; - . : .:
~ ' . ~ : ~ '', . :
- 7 ~ 3~i 10. Co2R3, 11 . methanesul f onylamino, 12. trifluoxome~hanesulfoTIylamino, 13 . -Co-NH-oR9, 14. -So2-NR6R7, 1 5 . -CH2-OR7, 16 . ( C6-C12 ) -aryl, 17 . t C3~C8 ) -cycloalkyl, 18. (Cl C4)v-alkoxy~
19. (cl-c9)~heteroa~
2 0 . Co2R3, 21. NR6R7, 22. aulfo, 2 3 ~ -So3R3 r 2 4 . -So2-NR7-Co-NR~R9, 2 5 . -NR7-Co-NR6-So2-CH2-R5, 26. -C~CF3)aOH, O
2 7 . pho~phonooxy, ~O-P-OH
2 8 . -PO3H2 r bH
29. -NX-PO(oH) 30. ~S(O)rR6, 31. -Co-R3 and 3 2 . -Co-NR6R3;
p ~ ~ 1. a single bond 2. -CO-, 3. -CH2-, 4 . -O-, 5 . -$-, 6 . -MR21-, 3 0 7 . ~ O-NR21-, ~ . -NR2~-co_, 9. -O-CH2-, :
1 0 . -CH2-C)-, S-CH2- ~
12. -CH2-S-, 13. -~I-CR20R22_, 14. -NR2l-SO2-, 15 . ~ SO2-NR21-, ,, . ;
.. ~ , :
~S~i~36 17 . -CH=CH-, 18. CF-CF-, l9 . -CH=CF-, 2 0 . -CF=CH-, 21. -CH2-C~z~ ~
2 2 . -CF2-CF2-, 23 . -C}I(OR33~, 24 . -C~(oCoR5) -, 25. ~C-~R23 ~
2 6 . -C- or R240 ' 'olR25 27. ~
q ) E is a xadical 1. ~ with ~he proviso that in the ca~e < 1l where x=~r=cH ~ Rl4 i~ not COOH, . 2. ~ B
< I
y~X
S ( CH~5< R4 (CH2 )m R~
, , . . - , , , ' ~. ~ i ;~; , , ~ C~S~ t~
r) B is 0, NR7 or S;
6) L is (C1-C3)-alkanediyl;
t) R14 i~ -Co2R3, -CH2Co2R3, -PO3H2, -SO3H or tetrazolyl, u) m is an integer from O tv 5;
v) n is ~n integer from 1 to 5;
w) o is an integer from l to 10;
x) r i5 0 r l or ~, and y) v is an integer from 1 to 6;
and their physiologically tolerable 8alt~.
Alkyl, alkenyl and alkynyl can be s~raigh~-chain or branched. The same applie6 to radicals derived therefrom, such as alkanoyl or alkoxy.
Cycloalkyl is also understosd as meaning alkyl-8ubstitu-ted rings.
(C6-Cl23-aryl is, for example, phenyl, naphthyl or bi-phenylyl, pre~erably phenyl. The same ~pplies to r~dical~
: derived therefrom, such ~ aroyl or aralkyl.
(Cl-Cg)-heteroaryl i8 in particular under~tood a~ meaning radical~ which ~re derived from phe~l or naphthyl, in which one or more CH groups are replaced ~y nitro~en and/or in which at lesst two ad~acent CH groups re replaoed (with the formation o~ a ~ive-me~bered aro~atic ring) by S, NH or 0. In addition, one or two atom~ of the condensation ~ite of bicyclic radicals ( ~u~h a6 in ~5 indolizinyl) can also be a nitrogen atom.
These are, for example, furanyl, thienyl, pyrrolyl, - , lo ~ 5~.s3~;
imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyxidyl, pyraxinyl, pyrimidinyl, pyridazinyl, indolyl, inda~olyl, quinolyl/
i~oquinolyl, phthalazinyl, guinoxalinyl, quinazolinyl and cinnolinyl.
The fused heterobicyclic ~ys~em iB understood as meaning, in particular, a bicyclic ring sy~tem having 8 to 10 rin~
atoms, of which up to 9 are carbon atoms, in which two adjacent atoms are common componenkR of both ring~ . One or both of these rings ls/are formally derived from benzene in which one or more CH groups are repl~ced by N, O+ and S~ and/or in which two ad;acent CH group are replaced by S, NH or O (with the formation of a five-membered aromatic ring).
These are, for e~ample, a radical of benzothiophene, benzo~uran, indole, isoindole, indazole, benzimidaxole, quinoline, isoquinoline, phthalazine, quinoxaline, quinazoline, cinnolinel benzothiazole, ben~othiazole-l,1-dioxide, coumarin, chroman, benzoxazole, benziso-thiazole, benzodiazines, benzotriazol~, benzotriazine,benzoxazine, imidazopyridine, imidazopyrimidine, imidazopyrazine, imidazopyridazine, imidazothiazole, pyrazolopyridine, thienopyridine and pyrrolopyrLmidine.
Said heterobicyclic ~ystem can also be partially or completely hydrogenated. However, one ring preferably remains aromatic, a benzo-fu~ed heterobicyclic aystem being particularly preferred.
In the ca~e of S-containin~ and/or partially saturated radicals, the bicyclic ~ystem ~an also, for e~ample, be oxo-substituted, a~ is the ca~ with the radical of the benzo-1,2,3-triazinone.
Physiologically tolerable ~alt~ of compounds of the formula I ~re understood a6 meaning both their organic and their ino:rgani~ salts, such a~ are described in Remington's Pharmaceutical Sciences, (17th editiont page , ~
:
'5~
1418 (1985). Owing to phy~ical and chemical ~tability and solubility, ~odium, potassi~m~ calcium and nmmonium salts, inter ~lia, are pre~erred for acid group ; ~alt~
with hydrochloric acid, sulfuric ~cid, pho6phoric acid or S with carboxylic acid~ or sulfoni.c acid~, such as 2cetic acid, citric acid, benzoic acidg maleic acid, fu~aric acid, tartaric acid and p-toluenesulfoni~ acid~ inter alial for basic groups.
Preferred compounds of the ~ormula I are tho~e in which a) X i~ N, Y is CR2 and Z i8 CR2~
b) X is CR2, Y i8 N and Z i CR2;
c) X is CR2, Y is CR2 and Z 1~ N
or d) X, Y and Z are in each case N.
Compounds of the formula I are additionally preferred in which a) Rl is 1. (~3-Clo)-alkyl, 2. ( C3 Clo ) -alkenyl, 3. ( C3 Clo )-al~ynyl, 4. (C3-C8)-cycloalkyl, 5. benzyl or 6. benzyl which i~ ~ubstituted as defined above, or 7. -(CH2)~-B-(CH3)n-R4;
~5 b) R2 is 1. hydrosen, 2. halogen, 3. nitro, 4. CvF2~l, 5~ SFs~
6. pen~afluorophenyl, 7. cyano, 8. (Cl-C4~-alkoxy, benzyloxy, 9. phenyl, 10. phenyl-(C1 C3 )-alkyl, 11. (C1-C,0)-alkyl, .
.~ .': ~ `. , -- 12 - 2C,~55~j3~D
12 . ( C3-Clo ) -alkenyl, 13 . phenyl- ( C2 C~ ) -alkenyl, 14 . l-imidazolyl- ( CH2 ) m-15 . 1, 2, 3~triazolylD ( CH2 ) O-16 . tetrazolyl ~ ~ CH2 ) m~
17 . --( CH2 ) o 1 -CHR7-oR5 18 . -(CH2)o-o-CoR3, 1g. -COR8, 20. -(CH2~ CO-Ra, 21. -S(O)rR6t .2 2 . -CH=CH- ( CH2 ) ,"-CHR3- OR6, X 3 . ~ CH2=CH- ( CH2 ) " Co-~8, 2 4 . - ( CH;I ) o~NH~CO~ORD, 2 5 . - ( CH2 ) O ~H-SO2-R, 26. -(CH2)n~, 2 7 . - ( C~z ) o-SO3R ~
2 8 . - ( CH2 ) n~ SO2-NH- CO-NR6R~ t or 29. a radical defined a~ under b) 9., 10., 11., 12. or 15., which is ~ub~ti~u~ed as defined above under c) 45., 47, or 4~. ln each case a~ described for ~uch a radical;
c ) R8 is hydrogen, ( Cl-C5 ) -alkyl, O~s, ~RllRl2 or morphollno;
d) T is 1. a ~ingle bond, 2 5 2 . -CO-, 3 . -CONR21-, 4. CH2-CH2-, 5 . -NR71-Co-6. t)-C:H2 3 0 7 . -CH2-O-8 . -S~C~a-9. -CH2-S-, 10. ~ CH2-, 1 1 . -C~2~
12 . -CH=C~I- t or .
.
- 13 ` ~ i5~
o 13 . _l _ O
and the other radica.ls and variable~ are a~
def ined abs:)v0 .
Particularly preferred compounc1s of the formula I a:re those in which a) R1 iS ~C3-C,)-alk~ (C3 C,)-alkenyl or (C3--C,) -alkynyl;
b ) R~ is l . hydrogen l 0 2 . chlorine, 3. bromine, 4. CVF2V~l where v = 1, 2 or 3, 5 . pentaf luorophenyl, 6 . ( Cl-C4 ) -al3coxy, berlzylc~
7, --S(O)r~
8. SF5, 9 . ( CH2 ) o l-CHR'-t)R5 ~
(CH2)o-O~CO R3, 11. C ORa, 2 0 l 2 . - ( C~I2 ) o-CO-Ra ~
l 3 . -CH2~ CO-R3, 14. -(CH2~ SO2-R , 15 . -CH--CII-CHR3-OR5 l 6 . tetrazolyl- ( CE~2 ) m'- ~
2 5 l 7 . - ~ CH~ ) I,SOa-NH-CO-NR8R~, 18 . - ( CEI2 ) o-SO3R or 19 . ( Cl-Cs) -alkyl which 16 optionally sub-stituted by hydroxyl, pref~rably hydroxy-m~3thyl;
30 c) R3 is hydrogen or ~Cl Cb)-alkyl;
d) R6 is hydrogen, (Cl-C4)-alkyl, (Cl-C:4~allcanoyl! phenyl which can op~ionally ba sub~tituted by l or 2 . .
iden~ical or di~ferent radicals from the s~rie~
- 14 ~ 5~
compri~ing halogen, hydxoxyl, metho~y, nitro, cyano, Co2R3 and trifluoromethy1, or tC1-C~)-heteroaryl which can al80 be partially or completely hydrogenated, preferably 2-pyrimidyl;
e) R7 is hydrogen, (Cl-C")-alkyl., (Cl-C~)-hetç!roaryl, or ( C6-Cl2 ) -aryl - ( Cl-C4 ) -allcyl;
f ) RB i8 hydrogen, ( Cl-c4 ) -allcyl ~ oR5 or ms:~rpholino;
g) R~ is CF3, (Cl-C6)-alkyl or phenyl;
h) A is ct) a (C6-C10~-aryl radical or ) ( Cl-C4 ) -heteroaryl which can aither ba aromatic, paxtially hydrogenated or com-plately hydrogenated, or ~ the radical of a fused heterobicyclic ~ystem having 8 to 10 ring a~oms, o~ which up to 9 are carbon atoms;
where A in each case can be 6ubs~ituted by up to 3 identical or different radical~ from the series comprising halogen, nitro, cyano, hydroxyl, -NR~R7, phenyl, -S(O) rR6 and -Co2R3;
1) T is a single bond, -O-, CO-, N~CO-, OCH2- or -S-11 ~.
and the other radioals and v~riable~ are as defined above.
Very particula:rly preferred compounds of the ~onmula I
are those ln which ~.
a) ~1 is (C3-~5)-b) R~ is hydrogen, chlorine, methoxy, -S(O)rR~ or $3 henzyloxy, c ) R3 i~ hydrogen or ( C~ 4 ) -alkyl, d) R4 and R5 axe idenkical or diff~erent and are hydrogen or ( Cl~ 4 ) -alkyl, e~ R5 is hydrogan, (cl-c4)-alkyll phenyl or 4-tolyl, f) R14 is-COOH, ~PO3Hz~ -S~3~ or S-tetrazolyl, g) A is phenyl or the radical o~ a fu~ed heterocyclic system having 8 to lO ring atom~, o~ which up to 9 are c~rbon atoms~ it being po~ible, however~ ~or A to be sub~tituted by up to 2 identical or di~ferenk radic~ rom the ~eries comprising halogen, nitro, cyano, phenyl, -S(O)rR~ and -CO2~ , h) B i8 0, NH or S, i) L is CH2-, ; ) r is 0, 1 or 2, k) q is 0, a ~ingle bond, m ) m is a, 1, 2 or 3 and n) n i8 1, 2 or 3 and X, Y and Z are as defined above.
Th~ invention al80 x~late~ to a process for the prepara-tion of compolmd~ of the formula I, which compri~es aIkylating ~Qmpound~ of the or~ula II
Y ~II) -~
X
H
.
. .
16 - 2~5~3~
in which R1, X, Y and Z ~ra a~ defined above, with com-pounds of the formula III
U-L-A~'r-E (II~) in which L, A, T and E are a~ de~fined above, and U i~ a leaving group, i~ appropriatel removing temporarily introduced protec~ive groups and converting the co~pound~
of the formula I ob~ained, i~ ,appropriate, into their physiologically tolerable alts.
Suitable leaving ~roups U ~re preferably a nucleofugic group (cf. Angew. Chem. 72 [1960] 713 such a~ halogen, o-toluenesulfonate, mesyl~te or triflate.
Processes for the preparation of the precur~ors of the formula (II) are known, inter alia, from ~S Patent No.
4,355,044, EP-A-324,377 snd EP-A-323,841.
lS Other processes are described in G. L'abbe Chem. Rev. 69, 345 (1969); T. Srodsky in ~The Chemis~ry of ~he Azido ~roup", Wiley, Nsw York, 1971, p. 331; H. W~mhof~ in "Comprehensive Heterocyclic Chemi~try", S. ~atxi~zky Ed., Pergamon Press, New York (1984).
To alkyla~s the azole~ o~ the ~ormula II, suitable alkylating agents are, for ex~mple, appropri~te benzyl halides, tosylate~, me~ylate~ or trifla~e~ or appropriate alkyl halides, to8ylat08~ mesylates or trlflate~
~ he synthesis of derivatives such a~ benzofuran~, benzo-thioph0ne and indole~ havlng a ben3yllc -CH3 group wa~
described, inter aIia, by R.P. Dick~on,o et al. in J. ~ed.
Chem. 29, 1637 (1986)~ and ibid. 29, 16~3 (1986). The preparation o~ benzimidazoles, benzothiazole~, b~nzo-diazines, benzopyrone~, benzothlazolones, benzotria~ines, b~nzoxazines and benzo~azoles i~ ou~lined in ~he edi~ion "Comprehensive Heterocyclic Chemistry~, S. Ratrit2ky Ed.
Pergamon Pres~ New York (1984) cited above.
:: : .
~ .
- -:
- 17 ~ 5~3~
The alkylation is carried out in an analogous manner to proce~ses which are known in principle.
The azole deri~ati~e of the formula II i~ metalated, for ex~mple, in ~he pre~ence of a ba~e. Preferred base~ ~re metal hydrides of the formula ~1 ~uch as, for example, lithium hydride, 80dlum hydride or pota~ium hydride in, for example, D~F or DM~O 88 a solvent or metal alkoxides of the formula MOR, where R i8 methyl, ethyl or ~butyl~
and ~he reaction i5 carried out in the corre~ponding alcohol, DMF or DNSO. The 8al~8 of the azoles thus formed are dissolved in an apro~ic ~olvent such as D~F or DMSO
and treated with a suitable amount of alkylating reagent.
An alternative pofi~ibility for the deprotonation of the a201e derivatives is, for example, r~action with potas-15 6ium carbonate in DM~I or DMSO.
The reaction~ are carried out at temperature~ below roomtemperature up to the boiling poin~ of the reaction mixture, preferably between ~20C and the boiling point of the reaction mix~urel for about 1 to 10 hour~.
Fragments of the fonmula II
A - T ~ (II) are synthe6ized via the addition of metalated ~sonitriles ~Angew. Chem. 86, 878 (1974), 89, 351 (1977) to acid chlorides of the formula III
A - ~ - CO-C:l (~II) in inert solvents at -78C up to the boiling point cf the solvent, preferably in diethyl ether or THF at 78C to OC.
18 - ~ ~ SS~ ~6 The synthe~i~ of ~ragment~ of the fo.rmulaa IV and V
R14 ~H2~ R4 A - T ~ m "' X R5 IV) R14 ~V) A - T ~ R
is carrisd out by means of tha ~l~ylation, which i~ known in principle, of arylacetic acid derivative~ or aryl-acetonitrile~ in an nnalogous m~nner, elkher in ethers such as diethyl ether, ~HF or dimethoxyethane with LDA at -78C or with ROtBu at room tempera~ure in t butanol.
The compounds of the formula I according to the invantion have antagonistic action on an~iot2nsin II receptor~ and can therefoxe ~e u~ed for the treatment of angiotensin II-dependent hypertension. Po~sibilities of application furthermore exist in cardiac in~ufficiency, cardioprotec-tion, myocardial infarct, cardiac hypertrophy, arterio-sclerosis, nephropathy, kid~ey failure ~nd v~culardiseases of the brain such as transitory ischemic attack~
and stroke.
Renin is a proteolytic enzyme o~ the aspartylprotease cla~s, which is ~ecr~t~d into the bl~d circulation ~y the juxtaglomerular cell~ of the kid~ey as a consequence of various stimuli tvolume depletion, 30dium deficiency, ~-receptor:~timulation). In ths blood, it clea~es the ; ~ decapeptide angiotenBin I from th~ an~ioten~inogen excreted from the liver. ~he former is conver~ed into angio~ensin II by the "an~iotensin convertin~ ~nzyme~
(ACE). Angiotensin~ plays an essential role in ~lood pressure regula~ion,~a~ it directly increases ~he ~lood : pre sure by ~ans~ of vascular contraction. It addi-~ioDally ~timulates the secretion of aldos~erone from ~he adrenal gland and in this w~y increa~es the extracellular : ~ : :
fluid volume via the inhibitlon of sodium excr~atio~, which for it_ part contribute~ to an increa~e in blood pressure.
Post-receptor actionq are inter alia 6timulation of pho~phoinositol conversion (CaZ+ release), activa~ion of protein kinase C) and facilitation of ~A~æ-dependenk hormone receptors.
The affinity of the compounds of the ~ormula I ~or the angiotensin II r~ceptor can be deater~ined by measurement of 125I-angiotensin II or 3H-angiotensin II displacement from receptor6 on Zona glomerulosa membranes o~ bovine adrenal glands. For this purpose, the prepared me~rane~
are su6pended in buffer at pH 7.4. Aprotinln, a p~ptidase inhibitor, i8 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 T~q/mmol (available from Amersham Buchler~ and a guantity of receptor protein which binds 50% of the tracer are additionally used. The reaction i8 begun by addition of 50 ~1 of membrane su6pension to a mixture of 100 ~1 of buffer + aprotinin, 50 ~1 of buffer with or without angiotensin II or r~ceptor antagonist and 50 ~1 of tracer. After an incubatio~ time of 60 minutes at a temperature of 25C, bound and free radioligand are ~eparated on a Skatron0 cell collector using ~hatmann GFIC filtars by means o~ a filtration as~ay.
Non-specific bindin~ is prevented by treatment of the filter with 0.3% polyethyleneimine pH=10 (Sigma, NoO
3143). The amount of displacement of the radioligand from 3~ the receptor i5 determined by measurement of the radio-activity in a gamma scintillation counter. ~he IC50 values, which denote the concentrativn of inhibitor for displacing 50% of the ligand, are de~ermin~d according to Chem. et al. .J. Theor. Biol. 59, 253 ~1970). For the compound~ of the formula (I) ~hey are in the range from 10-4-10~ M.
, 3~;
~ 20 -rro dete~nine the antagoni~tic ac~ion of the cumpound~ of the formula (I), their e~fect on the Angio^ten~in II-induced blood pre~ure ri~e in ane~the~ized Sprague-Dawley rats can be mea~ured. Na thiobarbital (Trapanal, Byk Gulden) i8 used a~ an ane~thetic in the dose 100 mg/kg i.p. I.~. administrakion i8 carried out in the jugular vein. The blood pre~sure i~ mea~ured in the carotid artery. The animals arle firat pretreated with pentolinium ~artrate (10 mg/kg i.m.) 80 that a lower blood pxessure level i8 achieved (ganglia blockada). ~N~
II (~yperten~in, CIBA) i~ a~mini3tered i.v. in the volume O.1 ml~100 g at 10 minute intervals. ~he do~e is 0.5 ~g/kg. The compounds of the formula (I) are di~solved in distilled water and administered intra~enously or intraduodenally in the doses 0.1; 1; 10 and 100 mg/kg.
The compounds o~ ths formula ~I) are ef~e~tive 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 acti~e compounds, ~uch as, ~or example, diuretics or non-~teroi-dal anti-inflammatory active compound~. The compounds of the formula I can al80 be u~ed as diagnostics for the renin-angioten~in Gystem.
Pharma~eutical preparation~ cont~in an effective amount o the active compound of the formula T and if nscessary other active compounds together with an inorganic or organic pharmaceutically utilizable e~cipient. A*minis-tration can be carried out intranasally, intravenously, subcutaneou~ly or orally. The do~age of the active compound depends on the mammalian 6pecies, the body weight, the age and the manner of administration.
The pharmaceut.ical preparations of the present invention are prepared in a dissolving, mixing, ~ranulating or coatin~ process known per ~e.
.
. .
For a form for oral at~minigtra~ion~ the active compounds are mixed with the addi~ives cu~tomary ~.herefor such a6 excipien~s, s~abilizers or iner~ diluen~i and brought by means of customary method~ into ~uitable admini~tration forms, such as tablets, coa~ed tableks, hard gelatin capsules, aqueous, alcoholic or oily ~uspension~ ox aqueousl alcoholic or oily solutions. ~nert excipients which can be used are, for examplle, gum ~rabic, magnesia, magnesium carbonate, pota~si~n phosphate, lactose, gluco~e, magnesium stearyl fumarate or ~tarch, in parti-cular maize ~tarch. The preparation in thiEt cas~ can be both a~ dry and moist granule~. 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 phy6iologically tolerable salts are brought into solutions, suspensions or emul~ions, if appropria~e with the substances customary therefor such as ~olubilizer~, emulsifiers or other auxiliaries.
Suitable solvents are, for example, water, physiological saline solu~ions or alcoholt~, for exa~ple ethanol, propanediol or glycerol, in addition al~o ~ugar solutions such as glucose or mannitol solutions or alternatively a mixture of the different ~aid solvents.
List of abbreviations:
DMF N,N-dimethylformamide NBS N-bromosuccinimide AIBN ~ azobi~isobutyronitrile EI electron impact DCI desorption-chemical ionization RT room temperakure EA ethyl atetate (EtOAc) DIP diisoprt?pyl ether THF tetrahydrofuran M.p. melting point ~TB methyl t-butyl ether :: .
~ ~2 ~
B.p.~ boiling point at xx torr Et3N triethylamine MS ma~s spectrum FAB fast atom bombardment LDA lithium diisopropylamide ~he following examples illu~trate the inven~ion withou~
restrictin~ ~he invention theretoo Example 1 1-[4~ Carboxy-1-cyclopentyl)benzyl] 2-n-butyl-4-chloro-5-formylLmidazole a) Ethyl 1-(p-tolyl)~yclopentanecarboxylate g of 1-(p-~olyl)cyclopentanecarboxylic acid are su~pended in 200 ml of ethanol, and the 301ution iQ
slowly treated with 4.3 ml of SOCl~ and heated to reflux for 24 h. ~xces~ SOc12 i8 remoYed in vacuo, and the residue is taken up with 100 ml of EA, wa~hed twice with 50 ml of ~atd. aq. Na2SO3 solution and dried over ~a2SO
The solvent is then removed in vacuo and 11.3 g of th~
title compound are obtained a~ light br~wn cry~tal~
melting point: 47C.
b) Ethyl 1-(4-bromomethyl)phenylcyclopentanecarboxylate : 2.5 g of ethyl l-~p-tolyl)cyclopentanecarboxyl~te, 1094 g of NBS and 200 mg of benzoyl peroxide are heated to reflux in 50 ml of ~hlorobenzene ~or 3 h. The solvant i8 then removed in vacuo, and the re~idue i~ t~ken up in 300 ml of EA, wa~hed once with S% strength ~q. Na2SO3 solu~ion and twice wi~h 5atd. aq~ NaHCO3 ~olution ~nd dried over Naa~O4~ ~he sol~ent iz finally remo~ed in vacuo and 3.2 g of the title compound are obtained as an oil.
30: R~ (SiO2; EA/heptane 1:4) - 0.50 M5 (DCI) : 311 (N~1) -. : , ~
.. ..
, : ' : .
..
., ~ . , - ~3 ~ r~
c) 1-[4~ ethoxycarbonyl-1-cyclopentyl)b~nzylJ-~-n-butyl -4-chloro-5-formylimidazole 342 my of ethyl 1-(4-bromomethyl)phenylcyclopentane-carboxylate, 187 mg of 2-n-butyl-4-chloro~5-~ormyl-Lmidazole and 138 mg of R2C03 are stirred in 10 ml of DNF
at RT for 22 h. The mixture is dilu~ed with 100 ~1 of ~, washed once with 50 ml of }120 and once with 5% strength aq. NaCl solution and dried over Na2SO4, and the ~olvent is removed in vacuo. Chromatogr~lphy on ~ilica gel ~sing DIP yields 240 mg of the title compound a~ a colorle~s oil.
R~ (SiO2; DIP/MTB 1~ 0.68 MS (DCI) : 417 ~M~
d) 1-[4~ carboxy-1-cyclopentyl3benzyl~-2-n-butyl-4-chloro-5-formylimidazole 115 mg of 1-[4-(1-etho~ycarbonyl-1-cyclopentyl)benæyl]~
2-n-butyl-4-chloro-5-~ormylimidazole snd 415 ~1 of 1 N
NaOH are heated to reflux in 8 ml of EtOH for 29 h~ ~he e~hanol is removed in vacuo, and the residue i~ dilu~ed with 30 ml Of ~2 and washed with 10 ml vf DXP. It i~ then adju~ted to pH = 1-2 and extracted twice with SO ml of EA
each tLme. The extracts are dried oYer Na2SO4 and the solvent is removed in vacuo. Chromatoqraphy on ~ilica gel using MT~ yields 68 mg of the title compound as a light brown solid.
M.p: 134~C
R~ (SiO2; N~B3 = 0.30 MS ~DCI) : 389 (M+13 The title compounds o Examples 2 and 3 axe synthesised ~ia the methyl e~ter analogously to Example 1: :
Example 2 30: 1-[4-(1-Carboxy-l-cyclohexyl)benzyl]-2-n-butyl-4 chloro-S-formylimida~ole ':
, : ' ~'5S~i3~
Ex~nple 3 1-~4~ carboxy~l-cyclohexyl)benzyl~-2-n-butyl 4-me~hoxy-5-formylimidazole 670 m~ of 1 [4~ methoxycar~onyl-1-cyclohexyl)benzyl]-2-n-butyl~4-chloro 5-formylimidazole are reacted a~ de~-cribed under ~xample ld). 300 m~ of the title compound of Example 2 R~ (SiO2; ~TB/DIP 1:1) = 0.35 MS (DCI) : 403 (M + 1) malting point 147C
and 160 mg of the title compound of Example 3 R~ (SiO2; M~B/DIP 1~ 0.25 MS (DCI) s 399 (M ~ 1) melting point 167 DC
are obtained, and can be ~eparated by chromatogr~phy on silica gel using MTB/DIP lsl.
Example 4 1-~4~ caxboxy~ 4~4-dimethyl)cyclohe~l]benzyl)-2-n-butyl-4~chloro-5-formylimidazole a) l-p-Tolyl-4,4-dimethylcyclohexanecarbonitrile 27.S g of potas~ium t-butylate are taken up in 200 ml of t-butanol and the mixture i~ heatad to reflux. A solution of 32 g of 195-dibromo-3,3-dimethylpentane and 16.3 ml of 4-tolylacetonitrile in 100 ml o~ t-butanol is then added dropwi~e in the course of 1 h. The miscture i~ heated under reflux for 4 h, the solvent i~ removed in ~acuo and the residue is taken up ln 200 ml of ~atd. a~. ~aHC03 and 200 ml of ~B. It is extr~cted twice with 200 ml o~ NTB
each time and dried over Na25O4, and the solvent is removed in vacuo. Di~tillation in a fine vacuum yields 9 . 7 g of a colorless oil .
:
:
- 25 - 2 ~ ~ S6 B.P.02 - 135-140C MS (DCI) 5 228 (M~1) b) l-p-Tolyl-4,4 dimethylcyclohexanscarbo~ylic acid 4.0 g ~f 1-p-tolyl~4,4-dLmethy:Lcyclohexanec~rbonitrile and 3.0 g of ROH are heated under reflux in 50 ml of diethyl~ne glycol ~or 3 h. The mixture is allowed to cool, and .is poured into 100 ml of 0.1 ~ NaOH and washed twice with 30 ml of DIP each time. It i8 then adju~ted to pH = 1-2 wi~h HCl and ex~rac~ed 3 times wi~h 100 ml of diethyl ethçr each time. The extrac~s ~re dried over Na2SO4 and the solvent i8 removed in vacuo. 4.0 g of pale yellow cxystals are obtained.
Melting point: 128C MS (DCI) : 241 (~) c) Ethyl l-p-tolyl-4,4-dLmethylcyclohexanecarboxylate 4.0 g o~ l~p-tolyl-4,4-dLmethylcyclohexanecarboxylic acid are dissolved in 50 ml of ethanol and trea~ed with l.S ml of SOCl2. The mixture i~ stirred at 50C for 3 h, then at reflux for 3~5 h. The ~olvent is removed in vacuo, and the residue is taken up in ~00 ml of EA and washed 3 tLmes with 50 ml of ~atd. aq. Na2CO3 ~ach time. The extracts are dried o~er Na2SOq and the solvent 1~ removed in vacuo. 5.0 g of a slightly con~aminated bxown oil are obtained, which is employed again without purification.
~S ~DCI) : 275 (M+l~
d) Ethyl 1-(4-bromomethyl)phenyl-4,4-dimethylcyclohaxane-~5 carboxylate 5.0 g of ethyl 1-p-tolyl-4,4-dLmethylryclohexane-carboxyla~e, 2.g g of NBS and 50 mg o~ benzoyl p~roxi~e are heated to reflux in 50 ml of chlorobenzene ~or 1.5 h.
The ~olvent is then removed in vacuo, and the residue is taken up in 200 ml of EA, and washed once with 100 ml of satd. aq. Na2SO3 and once wlth NaCl solution. The ~olution is dried over Na2SO4 and the solvent i~ removed in vacuo.
.
- 26 - HOE 90/F' ~
Z ~ ~4~>~6 5.4 g of a brown oil ar~ obtained.
R, (SiO2; EA/hep~ane 1:8) = 0.39 MS (DCI) : 353 (M~l) Further reaction is carried out analogously to Examples lc and ld to give 1-(4~ carboxy-1 (4,4-dimethyl)cyclo-hexyl]benæyl)-2-n-butyl-4-chloro--5-formyl~idazole R, (SiO2; DIP) = 0.16 ~S (DCI) : 431 (~+1) Example 5 1-(4-~1-(5-tetrazolyl)cyclohex~l]benzyl) 2-n-butyl-4-chloro-5-hydroxymethylLmidazole z) 1-(4-Tolyl)cyclohexanecarbonitrile mhs co~ound was sy~lthesized analogously to Example 3a) 3 ? ~3 = 9S-100C u~ (D~ 200 (Y~l) b) 1-(4-Bromo~ethylphenyl)cyclohexanecarbonitrlle The compound was synthesized analogously to Example 3 d) Rf (SiO2; EE/Hep 1:4) = 0,~6 MS (DCI) : 278 ~M~l) c) 1-[4-(1-Cyano-l-cyclohexyl)benzyl]-2-n-butyl-4-chloro-5-formylimi~azole ~he compound was synthesized analogously to Example lc).
R~ (SiO2; DIP) = 0.33 ~S ~DCI) : 384 (~+1) d) l-[4~ Cyano-l-cyclohexyl)benzyl~-2-n-butyl-4-chloro-5-hydroxymethylimidazole 1.0 g of l-[4-~1-cyano-1-cyclohexyl)benzyl]-2-n~butyl-4-chloro-5-formylLmidazole and 400 mg of NaBH~ arP dis~olved in 25 ml of ethanol and the solution is ~tiTred at R~ for 18 h. 5~ aq. NaHSO4 soluti2n is then slowly added to pH =
2, the ethanol is removed in vac~o and the resldue is extracted 3 tLmes with 5~ ml of EA. Th~ extracts are dried over Na2SO4 and the solvent is removed in vacuo. 1.0 g of a colorless oil is obtai~ed.
.
, , ~ ~
- ' .:
- : .
~S~4 R~SiO2; NT~) - 0.54 ~S (DCI s 386 ~
e) 1-(4~ (2-Trim~thyl~tanny;L-5-~e~razolyl)-1-cyclohexyl]benzyl-2-n-butyl-4 chloro-5-hydroxymethyl imidazole 1.1 g of 1-[4~ yano-1-cycloh~yl)ben~yl]-2-n-butyl-4chloro-5~hydxo~methylimidazol~ ~nd 1.1 ~ of trimethyl-tin azide are h~ated ~o re~lux in 25 ml o~ tolueno ~or 48 h. The solvent $ 8 removed in ~cuo ~nd th3 re~idue i~
employed again with~ut pur~icatio~.
f) 1-(4-[1-(1-Triph~nylm0thyl-5-tekr~olyl)-1-cyclo-hexyl~benzyl-~-n-butyl-4-chloro~S-hydroxy~ethyl-Lmidazole ~he unpurified title compound of Example Se) is dis~olved in 7 ml o~ CH2C12 and 1.5 ml o~ ~HF, ~reated wi~h 0.35 ~1 of 10 N NaOH and ~irred a~ RT ~or 5 min. The ~ixture is then treated with 9~0 ~g of trityl ~hloride and ~tirred at RT for 3 days. It is diluted with 100 ml of ~A, w~h~d twice with 10 ml of 0.1 N NaO~ e~ch time and tw~ce with 10 ml o satd. ~g. NaCl ea~h ti~e ~nd dried sver Ma2SO~, and the solvent i~ removed in vacuo. Chromato~raphy on ~ilica gel usin~ NTB/DIP 1:1 yield~ ~00 mg of tho t~tle compound a~ white fOamJ
Rf (SiO2~o DIP/NTB 1~ 0,32 ~S (F~) ~ 677 (~+Li) g) 1-(4-~1 (5-Tetrazolyl)-l-cyclohe~yl~benzyl)~2 n-~utyl-4-chloro-5 hydroxymethylimidazole 400 mg of 1-(4~ (1 Triph~nylmPthyl-5-tetrazolyl~-l-cyclohexyl~benzyl) 2-n-butyl 4-~hloro-5-hydro~y~*thyl-imidazole and 300 ~1 of 4 N ag. HCl are dissolved i~ 4 ml of methanol and the mixtur~ tirred ~t RT ~or 2 h~ It is then diluted with 10 ml Of ~2~ the methanol i~ r~mo~d in ~acuo and the xe~idu~ i~ ad~usted to pH ~ 13 with 2 N
NaOH. It i~ wa hed 3 times with 5 ml of So~u~ne each , .; ~ -' , , ~
., ,. .
:
i3~i time, then adjusted to pH - 4 with 10~ R~2PO~ ~olu~ion ~nd extracted 3 ~imeR with 50 ml o ~ each t.i~. The ex-tract~ are ~ried over NazSO4 and the ~olvent is r~movad in vacuo. The residue is then dige~ted ~ikh 20 ml of ~A ~n an ultrasoni~ ~ath~ erad off ~ld wa~hed ~wic~ with 2 ml of EA e~ch tim~. ~be residue i~ dried i~ ~ ~lne vacuum and 170 mg of the titlo compou~d ~re obt~ined a colorlea~ cry~tal~.
Melting point: 179C/dec.
R~ (SiO2; EA/M~OH 10~ 3.44 ~S (FAB) ~ 4~9 (~
Example 6 1-~4-(4-Carboxy-5-oxazolyl)benzyl]-2-n-butyl-4-chloro-5-formylLmidazole a) Methyl 4-bromQmethyl~enzoate 50 g of methyl p-tolylc~rboxylate, 60 g of N~S ~nd 200 mg of benzoyl peroxide are suspended in 300 ml of chloro-benzene and the mixture is cautiou~ly h~ted to r~lux.
The reaction ~tart~ vigorou~ly. The-~ixture i~ directly allowed to eool ~gain, the chlorobenzene is removed in vacuo and the re~idue is di~tilled. 6B g o~ the title compound are obtained as colorless cry~t 1 B.p.5 = 145C
R~ (SiO2; E~/heptane 1s4) ~ 0.50 ~S (DCI) ~ 299 (~+1) b~ 4-Bromomethylbenzoic ~id 5.0 g of methyl 4 br~momethylbenzo~t~ ~re su~pandad in 15 ml of 48% ~q. 8Br ~nd he~ted to reflu~ for 30 min, ~he mixture i~ ad~u~ted to pH ~ 8 with NaHCO3 and wa~hed twice with DIP. ~he agueous pha~e i~ then ad~u~ted to pH ~ 2 with NaHSO~ and extra~ted 3 time~ with 150 ml of ~4 The extra~s are driecl o~er ~a~SO~ and ~he ~olvent i~ r~movQd in vacuo. 3.8 g of the title compound ars obt~ine~ as 2~ 3~
colorless hygroscopic crystal~.
Meltin~ point- 45C
R~ (5iO2; EA) a 0.43 MS (DCI) : 215 (M~1) c) 4-Bromomethylb0nzoyl chloride 3.8 g o~ 4-bromomethylbenzoic acid are su~pended in 10 ~1 of SOCl2 and ~he mixture i~ hea~ted to reflux for 1 h.
Excess SOC12 i~ removed in vacuo, and the re3idue i~ dried in a fine vacuum and employed again in crude form.
d) 5-(4-Bromomethyl)benzyl-4-methoxycarbonyloxa201e The ~rude product from Example 5c) i~ di~solvad in 50 ml of anhyd~ous THF togsther with 5.4 ml of Et3N~ 1.8 ml of methyl .isocyanoacetate are adde~ dropwi~e at 5C and the mixture i~ stirred at R.T. for 3 days. It i~ then dill~ted with 300 ml of EA, washed 3 times with 100 ml of 0.7 M
KH2PO4 each time, 3 times with 100 ml of satd. aq. NaHC03 and once with 100 ml of NaCl ~olution and dried over Na2S04, and the solvent is removed in v~cuo. Chroma-tograph~ on silica ~el u~iny MTB yields 2.~ ~ of yellow crystals.
Meltin~ point: 79C
Rf (SiO2; ~TB) = 0.36 e) 1-~4-~4-~etho~ycarbonyl-5-ox~zolyl~banzyl]-2-n-butyl-4-chloro-5-fonnylimidazolQ
2~6 mg of 5-(4-bromomethyl)benzyl-4 metho~ycarbonyl-oxazole~ 187 mg of 2-n-butyl-4-chloro-5-fo~m~limidazole and 139 mg of R2CO3 are ~tirred i~ 10 ml o~ D~ at RT for 21 h. Th~ mixture i~ then dilu~ed with 150 ml of EA, wa~hed twice w.;th 50 ml of satd. aq. Na~CO3 ~olution eaoh time and once with 50 ml of aq. NaCl ~olution and dried over Na2SO4, ~nd th~ solvent is remo~ed in vacuo. Chroma-tography on ~ilica gel using MT~DIP 1:1 yields 250 mg of .
, ,, ~
a colorle~s oil. ~ 5~3~
R~ (SiO2; NTB/DIP 1:1) ~ 0.35 ~S (DCI) s 402 (~
f) 1-[4-(4-Carboxy-5-oxazolyl)benzyl]-2-n-hutyl 4-chloro-S-formylLmidazale 240 mg of 1-[4-(4 methoxycarbonyl-5-oxazolyl)benzyl]~2-n-butyl-4-chloro-5-~oxmylimidazole are dis~ol~ed in 15 ml of methanol, treated with 2.5 ml of 1 ~ a~. NaOH and stirred at RT for 20 h. The methanol i~ removed in ~cuo, and the residue iB diluted with 20 ml of H2O and wa~hed twice with 10 ml of DIP each time. It i8 then ad~u~ted to pH = 2, extract2d 3 times with 50 ml of EA each kime, the extracts are dried over Na2SO4 and khe solvent i~ removed in vacuo. Chromakography on silica gel using ~A/glacial acetic acid 10:1 yields 90 mg of a light yellow ~oam.
R~ (SiO2; EA/glacial acetic acid 10:1) = 0.16 MS (DCI): 38~(M~l) ::
, ': ' ' ~ .
, .
Claims (32)
1. A compound of the formula I
(I) in which a) X, Y and Z are identical or different and are N or CR2, b) R1 i 1. (C2-C10)-alkyl,
(I) in which a) X, Y and Z are identical or different and are N or CR2, b) R1 i 1. (C2-C10)-alkyl,
2. (C3-Cl0)-alkenyl,
3. (C3-C10)-alkynyl,
4. OR3,
5. (C3-C8)-cycloalkyl,
6. (C4-C10)-cycloalkylalkyl,
7. (C5-C10)-cycloalkylalkenyl,
8. (C5-C10)-cycloalkylalkynyl,
9. -(CH2)m-B-(CH2)n-R4,
10. benzyl,
11. a radical as defined under b) 1., 2., 3.
or 9 ., which is monosubstituted by CO2R3,
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 fuorine, or
13. the radical defined under by 10., which is substituted on the phenyl by 1 or 2 identi-cal or different radicals from the series comprising halogen, (C1-C4) alkoxy and nitro, C) R2 is 1. hydrogen, 2. halogen, 3. nitro, 4. CvF2v+1, 5. SF5, 6. pentafluorophenyl, 7. cyano, 8. (C1-C4)-alkoxy, benzyloxy, 9. phenyl, 10. phenyl-C1-C3)-alkyl, 11. (C1-C10)-alkyl, 12. (C3-C10)-alkenyl, 13. phenyl-(C2-C6)-alkenyl,
14. 1-imidazolyl-(CH2)m-,
15. 1,2,3-triazolyl-(CH2)n, l6. tetrazolyl-(CH2)m-, 17. -(CH2)o-1-CHR7-OR5, 18. -(CH2)o-O-CO-R3, 19. -(CH2)o-S-R6, 20. -S(O)r-R6, 21. -CH=CH-(CH2)m-(CHR3-OR6, 22. -CH2=CH-(CH2)m-CO-R8, 23. -CO-R8, 24. -CH=CH-(CH2)m-O-CO-R7, 25. -(CH2)m-CH(CH3)-CO-R7, 26. -(CH2)o-COR8, 27. 28. 29. -(CH2)o-NR7-CO-NHR9, 30. -(CH2)0-NR7-SO2R9, 31. 32. -(CH2)nF, 33. -(CH2)n-O-NO2, 34. -CH2-N3, 35. -CH2)n-NO2, 36. -CH=N-NR5R7, 37. phthalimido-(CH2)n-, 38. , 39. , 40. , 41. , 42. phenyl-SO2-NH-N=CH-, 43. , 44. -(CH2n-SO2-NR7-CO-NR6R9, 45. -(CH2)o-SO2R8, 46. a radical defined as under c) 9, or 10., which is substituted on the phenyl by 1 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 20., 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 differ-ent radicals from the series comprising methoxycarbonyl and (C1-C4)-alkyl;
d) R3 is 1. hydrogen, 2. (C1-C8)-alkyl, 3. (C3-C8)-cycloalkyl, 4. phenyl, 5. benzyl or 6. The radical defined under d) 2., in which 1 to all of the hydrogen atoms are substitu-ted by fluorine;
e) R4 is 1. hydrogen, 2. (C1-C6)-alkyl, 3. (C3-C8)-cycloalkyl, 4. (C2-C4)-alkenyl or 5. (C2-C4)-alkynyl;
f) R5 is 1. hydrogen, 2. (Cl-C6)-alkyl, 3. (C3-C8)-cycloalkyl, 4. phenyl or 5. benzyl;
g) R6 is 1. hydrogen, 2. (C1-C6)-alkyl, 3. (C3-C8)-cycloalkyl, 4. (C6-Cl2)-aryl, 5. benzyl, 6. (C1-C8)-heteroaryl which can also be partially or completely hydrogenated, 7. (C1-C4)-alkanoyl, 8. (C1-C9)-heteroaryl-(C1-C3)-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 differ-ent radicals from the series comprising halogen, hydroxyl, methoxy, nitro, cyano, CO2R3 -NR11R12 and trifluoromethyl;
h) R7 is 1. hydrogen, 2. (C1-C6)-alkyl, 3. (C3-C8)-cycloalkyl, 4. (C6-C12)-aryl(C1-C6)-alkyl, 5. phenyl or 6. (C1-C8)-heteroaryl;
i) R8 is 1. hydrogen, 2. (C1-C6)-alkyl, 3. (C3-C8)-cycloalkyl, 4. phenyl (CH2)q-, 5. OR5, 6. NR11Rl2 or 7. j) R9 is 1. (C1-C6)-alkyl, 2. 1-adamantyl, 3. 1-naphthyl, 4. 1-naphthylethyl, 5. phenyl-(CH2)q- or 6. the radical defined under j) 1., in which 1 to all of the hydrogen atoms are substitu-ted by fluorine;
or R6 and R8 together with the nitrogen atom carrying them are k) R10 is cyano, nitro or CO2R7;
1) R11 and R12 are identical or different and are 1. hydrogen, 2. (C1-C4)-alkyl, 3. phenyl, 4. benzyl or 5. .alpha.-methylbenzyl, m) D is NR13, 0 or CH2;
n) R13 is hydrogen, (C1-C2)-alkyl or phenyl;
n) A is .alpha.) a (C6-C14)-aryl radical or .beta.) (C1-C9-heteroaryl, which can either be aromatic, partially hydrogenated or completely hydrogenated or .gamma.) 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, 5. cyano, 6. hydroxyl, 7. (Cl-C6)-alkyl, 8. (C1-C4)-alkanoyl, 9. (C1-C4)-alkanoyloxy, 10. CO2R3, 11. methanesulfonylamino, 12. trifluoromethanesulfonylamino, 13. -CO-NH-OR9, 14. -SO2-NR5R7, 15. -CH2-OR7,
d) R3 is 1. hydrogen, 2. (C1-C8)-alkyl, 3. (C3-C8)-cycloalkyl, 4. phenyl, 5. benzyl or 6. The radical defined under d) 2., in which 1 to all of the hydrogen atoms are substitu-ted by fluorine;
e) R4 is 1. hydrogen, 2. (C1-C6)-alkyl, 3. (C3-C8)-cycloalkyl, 4. (C2-C4)-alkenyl or 5. (C2-C4)-alkynyl;
f) R5 is 1. hydrogen, 2. (Cl-C6)-alkyl, 3. (C3-C8)-cycloalkyl, 4. phenyl or 5. benzyl;
g) R6 is 1. hydrogen, 2. (C1-C6)-alkyl, 3. (C3-C8)-cycloalkyl, 4. (C6-Cl2)-aryl, 5. benzyl, 6. (C1-C8)-heteroaryl which can also be partially or completely hydrogenated, 7. (C1-C4)-alkanoyl, 8. (C1-C9)-heteroaryl-(C1-C3)-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 differ-ent radicals from the series comprising halogen, hydroxyl, methoxy, nitro, cyano, CO2R3 -NR11R12 and trifluoromethyl;
h) R7 is 1. hydrogen, 2. (C1-C6)-alkyl, 3. (C3-C8)-cycloalkyl, 4. (C6-C12)-aryl(C1-C6)-alkyl, 5. phenyl or 6. (C1-C8)-heteroaryl;
i) R8 is 1. hydrogen, 2. (C1-C6)-alkyl, 3. (C3-C8)-cycloalkyl, 4. phenyl (CH2)q-, 5. OR5, 6. NR11Rl2 or 7. j) R9 is 1. (C1-C6)-alkyl, 2. 1-adamantyl, 3. 1-naphthyl, 4. 1-naphthylethyl, 5. phenyl-(CH2)q- or 6. the radical defined under j) 1., in which 1 to all of the hydrogen atoms are substitu-ted by fluorine;
or R6 and R8 together with the nitrogen atom carrying them are k) R10 is cyano, nitro or CO2R7;
1) R11 and R12 are identical or different and are 1. hydrogen, 2. (C1-C4)-alkyl, 3. phenyl, 4. benzyl or 5. .alpha.-methylbenzyl, m) D is NR13, 0 or CH2;
n) R13 is hydrogen, (C1-C2)-alkyl or phenyl;
n) A is .alpha.) a (C6-C14)-aryl radical or .beta.) (C1-C9-heteroaryl, which can either be aromatic, partially hydrogenated or completely hydrogenated or .gamma.) 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, 5. cyano, 6. hydroxyl, 7. (Cl-C6)-alkyl, 8. (C1-C4)-alkanoyl, 9. (C1-C4)-alkanoyloxy, 10. CO2R3, 11. methanesulfonylamino, 12. trifluoromethanesulfonylamino, 13. -CO-NH-OR9, 14. -SO2-NR5R7, 15. -CH2-OR7,
16. (C6-C12)-aryl,
17. (C3-C8)-cycloalkyl,
18. (C1-C4)-alkoxy,
19. (C1-C9)-heteroaryl,
20. CO2R3,
21. NR6R7,
22. sulfo,
23. -SO3R3,
24. -SO2-NR7-CO-NR6R9,
25. -NR7-CO-NR6-SO2-CH2-R5,
26. -C(CF3)2OH,
27. phosphonooxy, ,
28. -PO3H2,
29. -NH-PO)OH)2,
30. -S(O)rR6,
31. -CO-R6 and
32. -CO-NR6R9;
p) T 1. a single bond 2. -CO-, 3. -CH2-, 4. -O-, 5. -S-, 6. -NR21-, 7. -CO-NR21-, 8. -NR2l-CO-, 9. -O-CH2-, 10. -CH2-O-, 11. -S-CH2-, 12. -CH2-S-, 13. -NH-CR20R22-, 14. -NR21-SO2-, 15. SO2-NR21-, 16. -CR20R22-NH-17. -CH=CH-, 18. -CF-CF-, 19. -CH=CF-, 20. -CF=CH-, 21. -CH2-CH2-, 22. -CF2-CF2-, 23. -CH(OR3)-, 24. -CH(OCOR5)-, 25. 26. or 27. q) E is a radical 1. with the proviso that in the case where X=Y=CH, R14 is not COOH, 3. 4. r) B is O, NR7 or S;
s) L is (C1-C3)-alkanediyl;
t) R14 is -CO2R3, -CH2CO2R3, -PO3H2, -SO3H or tetrazolyl;
u) m 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 ID, 1 or 2, and y) v is an integer from 1 to 6;
and its physiologically tolerable salts.
2. A compound of the formula I as claimed in claim 1, in which 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, and is physiologically tolerable salts.
3. A compound of the formula I as claimed in claim 1 or 2, in which a) R1 is 1. (C3-C10)-alkyl, 2. (C3-C10)-alkenyl, 3 (C3-C10)-alkynyl 4. (C3-C8)-cycloalkyl, 5. benzyl, 6. benzyl which is substituted as defined in claim 1 or 7. -(CH2)m,-B-(CH3)n-R4;
b) R2 is 1. hydrogen, 2. halogen, 3. nitro, 4. CvF2v+1, 5. SF5 6. pentafluorophenyl, 7. cyano, 8. (C1-C4)-alkoxy, benzyloxy, 9. phenyl, 10. phenyl-(C1-C3)-alkyl, 11. (C1-C10)-alkyl, 12. (C3-C10)-alkenyl, 13. phenyl(C2-C6)-alkenyl, 14. 1-imidazolyl-(CH2)m-, 15. 1,2,3-triazolyl-(CH2)o-, 16. tetrazolyl-(CH2)m-, 17. -(CH2)-o-1-CHR7-OR5, 18. -(CH2)o-O-COR3, 19. -COR8, 20. -(CH2)o-CO-R6, 21. -S(O)rR6, 22. -CH=CH-(CH2)m-CHR9-OR6, 23. -CH2=CH-(CH2)m-CO-R6, 24. -(CH2)o-NH-CO-OR9, 25. -(CH2)o-NH-SO2-R9, 26. -(CH2)nF, 27. -(CH2)o-SO3R9, 28. -(CH2)n-SO2-NH-CO-NR6R9 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, (C1-C5)-alkyl, OR5, NR11R12 or morpholino;
d) T is 1. a single bond, 2. -CO-, 3. -CONR21-, 4. -CH2-CH2-, 5. -NR21-CO-, 6. -O-CH2-, 7. -CH2-O-, 8. -S-CH2-, 9. -CH2-S-, 10. -NH-CH2-, 11. -CH2-NH-, 12. -CH=CH-, or 13. and the other radicals and variables are as defined in the preceding claims and its physiologically tolerable salts.
4. A compound of the formula I as claimed in one of claims 1-3, in which a) R1 is (C3-C7)-alkyl, (C3-C7)-alkenyl or (C3-C7)alkynyl;
b) R2 is 1. hydrogen 2. chlorine, 3. bromine, 4. CvF2v+1 where v = 1, 2 or 3, 5. pentafluorophenyl, 6. (C1-C4)-alkoxy, benzyloxy, 7. -S(O)rR5, 8. SF5, 9. (CH2)o-1-CHR7-OR5, 10. (CH2)o-O-CO-R3, 11. -COR8, 12. (CH2)o-CO-R8, 13. -CH2-NH-CO-R8, 14. -(CH2)o-NH-SO2-R9, 15. -CH=CH-CHR3-OR6, 16. tetrazolyl-(CH2)m-, 17. -(CH2)nSO2-NH-CO-NR6R9, 18. -(CH2)o-SO3R9 or 19. (C1-C6)-alkyl which is optionally substitu-ted by hydroxyl, preferably hydroxy-methyl;
c) R3 is hydrogen or (C1-C4)-alkyl;
d) R6 is hydrogen,(C1-C4)-alkyl,(C1-C4)-alkanoyl, phenyl, which can be optionally substituted by 1 or 2 identical or different radicals from the series comprising halogen, hydroxyl, methoxy nitro, cyano, CO2R3 and trifluoromethyl, or (C1-C8)-heteroaryl, which can also be partially or completely hydrogenated;
e) R7 is hydrogen, (C1-C4)-alkyl, (C1-C9)-heteroaryl, or (C6-C12)-ary1-(C1-C4)-alkyl;
f) R8 is hydrogen, (C1-C4)-alkyl, OR5 or morpholino, g) R9 is CF3, (C1-C6)-alkyl or phenyl;
h) A is .alpha.) (C6-C10)-aryl radical or .beta.) (C1-C4-heteroaryl which can either be aromatic, partially hydrogenated or completely hydrogenated, or .gamma.) the radical of a fused heterobicyclic system have 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 identical or different radicals from the series comprising halogen, nitro, cyano, hydroxyl, -NR6R7, phenyl, -S(O)rR5 and -CO2R3;
1) T is a single bond, -O-, -CO-, -NHCO-, -OCH2- or and the other radicals and variables are as defined in the preceding claims, and its physiologically tolerable salts.
5. A compound of the formula I as claimed in one of claims 1-4, in which a) R1 is (C3-C5)alkyl, b) R2 is hydrogen, chlorine, methoxy, benzyloxy, or S(O)rR6 c) R3 is hydrogen or (C1-C4)-alkyl, d) R4 and R5 are identical or different and are hydrogen or (C1-C4)-alkyl, e) R6 is hydrogen, (C1-C4)-alkyl, phenyl or 4-tolyl, f) R14 is -COOH, -PO3H2, -SO3H or 5-tetrazolyl, 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 -C02R3 h) B is O, NH or S, i) L is -CH2-, j) r is 0, 1 or 2, k) q is 0, l) T is a single bond, m) m is 0, l, 2 or 3 and n) n is 1, 2 or 3 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 com-prises alkylating a compound of the formula II
in which R1, 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 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.
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 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 com-pounds of the formula 1 or their physiologically toler-able salts into a suitable administration form together with a physiologically acceptable excipient and, if appropriate, other additives and auxiliaries.
p) T 1. a single bond 2. -CO-, 3. -CH2-, 4. -O-, 5. -S-, 6. -NR21-, 7. -CO-NR21-, 8. -NR2l-CO-, 9. -O-CH2-, 10. -CH2-O-, 11. -S-CH2-, 12. -CH2-S-, 13. -NH-CR20R22-, 14. -NR21-SO2-, 15. SO2-NR21-, 16. -CR20R22-NH-17. -CH=CH-, 18. -CF-CF-, 19. -CH=CF-, 20. -CF=CH-, 21. -CH2-CH2-, 22. -CF2-CF2-, 23. -CH(OR3)-, 24. -CH(OCOR5)-, 25. 26. or 27. q) E is a radical 1. with the proviso that in the case where X=Y=CH, R14 is not COOH, 3. 4. r) B is O, NR7 or S;
s) L is (C1-C3)-alkanediyl;
t) R14 is -CO2R3, -CH2CO2R3, -PO3H2, -SO3H or tetrazolyl;
u) m 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 ID, 1 or 2, and y) v is an integer from 1 to 6;
and its physiologically tolerable salts.
2. A compound of the formula I as claimed in claim 1, in which 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, and is physiologically tolerable salts.
3. A compound of the formula I as claimed in claim 1 or 2, in which a) R1 is 1. (C3-C10)-alkyl, 2. (C3-C10)-alkenyl, 3 (C3-C10)-alkynyl 4. (C3-C8)-cycloalkyl, 5. benzyl, 6. benzyl which is substituted as defined in claim 1 or 7. -(CH2)m,-B-(CH3)n-R4;
b) R2 is 1. hydrogen, 2. halogen, 3. nitro, 4. CvF2v+1, 5. SF5 6. pentafluorophenyl, 7. cyano, 8. (C1-C4)-alkoxy, benzyloxy, 9. phenyl, 10. phenyl-(C1-C3)-alkyl, 11. (C1-C10)-alkyl, 12. (C3-C10)-alkenyl, 13. phenyl(C2-C6)-alkenyl, 14. 1-imidazolyl-(CH2)m-, 15. 1,2,3-triazolyl-(CH2)o-, 16. tetrazolyl-(CH2)m-, 17. -(CH2)-o-1-CHR7-OR5, 18. -(CH2)o-O-COR3, 19. -COR8, 20. -(CH2)o-CO-R6, 21. -S(O)rR6, 22. -CH=CH-(CH2)m-CHR9-OR6, 23. -CH2=CH-(CH2)m-CO-R6, 24. -(CH2)o-NH-CO-OR9, 25. -(CH2)o-NH-SO2-R9, 26. -(CH2)nF, 27. -(CH2)o-SO3R9, 28. -(CH2)n-SO2-NH-CO-NR6R9 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, (C1-C5)-alkyl, OR5, NR11R12 or morpholino;
d) T is 1. a single bond, 2. -CO-, 3. -CONR21-, 4. -CH2-CH2-, 5. -NR21-CO-, 6. -O-CH2-, 7. -CH2-O-, 8. -S-CH2-, 9. -CH2-S-, 10. -NH-CH2-, 11. -CH2-NH-, 12. -CH=CH-, or 13. and the other radicals and variables are as defined in the preceding claims and its physiologically tolerable salts.
4. A compound of the formula I as claimed in one of claims 1-3, in which a) R1 is (C3-C7)-alkyl, (C3-C7)-alkenyl or (C3-C7)alkynyl;
b) R2 is 1. hydrogen 2. chlorine, 3. bromine, 4. CvF2v+1 where v = 1, 2 or 3, 5. pentafluorophenyl, 6. (C1-C4)-alkoxy, benzyloxy, 7. -S(O)rR5, 8. SF5, 9. (CH2)o-1-CHR7-OR5, 10. (CH2)o-O-CO-R3, 11. -COR8, 12. (CH2)o-CO-R8, 13. -CH2-NH-CO-R8, 14. -(CH2)o-NH-SO2-R9, 15. -CH=CH-CHR3-OR6, 16. tetrazolyl-(CH2)m-, 17. -(CH2)nSO2-NH-CO-NR6R9, 18. -(CH2)o-SO3R9 or 19. (C1-C6)-alkyl which is optionally substitu-ted by hydroxyl, preferably hydroxy-methyl;
c) R3 is hydrogen or (C1-C4)-alkyl;
d) R6 is hydrogen,(C1-C4)-alkyl,(C1-C4)-alkanoyl, phenyl, which can be optionally substituted by 1 or 2 identical or different radicals from the series comprising halogen, hydroxyl, methoxy nitro, cyano, CO2R3 and trifluoromethyl, or (C1-C8)-heteroaryl, which can also be partially or completely hydrogenated;
e) R7 is hydrogen, (C1-C4)-alkyl, (C1-C9)-heteroaryl, or (C6-C12)-ary1-(C1-C4)-alkyl;
f) R8 is hydrogen, (C1-C4)-alkyl, OR5 or morpholino, g) R9 is CF3, (C1-C6)-alkyl or phenyl;
h) A is .alpha.) (C6-C10)-aryl radical or .beta.) (C1-C4-heteroaryl which can either be aromatic, partially hydrogenated or completely hydrogenated, or .gamma.) the radical of a fused heterobicyclic system have 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 identical or different radicals from the series comprising halogen, nitro, cyano, hydroxyl, -NR6R7, phenyl, -S(O)rR5 and -CO2R3;
1) T is a single bond, -O-, -CO-, -NHCO-, -OCH2- or and the other radicals and variables are as defined in the preceding claims, and its physiologically tolerable salts.
5. A compound of the formula I as claimed in one of claims 1-4, in which a) R1 is (C3-C5)alkyl, b) R2 is hydrogen, chlorine, methoxy, benzyloxy, or S(O)rR6 c) R3 is hydrogen or (C1-C4)-alkyl, d) R4 and R5 are identical or different and are hydrogen or (C1-C4)-alkyl, e) R6 is hydrogen, (C1-C4)-alkyl, phenyl or 4-tolyl, f) R14 is -COOH, -PO3H2, -SO3H or 5-tetrazolyl, 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 -C02R3 h) B is O, NH or S, i) L is -CH2-, j) r is 0, 1 or 2, k) q is 0, l) T is a single bond, m) m is 0, l, 2 or 3 and n) n is 1, 2 or 3 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 com-prises alkylating a compound of the formula II
in which R1, 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 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.
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 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 com-pounds of the formula 1 or their physiologically toler-able salts into a suitable administration form together with a physiologically acceptable excipient and, if appropriate, other additives and auxiliaries.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP4036645.6 | 1990-11-16 | ||
| DE4036645A DE4036645A1 (en) | 1990-11-16 | 1990-11-16 | SUBSTITUTED AZOLE, METHOD FOR THE PRODUCTION THEREOF, THE AGENT, AND THEIR USE THEREOF |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2055636A1 true CA2055636A1 (en) | 1992-05-17 |
Family
ID=6418438
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002055636A Abandoned CA2055636A1 (en) | 1990-11-16 | 1991-11-15 | Substituted azoles, process for their preparation, agents containing 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) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6451734B1 (en) | 1996-11-04 | 2002-09-17 | Basf Aktiengesellschaft | Substituted 3-benzylpyrazoles and their use as herbicides |
| US7297713B2 (en) | 2005-07-29 | 2007-11-20 | Wyeth | Cyanopyrrole-phenyl amide progesterone receptor modulators and uses thereof |
Families Citing this family (16)
| 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. |
| 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 |
| 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 |
| WO2008151257A2 (en) | 2007-06-04 | 2008-12-11 | Synergy Pharmaceuticals Inc. | 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 |
| WO2009149279A2 (en) | 2008-06-04 | 2009-12-10 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders |
| WO2010009319A2 (en) | 2008-07-16 | 2010-01-21 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase useful for the treatment of gastrointestinal, 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 |
| JP2016514671A (en) | 2013-03-15 | 2016-05-23 | シナジー ファーマシューティカルズ インコーポレイテッド | Guanylate cyclase agonists and uses thereof |
| EP2968439A2 (en) | 2013-03-15 | 2016-01-20 | Synergy Pharmaceuticals Inc. | Compositions useful for the treatment of gastrointestinal disorders |
| CA2913737A1 (en) | 2013-06-05 | 2014-12-11 | Synergy Pharmaceuticals, Inc. | Ultra-pure agonists of guanylate cyclase c, method of making and using same |
| WO2023274257A1 (en) * | 2021-07-01 | 2023-01-05 | 诸葛国琴 | Imidazole compound, and intermediate and application thereof |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1329614C (en) * | 1987-05-02 | 1994-05-17 | Rainer Buerstinghaus | N-substituted azoles |
| 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 HU HU913583A patent/HUT59673A/en unknown
- 1991-11-15 MX MX9102098A patent/MX9102098A/en unknown
- 1991-11-15 CS CS913470A patent/CS347091A3/en unknown
- 1991-11-15 CA CA002055636A patent/CA2055636A1/en not_active Abandoned
- 1991-11-15 ZA ZA919059A patent/ZA919059B/en unknown
- 1991-11-15 PT PT99521A patent/PT99521A/en not_active Application Discontinuation
- 1991-11-15 KR KR1019910020341A patent/KR920009802A/en not_active Application Discontinuation
- 1991-11-15 NO NO91914481A patent/NO914481L/en unknown
- 1991-11-15 AU AU87855/91A patent/AU8785591A/en not_active Abandoned
- 1991-11-15 JP JP3326662A patent/JPH04283569A/en active Pending
- 1991-11-15 IE IE399191A patent/IE913991A1/en not_active Application Discontinuation
- 1991-11-15 CN CN91110736A patent/CN1061410A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6451734B1 (en) | 1996-11-04 | 2002-09-17 | Basf Aktiengesellschaft | Substituted 3-benzylpyrazoles and their use as herbicides |
| US7297713B2 (en) | 2005-07-29 | 2007-11-20 | Wyeth | Cyanopyrrole-phenyl amide progesterone receptor modulators and uses thereof |
| US7652062B2 (en) | 2005-07-29 | 2010-01-26 | Wyeth Llc | Cyanopyrrole-phenyl amide progesterone receptor modulators and uses thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| KR920009802A (en) | 1992-06-25 |
| EP0485929A1 (en) | 1992-05-20 |
| ZA919059B (en) | 1992-07-29 |
| IE913991A1 (en) | 1992-05-20 |
| HU913583D0 (en) | 1992-01-28 |
| NO914481L (en) | 1992-05-18 |
| BR9104948A (en) | 1992-06-23 |
| JPH04283569A (en) | 1992-10-08 |
| NO914481D0 (en) | 1991-11-15 |
| DE4036645A1 (en) | 1992-05-21 |
| CS347091A3 (en) | 1992-06-17 |
| CN1061410A (en) | 1992-05-27 |
| PT99521A (en) | 1992-09-30 |
| FI915381A0 (en) | 1991-11-14 |
| MX9102098A (en) | 1992-07-08 |
| IL100058A0 (en) | 1992-08-18 |
| AU8785591A (en) | 1992-05-21 |
| FI915381A (en) | 1992-05-17 |
| HUT59673A (en) | 1992-06-29 |
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| Date | Code | Title | Description |
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| FZDE | Discontinued |