U.S. patent number RE42,462 [Application Number 12/481,594] was granted by the patent office on 2011-06-14 for carboxylic acid derivatives, their preparation and use.
This patent grant is currently assigned to Abbott GmbH & Co. KG. Invention is credited to Wilhelm Amberg, Ernst Baumann, Andreas Kling, Dagmar Klinge, Stefan Muller, Manfred Raschack, Joachim Rheinheimer, Hartmut Riechers, Liliane Unger, Uwe Josef Vogelbacher, Wolfgang Wernet.
United States Patent |
RE42,462 |
Riechers , et al. |
June 14, 2011 |
**Please see images for:
( Certificate of Correction ) ** |
Carboxylic acid derivatives, their preparation and use
Abstract
Carboxylic acid derivatives ##STR00001## where R-R.sup.6, X, Y
and Z have the meanings stated in the description, and the
preparation thereof, are described. The novel compounds are
suitable for controlling diseases.
Inventors: |
Riechers; Hartmut (Neustadt,
DE), Klinge; Dagmar (Heidelberg, DE),
Amberg; Wilhelm (Friedrichsdorf, DE), Kling;
Andreas (Mannheim, DE), Muller; Stefan (Speyer,
DE), Baumann; Ernst (Dudenhofen, DE),
Rheinheimer; Joachim (Ludwigshafen, DE), Vogelbacher;
Uwe Josef (Ludwigshafen, DE), Wernet; Wolfgang
(Hassloch, DE), Unger; Liliane (Ludwigshafen,
DE), Raschack; Manfred (Weisenheim, DE) |
Assignee: |
Abbott GmbH & Co. KG
(Wiesbaden, DE)
|
Family
ID: |
6530833 |
Appl.
No.: |
12/481,594 |
Filed: |
October 7, 1995 |
PCT
Filed: |
October 07, 1995 |
PCT No.: |
PCT/EP95/03963 |
371(c)(1),(2),(4) Date: |
March 27, 1997 |
PCT
Pub. No.: |
WO96/11914 |
PCT
Pub. Date: |
April 25, 1996 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
Reissue of: |
08809699 |
Mar 27, 1997 |
5932730 |
Aug 3, 1999 |
|
|
Current U.S.
Class: |
544/298; 544/301;
544/318; 544/314; 544/310; 544/312; 544/300; 544/299; 544/327;
544/322; 544/316; 544/309; 544/302; 544/319; 544/328; 544/329;
544/326; 544/317; 544/315; 544/335 |
Current CPC
Class: |
A61P
25/06 (20180101); C07D 239/96 (20130101); A61P
13/02 (20180101); A61P 43/00 (20180101); A61P
9/10 (20180101); A61P 13/12 (20180101); C07D
413/12 (20130101); A61P 7/02 (20180101); A61P
9/12 (20180101); C07D 403/12 (20130101); C07D
491/04 (20130101); C07D 239/60 (20130101); C07D
405/14 (20130101); C07D 251/26 (20130101); C07D
251/52 (20130101); C07D 403/06 (20130101); C07D
405/12 (20130101); A61P 9/00 (20180101); A61P
11/06 (20180101); A61P 13/08 (20180101); A61P
25/08 (20180101); C07D 239/48 (20130101); A61P
25/04 (20180101); C07D 239/34 (20130101); C07D
251/20 (20130101); C07D 239/52 (20130101); C07D
487/04 (20130101); C07D 491/048 (20130101); C07D
495/04 (20130101); A61P 15/00 (20180101); C07D
417/12 (20130101); C07D 239/70 (20130101); A61P
9/08 (20180101); A61P 11/08 (20180101) |
Current International
Class: |
C07D
239/60 (20060101); C07D 251/30 (20060101); C07D
239/96 (20060101); C07D 403/12 (20060101) |
Field of
Search: |
;544/298,299,300,301,302,309,310,312,314,315,316,317,318,319,322,326,327,328,329,335 |
References Cited
[Referenced By]
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4029648 |
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4123469 |
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517 215 |
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EP |
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517215 |
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EP |
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548710 |
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567014 |
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581184 |
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Jan 1976 |
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H03-031266 |
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JP |
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JP |
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2730021 |
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JP |
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WO |
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WO |
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Jan 1996 |
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WO |
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PCT/US2008/009236 |
|
Jul 2008 |
|
WO |
|
Other References
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cited by other .
Agr. Biol. Chem., 40(5), 993-1000, 1976, on the Sterochemistry . .
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Journal (1994). cited by other .
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Riechers et al., Journal of Medicinal Chemistry (1996), 39(11),
2123-8. cited by other .
Yanagisawa et al., Nature, 332:411-415 (1988). cited by other .
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|
Primary Examiner: Kifle; Bruck
Attorney, Agent or Firm: Mueller; Lisa V. Polsinelli
Shughart PC
Claims
We claim:
1. A compound of the formula I ##STR00016## where R is formyl,
tetrazole, nitrile, .[.a COOH group.]. .Iadd.--CO.sub.2H
.Iaddend.or a radical which can be hydrolyzed to .[.COOH, and the
other substituents have the following meanings:.].
.Iadd.--CO.sub.2H;.Iaddend. R.sup.2 .Iadd.is .Iaddend.hydrogen,
hydroxyl, .Iadd.--.Iaddend.NH.sub.2,
.Iadd.--.Iaddend.NH(C.sub.1-C.sub.4-alkyl),
.Iadd.--.Iaddend.N(C.sub.1-C.sub.4-alkyl).sub.2, halogen,
C.sub.1-C.sub.4-alkyl, .Iadd.or
.Iaddend.C.sub.1-C.sub.4-haloalkyl.[., C.sub.1-C.sub.4-alkoxy,
C.sub.1-C.sub.4-haloalkoxy or C.sub.1-C.sub.4-alkylthio.].; .Iadd.X
is CR.sup.14, where R.sup.14 is hydrogen or
C.sub.1-C.sub.5-alkyl;.Iaddend. R.sup.3 .Iadd.is .Iaddend.hydrogen,
hydroxyl, .Iadd.--.Iaddend.NH.sub.2,
.Iadd.--.Iaddend.NH(C.sub.1-C.sub.4-alkyl),
.Iadd.--.Iaddend.N(C.sub.1-C.sub.4-alkyl).sub.2, halogen,
C.sub.1-C.sub.4-alkyl, .Iadd.or
.Iaddend.C.sub.1-C.sub.4-haloalkyl.[., C.sub.1-C.sub.4-alkoxy,
C.sub.1-C.sub.4-haloalkoxy, NH--O--C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-alkylthio or CR.sup.3 is linked to CR.sup.14 as
indicated above to give a 5- or 6-membered ring.].; R.sup.4 and
R.sup.5, which can be identical or different, are phenyl or
naphthyl, which can be substituted by one or more of the following
.[.radicals.]. .Iadd.selected from the group consisting
of.Iaddend.: halogen, nitro, cyano, hydroxyl,
C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl,
C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-haloalkoxy, phenoxy,
C.sub.1-C.sub.4-alkylthio, amino, C.sub.1-C.sub.4-alkylamino
.[.or.]. .Iadd.and .Iaddend.C.sub.1-C.sub.4-dialkylamino; or
.Iadd.R.sup.4 and R.sup.5 are .Iaddend. phenyl or naphthyl, which
are connected together in the ortho position via a direct linkage,
a methylene, ethylene or ethenylene group, an oxygen or sulfur atom
.[.or.]..Iadd., .Iaddend.an SO.sub.2, NH or N-alkyl group.[.;.]. or
.Iadd.a .Iaddend.C.sub.3-C.sub.7-cycloalkyl .Iadd.group.Iaddend.;
R.sup.6 .Iadd.is .Iaddend.hydrogen, .Iadd.or R.sup.6 is
.Iaddend.C.sub.1-C.sub.8-alkyl, C.sub.3-C.sub.6-alkenyl,
C.sub.3-C.sub.6-alkynyl or C.sub.3-C.sub.8-cycloalkyl, where each
of these .[.radicals.]. can be substituted .Iadd.by .Iaddend.one or
more .[.times by.]. .Iadd.substituents selected from the group
consisting of.Iaddend.: halogen, nitro, cyano,
C.sub.1-C.sub.4-alkoxy, C.sub.3-C.sub.6-alkenyloxy,
C.sub.3-C.sub.6-alkynyloxy, C.sub.1-C.sub.4-alkylthio,
C.sub.1-C.sub.4-haloalkoxy, C.sub.1-C.sub.4-alkylcarbonyl,
C.sub.1-C.sub.4-alkoxycarbonyl, C.sub.3-C.sub.8-alkylcarbonylalkyl,
C.sub.1-C.sub.4-alkylamino, di-C.sub.1-C.sub.4-alkylamino, phenyl
.[.or.]. .Iadd.and .Iaddend.phenoxy which .Iadd.phenyl or phenoxy
.Iaddend.is substituted .Iadd.by .Iaddend.one or more .[.times
by.]. .Iadd.substituents selected from the group consisting of:
.Iaddend.halogen, nitro, cyano, C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-alkoxy,
C.sub.1-C.sub.4-haloalkoxy .[.or.]. .Iadd.and
.Iaddend.C.sub.1-C.sub.4-alkylthio; .Iadd.or.Iaddend. phenyl or
naphthyl, each of which can be substituted by one or more of the
following .[.radicals.]. .Iadd.selected from the group consisting
of.Iaddend.: halogen, nitro, cyano, hydroxyl, amino,
C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl,
C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-haloalkoxy, phenoxy,
C.sub.1-C.sub.4-alkylthio, C.sub.1-C.sub.4-alkylamino,
C.sub.1-C.sub.4-dialkylamino .Iadd., .Iaddend.dioxomethylene
.[.or.]. .Iadd.and .Iaddend.dioxoethylene; .Iadd.or.Iaddend. a five
or six-membered heteroaromatic moiety containing .Iadd.(i)
.Iaddend.one to three nitrogen atoms.Iadd., .Iaddend..[.and/or one
sulfur or oxygen atom.]. .Iadd.(ii) one sulfur atom, (iii) one
oxygen atom, (iv) one to three nitrogen atoms and one sulfur atom,
or (v) one to three nitrogen atoms and one oxygen atom.Iaddend.,
which .Iadd.heteroaromatic moiety .Iaddend.can carry .Iadd.one or
more substituents selected from the group consisting of:
.Iaddend.one to four halogen atoms .[.and/or.]..Iadd., and
.Iaddend.one or two of the following .[.radicals.]. .Iadd.selected
from the group consisting of.Iaddend.: C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-alkoxy,
C.sub.1-C.sub.4-haloalkoxy, C.sub.1-C.sub.4-alkylthio, phenyl,
phenoxy .[.or.]. .Iadd.and .Iaddend.phenylcarbonyl, it being
possible for the phenyl .[.radicals.]. in turn to carry .Iadd.one
or more substituents selected from the group consisting of:
.Iaddend.one to five halogen atoms .[.and/or.]..Iadd., and
.Iaddend.one to three of the following .[.radicals.].
.Iadd.selected from the group consisting of.Iaddend.:
C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl,
C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-haloalkoxy and.[./or.].
C.sub.1-C.sub.4-alkylthio.[.;.]..Iadd.,.Iaddend. Y .Iadd.is
.Iaddend.sulfur .[.or.]..Iadd., .Iaddend.oxygen or a single bond;
.Iadd.and.Iaddend. Z .Iadd.is .Iaddend.sulfur, oxygen, --SO-- or
--SO.sub.2--.
2. The compound of the formula I as defined in claim 1, wherein X
is CR.sup.14 and R.sup.14 is hydrogen.
3. The compound of the formula I as defined in claim 2, wherein R
is CO.sub.2H.
.[.4. The compound of the formula I as defined in claim 2, wherein
R.sup.2 and R.sup.3 each is methoxy..].
5. The compound of the formula I as defined in claim 2, wherein
R.sup.4 and R.sup.5 each is phenyl.
6. The compound of the formula I as defined in claim 2, wherein
R.sup.6 is C.sub.1-C.sub.8-alkyl.
7. The compound of the formula I as defined in claim 2, wherein Y
is oxygen.
8. The compound of the formula I as defined in claim 2, wherein Z
is oxygen or sulfur.
9. The compound of the formula I as defined in claim 8, wherein Z
is oxygen.
.[.10. The compound of the formula I as defined in claim 1, wherein
X is CH, Y is oxygen, Z is oxygen, R is CO.sub.2H, R.sup.2 is
methoxy, R.sup.3 is methoxy, R.sup.4 is phenyl, R.sup.5 is phenyl,
R.sup.6 is methyl, ethyl or iso-propyl..].
11. The compound of the formula I as defined in claim 1, wherein R
is tetrazole, nitrile or a group ##STR00017## where R.sup.1 has the
following meanings: a) hydrogen; b) succinylimidoxy; c) a
five-membered heteroaromatic ring linked by a nitrogen atom,
selected from the group consisting of: pyrrolyl, pyrazolyl,
imidazolyl and triazolyl, which ring can carry .Iadd.one or more
substituents selected from the group consisting of: .Iaddend.one or
two halogen atoms .[.and or.]..Iadd., and .Iaddend.one or two of
the following .[.radicals.]. .Iadd.selected from the group
consisting of.Iaddend.: C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-alkoxy,
C.sub.1-C.sub.4-haloalkoxy .[.or.]. .Iadd.and
.Iaddend.C.sub.1-C.sub.4-alkylthio; d) a radical ##STR00018## where
m is 0 or 1 and R.sup.7 and R.sup.8, which can be identical or
different, have the following meanings: hydrogen,
C.sub.1-C.sub.8-alkyl, C.sub.3-C.sub.6-alkenyl,
C.sub.3-C.sub.6-alkynyl, C.sub.3-C.sub.8-cycloalkyl, where these
alkyl, cycloalkyl, alkenyl and alkynyl groups can each carry
.Iadd.one or more substituents selected from the group consisting
of: .Iaddend.one to five halogen atoms .[.and/or.]..Iadd., and
.Iaddend.one or two of the following groups .Iadd.selected from the
group consisting of.Iaddend.: C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-alkylthio,
C.sub.1-C.sub.4-haloalkoxy, C.sub.3-C.sub.6-alkenyloxy,
C.sub.3-C.sub.6-alkenylthio, C.sub.3-C.sub.6-alkynyloxy .[.or.].
C.sub.3-C.sub.6-alkynylthio, C.sub.1-C.sub.4-alkylcarbonyl,
C.sub.1-C.sub.4-alkoxycarbonyl, C.sub.3-C.sub.6-alkenylcarbonyl,
C.sub.3-C.sub.6-alkynylcarbonyl, C.sub.3-C.sub.6-alkenyloxycarbonyl
.[.or.]. .Iadd.and
.Iaddend.C.sub.3-C.sub.6-alkynyloxycarbonyl.[.,.]..Iadd.;.Iaddend.
phenyl, which can be substituted .Iadd.by .Iaddend.one or more
.[.times by.]. .Iadd.substituents selected from the group
consisting of: .Iaddend.halogen, nitro, cyano,
C.sub.3-C.sub.6-alkenylcarbonyl, C.sub.3-C.sub.6-alkynylcarbonyl,
C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl,
C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-haloalkoxy .[.or.]..Iadd.,
.Iaddend.C.sub.1-C.sub.4-alkylthio, .Iadd.and
.Iaddend.di-C.sub.1-C.sub.4-alkylamino, or R.sup.7 and R.sup.8
together form a C.sub.4-C.sub.7-alkylene chain which can be
substituted by C.sub.1-C.sub.4-alkyl, and may contain a hetero atom
selected from the group consisting of.Iadd.: .Iaddend.oxygen,
sulfur and nitrogen, or R.sup.7 and R.sup.8 together form a
CH.sub.2--CH.dbd.CH--CH.sub.2 or CH.dbd.CH--(CH.sub.2).sub.3 chain;
e) a radical ##STR00019## where k is 0, 1 and 2, p is 1, 2, 3 and
4, and R.sup.9 is C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl,
C.sub.3-C.sub.6-alkenyl, C.sub.3-C.sub.6-alkynyl or phenyl, which
can be substituted .Iadd.by .Iaddend.one or more .[.times by.].
.Iadd.substituents selected from the group consisting of:
.Iaddend.halogen, nitro, cyano, C.sub.3-C.sub.6-alkenylcarbonyl,
C.sub.3-C.sub.6-alkynylcarbonyl, C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-alkoxy,
C.sub.1-C.sub.4-haloalkoxy .[.or.]. .Iadd.and
.Iaddend.C.sub.1-C.sub.4-alkylthio; f) a radical OR.sup.10, where
R.sup.10 is hydrogen, the cation of an alkali metal or an alkaline
earth metal or an environmentally compatible organic ammonium ion;
C.sub.3-C.sub.8-cycloalkyl which may carry one to three
C.sub.1-C.sub.4-alkyl groups; C.sub.1-C.sub.8-alkyl which may carry
.Iadd.one or more substituents selected from the group consisting
of: .Iaddend.one to five halogen atoms .[.and/or.]..Iadd., and
.Iaddend.one of the following .[.radicals.]. .Iadd.selected from
the group consisting of.Iaddend.: C.sub.1-C.sub.4-alkoxy,
C.sub.1-C.sub.4-alkylthio, cyano, C.sub.1-C.sub.4-alkylcarbonyl,
C.sub.3-C.sub.8-cycloalkyl, C.sub.1-C.sub.4-alkoxycarbonyl, phenyl,
phenoxy .[.or.]. .Iadd.and .Iaddend.phenylcarbonyl, where the
aromatic .[.radicals.]. .Iadd.substituents .Iaddend.in turn may
carry .Iadd.one or more substituents selected from the group
consisting of: .Iaddend.one to five halogen atoms
.[.and/or.]..Iadd., and .Iaddend.one to three of the following
.[.radicals.]. .Iadd.selected from the group consisting
of.Iaddend.: nitro, cyano, C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-alkoxy,
C.sub.1-C.sub.4-haloalkoxy and.[./or.]. C.sub.1-C.sub.4-alkylthio;
C.sub.1-C.sub.8-alkyl which may carry one to five halogen atoms and
which carries one of the following .[.radicals.]. .Iadd.selected
from the group consisting of.Iaddend.: a 5-membered heteroaromatic
ring containing one to three nitrogen atoms .[.or.]..Iadd.,
.Iaddend.a nitrogen atom and an oxygen .[.or.]. .Iadd.and a
nitrogen atom and a .Iaddend.sulfur atom, which may carry .Iadd.one
or more substituents selected from the group consisting of:
.Iaddend.one to four halogen atoms .[.and/or.]..Iadd., and
.Iaddend.one or two of the following .[.radicals.]. .Iadd.selected
from the group consisting of.Iaddend.: nitro, cyano,
C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl,
C.sub.1-C.sub.4-alkoxy, phenyl, C.sub.1-C.sub.4-haloalkoxy
and.[./or.]. C.sub.1-C.sub.4-alkylthio; C.sub.2-C.sub.6-alkyl which
carries one of the following .[.radicals.]. in position 2:
C.sub.1-C.sub.4-alkoxyimino, C.sub.3-C.sub.6-alkynyloxyimino,
C.sub.3-C.sub.6-haloalkenyloxyimino or benzyloxyimino;
C.sub.3-C.sub.6-alkenyl or C.sub.3-C.sub.6-alkynyl which may carry
one to five halogen atoms; phenyl which may carry .Iadd.one or more
substituents selected from the group consisting of: .Iaddend.one to
five halogen atoms .[.and/or.]..Iadd., and .Iaddend.one to three of
the following .[.radicals.]. .Iadd.selected from the group
consisting of.Iaddend.: nitro, cyano, C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-alkoxy,
C.sub.1-C.sub.4-haloalkoxy and.[./or.]. C.sub.1-C.sub.4-alkylthio;
a 5-membered heteroaromatic ring which is bonded via a nitrogen
atom and containing one to three nitrogen atoms, which may carry
.Iadd.one or more substituents selected from the group consisting
of: .Iaddend.one or two halogen atoms.Iadd., .Iaddend.and .[.or.].
one or two of the following .[.radicals.]. .Iadd.selected from the
group consisting of.Iaddend.: C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-alkoxy, phenyl,
C.sub.1-C.sub.4-haloalkoxy and.[./or.]. C.sub.1-C.sub.4-alkylthio;
a radical ##STR00020## where .[.R.sup.1.]. .Iadd.R.sup.11
.Iaddend.and R.sup.12, which may be identical or different are:
C.sub.1-C8-alkyl, C.sub.3-C.sub.6-alkenyl, C.sub.3-C.sub.6-alkynyl,
C.sub.3-C.sub.8-cycloalkyl, it being possible for these
.[.radicals.]. to carry .[.a.]. .Iadd.one or more substituents
selected from the group consisting of:
.Iaddend.C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-alkylthio.Iadd.,
.Iaddend.and.[./or.]. phenyl.Iadd., .Iaddend.which may carry
.Iadd.one or more substituents selected from the group consisting
of: .Iaddend.one to five halogen atoms .[.and/or.]..Iadd., and
.Iaddend.one to three of the following .[.radicals.].
.Iadd.selected from the group consisting of.Iaddend.: nitro, cyano,
C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl,
C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-haloalkoxy and.[./or.].
C.sub.1-C.sub.4alkylthio; phenyl which may carry one or more of the
following .[.radicals.]. .Iadd.selected from the group consisting
of.Iaddend.: halogen, nitro, cyano, C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-alkoxy,
C.sub.1-C.sub.4-haloalkoxy .[.or.]. .Iadd.and
.Iaddend.C.sub.1-C.sub.4-alkylthio; or R.sup.11 and R.sup.12
together form a C.sub.3-C.sub.12-alkylene chain which may carry one
to three C.sub.1-C.sub.4-alkyl groups and which may contain a
hetero atom selected from the group consisting of.Iadd.: a
.Iaddend.nitrogen, oxygen and sulfur; g) a radical ##STR00021##
where R.sup.13 is C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.6-alkenyl,
C.sub.3-C.sub.6-alkynyl, C.sub.3-C.sub.8-cycloalkyl, it being
possible for these .[.radicals.]. to carry .Iadd.one or more
substituents selected from the group consisting of: .Iaddend.a
C.sub.1-C.sub.4-alkoxy, .Iadd.a .Iaddend.C.sub.1-C.sub.4-alkylthio
.[.and/or a phenyl radical,.]. .Iadd.and a phenyl; .Iaddend.or
phenyl which may carry one or more of the following .[.radicals.].
.Iadd.selected from the group consisting of.Iaddend.: halogen,
nitro, cyano, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl,
C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-haloalkoxy .[.or.].
.Iadd.and .Iaddend.C.sub.1-C.sub.4-alkylthio.
.Iadd.12. The compound of the formula I as defined in claim 1,
wherein R is --CO.sub.2H or a radical which can be hydrolyzed to
--CO.sub.2H; R.sup.4 is phenyl; and R.sup.5 is phenyl..Iaddend.
.Iadd.13. The compound of the formula I as defined in claim 12,
wherein X is CH; Y is oxygen; Z is oxygen; R is --CO.sub.2H;
R.sup.2 is C.sub.1-C.sub.4-alkyl; R.sup.3 is C.sub.1-C.sub.4-alkyl;
and R.sup.6 is C.sub.1-C.sub.8-alkyl..Iaddend.
.Iadd.14. The compound of the formula I as defined in claim 13,
wherein R.sup.2 is methyl; and R.sup.3 is methyl..Iaddend.
.Iadd.15. The compound of the formula as defined in claim 1,
wherein R is formyl, --CO.sub.2H or a radical which can be
hydrolyzed to --CO.sub.2H; R.sup.2 is C.sub.1-C.sub.4-alkyl; X is
CR.sup.14, where R.sup.14 is hydrogen or C.sub.1-C.sub.5-alkyl;
R.sup.3 is C.sub.1-C.sub.4-alkyl; R.sup.4 and R.sup.5 which can be
identical or different, are phenyl, which can be substituted by one
or more of the following selected from the group consisting of:
halogen, nitro, hydroxyl, C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-alkoxy and C.sub.1-C.sub.4-alkylthio; or phenyl
which are connected together in the ortho positions by a direct
linkage, methylene, ethylene, ethenylene, oxygen, sulfur,
--SO.sub.2--, --NH-- or N-alkyl group; or
C.sub.3-C.sub.7-cycloalkyl; R.sup.6 is C.sub.1-C.sub.8-alkyl,
C.sub.3-C.sub.6-alkenyl or C.sub.3-C.sub.8-cycloalkyl, where each
of these can be substituted by one or more substituents selected
from the group consisting of: halogen, hydroxyl, nitro, cyano,
C.sub.1-C.sub.4-alkoxy, C.sub.3-C.sub.6-alkenyloxy and
C.sub.1-C.sub.4-alkylthio; or phenyl or naphthyl, each of which can
be substituted by one or more of the following selected from the
group consisting of: halogen, nitro, cyano, hydroxyl, amino,
C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl,
C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-haloalkoxy, phenoxy,
C.sub.1-C.sub.4-alkylthio, C.sub.1-C.sub.4-alkylamino and
C.sub.1-C.sub.4-dialkylamino; or a five- or six-membered
heteroaromatic moiety containing (i) a nitrogen atom, (ii) a sulfur
atom, (iii) an oxygen atom, (iv) a nitrogen atom and a sulfur atom,
or (v) a nitrogen atom and an oxygen atom, which heteroaromatic
moiety can carry one or more substituents selected from the group
consisting of: one to four halogen atoms, and one or two of the
following selected from the group consisting of:
C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl,
C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-alkylthio, phenyl, phenoxy
and phenylcarbonyl, it being possible for the phenyl in turn to
carry one or more substituents selected from the group consisting
of: one to five halogen atoms, and one to three of the following
selected from the group consisting of: C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-alkoxy and
C.sub.1-C.sub.4-alkylthio; Y is sulfur, oxygen or a single bond;
and Z is sulfur, oxygen, SO or SO.sub.2..Iaddend.
.Iadd.16. The compound of the formula I as defined in claim 15,
wherein R is --CO.sub.2H; R.sup.2 is C.sub.1-C.sub.4-alkyl; X is
CR.sup.14, where R.sup.14 is hydrogen; R.sup.3 is
C.sub.1-C.sub.4-alkyl; R.sup.4 and R.sup.5 which can be identical
or different, are phenyl, which can be substituted by one or more
of the following selected from the group consisting of: halogen,
nitro, hydroxyl, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkoxy and
C.sub.1-C.sub.4-alkylthio; R.sup.6 is C.sub.1-C.sub.8-alkyl, which
can by substituted by one or more substituents selected from the
group consisting of: halogen, hydroxyl, nitro, cyano,
C.sub.1-C.sub.4-alkoxy, C.sub.3-C.sub.6-alkenyloxy and
C.sub.1-C.sub.4-alkylthio; Y is oxygen; and Z is
oxygen..Iaddend.
.Iadd.17. The compound of the formula I as defined in claim 16,
where R.sup.4 and R.sup.5 are each phenyl..Iaddend.
.Iadd.18. The compound of the formula I as defined in claim 1,
wherein R is --CO.sub.2H or a radical which can be hydrolyzed to
--CO.sub.2H; R.sup.2 is C.sub.1-C.sub.4-alkyl; X is CR.sup.14,
where R.sup.14 is hydrogen; R.sup.3 is C.sub.1-C.sub.4-alkyl;
R.sup.4 and R.sup.5 which can be identical or different, are
phenyl, which can be substituted by one or more of the following
selected from the group consisting of: halogen, nitro, hydroxyl,
C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkoxy and
C.sub.1-C.sub.4-alkylthio; R.sup.6 is C.sub.1-C.sub.8-alkyl, which
can be substituted by one or more substitutents selected from the
group consisting of: halogen, hydroxyl, nitro, cyano,
C.sub.1-C.sub.4-alkoxy, C.sub.3-C.sub.6-alkenyloxy and
C.sub.1-C.sub.4-alkylthio; Y is oxygen; and Z is
oxygen..Iaddend.
.Iadd.19. The compound of the formula I as defined in claim 18,
where R.sup.4 and R.sup.5 are each phenyl..Iaddend.
.Iadd.20. The compound of the formula I as defined in claim 1,
wherein R is --CO.sub.2H; R.sup.2 is C.sub.1-C.sub.4-alkyl; X is
CR.sup.14, where R.sup.14 is hydrogen or C.sub.1-C.sub.5-alkyl;
R.sup.3 is C.sub.1-C.sub.4-alkyl; R.sup.4 and R.sup.5 are phenyl
which can be substituted by one or more halogen atoms; R.sup.6 is
C.sub.1-C.sub.8-alkyl or C.sub.3-C.sub.8-cycloalkyl, where each of
these can be substituted one or more times by phenyl, or phenyl; Y
is oxygen; and Z is sulfor or oxygen..Iaddend.
.Iadd.21. The compound of the formula I as defined in claim 1,
wherein R is --CO.sub.2H or a radical which can be hydrolyzed to
CO.sub.2H; R.sup.2 is halogen, C.sub.1-C.sub.4-alkyl or
C.sub.1-C.sub.4-haloalkyl; X is CR.sup.14, where R.sup.14 is
hydrogen or C.sub.1-C.sub.5-alkyl; R.sup.3 is halogen,
C.sub.1-C.sub.4-alkyl or C.sub.1-C.sub.4-haloalkyl; R.sup.4 and
R.sup.5 are phenyl, which can be substituted by one or more of the
following selected from the group consisting of: halogen, nitro,
C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl,
C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-alkylamino and
C.sub.1-C.sub.4-dialkylamino; R.sup.6 is hydrogen, or R.sup.6 is
C.sub.1-C.sub.8-alkyl or C.sub.3-C.sub.8-cycloalkyl, where each of
these can be substituted by one or more substituents selected from
the group consisting of: halogen, hydroxyl, C.sub.1-C.sub.4-alkoxy,
C.sub.1-C.sub.4-alkylthio and phenyl which is substituted by one or
more substituents selected from the group consisting of: halogen,
C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl,
C.sub.1-C.sub.4-alkoxy and C.sub.1-C.sub.4-alkylthio; or phenyl
which can be substituted by one or more of the following selected
from the group consisting of: halogen, nitro, hydroxyl,
C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkoxy,
C.sub.1-C.sub.4-alkylthio and dioxomethylene; or a five or
six-membered heteroaromatic moiety containing (i) one to three
nitrogen atoms, (ii) one sulfur atom, (iii) one oxygen atom, (iv)
one to three nitrogen atoms and one sulfur atom, or (v) one to
three nitrogen atoms and one oxygen atom which heteroaromatic
moiety can carry one to four halogen atoms; Y is sulfur or oxygen;
and Z is sulfur or oxygen..Iaddend.
.Iadd.22. The compound of claim 21, wherein R is --CO.sub.2H,
--COOCH.sub.3, --COON(CH.sub.3).sub.2, --COOCH.sub.2C.ident.CH,
--COOC.sub.2H.sub.5, --COON.dbd.C(CH.sub.3).sub.2, --COONH-phenyl,
--COOCH.dbd.CH.sub.2 or --CONH--SO--C.sub.6H.sub.5; R.sup.2 is
--Cl, --CH.sub.3, --CH.sub.2CH.sub.3 or --CF.sub.3; X is CR.sup.14,
where R.sup.14 is hydrogen; R.sup.3 is --Cl, --CH.sub.3,
--CH.sub.2CH.sub.3 or --CF.sub.3; R.sup.4 and R.sup.5 are phenyl,
which can be substituted by one or more groups selected from the
group consisting of: --F, --Cl, --Br, --CH.sub.3,
--CH.sub.2CH.sub.3, --CF.sub.3, --OCH.sub.3, --NO.sub.2 and
--N(CH.sub.3).sub.2; R.sup.6 is --H, --CH.sub.3,
--CH.sub.2CH.sub.3, --CH.sub.2CH.sub.2CH.sub.3,
--C(CH.sub.3).sub.3, --CH.sub.2CH(CH.sub.3).sub.2, cyclopropyl,
--CH.sub.2CH.sub.2CH.sub.2CH(CH.sub.3).sub.2,
--CH.sub.2--CH.sub.2--S--CH.sub.3, --CH.sub.2CH.sub.2OH, phenyl,
trifluoroethyl, p-isopropyl-phenyl, p-methyl-S-phenyl,
p-methyl-O-phenyl, m-ethyl-phenyl, o-methyl-phenyl, o-Cl-phenyl,
m-Br-phenyl, p-F-phenyl, p-methyl-phenyl, m-NO.sub.2-phenyl,
o-HO-phenyl, 3,4-dimethoxy-phenyl, 3,4-dioxomethylene-phenyl,
3,4,5-trimethoxy-phenyl, benzyl, o-Cl-benzyl, m-Br-benzyl,
p-F-benzyl, o-methyl-benzyl, m-ethyl-benzyl or p-isopropyl-benzyl;
Y is sulfur or oxygen; and Z is sulfur or oxygen..Iaddend.
.Iadd.23. The compound of claim 22, wherein R.sup.4 and R.sup.5 are
each phenyl..Iaddend.
.Iadd.24. A compound of the formula I: ##STR00022## where R is
--CO.sub.2H; R.sup.2 is C.sub.1-C.sub.4-alkyl; X is CR.sup.14,
where R.sup.14 is hydrogen; R.sup.3 is C.sub.1-C.sub.4-alkyl;
R.sup.4 and R.sup.5 which can be identical or different, are
phenyl, which can be substituted by one or more of the following
selected from the group consisting of: halogen, nitro, hydroxyl,
C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkoxy and
C.sub.1-C.sub.4-alkylthio; R.sup.6 is a C.sub.1-C.sub.8-alkyl,
which can be substituted by one or more substituents selected from
the group consisting of: halogen, hydroxyl, nitro, cyano,
C.sub.1-C.sub.4-alkoxy, C.sub.3-C.sub.6-alkenyloxy and
C.sub.1-C.sub.4-alkylthio; Y is oxygen; and Z is
oxygen..Iaddend.
.Iadd.25. The compound of the formula I as defined in claim 24,
wherein R.sup.4 and R.sup.5 are each phenyl..Iaddend.
Description
.Iadd.Two (2) reissue applications have been co-filed for the
reissue of U.S. Pat. No. 5,932,730. The reissue applications are
U.S. Ser. No. 12/481,594 (the present application) and U.S. Ser.
No. 12/481,598 (a co-filed reissue application), all of which are
co-filed reissues of U.S. Pat. No. 5,932,730..Iaddend.
The present invention relates to novel carboxylic acid derivatives,
their preparation and use.
Endothelin is a peptide which is composed of 21 amino acids and is
synthesized and released by the vascular endothelium. Endothelin
exists in three isoforms, ET-1, ET-2 and ET-3. In the following
text, "endothelin" or "ET" signifies one or all isoforms of
endothelin. Endothelin is a potent vasoconstrictor and has a potent
effect on vessel tone. It is known that this vasoconstriction is
caused by binding of endothelin to its receptor (Nature, 332,
(1988) 411-415; FEBS Letters, 231, (1988) 440-444 and Biochem.
Biophys. Res. Commun., 154, (1988) 868-875).
Increased or abnormal release of endothelin causes persistent
vasoconstruction in the peripheral, renal and cerebral blood
vessels, which may lead to illnesses. It has been reported in the
literature that elevated plasma levels of endothelin were found in
patients with hypertension, acute myocardial infarct, pulmonary
hypertension, Raynaud's syndrome, atherosclerosis and in the
airways of asthmatics (Japan J. Hypertension, 12, (1989) 79, J.
Vascular Med. Biology 2, (1990) 207, J. Am. Med. Association 264,
(1990) 2868).
Accordingly, substances which specifically inhibit the binding of
endothelin to the receptor ought also to antagonize the various
abovementioned physiological effects of endothelin and therefore be
valuable drugs.
We have found that certain carboxylic acid derivatives are good
inhibitors of endothelin receptors.
The invention relates to carboxylic acid derivatives of the formula
I
##STR00002## where R is formyl, tetrazole .[.[sic].]., nitrile
.[.[sic].]., .[.a COOH group.]. .Iadd.--COOH .Iaddend.or a radical
which can be hydrolyzed to .Iadd.--.Iaddend.COOH, and the other
substituents have the following meanings: R.sup.2 .Iadd.is
.Iaddend.hydrogen, hydroxyl, .Iadd.--.Iaddend.NH.sub.2,
.Iadd.--.Iaddend.NH(C.sub.1-C.sub.4-alkyl),
.Iadd.--.Iaddend.N(C.sub.1-C.sub.4-alkyl).sub.2, halogen,
C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl,
C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-haloalkoxy or
C.sub.1-C.sub.4-alkylthio; X .Iadd.is .Iaddend.nitrogen or
CR.sup.14 where R.sup.14 is hydrogen or .[.C.sub.1-5.].
.Iadd.C.sub.1-C.sub.5.Iaddend.-alkyl, or CR.sup.14 forms together
with CR.sup.3 a 5- or 6-membered alkylene or alkenylene ring which
can be substituted by one or two .[.C.sub.1-4.].
.Iadd.C.sub.1-C.sub.4.Iaddend.-alkyl groups and in which in each
case a methylene group can be replaced by oxygen, sulfur,
--NH.Iadd.--.Iaddend. or
--N.[.C.sub.1-4.]..Iadd.(C.sub.1-C.sub.4.Iaddend.-alkyl.Iadd.)--.Iadde-
nd.; R.sup.3 .Iadd.is .Iaddend.hydrogen, hydroxyl,
.Iadd.--.Iaddend.NH.sub.2,
.Iadd.--.Iaddend.NH(C.sub.1-C.sub.4-.[.Alkyl.].
.Iadd.alkyl.Iaddend.),
.Iadd.--.Iaddend.N(C.sub.1-C.sub.4-alkyl).sub.2, halogen,
C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl,
C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-haloalkoxy,
--NH--O--.[.C.sub.1-4.]..Iadd.C.sub.1-C.sub.4.Iaddend.-alkyl,
C.sub.1-C.sub.4-alkylthio or CR.sup.3 is linked to CR.sup.14 as
indicated above to give a 5- or 6-membered ring; R.sup.4 and
R.sup.5 (which can be identical or different) .Iadd.are.Iaddend.:
phenyl or naphthyl, which can be substituted by one or more of the
following radicals: halogen, nitro, cyano, hydroxyl,
C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl,
C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-haloalkoxy, phenoxy,
C.sub.1-C.sub.4-alkylthio, amino, C.sub.1-C.sub.4-alkylamino or
C.sub.1-C.sub.4-dialkylamino; or phenyl or naphthyl, which are
connected together in the ortho positions via a direct linkage, a
methylene, ethylene or ethenylene group, an oxygen or sulfur atom
or an .Iadd.--.Iaddend.SO.sub.2--, .Iadd.--.Iaddend.NH-- or N-alkyl
group, or C.sub.3-C.sub.7-cycloalkyl; R.sup.6 .Iadd.is
.Iaddend.hydrogen, C.sub.1-C.sub.8-alkyl, C.sub.3-C.sub.6-alkenyl,
C.sub.3-C.sub.6-alkynyl or C.sub.3-C.sub.8-cycloalkyl, where each
of these radicals can be substituted one or more times by: halogen,
nitro, cyano, C.sub.1-C.sub.4-alkoxy, C.sub.3-C.sub.6-alkenyloxy,
C.sub.3-C.sub.6-alkynyloxy, C.sub.1-C.sub.4-alkylthio,
C.sub.1-C.sub.4-haloalkoxy, C.sub.1-C.sub.4-alkylcarbonyl,
C.sub.1-C.sub.4-alkoxycarbonyl, .[.C.sub.3-8.].
.Iadd.C.sub.3-C.sub.8.Iaddend.-alkylcarbonylalkyl,
C.sub.1-C.sub.4-alkylamino, di-C.sub.1-C.sub.4-alkylamino, phenyl
or phenyl or phenoxy which is substituted one or more times,
.[.eg..]. .Iadd.e.g., .Iaddend.one to three times, by halogen,
.[.mitro.]. .Iadd.nitro.Iaddend., cyano, C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-alkoxy,
C.sub.1-C.sub.4-haloalkoxy or C.sub.1-C.sub.4-alkylthio; phenyl or
naphthyl, each of which can be substituted by one or more of the
following radicals: halogen, nitro, cyano, hydroxyl, amino,
C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl,
C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-haloalkoxy, phenoxy,
C.sub.1-C.sub.4-alkylthio, C.sub.1-C.sub.4-alkylamino,
C.sub.1-C.sub.4-dialkylamino, dioxomethylene .[.[sic].]. or
dioxoethylene .[.[sic].].; .Iadd.or.Iaddend. a five- or
six-membered heteroaromatic moiety containing one to three nitrogen
atoms and/or one sulfur or oxygen atom, which can carry one to four
halogen atoms and/or one or two of the following radicals:
C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl,
C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-haloalkoxy,
C.sub.1-C.sub.4-alkylthio, phenyl, phenoxy or phenylcarbonyl, it
being possible for the phenyl radicals in turn to carry one to five
halogen atoms and/or one to three of the following radicals:
C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl,
C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-haloalkoxy and/or
C.sub.1-C.sub.4-alkylthio; with the proviso that R.sup.6 can be
hydrogen only when Z is not a single bond; Y .Iadd.is
.Iaddend.sulfur .[.or.]..Iadd., .Iaddend.oxygen or a single bond; Z
.Iadd.is .Iaddend.sulfur .[.or.]..Iadd., .Iaddend.oxygen or a
single bond.
The compounds, and the intermediates for preparing them, such as IV
and VI, may have one or more asymmetrical substituted carbon atoms.
Such compounds may be in the form of the pure enantiomers or pure
diastereomers or a mixture thereof. The use of an enantiomerically
pure compound as active substance is preferred.
The invention furthermore relates to the use of the above-mentioned
carboxylic acid derivatives for producing drugs, in particular for
producing endothelin receptor inhibitors.
The invention furthermore relates to the preparation of the
compounds of the formula IV in enantiomerically pure form.
Enantioselective epoxidation of an olefin with two phenyl
substituents is known (J. Org. Chem. 59, 1994, 4378-4380). We have
now found, surprisingly, that even ester groups in these systems
permit epoxidation in high optical purity.
The preparation of the compounds according to the invention where Z
is sulfur or oxygen starts from the epoxides IV, which are obtained
in a conventional manner, .[.eg..]. .Iadd.e.g., .Iaddend.as
described in J. March, Advanced Organic Chemistry, 2nd ed., 1983,
page 862 and page 750, from the ketones II or the olefins III:
##STR00003##
Carboxylic acid derivatives of the general formula VI can be
prepared by reacting the epoxides of the general formula IV
(.[.eg..]. .Iadd.e.g., .Iaddend.with R.dbd.ROOR.sup.10 .[.[sic].].)
with alcohols or thiols of the general formula V where R.sup.6 and
Z have the meanings stated in claim 1.
##STR00004##
To do this, compounds of the general formula IV are heated with
compounds of the formula V, in the molar ratio of about 1:1 to 1:7,
preferably 1 to 3 mole equivalents, to 50-200.degree. C.,
preferably 80-150.degree. C.
The reaction can also take place in the presence of a diluent. All
solvents which are inert toward the reagents used can be used for
this purpose.
Examples of such solvents or diluents are water, aliphatic,
alicyclic and aromatic hydrocarbons, which may in each case be
chlorinated, such as hexane, cyclohexane, petroleum ether, naphtha,
benzene, toluene, xylene, methylene chloride, chloroform, carbon
tetrachloride, ethyl chloride and trichloroethylene, ethers such as
diisopropyl ether, dibutyl ether, methyl tert-butyl ether,
propylene oxide, dioxane and tetrahydrofuran, ketones such as
acetone, methyl ethyl ketone, methyl isopropyl ketone and methyl
isobutyl ketone, nitriles such as acetonitrile and propionitrile,
alcohols, such as methanol, ethanol, isopropanol, butanol and
ethylene glycol, esters such as ethyl acetate and amyl acetate,
amides such as dimethylformamide, dimethylacetamide and
N-methylpyrrolidone, sulfoxides and sulfones, such as dimethyl
sulfoxide and sulfolane, bases such as pyridine, cyclic ureas such
as 1,3-dimethylimidazolidin-2-one and
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone.
The reaction is preferably carried out at a temperature in the
range from 0.degree. C. to the boiling point of the solvent or
mixture of solvents.
The presence of a catalyst may be advantageous. Suitable catalysts
are strong organic and inorganic acids, and Lewis acids. Examples
thereof are, inter alia, sulfuric acid, hydrochloric acid,
trifluoroacetic acid, p-toluenesulfonic acid, boron trifluoride
etherate and titanium(IV) alcoholates.
Compounds of the formula VI where R.sup.4 and R.sup.5 are
cycloalkyl can also be prepared by subjecting compounds of the
formula VI where R.sup.4 and R.sup.5 are phenyl, naphthyl, or
phenyl or naphthyl substituted as described above, to a nuclear
hydrogenation.
Compounds of the formula VI can be obtained in enantiomerically
pure form by starting from enantiomerically pure compounds of the
formula IV and reacting them in the manner described with compounds
of the formula V.
It is furthermore possible to obtain enantiomerically pure
compounds of the formula VI by carrying out a classical racemate
resolution on racemic or diastereomeric compounds of the formula VI
using suitable enantiomerically pure bases such as brucine,
strychnine, quinine, quinidine, chinchonidine .[.[sic].].,
chinchonine .[.[sic].]., yohimbine, morphine, dehydroabietylamine,
ephedrine (-), (+), deoxyephedrine (+), (-),
threo-2-amino-1-(p-nitrophenyl)-1,3-propanediol (+), (-),
threo-2-(N,N-dimethylamino)-1-(p-nitrophenyl)-1,3-propanediol (+),
(-) threo-2-amino-1-phenyl-1,3-propanediol (+), (-),
.alpha.-methylbenzylamine (+), (-), .alpha.-(1-naphthyl)ethylamine
(+), (-), .alpha.-(2-naphthyl)ethylamine (+), (-),
aminomethylpinane, N,N-dimethyl-1-phenylethylamine,
N-methyl-1-phenylethylamine, 4-nitrophenylethylamine,
pseudoephedrine, norephedrine, norpseudoephedrine, amino acid
derivatives, peptide derivatives.
The compounds according to the invention where Y is oxygen, and the
remaining substituents have the meanings stated under the general
formula I, can be prepared, for example, by reacting the carboxylic
acid derivatives of the general formula VI where the substituents
have the stated meanings with compounds of the general formula
VII
##STR00005## where R.sup.15 is halogen or R.sup.16--SO.sub.2--,
where R.sup.16 can be C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-haloalkyl or phenyl. The reaction preferably takes
place in one of the abovementioned inert diluents with the addition
of a suitable base, .[.ie..]. .Iadd.i.e., .Iaddend.of a base which
deprotonates the intermediate VI, in a temperature range from room
temperature to the boiling point of the solvent.
Compounds of the formula VII are known, some of them can be bought,
or they can be prepared in a generally known manner.
It is possible to use as .Iadd.a .Iaddend.base an alkali metal or
alkaline earth metal hydride such as sodium hydride, potassium
hydride or calcium hydride, a carbonate such as an alkali metal
carbonate, .[.eg..]. .Iadd.e.g., .Iaddend.sodium or potassium
carbonate, an alkali metal or alkaline earth metal hydroxide such
as sodium or potassium hydroxide, an organometallic compound such
as butyllithium, or an alkali metal amide such as lithium
diisopropylamide.
The compounds according to the invention where Y is sulfur, and the
remaining substituents have the meanings stated under the general
formula I, can be prepared, for example, by reacting carboxylic
acid derivatives of the general formula VIII, which can be obtained
in a known manner from compounds of the general formula VI and in
which the substituents have the abovementioned meanings, with
compounds of the general formula IX, where R.sup.2, R.sup.3 and X
have the meanings stated under general formula I.
##STR00006##
The reaction preferably takes place in one of the above-mentioned
inert diluents with the addition of a suitable base, .[.ie..].
.Iadd.i.e., .Iaddend.a base which deprotonates the intermediate IX,
in a temperature range from room temperature to the boiling point
of the solvent.
It is possible to use as .Iadd.a .Iaddend.base, besides those
mentioned above, organic bases such as triethylamine, pyridine,
imidazole or diazabicycloundecane .[.[sic].]..
Carboxylic acid derivatives of the formula VIa (z in formula
VI=direct linkage) can be prepared by reacting epoxides of the
formula IV with cuprates of the formula XI:
##STR00007##
The cuprates can be prepared as described in Tetrahedron Letters
23, (1982) 3755.
Compounds of the formula I can also be prepared by starting from
the corresponding carboxylic acids, .[.ie..]. .Iadd.i.e.,
.Iaddend.compounds of the formula I where R is COOH, and initially
converting these in a conventional manner into an activated form,
such as a halide, an anhydride or imidazolide, and then reacting
the latter with an appropriate hydroxy compound HOR.sup.10. This
reaction can be carried out in the usual solvents and often
requires addition of a base, in which case those mentioned above
are suitable. These two steps can also be simplified, for example,
by allowing the carboxylic acid to act on the hydroxy compound in
the presence of a dehydrating agent such as a carbodiimide.
In addition, it is also possible for compounds of the formula I to
be prepared by starting from the salts of the corresponding
carboxylic acids, .[.ie..]. .Iadd.i.e., .Iaddend.from compounds of
the formula I where R is COR.sup.1 and R.sup.1 is OM, where M can
be an alkali metal cation or the equivalent of an alkaline earth
metal cation. These salts can be reacted with many compounds of the
formula R.sup.1-A where A is a conventional nucleofugic leaving
group, for example halogen such as chlorine, bromine, iodine or
aryl- or alkylsulfonyl which is unsubstituted or substituted by
halogen, alkyl or haloalkyl, such as toluenesulfonyl and
methylsulfonyl, or another equivalent leaving group. Compounds of
the formula R.sup.1-A with a reactive substituent A are known or
can be easily obtained with general expert knowledge. This reaction
can be carried out in conventional solvents and advantageously
takes place with the addition of a base, in which case those
mentioned above are suitable.
The radical R in formula I may vary widely. For example, R is a
group
##STR00008## where R.sup.1 has the following meanings: a) hydrogen;
b) succinylimidoxy .[.[sic].].; c) a five-membered heteroaromatic
moiety linked by a nitrogen atom, such as pyrrolyl, pyrazolyl,
imidazolyl and triazolyl, which may carry one or two halogen atoms,
in particular fluorine and chlorine and/or one or two of the
following radicals: C.sub.1-C.sub.4-alkyl such as methyl, ethyl,
1-propyl, 2-propyl, 2-methyl-2-propyl, 2-methyl-1-propyl, 1-butyl,
2-butyl; C.sub.1-C.sub.4-haloalkyl, in particular
C.sub.1-C.sub.2-haloalkyl such as fluoromethyl, difluoromethyl,
trifluoromethyl, chlorodifluoromethyl, dichlorofluoromethyl,
trichloromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl,
2,2,2-trifluoroethyl, 2-chloro-2,2-difluoroethyl,
2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl and
pentafluoroethyl; C.sub.1-C.sub.4-haloalkoxy, in particular
C.sub.1-C.sub.2-haloalkoxy such as difluoromethoxy,
trifluoromethoxy, chlorodifluoromethoxy, 1-fluoroethoxy,
2-fluoroethoxy, 2,2-difluoroethoxy, 1,1,2,2-tetrafluoroethoxy,
2,2,2-trifluoroethoxy, 2-chloro-1,1,2-trifluoroethoxy and
pentafluoroethoxy, in particular trifluoromethoxy;
C.sub.1-C.sub.4-alkoxy such as methoxy, ethoxy, propoxy,
1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy,
1,1-dimethylethoxy, in particular methoxy, ethoxy, 1-methylethoxy;
C.sub.1-C.sub.4-alkylthio such as methylthio, ethylthio,
propylthio, 1-methylethylthio, butylthio, 1-methylpropylthio,
2-methylpropylthio, 1,1-dimethylethylthio, in particular methylthio
and ethylthio; d) R.sup.1 .Iadd.is .Iaddend.furthermore a
radical
##STR00009## where m is 0 or 1 and R.sup.7 and R.sup.8, which can
be identical or different, have the following meanings:
hydrogen.Iadd.;.Iaddend. C.sub.1-C.sub.8-alkyl, in particular
C.sub.1-C.sub.4-alkyl as mentioned above; C.sub.3-C.sub.6-alkenyl
such as 2-propenyl, 2-butenyl, 3-butenyl, 1-methyl-2-propenyl,
2-methyl-2-propenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl,
1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl,
1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl,
1,1-dimethyl-2-propenyl, 1,2-dimethyl-2-propenyl,
1-ethyl-2-propenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl,
1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl,
4-methyl-2-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl,
1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl,
4-methyl-4-pentenyl, 1,1-dimethyl-2-butenyl,
1,1-dimethyl-3-butenyl, 1,2-dimethyl-2-butenyl,
1,2-dimethyl-3-butenyl, 1,3-dimethyl-2-butenyl,
1,3-dimethyl-3-butenyl, 2,2-dimethyl-3-butenyl,
2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl, 1-ethyl-2-butenyl,
1-ethyl-3-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl,
1,1,2-trimethyl-2-propenyl, 1-ethyl-1-methyl-2-propenyl and
1-ethyl-2-methyl-2-propenyl, in particular 2-propenyl, 2-butenyl,
3-methyl-2-butenyl and 3-methyl-2-pentenyl; C.sub.3-C.sub.6-alkynyl
such as 2-propynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl,
2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-3-butynyl,
2-methyl-3-butynyl, 1-methyl-2-butynyl, 1,1-dimethyl-2-propynyl,
1-ethyl-2-propynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl,
1-methyl-2-pentynyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl,
1-methyl-4-pentynyl, 2-methyl-3-pentynyl, 2-methyl-4-pentynyl,
3-methyl-4-pentynyl, 4-methyl-2-pentynyl, 1,1-dimethyl-2-butynyl,
1,1-dimethyl-3-butynyl, 1,2-dimethyl-3-butynyl,
2,2-dimethyl-3-butynyl, 1-ethyl-2-butynyl, 1-ethyl-3-butynyl,
2-ethyl-3-butynyl and 1-ethyl-1-methyl-2-propynyl, preferably
2-propynyl, 2-butynyl, 1-methyl-2-propynyl and 1-methyl-2-butynyl,
in particular 2-propynyl.Iadd.; or.Iaddend.
C.sub.3-C.sub.8-cycloalkyl such as cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl .[.and.]..Iadd., .Iaddend.cycloheptyl,
.Iadd.and .Iaddend.cyclooctyl, where these alkyl, cycloalkyl,
alkenyl and alkynyl groups can each carry one to five halogen
atoms, in particular fluorine or chlorine and/or one or two of the
following groups: C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkoxy,
C.sub.1-C.sub.4-alkylthio, C.sub.1-C.sub.4-haloalkoxy as mentioned
above, C.sub.3-C.sub.6-alkenyloxy, C.sub.3-C.sub.6-alkenylthio,
C.sub.3-C.sub.6-alkynyloxy, C.sub.3-C.sub.6-alkynylthio, where the
alkenyl and alkynyl constituents present in these radicals
preferably have the abovementioned meanings;
C.sub.1-C.sub.4-alkylcarbonyl such as, in particular,
methylcarbonyl, ethylcarbonyl, propylcarbonyl,
1-methylethylcarbonyl, butylcarbonyl, 1- methylpropylcarbonyl,
2-methylpropylcarbonyl, 1,1-dimethylethylcarbonyl;
C.sub.1-C.sub.4-alkoxycarbonyl such as methoxycarbonyl,
ethoxycarbonyl, propyloxycarbonyl, 1-methylethoxycarbonyl,
butyloxycarbonyl, 1-methylpropyloxycarbonyl,
2-methylpropyloxycarbonyl, 1,1-dimethylethoxycarbonyl;
C.sub.3-C.sub.6-alkenylcarbonyl, C.sub.3-C.sub.6-alkynylcarbonyl,
C.sub.3-C.sub.6-alkenyloxycarbonyl and
C.sub.3-C.sub.6-alkynyloxycarbonyl, where the alkenyl and alkynyl
radicals are preferably defined as detailed above; phenyl,
unsubstituted or substituted one or more times, .[.eg..].
.Iadd.e.g., .Iaddend.one to three times, by halogen, nitro, cyano,
C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl,
C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-haloalkoxy or
C.sub.1-C.sub.4-alkylthio, such as 2-fluorophenyl, 3-chlorophenyl,
4-bromophenyl, 2-methylphenyl, 3-nitrophenyl, 4-cyanophenyl,
2-trifluoromethylphenyl, 3-methoxyphenyl, 4-trifluoroethoxyphenyl,
2-methylthiophenyl, 2,4-dichlorophenyl, 2-methoxy-3-methylphenyl,
2,4-dimethoxyphenyl, 2-nitro-5-cyanophenyl, 2,6-difluorophenyl;
di-C.sub.1-C.sub.4-alkylamino such as, in particular,
dimethylamino, dipropylamino, N-propyl-N-methylamino,
N-propyl-N-ethylamino, diisopropylamino, N-isopropyl-N-methylamino,
N-isopropyl-N-ethylamino, N-isopropyl-N-propylamino; R.sup.7 and
.[.R8.]. .Iadd.R.sup.8 are .Iaddend.furthermore phenyl which can be
substituted by one or more, .[.eg..]. .Iadd.e.g., .Iaddend.one to
three, of the following radicals: halogen, nitro, cyano,
C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl,
C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-haloalkoxy or
C.sub.1-C.sub.4-alkylthio, as mentioned above in particular; or
R.sup.7 and R.sup.8 together form a C.sub.4-C.sub.7-alkylene chain
which is closed to form a ring, is unsubstituted or substituted,
.[.eg..]. .Iadd.e.g., .Iaddend.substituted by
C.sub.1-C.sub.4-alkyl, and may contain a heteroatom selected from
the group consisting of oxygen, sulfur or nitrogen, such as
--(CH.sub.2).sub.4--, --(CH.sub.2).sub.5--, --(CH.sub.2).sub.6--,
--(CH.sub.2).sub.7--, --(CH.sub.2).sub.2--O--(CH.sub.2).sub.2--,
--CH.sub.2--S--(CH.sub.2).sub.3--,
--(CH.sub.2).sub.2--O--(CH.sub.2).sub.3--,
--NH--(CH.sub.2).sub.3--, --CH.sub.2--NH--(CH.sub.2).sub.2--,
--CH.sub.2--CH.dbd.CH--CH.sub.2--,
--CH.dbd.CH--(CH.sub.2)--.sub.3--; e) R.sup.1 .Iadd.is
.Iaddend.furthermore a group
##STR00010## where k is 0, 1 and 2.[.,.]..Iadd.;.Iaddend. p is 1,
2, 3 and 4.Iadd.; .Iaddend.and R.sup.9 is C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-haloalkyl, C.sub.3-C.sub.6-alkenyl,
C.sub.3-C.sub.6-alkynyl or unsubstituted or substituted phenyl, as
mentioned above in particular.[...]..Iadd.;.Iaddend. f) R.sup.1
.Iadd.is .Iaddend.furthermore a radical OR.sup.10, where R.sup.10
is: hydrogen, the cation of an alkali metal such as lithium,
sodium, potassium or the cation of an alkaline earth metal such as
calcium, magnesium and barium or an environmentally compatible
organic ammonium ion such as tertiary C.sub.1-C.sub.4-alkylammonium
or the ammonium ion; C.sub.3-C.sub.8-cycloalkyl as mentioned above,
which may carry one to three C.sub.1-C.sub.4-alkyl groups;
C.sub.1-C.sub.8-alkyl such as, in particular, methyl, ethyl,
propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl,
1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl,
3-methylbutyl, 1,2-dimethylpropyl, 1,1-dimethylpropyl,
2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-methylpentyl,
2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,2-dimethylbutyl,
1,3-dimethylbutyl, 2,3-dimethylbuty 1,1-dimethylbutyl,
2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,1,2-trimethylpropyl,
1,2,2-trimethylpropyl, 1-ethylbutyl, 2-ethylbutyl,
1-ethyl-2-methylpropyl, which can carry one to five halogen atoms,
in particular fluorine and chlorine and/or one of the following
radicals: C.sub.1-C.sub.4alkoxy, C.sub.1-C.sub.4-alkylthio, cyano,
C.sub.1-C.sub.4-alkylcarbonyl, C.sub.3-C.sub.8-cycloalkyl,
C.sub.1-C.sub.4-alkoxycarbonyl, phenyl, phenoxy or phenylcarbonyl,
where the aromatic radicals in turn can carry in each case one to
five halogen atoms and/or one to three of the following radicals:
nitro, cyano, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl,
C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-haloalkoxy and/or
C.sub.1-C.sub.4-alkylthio, as mentioned above in particular;
.[.a.]. C.sub.1-C.sub.8-alkyl as mentioned above, which can carry
one to five halogen atoms, in particular fluorine and/or chlorine,
and carries one of the following radicals: a 5-membered
heteroaromatic moiety containing one to three nitrogen atoms, or a
5-membered heteroaromatic moiety containing a nitrogen atom and an
oxygen or sulfur atom, which can carry one to four halogen atoms
and/or one or two of the following radicals: nitro, cyano,
C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl,
C.sub.1-C.sub.4-alkoxy, phenyl, C.sub.1-C.sub.4-haloalkoxy and/or
C.sub.1-C.sub.4-alkylthio. Particular mention may be made of:
1-pyrazolyl, 3-methyl-1-pyrazolyl, 4-methyl-1-pyrazolyl,
3,5-dimethyl-1-pyrazolyl, 3-phenyl-1-pyrazolyl,
4-phenyl-1-pyrazolyl, 4-chloro-1-pyrazolyl, 4-bromo-1-pyrazolyl,
1-imidazolyl, 1-benzimidazolyl, 1,2,4-triazol-1-yl,
3-methyl-1,2,4-triazol-1-yl, 5-methyl-1,2,4-triazol-1-yl,
1-benzotriazolyl, 3-isopropyl-5-isoxazolyl, 3-methyl-5-isoxazolyl,
2-oxazolyl, 2-thiazolyl, 2-imidazolyl, 3-ethyl-5-isoxazolyl,
3-phenyl-5-isoxazolyl, 3-tert-butyl-5-isoxazolyl; .[.a.].
C.sub.2-C.sub.6-alkyl .[.group.]. which carries one of the
following radicals in position 2: C.sub.1-C.sub.4-alkoxyimino,
C.sub.3-C.sub.6-alkynyloxyimino,
C.sub.3-C.sub.6-haloalkenyloxyimino or benzyloxyimino;
.Iadd.or.Iaddend. .[.a.]. C.sub.3-C.sub.6-alkenyl or
C.sub.3-C.sub.6-alkynyl .[.group.]., it being possible for these
groups in turn to carry one to five halogen atoms; R.sup.10
.Iadd.is .Iaddend.furthermore a phenyl radical which can carry one
to five halogen atoms and/or one to three of the following
radicals: nitro, cyano, C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-alkoxy,
C.sub.1-C.sub.4-haloalkoxy and/or C.sub.1-C.sub.4-alkylthio, as
mentioned above in particular; a 5-membered heteroaromatic moiety
which is linked via a nitrogen atom, contains one to three nitrogen
atoms and can carry one or two halogen atoms and/or one or two of
the following radicals: C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-alkoxy, phenyl,
C.sub.1-C.sub.4-haloalkoxy and/or C.sub.1-C.sub.4-alkylthio.
Particular mention may be made of: 1-pyrazolyl,
3-methyl-1-pyrazolyl, 4-methyl-1-pyrazolyl,
3,5-dimethyl-1-pyrazolyl, 3-phenyl-1-pyrazolyl,
4-phenyl-1-pyrazolyl, 4-chloro-1-pyrazolyl, 4-bromo-1-pyrazolyl,
1-imidazolyl, 1-benzimidazolyl, 1,2,4-triazol-1-yl,
3-methyl-1,2,4-triazol-1-yl, 5-methyl-1,2,4-triazol-1-yl,
1-benzotriazolyl, 3,4-dichloro-1-imidazolyl; R.sup.10 .Iadd.is
.Iaddend.furthermore a group
##STR00011## where R.sup.11 and R.sup.12, which can be identical or
different, are: C.sub.1-C.sub.8-alkyl, C.sub.3-C.sub.6-alkenyl,
C.sub.3-C.sub.6-alkynyl, C.sub.3-C.sub.8-cycloalkyl, it being
possible for these radicals to carry a C.sub.1-C.sub.4-alkoxy,
C.sub.1-C.sub.4-alkylthio and/or an unsubstituted or substituted
phenyl radical, as mentioned above in particular; phenyl which can
be substituted by one or more, .[.eg..]. .Iadd.e.g., .Iaddend.one
to three, of the following radicals: halogen, nitro, cyano,
C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl,
C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-haloalkoxy or
C.sub.1-C.sub.4-alkylthio, where these radicals are, in particular,
those mentioned above; or R.sup.11 and R.sup.12 together form a
C.sub.3-C.sub.12-alkylene chain which can carry one to three
C.sub.1-C.sub.4-alkyl groups and contain a heteroatom from the
group consisting of oxygen, sulfur and nitrogen, as mentioned in
particular for R.sup.7 and R.sup.8.[...]..Iadd.;.Iaddend. g)
R.sup.1 .Iadd.is .Iaddend.furthermore a radical
##STR00012## where R.sup.13 is: C.sub.1-C.sub.4-alkyl,
C.sub.3-C.sub.6-alkenyl, C.sub.3-C.sub.6-alkynyl,
C.sub.3-C.sub.8-cycloalkyl as mentioned above in particular, it
being possible for these radicals to carry a
C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-alkylthio and/or a phenyl
radical as mentioned above; .Iadd.or.Iaddend. phenyl, unsubstituted
or substituted, in particular as mentioned
above.[...]..Iadd.;.Iaddend. h) R.sup.1 .Iadd.is .Iaddend.a
radical
##STR00013## where R.sup.13 has the abovementioned meaning. R can
furthermore be: tetrazole .[.[sic].]. or nitrile .[.[sic].]..
In respect of the biological effect, preferred carboxylic acid
derivatives of the general formula I, both as pure enantiomers and
pure diastereomers or as mixture thereof, are those where the
substituents have the following meanings: R.sup.2 .Iadd.is
.Iaddend.hydrogen, hydroxyl, N(C.sub.1-C.sub.4-alkyl).sub.2,
.[.the.]. C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl,
C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-haloalkoxy,
C.sub.1-C.sub.4-alkylthio groups and halogen atoms mentioned in
detail for R.sup.1, especially chlorine, methyl, methoxy, ethoxy,
difluoromethoxy, trifluoromethoxy; X .Iadd.is .Iaddend.nitrogen or
CR.sup.14 where R.sup.14 is hydrogen or alkyl, or CR.sup.14 forms
together with CR.sup.3 a 4- to 5-membered alkylene or alkenylene
ring in which, in each case, a methylene group can be replaced by
oxygen or sulfur, such as --CH.sub.2--CH.sub.2--O--,
--CH.dbd.CH--O--, --CH.sub.2--CH.sub.2--CH.sub.2--O--,
--CH.dbd.CH--CH.sub.2O--, in particular hydrogen,
--CH.sub.2--CH.sub.2--O--, --CH(CH.sub.3)--CH(CH.sub.3)--O--,
--C(CH.sub.3).dbd.C(CH.sub.3)--O--, --CH.dbd.C(CH.sub.3)--O-- or
--C(CH.sub.3).dbd.C(CH.sub.3)--S.Iadd.--.Iaddend.; R.sup.3
.[.the.]. .Iadd.is .Iaddend.hydrogen, hydroxyl,
N(C.sub.1-C.sub.4-alkyl).sub.2, C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-alkoxy,
C.sub.1-C.sub.4-haloalkoxy, C.sub.1-C.sub.4-alkylthio groups and
halogen atoms mentioned for R.sup.1, especially chlorine, methyl,
methoxy, ethoxy, difluoromethoxy, trifluoromethoxy or .Iadd.R.sup.3
.Iaddend.is linked to R.sup.14 as mentioned above to give a 5- or
6-membered ring; R.sup.4 and R.sup.5 .Iadd.are .Iaddend.phenyl or
naphthyl, which can be substituted by one or more, .[.eg..].
.Iadd.e.g., .Iaddend.one to three, of the following radicals:
halogen, nitro, cyano, hydroxyl, mercapto, amino,
C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl,
C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-haloalkoxy,
C.sub.1-C.sub.4-alkylthio, C.sub.1-C.sub.4-alkylamino,
di-C.sub.1-C.sub.4-alkylamino, C.sub.1-C.sub.4-alkylcarbonyl,
C.sub.1C.sub.4-alkoxycarbonyl; phenyl or naphthyl, which are
connected together in the ortho positions by a direct linkage, a
methylene, ethylene or ethenylene group, an oxygen or sulfur atom
or an .Iadd.--.Iaddend.SO.sub.2.Iadd.--.Iaddend.,
.Iadd.--.Iaddend.NH.Iadd.--.Iaddend. .[.or.]..Iadd.,
.Iaddend.N-alkyl group, or C.sub.3-C.sub.7-cycloalkyl; R.sup.6
.Iadd.is .Iaddend.C.sub.1-C.sub.8-alkyl, C.sub.3-C.sub.6-alkenyl,
C.sub.3-C.sub.6-alkynyl or C.sub.3-C.sub.8-cycloalkyl as mentioned
above in particular, it being possible for these radicals in each
case to be substituted one or more times by: halogen, hydroxyl,
nitro, cyano, C.sub.1-C.sub.4-alkoxy, C.sub.3-C.sub.6-alkenyloxy,
C.sub.3-C.sub.6-alkynyloxy, C.sub.1-C.sub.4-alkylthio,
C.sub.1-C.sub.4-haloalkoxy, C.sub.1-C.sub.4-alkylcarbonyl,
hydroxycarbonyl, C.sub.1-C.sub.4-alkoxycarbonyl,
C.sub.1-C.sub.4-alkylamino, di-C.sub.1-C.sub.4-alkylamino or
unsubstituted or substituted phenyl or phenoxy, as mentioned above
in particular; phenyl or naphthyl, which can be substituted by one
or more of the following radicals: halogen, nitro, cyano, hydroxyl,
amino, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl,
C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-haloalkoxy, phenoxy,
C.sub.1-C.sub.4-alkylthio, C.sub.1-C.sub.4-.[.akylamino [sic].].
.Iadd.alkylamino .Iaddend.or C.sub.1-C.sub.4-dialkylamino, as
mentioned in particular for R.sup.7 and R.sup.4; .Iadd.or.Iaddend.
a five- or six-membered heteroaromatic moiety which contains one to
three nitrogen atoms and/or one sulfur or oxygen atom and which can
carry one to four halogen atoms and/or one or two of the following
radicals: C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl,
C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-haloalkoxy,
C.sub.1-C.sub.4-alkylthio, phenyl, phenoxy or phenylcarbonyl, it
being possible for the phenyl radicals in turn to carry one to five
halogen atoms and/or one to three of the following radicals:
C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl,
C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-haloalkoxy and/or
C.sub.1-C.sub.4-alkylthio, as mentioned for R.sup.4 in particular;
Y .Iadd.is .Iaddend.sulfur, oxygen or a single bond; Z .Iadd.is
.Iaddend.sulfur, oxygen, --SO--, --SO.sub.2--or a single bond.
Particularly preferred compounds of the formula I, both as pure
enantiomers and pure diastereomers or as mixture thereof, are those
in which the substituents have the following meanings: R.sup.2
.Iadd.is .Iaddend.C.sub.1-C.sub.4-alkyl, .Iadd.or
.Iaddend.C.sub.1-C.sub.4-alkoxy.Iadd.;.Iaddend. X .Iadd.is
.Iaddend.nitrogen or CR.sup.14, where R.sup.14 is hydrogen or
alkyl, or CR.sup.14 forms together with CR.sup.3 a 4- or 5-membered
alkylene or alkenylene ring such as
--CH.sub.2--CH.sub.2--CH.sub.2--, --CH.dbd.CH--CH.sub.2--, in which
in each case a methylene group can be replaced by oxygen or sulfur,
such as --CH.sub.2--CH.sub.2--O--, --CH.dbd.CH--O--,
--CH.sub.2--CH.sub.2--CH.sub.2--O--, --CH.dbd.CH--CH.sub.2O--, in
particular hydrogen, --CH.sub.2--CH.sub.2--O--,
--CH(CH.sub.3)--CH(CH.sub.3)--O--,
--C(CH.sub.3).dbd.C(CH.sub.3)--O--, --CH.dbd.C(CH.sub.3)--O-- or
--C(CH.sub.3).dbd.C(CH.sub.3)--S.Iadd.--.Iaddend.; R.sup.3
.[.the.]. .Iadd.is .Iaddend.C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-alkylthio groups mentioned
for R.sup.1, or .Iadd.R.sup.3 .Iaddend.is linked to R.sup.14 as
mentioned above to give a 5- or 6-membered ring; R.sup.4 and
R.sup.5 .Iadd.are .Iaddend.phenyl (identical or different) which
can be substituted by one or more, .[.eg..]. .Iadd.e.g.,
.Iaddend.one to three, of the following radicals: halogen, nitro,
hydroxyl, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkoxy,
C.sub.1-C.sub.4-alkylthio.Iadd.; .Iaddend.or R.sup.4 and R.sup.5
are phenyl groups which are connected together in the ortho
positions by a direct linkage, a methylene, ethylene or ethenylene
group, an oxygen or sulfur atom or an SO.sub.2, NH or N-alkyl
group; or R.sup.4 and R.sup.5 are C.sub.3-C.sub.7-cycloalkyl;
R.sup.6 .Iadd.is .Iaddend.C.sub.1-C.sub.8-alkyl,
C.sub.3-C.sub.6-alkenyl or C.sub.3-C.sub.8-cycloalkyl, it being
possible for these radicals in each case to be substituted one or
more times by: halogen, hydroxyl, nitro, cyano,
C.sub.1-C.sub.4-alkoxy, C.sub.3-C.sub.6-alkenyloxy,
C.sub.1-C.sub.4-alkylthio; .Iadd.or.Iaddend. .Iadd.R.sup.6 is
.Iaddend.phenyl or naphthyl, which can be substituted by one or
more of the following radicals: halogen, nitro, cyano, hydroxyl,
amino, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl,
C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-haloalkoxy, phenoxy,
C.sub.1-C.sub.4-alkylthio, C.sub.1-C.sub.4-akylamino .[.[sic].]. or
C.sub.1-C.sub.4-dialkylamino; .Iadd.or.Iaddend. .Iadd.R.sup.6 is
.Iaddend.a five- or six-membered heteroaromatic moiety which
contains a nitrogen atom and/or a sulfur or oxygen atom and which
can carry one to four halogen atoms and/or one or two of the
following radicals: C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-alkoxy,
C.sub.1-C.sub.4-alkylthio, phenyl, phenoxy or phenylcarbonyl, it
being possible for the phenyl radicals in turn to carry one to five
halogen atoms and/or one to three of the following radicals:
C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl,
C.sub.1-C.sub.4-alkoxy and/or C.sub.1-C.sub.4-alkylthio; Y .Iadd.is
.Iaddend.sulfur, oxygen or a single bond; Z .Iadd.is
.Iaddend.sulfur, oxygen, --SO--, --SO.sub.2-- or a single bond.
The compounds of the present invention provide a novel therapeutic
potential for the treatment of hypertension, pulmonary
hypertension, myocardial infarct, angina pectoris, acute kidney
failure, renal insufficiency, cerebral vasospasms, cerebral
ischemia, subarachnoid hemorrhages, migraine, asthma,
atherosclerosis, endotoxic shock, endotoxin-induced organ failure,
intravascular coagulation, restenosis after angioplasty, benign
prostate hyperplasia, or hypertension or kidney failure caused by
ischemia or intoxication.
The good effect of the compounds can be shown in the following
tests:
Receptor binding studies
Cloned human ET.sub.A receptor-expressing CHO cells and guinea pig
cerebellar membranes with >60% ET.sub.B compared with ET.sub.A
receptors were used for binding studies.
The ET.sub.A receptor-expressing CHO cells were grown in F.sub.12
medium containing 10% fetal calf serum, 1% glutamine, 100 U/ml
penicillin and 0.2% streptomycin (Gibco BRL, Gaithersburg, Md.,
USA).
After 48 h, the cells were washed with PBS and incubated with 0.05%
trypsin-containing PBS for 5 min. Neutralization was then carried
out with F.sub.12 medium, and the cells were collected by
centrifugation at 300.times.g. To .[.lyze.]. .Iadd.lyse
.Iaddend.the cells, the pellet was briefly washed with lysis buffer
(5 mM Tris-IICl, pII 7.4 with 10% glycerol) and then incubated at a
concentration of 107 cells/ml of lysis buffer at 4.degree. C. for
30 min. The membranes were centrifuged at 20,000.times.g for 10
min, and the pellet was stored in liquid nitrogen.
Guinea pig cerebella were homogenized in a Potter-Elvejhem
homogenizer and .[.[lacuna].]. obtained by differential
centrifugation at 1000.times.g for 10 min and repeated
centrifugation of the supernatant at 20,000.times.g for 10 min.
Binding assays
For the ET.sub.A and ET.sub.B receptor binding assay, the membranes
were suspended in incubation buffer (50 mM Tris-HCl, pH 7.4 with 5
mM MnCl.sub.2, 40 .mu.g/ml bacitracin and 0.2% BSA) at a
concentration of 50 .mu.g of protein per assay mixture and
incubated with 25 pM .[.[125I].].
.Iadd.[.sup.125I].Iaddend.-ET.sub.1 (ET.sub.A receptor assay) or 25
pM .[.[125I].]. .Iadd.[.sup.125I].Iaddend.-RZ.sub.3 (ET.sub.B
receptor assay) in the presence and absence of test substance at
25.degree. C. The nonspecific binding was determined using
.[.10.sup.--7.]. .Iadd.10.sup.-7 .Iaddend.M ET.sub.1. After 30 min,
the free and bound radioligand were separated by filtration through
GF/B glass fiber filters (Whatman, England) on a Skatron cell
collector (Skatron, Lier, Norway) and the filters were washed with
ice-cold Tris-HCl buffer, pH 7.4 with 0.2% BSA. The radioactivity
collected on the filters was quantified using a Packard 2200 CA
liquid scintillation counter.
Functional in vitro assay system to look for endothelin receptor
(subtype A) antagonists
This assay system is a functional, cell-based assay for endothelin
receptors. When certain cells are stimulated with endothelin 1
(ET1) they show an increase in the intracellular calcium
concentration. This increase can be measured in intact cells loaded
with calcium-sensitive dyes.
1-Fibroblasts which had been isolated from rats and in which an
endogenous endothelin receptor of the A subtype had been detected
were loaded with the fluorescent dye .[.Fura 2-an.]. .Iadd.Fura
2-am .Iaddend.as follows: after trypsinization, the cells were
resuspended in buffer A (120 mM NaCl, 5 mM KCl, 1.5 mM MgCl.sub.2,
1 mM CaCl.sub.2, 25 mM HEPES, 10 mM glucose, pH 7.4) to a density
of 2.times.10.sup.6/ml and incubated with Fura 2-am (2 .mu.M),
Pluronics F-127 (0.04%) .[.und.]. .Iadd.and .Iaddend.DMSO (0.2%) at
37.degree. C. in the dark for 30 min. The cells were then washed
twice with buffer A and resuspended at 2.times.10.sup.6/ml.
The fluorescence signal from 2.times.10.sup.5 cells per ml with
Ex/Em 380/510 was recorded continuously at 30.degree. C. The test
substances and, after an incubation time of 3 min, ET1
.[.[lacuna].]. to the cells, the maximum change in the fluorescence
was determined. The response of the cells to ET1 without previous
addition of a test substance was used as control and was set equal
to 100%.
Testing of ET antagonists in vivo
Male SD rats weighting 250-300 g were anesthetized with
amobarbital, .[.artifically.]. .Iadd.artificially
.Iaddend.ventilated, vagotomized and pithed. The carotid artery and
jugular vein were .[.cathetized [sic].].
.Iadd.catheterized.Iaddend..
In control animals, intravenous administration of 1 .mu.g/kg ET1
led to a distinct rise in blood pressure which persisted for a
lengthy period.
The test animals received an i.v. injection of the test compounds
(1 ml/kg) 5 min before the administration of ET1. To determine the
ET-antagonistic properties, the rise in blood pressure in the test
animals was compared with that in the control animals.
Endothelin-1-induced sudden death in mice
The principle of the test is the inhibition of the sudden heart
death caused in mice by endothelin, which is probably induced by
constriction of the coronary vessels, by pretreatment with
endothelin receptor antagonists. Intravenous injection of 10
nmol/kg endothelin in a volume of 5 ml/kg of body weight results in
death of the animals within a few minutes.
The lethal endothelin-1 dose is checked in each case on a small
group of animals. If the test substance is administered
intravenously, the endothelin-1 injection which was lethal in the
reference group usually takes place 5 min thereafter. With other
modes of administration, the times before administration are
extended, where appropriate up to several hours.
The survival rate is recorded, and effective doses which protect
50% of the animals (ED 50) from endothelin-induced heart death for
24 h or longer are determined.
Functional test on vessels for endothelin receptor antagonists
Segments of rabbit aorta are, after an initial tension of 2 g and a
relaxation time of 1 h in Krebs-Henseleit solution at 37.degree. C.
and pH 7.3-7.4, first induced to contract with K.sup.+. After
washing out, an endothelin dose-effect plot up to the maximum is
constructed.
Potential endothelin antagonists are administered to other
preparations of the same vessel 15 min before starting the
endothelin dose-effect plot. The effects of the endothelin are
calibrated as a % of the K.sup.+-induced contraction. Effective
endothelin antagonists result in a shift to the right in the
endothelin dose-effect plot.
The compounds according to the invention can be administered orally
or parenterally (subcutaneously, intravenously, intramuscularly,
.[.intraperotoneally.]. .Iadd.intraperitoneally.Iaddend.) in a
conventional way. Administration can also take place with vapors or
sprays through the nasopharyngeal space.
The dosage depends on the age, condition and weight of the patient
and on the mode of administration. The daily dose of active
substance is, as a rule, about 0.5-50 mg/kg of body weight on oral
administration and about 0.1-10 mg/kg of body weight on parenteral
administration.
The novel compounds can be used in conventional solid or liquid
pharmaceutical forms, .[.eg..]. .Iadd.e.g., .Iaddend.as uncoated or
(film-) coated tablets, capsules, powders, granules, suppositories,
solutions, ointments, creams or sprays. These are produced in a
conventional way. The active substances can for this purpose be
processed with conventional pharmaceutical aids such as tablet
binders, fillers, preservatives, tablet disintegrants, flow
regulators, plasticizers, wetting agents, dispersants, emulsifiers,
solvents, release-slowing agents, antioxidants and/or propellent
gases (cf. H. Sucker et al.: Pharmazeutische Technologie,
Thieme-Verlag, Stuttgart, 1991). The administration forms obtained
in this way normally contain from 0.1 to 90% by weight of the
active substance.
Synthesis examples
Example 1
Methyl 2-hydroxy-3-methoxy-3,3-diphenylpropionate
5 g (19.6 mmol) of methyl 3,3-diphenyl-2,3-epoxypropionate were
dissolved in 50 ml of absolute methanol and, at 0.degree. C., 0.1
ml of boron trifluoride etherate was added. The mixture was stirred
at 0.degree. C. for 2 h and at room temperature for a further 12 h.
The solvent was distilled out, the residue was taken up in ethyl
acetate, washed with sodium bicarbonate solution and water and
dried over magnesium sulfate. After removal of the solvent by
distillation there remained 5.5 g (88%) of a pale yellow oil.
Example 2
Methyl 2-hydroxy-3-phenoxy-3,3-diphenylpropionate
5 g (19.6 mmol) of methyl 3,3-diphenyl-2,3-epoxypropionate and 5.6
g (60 mmol) of phenol were heated together at 100.degree. C. for 6
h. Removal of the excess phenol by distillation under high vacuum
and purification of the residue by chromatography on silica gel
with hexane/ethyl acetate mixtures resulted in 4.9 g (77%) of a
pale yellow oil.
Example 3
Methyl
2-(4,6-dimethoxy-pyrimidin-2-yloxy)-3-methoxy-3,3-diphenylpropiona-
te
2.86 g (10 mmol) of methyl
2-hydroxy-3-methoxy-3,3-diphenylpropionate were dissolved in 40 ml
of dimethylformamide, and 0.3 g (12 mmol) of sodium hydride was
added. The mixture was stirred for 1 h and then 2.2 g (10 mmol) of
4,6-dimethoxy-2-methylsulfonylpyrimidine were added. After stirring
at room temperature for 24 h, cautious hydrolysis was carried out
with 10 ml of water, the pH was adjusted to 5 with acetic acid, and
the solvent was removed by distillation under high vacuum. The
residue was taken up in 100 ml of ethyl acetate, washed with water
and dried over magnesium sulfate, and the solvent was distilled
out. The residue was mixed with 10 ml of ether, and the resulting
precipitate was filtered off with suction. After drying, 3.48 g
(82%) of a white powder remained.
Melting point 81.degree. C.
Example 4
2-(4,6-Dimethoxy-pyrimidin-2-yloxy)-3-methoxy-3,3-diphenylpropionic
acid
2.12 g (5 mmol) of methyl
2-(4,6-dimethoxy-pyrimidin-2-yl-oxy)-3-methoxy-3,3-diphenylpropionate
were dissolved in 50 ml of dioxane, 10 ml of 1N KOH solution were
added, and the mixture was stirred at 100.degree. C. for 3 h. The
solution was diluted with 300 ml of water and extracted with ethyl
acetate to remove unreacted ester. The aqueous phase was then
adjusted to pH 1-2 with dilute hydrochloric acid and extracted with
ethyl acetate. After drying over magnesium sulfate and removal of
the solvent by distillation, the residue was mixed with an
ether/hexane mixture, and the precipitate which formed was filtered
off with suction. After drying, 1.85 g (90%) of a white powder
remained.
Melting point 167.degree. C.
Example 5
2-(4,6-Dimethoxy-2-pyrimidinyloxy)-3-methoxy-3,3-diphenyl sodium
[sic] propionate
1.68 g (4 mmol) of
2-(4,6-dimethoxy-2-pyrimidinyloxy)-3-methoxy-3,3-diphenylpropionic
acid are dissolved in 4 ml of 1N NaOH+100 ml of water. The solution
is freeze-dried, and the sodium salt of the carboxylic acid used is
obtained quantitatively.
10 g (34.9 mmol) of methyl
2-hydroxy-3-methoxy-3,3-diphenylpropionate were dissolved in 50 ml
each of methanol and glacial acetic acid, 1 ml of RuO(OH).sub.2 in
dioxane was added, and hydrogenation was carried out with H.sub.2
in an autoclave at 100.degree. C. under 100 bar for 30 h. The
catalyst was filtered off, the mixture was concentrated, mixed with
ether and washed with NaCl solution, and the organic phase was
dried and concentrated. 10.1 g of methyl
3,3-dicyclohexyl-2-hydroxy-3-methoxypropionate were obtained as an
oil.
Example 7
Methyl
2-[(4,6-dimethoxy-pyrimidin-2-yl)thio]-3-methoxy-3,3-diphenylpropi-
onate .[.[sic].].
7.16 g (25 mmol) of methyl
2-hydroxy-3-methoxy-3,3-diphenylpropionate were dissolved in 50 ml
of dichloromethane, 3 g (30 mmol) of triethylamine were added, and
3.2 g (28 mmol) of methanesulfonyl chloride were added dropwise
while stirring. The mixture was stirred at room temperature for 2
h, washed with water, dried over magnesium sulfate and concentrated
under reduced pressure. The residue was taken up in DMF and added
dropwise at 0.degree. C. to a suspension of 12.9 g (75 mmol) of
4,6-dimethoxypyrimidine-2-thiol and 8.4 g (100 mmol) of sodium
bicarbonate in 100 ml of DMF. After stirring at room temperature
for 2 h and at 60.degree. C. for a further 2 h, the mixture was
poured into 1 liter of ice-water, and the resulting precipitate was
filtered off with suction. After drying, 3.19 g (29%) of a white
powder remained.
Example 8
Methyl 2-hydroxy-3,3-diphenylbutyrate
1.5 g (5.9 mmol) of methyl 3,3-diphenyl-2,3-epoxypropionate
dissolved in 10 ml of absolute ether were added dropwise to a
cup-rate solution which had been prepared from 635 mg (7 mmol) of
copper(I) cyanide dissolved in 10 ml of absolute ether and 8.14 ml
(13 mmol) of a 1.6 normal methyllithium solution and had been
cooled to -78.degree. C. The solution was stirred at -78.degree. C.
for 1 h and then allowed to warm to room temperature. It was
subsequently diluted with 100 ml of ether and 100 ml of water, and
the ether phase was washed with dilute citric acid and with sodium
bicarbonate solution and dried over magnesium sulfate. The crude
product was purified by chromatography on silica gel with
cyclohexane/ethyl acetate mixtures to result in 250 mg (16%) of a
pale yellow oil.
Example 9
2-Hydroxy-3-methoxy-3,3-diphenylpropionic acid
91.11 g (0.5 mol) of benzophenone and 45.92 g (0.85 mol) of sodium
methoxide were suspended in 150 ml of methyl tert-butyl ether (MTB)
at room temperature. After cooling to -100.degree. C., 92.24 g
(0.85 mol) of methyl chloroacetate were added in such a way that
the internal temperature rose to 40.degree. C. while continuing to
cool in a bath at -10.degree. C. The mixture was then stirred
without cooling at the autogenous temperature for one hour. After
addition of 250 ml of water and brief stirring, the aqueous phase
was separated off. The MTB phase was washed with 250 ml of dilute
sodium chloride solution. After the solvent had been changed to
methanol (250 ml), a solution of 1 g of p-toluenesulfonic acid in
10 ml of methanol was added at room temperature. The mixture was
stirred at autogenous temperature for one hour and then heated to
reflux. While distilling out the methanol, 400 g of a 10% strength
sodium hydroxide solution was added dropwise, and finally 60 ml of
water were added. The methanol was distilled out until the bottom
temperature reached 97.degree. C. After cooling to 55.degree. C.,
190 ml of MTB were added and the mixture was acidified to pH 2 with
about 77 ml of concentrated HCl. After cooling to room temperature,
the aqueous phase was separated off and the organic phase was
concentrated by distilling out 60 ml of .[.MtB [sic].].
.Iadd.MTB.Iaddend.. The product was crystallized by adding 500 ml
of heptane and slowly cooling to room temperature. The coarsely
crystalline solid was filtered off with suction, washed with
heptane and dried to constant weight in a vacuum oven at 40.degree.
C.
Yield: 108.9 g (80%), HPLC >99.5% area.
Example 10
S-2-Hydroxy-3-methoxy-3,3-diphenylpropionic acid (racemate
resolution with L-proline methyl ester)
148.8 g of a 30% strength methanolic sodium methanolate solution
(0.826 mol) were added dropwise to 240 g of a 57% strength
methanolic L-proline methyl ester hydrochloride solution (0.826
mol) at room temperature, and 2.41 of MTB and 225 g (0.826 mol) of
2-hydroxy-3-methoxy-3,3-diphenylpropionic acid were added. After
2680 ml of MTB/methanol mixture had been distilled out with
simultaneous dropwise addition of 2.4 l of MTB, the mixture was
slowly cooled to room temperature, the crystals
(R-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid x L-proline
methyl (ester) were filtered off with suction, and the solid was
washed with 150 ml of MTB. The filtrate was concentrated by
distilling out 1.5 l of MTB, and 1.0 l of water was added. The pH
was adjusted to 1.2 with concentrated hydrochloric acid at room
temperature and, after stirring and phase separation, the aqueous
phase was separated off and extracted with 0.4 l of MTB. The
combined organic phases were extracted with 0.4 l of water. The
residue after the MTB had been stripped off was dissolved in 650 ml
of toluene under reflux, and the product was crystallized by
seeding and slow cooling. Filtration with suction, washing with
toluene and drying in a vacuum oven resulted in 78.7 g of
S-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid (yield 35% based
on the racemate).
Chiral HPLC: 100% pure; HPLC: 99.8%
Example 11
S-2-Hydroxy-3-methoxy-3,3-diphenylpropionic acid (racemate
resolution with (S)-1-(4-nitrophenyl)ethylamine)
30.5 g (0.184 mol) of (S)-1-(4-nitrophenyl)ethylamine were added to
100 g (0.368 mol) of 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid
in 750 ml of acetone and 750 ml of MTB under reflux, the mixture
was seeded, boiled under reflux for one hour and slowly cooled to
room temperature for crystallization. The crystals
(S-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid x
(S)-1-(4-nitrophenyl) ethylamine) were filtered off with suction
and washed with MTB. The residue was suspended in 500 ml of water
and 350 ml of MTB and then the pH was adjusted to 1.2 with
concentrated hydrochloric acid at room temperature, and, after
stirring and phase separation, the aqueous phase was separated off
and extracted with 150 ml of MTB. The combined organic phases were
extracted with 100 ml of water. 370 ml of MTB were distilled out
and then 390 ml of n-heptane were added under reflux, and the
mixture was slowly cooled to room temperature while the product
crystallized. Filtration with suction, washing with n-heptane and
drying in a vacuum oven resulted in 35.0 g of
S-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid (yield 35% based
on the racemate).
Chiral HPLC: 100% pure; HPLC: 99.8%
Example 12
Benzyl
3-methoxy-2-(4-methoxy-6,7-dihydro-5H-cyclopentapyrimidin-2-yloxy)-
-3,3-diphenylpropionate
24.48 g (90 mmol) of 3-methoxy-3,3-diphenyl-2-hydroxypropionic acid
were dissolved in 150 ml of DMF, and 13.7 g (99 mmol) of potassium
carbonate were added. The suspension was stirred at room
temperature for 30 min. Then 10.7 ml (90 mmol) of benzyl bromide
were added dropwise over the course of 5 min, and the mixture was
stirred for 1 h, during which the temperature rose to 32.degree.
C.
To this mixture were successively added 24.84 g (180 mmol) of
K.sub.2CO.sub.3 and 20.52 g (90 mmol) of
2-methanesulfonyl-4-methoxy-6,7-dihydro-5H-cyclopentapyridine
.[.[sic].]., and the mixture was stirred at 80.degree. C. for 3
h.
For workup, the contents of the flask were diluted with about 600
ml of H.sub.2O and cautiously acidified with concentrated HCl, and
250 ml of ethyl acetate were added. 31.4 g of pure product
precipitated and were filtered off.
The ethyl acetate phase was separated from the mother liquor, the
aqueous phase was extracted again with ethyl acetate, and the
combined organic phases were concentrated. The oily residue (19 g)
was purified by chromatography (cyclohexane/ethyl acetate=9/1) to
result in a further 10.5 g of pure product.
Total yield: 41.9 g (82.2 mmol)=91%; Melting point 143-147.degree.
C.; MS: MH.sup.+=511
Example 13
3-Methoxy-2-(4-methoxy-(6,7-dihydro-5H-cyclopentapyrimidin-2-yl-oxy)-3,3--
diphenylpropionic .[.[sic].]. acid
40 g (78.4 mmol) of benzyl
3-methoxy-2-(4-methoxy-6,7-dihydro-5H-cyclopentapyrimidin-2-yloxy)-3,3-di-
phenylpropionate were dissolved in 400 ml of ethyl acetate/methanol
(4:1), about 500 mg of palladium on active carbon (10%) were added,
and the mixture was exposed to a hydrogen atmosphere until no
further gas was taken up. The catalyst was filtered off, the
solution was evaporated, and the residue was crystallized from
ether.
Example 14
Ethyl 2S-3,3-diphenyloxirane-2-carboxylate
2.57 g (10.2 mnol) of ethyl 3,3-diphenylacrylate and 464 mg of
4-phenylpyridine N-oxide were dissolved in 24 ml of methylene
chloride, and 432 mg (6.5 mol %) of
(5,5)-(+)-N,N'-bis(3,5-ditert-butylsalicylidene)-1,2-cyclohexanediaminoma-
nganese(III) chloride were added. While cooling in ice, 6.4 ml of a
12% strength sodium hypochloride .[.[sic].]. solution were added,
and the mixture was stirred while cooling in ice for 30 min and at
room temperature overnight. The solution was diluted to 200 ml with
water, extracted with ether, dried and evaporated. 2.85 g of a
colorless oil were obtained. Purification by .[.NPLC [sic].].
.Iadd.HPLC .Iaddend.(cyclohexane:ethyl acetate=9:1) resulted in
1.12 g of oil with an enantiomer ratio of about 8:1 in favor of the
S configuration.
.sup.1H-NMR [CDCl.sub.3], .delta.=1.0 (t, 3H); 3.9 (m, 3H); 7.3 (m,
10H)
Example 15
2-Methylsulfonyl-6,7-dihydro-5H-cyclopentapyrimidin-4-ol
.[.[sic].].
46.9 g (330 mmol) of methyl cyclopentanone-2-carboxylate and 53.5 g
(192 mmol) of 5-methylisothiourea .[.[sic].]. sulfate were
successively added to 29.6 g (528 mmol) of KOH in 396 ml of
methanol, and the mixture was stirred at room temperature
overnight, acidified with 1N hydrochloric acid and diluted with
water. The crystals which separated out were filtered off with
suction and dried. 20 g of crystals were obtained.
Example 16
.[.sulfanyl.]. .Iadd.Sulfanyl .Iaddend.4-.[.Chloro.].
.Iadd.chloro.Iaddend.-2-methyl-6,7-dihydro-5H-cyclopentapyrimidine
.[.[sic].].
255 ml of phosphorus oxychloride were added to 20 g (110 mmol)
.[.[lacuna].]., and the mixture was stirred at 80.degree. C. for 3
hours. Phosphorus oxychloride was evaporated off, ice was added to
the residue, and the crystals which separated out were filtered off
with suction. 18.5 g of a brownish solid were obtained.
Example 17
4-Methoxy-2-methylsulfonyl-6,7-dihydro-5II-cyclopentapyrimidine
.[.[sic].].
18.05 g (90 mmol) of
4-chloro-2-methylsulfonyl-6,7-dihydro-5H-cyclopentapyrimidine
.[.[sic].]. were dissolved in 200 ml of methanol. At 45.degree. C.,
16.7 g of sodium methoxide (as 30% strength solutions .[.[sic].].
in methanol) were added dropwise, and the mixture was stirred for 2
hours. The solution was evaporated, taken up in ethyl acetate and
acidified with dilute hydrochloric acid, and the ethyl acetate
extract was evaporated. 15.5 g of an oil remained.
.sup.1H-NMR [DMSO], .delta.=2.1 (quintet, 2H); 2.5 (s, 3H); 2.8
(dt, 4H); 3.9 (s, 3H) ppm
Example 18
2-Methylsulfonyl-4-methoxy-6,7-dihydro-5H-cyclopentopyrimidine
.[.[sic].].
15 g (76.2 mmol) of
4-methoxy-2-methylsulfonyl-6,7-dihydro-5H-cyclopentapyrimidine
.[.[sic].]. were dissolved in 160 ml of glacial acetic
acid/methylene chloride (1:1), and 1.3 g of sodium tungstate were
added. At 35.degree. C., 17.5 ml (170 ml .[.[sic].].) of a 30%
strength H.sub.2O.sub.2 solution were added dropwise. The mixture
was then diluted with 500 ml of water and 100 ml of methylene
chloride, and the organic phase was separated off, dried and
evaporated. 14 g of oil remained and were crystallized from
ether.
.sup.1H-NMR [CDCl.sub.3], .delta.=2.2 (quintet, 2H); 3.0 (dt., 4H);
3.3 (s, 3H); 4.1 (s, 3H) ppm
Example 19
1-Benzenesulfonyl-3-(4,6-dimethoxy-2-pyrimidinyloxy)-4-methoxy-4,4-diphen-
yl-2-butanone
0.37 g (2.4 mmol) of phenyl methane .[.[sic].]. sulfone were
dissolved in 10 ml of dry THF and then, at -70.degree. C., 2 eq. of
butyllithium (2.94 ml; 1.6 molar solution in hexane) were added
dropwise. After 1 h at -70.degree. C., 1 g (2.4 mmol) of methyl
2-(4,6-dimethoxy-2-pyrimidinyloxy)-3-methoxy-3,3-diphenylpropynoate
.[.[sic].]. dissolved in 5 ml of THF was added dropwise. The
reaction mixture was then stirred at -70.degree. C. for 1 h and at
-10.degree. C. for 1 h and then warmed to room temperature. For
workup, about 10 ml of saturated NH.sub.4Cl solution were added
dropwise, thorough extraction with ethyl acetate was carried out,
and the combined organic phases .[.[lacuna].]. with-saturated N-Cl
.[.[sic].]. solution and dried over Na.sub.2SO.sub.4. The residue
obtained after drying and concentration was purified by
chromatography on silica gel (n-heptane/ethyl acetate
15%.fwdarw.30%) and subsequently .[.MPLC.]. .Iadd.HPLC .Iaddend.on
RP silica gel (acetonitrile/H.sub.2O+TFA); 0.3 g of a white
amorphous powder was obtained as product.
Example 20
3,3-Diphenyloxiram-2-carbonitrile .[.[sic].].
3.1 g (54.9 mmol) of sodium methoxide were suspended in 20 ml of
dry THF and then, at -10.degree. C., a mixture of 5 g (27.4 mmol)
of benzophenone and 4.2 g (54.9 mmol) of chloroacetonitrile was
added dropwise.
The reaction mixture was stirred at -10.degree. C. for about 2 h,
then poured into water and extracted several times with ethyl
acetate. The combined organic phases were dried over
Na.sub.2SO.sub.4 and concentrated, and the residue was purified by
chromatography on silica gel (n-heptane/ethyl acetate).
Yield: 1.2 g (20%)
.sup.1H-NMR [CDCl.sub.3], .delta.=3.9 (s, 1H); 7.4-7.5 (m, 10 H)
ppm
Example 21
2-Hydroxy-3-methoxy-3,3-diphenylpropionitrile
6.5 .[.[lacuna].]. .Iadd.g .Iaddend.(29.4 mmol) of
3,3-diphenyloxirane-2-carbonitrile were dissolved in 60 ml of
methanol and, at 0.degree. C., about 2 ml of boron triffuoride
etherate solution were added. The mixture was stirred further at
0.degree. C. for 1 h and then at room temperature overnight. For
workup it was diluted with diethyl ether and washed with saturated
NaCl solution, and the organic phase was dried over
Na.sub.2SO.sub.4 and concentrated. The residue comprised 7.3 g of a
white amorphous powder which was used directly in the subsequent
reactions.
.sup.1H-NMR .[.[CDC.sub.13].]. .Iadd.[CDCl.sub.3].Iaddend.,
.delta.=2.95 (broad s, OH), 3.15 (s, 3H), 5.3 (s, 1H), 7.3-7.5 (m,
10) ppm
Example 22
2-(4,6-Dimethoxy-2-pyrimidinyloxy)-3-methoxy-3,3-diphenylpropionitrile
7.3 g (28.8 mmol) of 2-hydroxy-3-methoxy-3,3-diphenylpropionitrile
were dissolved in 90 ml of DMF, and 4 g (28.8 mmol) of
K.sub.2CO.sub.3 and 6.3 g (28 mmol) of
2-methanesulfonyl-4,6-dimethoxypyrimidine were added. The mixture
was stirred at room temperature for about 12 h, then poured into
water and extracted with ethyl acetate. The combined organic phases
were washed again with H.sub.2O, dried and concentrated. The
residue obtained in this way was then purified by chromatography on
silica gel (n-hepane/ethyl acetate).
Yield: 6.9 g of white amorphous powder
FAB-MS: 392 (M+H.sup.+) .sup.1H-NMR [CDCl.sub.3], .delta.=3.3 (s,
3H); 4.95 (s, 6H), 5.85 (s, 1H); 6.3 (s, 1H); 7.3-7.5 (m, 10H)
ppm
Example 23
5-[2-(4,6-Dimethoxy-2-pyrimidinyloxy)-3-methoxy-3,3-diphenyl)propyl]-1H-t-
etrazole .[.[sic].].
0.5 g (1.3 mmol) of nitrile was dissolved in 10 ml of toluene, and
85 mg (1.3 mmol) of NaN.sub.3 and 460 mg (1.4 mmol) of Bu.sub.3SnCl
were successively added, and then the mixture was refluxed for
about 40 h. Cooling was followed by dilution with ethyl acetate and
washing with 10% aqueous KF solution and with NaCl solution. After
drying over MgSO.sub.4 and concentration there remained 1.0 g of a
yellow oil, which was purified by chromatography on silica gel
(n-heptane/ethyl acetate).
Concentration of the fractions resulted in 60 mg of the
1H-tetrazole and 110 mg of the 1-methyltetrazole, each as amorphous
white solids.
5-[2-(4,6-Dimethoxy-2-pyrimidinyloxy)-3-methoxy-3,3-diphenyl)propyl]-1H-t-
etrazole .[.[sic].].
Electrospray-MS: 435 (M+H.sup.+) .sup.1H-NMR (CDCl.sub.3): .delta.
(ppm) 3.28 (s, 3H), 3.85 (s, 6H), 5.75 (s, 1H), 7.25-7.40 (m, 10H),
7.50 (s, 1H).
5-[2-(4,6-Dimethoxy-2-pyrimidinyloxy)-3-methoxy-3,3-diphenyl)propyl]-1-me-
thyltetrazole .[.[sic].].
Electrospray-MS; 471 (M+H.sup.+) .sup.1H-NMR (CDCl.sub.3): .delta.
(ppm) 3.0 (s, 3H), 3.35 (s, 3H.[.9.]..Iadd.) .Iaddend..[.[sic].].,
3.80 (s, 6H), 5.75 (s, 1H), 7.30-7.40 (m, 11H).
Example 24
2-(4,6-Dimethoxy-2-pyrimidinyloxy)-3-methylsulfinyl-3,3-diphenylpropionic
acid
1.2 g (2.9 mmol) of
2-(4,6-dimethoxy-2-pyrimidinyloxy)-3-methylsulfonyl-3,3-diphenylpropionic
.[.[sic].]. acid were introduced into 15 ml of glacial acetic acid
at 0.degree. C. and 294 .mu.l of 30% strength H.sub.2O.sub.2 were
added dropwise. The mixture was stirred at room temperature
overnight, poured into water, extracted with CH.sub.2Cl.sub.2 and
washed with sodium thiosulfate solution and brine. After drying, 1
g of substance was isolated as a white foam.
Example 25
2-(4,6-Dimethoxy-2-pyrimidinyloxy)-3-methylsulfonyl-3,3-diphenylpropionic
acid
0.6 g (1.45 mmol) of
2-(4,6-dimethoxy-2-pyrimidinyloxy)-3-methyl-sulfonyl-3,3-diphenylpropioni-
c .[.[sic].]. acid was introduced into 15 ml of glacial acetic acid
at room temperature, and 294 .mu.l of 30% strength H.sub.2O.sub.2
were added dropwise. The mixture was stirred at room temperature
overnight, heated at 50.degree. C. for a further 3 h, poured into
water and washed with sodium thiosulfate solution and brine. After
drying, 400 mg were isolated as a white solid.
The compounds listed in Table 1 .[.[sic].]. can be prepared in a
similar way.
TABLE-US-00001 TABLE 1 ##STR00014## m.p. No. R.sup.1 R.sup.4,
R.sup.5 R.sup.6 R.sup.2 R.sup.3 X Y Z [.degree. C.]
.[.I-195.]..Iadd.I-1.Iaddend. .[.OMe.]..Iadd.OCH.sub.3.Iaddend.
Phenyl Met- hyl .[.OMe.]..Iadd.OCH.sub.3.Iaddend.
.[.OMe.]..Iadd.OCH.sub.3.Iaddend. CH- O O 81
.[.I-196.]..Iadd.I-2.Iaddend. OH Phenyl Methyl
.[.OMe.]..Iadd.OCH.sub.3.Ia- ddend.
.[.OMe.]..Iadd.OCH.sub.3.Iaddend. CH O O 167
.[.I-197.]..Iadd.I-3.Iaddend. OH Phenyl
CH.sub.2--CH.sub.2--S--CH.sub.3 .[- .OMe.]..Iadd.OCH.sub.3.Iaddend.
.[.OMe.]..Iadd.OCH.sub.3.Iaddend. CH O O
.[.I-198.]..Iadd.I-4.Iaddend. OH Phenyl Ethyl
.[.OMe.]..Iadd.OCH.sub.3.Iad- dend.
.[.OMe.]..Iadd.OCH.sub.3.Iaddend. CH O O 81 (decomp.)
.[.I-199.]..Iadd.I-5.Iaddend. OH Phenyl iso-Propyl
.[.OMe.]..Iadd.OCH.sub.- 3.Iaddend.
.[.OMe.]..Iadd.OCH.sub.3.Iaddend. CH O O 182
.[.I-200.]..Iadd.I-6.Iaddend. OH Phenyl Methyl
.[.OMe.]..Iadd.OCH.sub.3.Ia- ddend.
.[.OMe.]..Iadd.OCH.sub.3.Iaddend. CH O S 168
.[.I-201.]..Iadd.I-7.Iaddend. OH Phenyl
CH.sub.2--CH.sub.2--SO.sub.2-- .[.- OMe.]..Iadd.OCH.sub.3.Iaddend.
.[.OMe.]..Iadd.OCH.sub.3.Iaddend. CH O O CH(CH.sub.3).sub.2
.[.I-202.]..Iadd.I-8.Iaddend. OH Phenyl
CH.sub.2--CH.sub.2--SO.sub.2-- .[.- OMe.]..Iadd.OCH.sub.3.Iaddend.
.[.OMe.]..Iadd.OCH.sub.3.Iaddend. CH S O CH(CH.sub.3).sub.2
.[.I-203.]..Iadd.I-9.Iaddend. OH Phenyl
CH.sub.2--CH.sub.2--SO.sub.2-- .[.- OMe.]..Iadd.OCH.sub.3.Iaddend.
.[.OMe.]..Iadd.OCH.sub.3.Iaddend. C--CH(CH.- sub.3).sub.2 O O
CH(CH.sub.3).sub.2 .[.I-204.]..Iadd.I-10.Iaddend. OH Phenyl
CH.sub.2--CH.sub.2--SO.sub.2-- .[- .OMe.]..Iadd.OCH.sub.3.Iaddend.
.[.OMe.]..Iadd.OCH.sub.3.Iaddend. C--CH(CH- .sub.3).sub.2 O O
CH(CH.sub.3).sub.2 .[.I-205.]..Iadd.I-11.Iaddend. OH Phenyl
CH.sub.2--CH.sub.2--SO.sub.2-- .[- .OMe.]..Iadd.OCH.sub.3.Iaddend.
NH.cndot.OCH.sub.3 CH O O CH(CH.sub.3).sub.2
.[.I-206.]..Iadd.I-12.Iaddend. OH Phenyl n-Propyl
.[.OMe.]..Iadd.OCH.sub.3- .Iaddend.
.[.OMe.]..Iadd.OCH.sub.3.Iaddend. CH O O 174
.[.I-207.]..Iadd.I-13.Iaddend. .[.OMe.]..Iadd.OCH.sub.3.Iaddend.
Phenyl n-- Propyl .[.OMe.]..Iadd.OCH.sub.3.Iaddend.
.[.OMe.]..Iadd.OCH.sub.3.Iaddend.- CH O O
.[.I-208.]..Iadd.I-14.Iaddend. OH Phenyl n-Propyl
.[.OEt.]..Iadd.OC.sub.2H- .sub.5.Iaddend.
.[.OEt.]..Iadd.OC.sub.2H.sub.5.Iaddend. CH O O
.[.I-209.]..Iadd.I-15.Iaddend. OH Phenyl n-Butyl
.[.OMe.]..Iadd.OCH.sub.3.- Iaddend.
.[.OMe.]..Iadd.OCH.sub.3.Iaddend. CH O O
.[.I-210.]..Iadd.I-16.Iaddend. OH Phenyl iso-Butyl
.[.OMe.]..Iadd.OCH.sub.- 3.Iaddend.
.[.OMe.]..Iadd.OCH.sub.3.Iaddend. CH O O
.[.I-211.]..Iadd.I-17.Iaddend. OH Phenyl iso-Butyl
.[.OMe.]..Iadd.OCH.sub.- 3.Iaddend. O--CH.sub.2--CH.sub.2--C O O
.[.I-212.]..Iadd.I-18.Iaddend. OH Phenyl tert.-Butyl
.[.OMe.]..Iadd.OCH.su- b.3.Iaddend.
.[.OMe.]..Iadd.OCH.sub.3.Iaddend. CH O O
.[.I-213.]..Iadd.I-19.Iaddend. OH Phenyl Cyclopropyl
.[.OMe.]..Iadd.OCH.su- b.3.Iaddend.
.[.OMe.]..Iadd.OCH.sub.3.Iaddend. CH O O
.[.I-214.]..Iadd.I-20.Iaddend. OH Phenyl Cyclopentyl
.[.OMe.]..Iadd.OCH.su- b.3.Iaddend.
.[.OMe.]..Iadd.OCH.sub.3.Iaddend. CH O O
.[.I-215.]..Iadd.I-21.Iaddend. OH Phenyl Cyclohexyl
.[.OMe.]..Iadd.OCH.sub- .3.Iaddend.
.[.OMe.]..Iadd.OCH.sub.3.Iaddend. CH O O
.[.I-216.]..Iadd.I-22.Iaddend. OH Phenyl
(CH.sub.3).sub.3C--CH.sub.2--CH.s- ub.2
.[.OEt.]..Iadd.OC.sub.2H.sub.5
.[.OEt.]..Iadd.OC.sub.2H.sub.5.Iaddend- . CH O O
.[.I-217.]..Iadd.I-23.Iaddend. OH Phenyl
(CH.sub.3).sub.2CH--CH.sub.2-- .[- .OMe.]..Iadd.OCH.sub.3.Iaddend.
.[.OMe.]..Iadd.OCH.sub.3.Iaddend. CH O O 1- 73 CH.sub.2--CH.sub.2
.[.I-218.]..Iadd.I-24.Iaddend. OH Phenyl HO--CH.sub.2--CH.sub.2
.[.OMe.]..- Iadd.OCH.sub.3.Iaddend.
.[.OMe.]..Iadd.OCH.sub.3.Iaddend. CH O O
.[.I-219.]..Iadd.I-25.Iaddend. OH Phenyl
HO.sub.2C--CH.sub.2).sub.2-- .[.O- Me.]..Iadd.OCH.sub.3.Iaddend.
.[.OMe.]..Iadd.OCH.sub.3.Iaddend. CH O O
.[.I-220.]..Iadd.I-26.Iaddend. OH Phenyl Cyclopropyl-
.[.OMe.]..Iadd.OCH.s- ub.3.Iaddend.
.[.OMe.]..Iadd.OCH.sub.3.Iaddend. CH O O 115 methylene .[.[sic].].
.[.I-221.]..Iadd.I-27.Iaddend. OH Phenyl H
.[.OMe.]..Iadd.OCH.sub.3.Iadden- d.
.[.OMe.]..Iadd.OCH.sub.3.Iaddend. CH O O
.[.I-222.]..Iadd.I-28.Iaddend. OH Phenyl Methyl
.[.OMe.]..Iadd.OCH.sub.3.I- addend.
.[.OMe.]..Iadd.OCH.sub.3.Iaddend. CH O --
.[.I-223.]..Iadd.I-29.Iaddend. OH Phenyl Phenyl
.[.OMe.]..Iadd.OCH.sub.3.I- addend.
.[.OMe.]..Iadd.OCH.sub.3.Iaddend. CH O O 136
.[.I-224.]..Iadd.I-30.Iaddend. OH Phenyl Phenyl
.[.OMe.]..Iadd.OCH.sub.3.I- addend. O--CH(CH.sub.3)--CH.sub.2--C O
O .[.I-225.]..Iadd.I-31.Iaddend. OH Phenyl Phenyl
.[.OMe.]..Iadd.OCH.sub.3.I- addend.
.[.OMe.]..Iadd.OCH.sub.3.Iaddend. CH O O
.[.I-226.]..Iadd.I-32.Iaddend. OH Phenyl 4-Isopropyl-Phenyl
.[.OMe.]..Iadd- .OCH.sub.3.Iaddend.
.[.OMe.]..Iadd.OCH.sub.3.Iaddend. CH O O
.[.I-227.]..Iadd.I-33.Iaddend. OH Phenyl
4-Me.Iadd.thyl.Iaddend.-S-Phenyl -
.[.OMe.]..Iadd.OCH.sub.3.Iaddend. .[.OMe.]..Iadd.OCH.sub.3.Iaddend.
CH O O- .[.I-228.]..Iadd.I-34.Iaddend. OH Phenyl
4-Me.Iadd.thyl.Iaddend.-O-Phenyl -
.[.OMe.]..Iadd.OCH.sub.3.Iaddend. .[.OMe.]..Iadd.OCH.sub.3.Iaddend.
CH O O- .[.I-229.]..Iadd.I-35.Iaddend. OH Phenyl
3-Et.Iadd.hyl.Iaddend.-Phenyl .[.- OMe.]..Iadd.OCH.sub.3.Iaddend.
.[.OMe.]..Iadd.OCH.sub.3.Iaddend. CH O O
.[.I-230.]..Iadd.I-36.Iaddend. OH Phenyl
2-Me.Iadd.thyl.Iaddend.-Phenyl .[- .OMe.]..Iadd.OCH.sub.3.Iaddend.
.[.OMe.]..Iadd.OCH.sub.3.Iaddend. CH O O
.[.I-231.]..Iadd.I-37.Iaddend. OH Phenyl 2-Cl-Phenyl
.[.OMe.]..Iadd.OCH.su- b.3.Iaddend.
.[.OMe.]..Iadd.OCH.sub.3.Iaddend. CH O O
.[.I-232.]..Iadd.I-38.Iaddend. OH Phenyl 3-Br-Phenyl
.[.OMe.]..Iadd.OCH.su- b.3.Iaddend.
.[.OMe.]..Iadd.OCH.sub.3.Iaddend. CH O O
.[.I-233.]..Iadd.I-39.Iaddend. OH Phenyl 4-F-Phenyl
.[.OMe.]..Iadd.OCH.sub- .3.Iaddend.
.[.OMe.]..Iadd.OCH.sub.3.Iaddend. CH O O
.[.I-234.]..Iadd.I-40.Iaddend. OH Phenyl 4-F-Phenyl
.[.OMe.]..Iadd.OCH.sub- .3.Iaddend.
.[.OMe.]..Iadd.OCH.sub.3.Iaddend. CH S O
.[.I-235.]..Iadd.I-41.Iaddend. OH Phenyl 4-CH.sub.3--Phenyl
.[.OMe.]..Iadd- .OCH.sub.3.Iaddend.
.[.OMe.]..Iadd.OCH.sub.3.Iaddend. CH O O
.[.I-236.]..Iadd.I-42.Iaddend. OH Phenyl 3-NO.sub.2--Phenyl
.[.OMe.]..Iadd- .OCH.sub.3.Iaddend.
.[.OMe.]..Iadd.OCH.sub.3.Iaddend. CH O O
.[.I-237.]..Iadd.I-43.Iaddend. OH Phenyl 2-HO--Phenyl
.[.OMe.]..Iadd.OCH.s- ub.3.Iaddend.
.[.OMe.]..Iadd.OCH.sub.3.Iaddend. CH O O
.[.I-238.]..Iadd.I-44.Iaddend. OH Phenyl 3,4-
.[.OMe.]..Iadd.OCH.sub.3.Iad- dend.
.[.OMe.]..Iadd.OCH.sub.3.Iaddend. CH O O Dimethoxyphenyl
.[.I-239.]..Iadd.I-45.Iaddend. OH Phenyl 3,4-
.[.OMe.]..Iadd.OCH.sub.3.Iad- dend.
.[.OMe.]..Iadd.OCH.sub.3.Iaddend. CH O O Dioxomethylene-
phenyl-.[.[sic].]. .[.I-240.]..Iadd.I-46.Iaddend. OH Phenyl 3,4,5-
.[.OMe.]..Iadd.OCH.sub.3.I- addend.
.[.OMe.]..Iadd.OCH.sub.3.Iaddend. CH O O Triimethoxyphenyl
.[.I-241.]..Iadd.I-47.Iaddend. OH Phenyl Benzyl
.[.OMe.]..Iadd.OCH.sub.3.I- addend.
.[.OMe.]..Iadd.OCH.sub.3.Iaddend. CH O O
.[.I-242.]..Iadd.I-48.Iaddend. OH Phenyl 2-Cl--Benzyl
.[.OMe.]..Iadd.OCH.s- ub.3.Iaddend.
.[.OMe.]..Iadd.OCH.sub.3.Iaddend. CH O O
.[.I-243.]..Iadd.I-49.Iaddend. OH Phenyl 3-Br--Benzyl
.[.OMe.]..Iadd.OCH.s- ub.3.Iaddend.
.[.OMe.]..Iadd.OCH.sub.3.Iaddend. CH O O
.[.I-244.]..Iadd.I-50.Iaddend. OH Phenyl 4-F--Benzyl
.[.OMe.]..Iadd.OCH.su- b.3.Iaddend.
.[.OMe.]..Iadd.OCH.sub.3.Iaddend. CH O O
.[.I-245.]..Iadd.I-51.Iaddend. OH Phenyl
2-Me.Iadd.thyl.Iaddend.-Benzyl .[- .OMe.]..Iadd.OCH.sub.3.Iaddend.
.[.OMe.]..Iadd.OCH.sub.3.Iaddend. CH O O
.[.I-246.]..Iadd.I-52.Iaddend. OH Phenyl
2-Me.Iadd.thyl.Iaddend.-Benzyl .[- .OMe.]..Iadd.OCH.sub.3.Iaddend.
O--CH.dbd.CH--C O O .[.I-247.]..Iadd.I-53.Iaddend. OH Phenyl
3-Et.Iadd.hyl.Iaddend.-Benzyl .[.- OMe.]..Iadd.OCH.sub.3.Iaddend.
.[.OMe.]..Iadd.OCH.sub.3.Iaddend. CH O O
.[.I-248.]..Iadd.I-54.Iaddend. OH Phenyl 4-iso-Propyl-Benzyl
.[.OMe.]..Iad- d.OCH.sub.3.Iaddend.
.[.OMe.]..Iadd.OCH.sub.3.Iaddend. CH O O
.[.I-249.]..Iadd.I-55.Iaddend. OH Phenyl 4-NO.sub.2--Propyl-
.[.OMe.]..Iad- d.OCH.sub.3.Iaddend.
.[.OMe.]..Iadd.OCH.sub.3.Iaddend. CH O O Benzyl
.[.I-250.]..Iadd.I-56.Iaddend. OH Phenyl
2-Me.Iadd.thyl.Iaddend.-5-Propyl--
.[.OMe.]..Iadd.OCH.sub.3.Iaddend. .[.OMe.]..Iadd.OCH.sub.3.Iaddend.
CH O - O Benzyl .[.I-251.]..Iadd.I-57.Iaddend. OH Phenyl
2-Me.Iadd.thyl.Iaddend.-5-Propyl--
.[.OEt.]..Iadd.OC.sub.2H.sub.5.Iaddend.
.[.OEt.]..Iadd.OC.sub.2H.sub.5.Ia- ddend. CH O O Benzyl
.[.I-252.]..Iadd.I-58.Iaddend. OH Phenyl
4-Me.Iadd.thyl.Iaddend.-2-Propyl--
.[.OMe.]..Iadd.OCH.sub.3.Iaddend. .[.OMe.]..Iadd.OCH.sub.3.Iaddend.
CH O - O Benzyl .[.I-253.]..Iadd.I-59.Iaddend. OH Phenyl
3,4-Dioxomethyl- .[.OMe.]..Iadd.O- CH.sub.3.Iaddend.
.[.OMe.]..Iadd.OCH.sub.3.Iaddend. CH O O enebenzyl .[.[sic].].
.[.I-254.]..Iadd.I-60.Iaddend. OH 4-F--Phenyl
4-Me.Iadd.thyl.Iaddend.-2-Pr- opyl-
.[.OMe.]..Iadd.OCH.sub.3.Iaddend. .[.OMe.]..Iadd.OCH.sub.3.Iaddend.
- CH O O 163-165 Benzyl (decomp.) .[.I-255.]..Iadd.I-61.Iaddend.
.[.OMe.]..Iadd.OCH.sub.3.Iaddend. 4-F--Phen- yl Methyl
.[.OEt.]..Iadd.OC.sub.2H.sub.5.Iaddend. .[.OEt.]..Iadd.OC.sub.2H-
.sub.5.Iaddend. CH O O .[.I-256.]..Iadd.I-62.Iaddend. OH
4-Cl--Phenyl Methyl .[.OMe.]..Iadd.OCH.s- ub.3.Iaddend.
.[.OMe.]..Iadd.OCH.sub.3.Iaddend. CH O O
.[.I-257.]..Iadd.I-63.Iaddend. OH
4-Me.Iadd.thyl.Iaddend.--O--Phenyl Methy- l
.[.OMe.]..Iadd.OCH.sub.3.Iaddend. .[.OMe.]..Iadd.OCH.sub.3.Iaddend.
CH O- O .[.I-258.]..Iadd.I-64.Iaddend. OH
4-Me.Iadd.thyl.Iaddend.--O--Phenyl Ethyl-
.[.OMe.]..Iadd.OCH.sub.3.Iaddend. .[.OMe.]..Iadd.OCH.sub.3.Iaddend.
CH O - O .[.I-259.]..Iadd.I-65.Iaddend. OH
4-Me.Iadd.thyl.Iaddend.-Phenyl Methyl .[-
.OMe.]..Iadd.OCH.sub.3.Iaddend. .[.OMe.]..Iadd.OCH.sub.3.Iaddend.
CH O O .[.I-260.]..Iadd.I-66.Iaddend. OH
4-Me.Iadd.thyl.Iaddend.-Phenyl Methyl .[-
.OMe.]..Iadd.OCH.sub.3.Iaddend. O--CH.sub.2--CH.sub.2--C O O
.[.I-261.]..Iadd.I-67.Iaddend. OH 3-CF.sub.3--Phenyl n-Propyl
.[.OMe.]..Ia- dd.OCH.sub.3.Iaddend.
.[.OMe.]..Iadd.OCH.sub.3.Iaddend. CH O O
.[.I-262.]..Iadd.I-68.Iaddend. OH 3-CF.sub.3--Phenyl n-Propyl
.[.OMe.]..Ia- dd.OCH.sub.3.Iaddend. O--CH(CH.sub.3)--CH.sub.2--C O
O .[.I-263.]..Iadd.I-69.Iaddend. OH 4-NO.sub.2--Phenyl Methyl
.[.OMe.]..Iadd- .OCH.sub.3.Iaddend.
.[.OMe.]..Iadd.OCH.sub.3.Iaddend. CH O O
.[.I-264.]..Iadd.I-70.Iaddend. OH 4-NO.sub.2--Phenyl Methyl
.[.OMe.]..Iadd- .OCH.sub.3.Iaddend. O--CH.dbd.CH--C O O
.[.I-265.]..Iadd.I-71.Iaddend. OH 3-Cl--Phenyl Ethyl
.[.OMe.]..Iadd.OCH.su- b.3.Iaddend.
.[.OMe.]..Iadd.OCH.sub.3.Iaddend. CH O O
.[.I-266.]..Iadd.I-72.Iaddend. OH 2-F--Phenyl Methyl
.[.OMe.]..Iadd.OCH.su- b.3.Iaddend.
.[.OMe.]..Iadd.OCH.sub.3.Iaddend. CH O O 193-194 (decomp.)
.[.I-267.]..Iadd.I-73.Iaddend. OH 2-F--Phenyl Methyl
.[.OMe.]..Iadd.OCH.su- b.3.Iaddend.
.[.OMe.]..Iadd.OCH.sub.3.Iaddend. CH S O
.[.I-268.]..Iadd.I-74.Iaddend. OH
2-Me.Iadd.thyl.Iaddend.--O--Phenyl Methy- l
.[.OMe.]..Iadd.OCH.sub.3.Iaddend. .[.OMe.]..Iadd.OCH.sub.3.Iaddend.
CH O- O .[.I-269.]..Iadd.I-75.Iaddend. OH
2-Me.Iadd.thyl.Iaddend.--O--Phenyl Methy- l
.[.OMe.]..Iadd.OCH.sub.3.Iaddend. .[.OMe.]..Iadd.OCH.sub.3.Iaddend.
CH O- S .[.I-270.]..Iadd.I-76.Iaddend. OH 3,4-Dimethoxyphenyl
Methyl .[.OMe.]..Iad- d.OCH.sub.3.Iaddend.
.[.OMe.]..Iadd.OCH.sub.3.Iaddend. CH O O
.[.I-271.]..Iadd.I-77.Iaddend. OH 3,4-Dioxmethyl- Methyl
.[.OMe.]..Iadd.OC- H.sub.3.Iaddend.
.[.OMe.]..Iadd.OCH.sub.3.Iaddend. CH O O enephenyl .[.[sic].].
.[.I-272.]..Iadd.I-78.Iaddend. OH p-CF.sub.3--Phenyl Methyl
.[.OMe.]..Iadd- .OCH.sub.3.Iaddend.
.[.OMe.]..Iadd.OCH.sub.3.Iaddend. CH O O
.[.I-273.]..Iadd.I-79.Iaddend. OH Phenyl Methyl
.[.OMe.]..Iadd.OCH.sub.3.I- addend.
.[.OEt.]..Iadd.OC.sub.2H.sub.5.Iaddend. CH O O
.[.I-274.]..Iadd.I-80.Iaddend. .[.OMe.]..Iadd.OCH.sub.3.Iaddend.
Phenyl Me- thyl .[.OMe.]..Iadd.OCH.sub.3.Iaddend.
.[.OEt.]..Iadd.OC.sub.2H.sub.5.Iadd- end. CH O O
.[.I-275.]..Iadd.I-81.Iaddend. OH Phenyl Ethyl
.[.OMe.]..Iadd.OCH.sub.3.Ia- ddend. NH--.[.OMe.]. CH O O
.Iadd.OCH.sub.3.Iaddend. .[.I-276.]..Iadd.I-82.Iaddend. OH
p-Me.Iadd.thyl.Iaddend.-O--Phenyl n-Prop- yl
.[.OMe.]..Iadd.OCH.sub.3.Iaddend. OCF.sub.3 CH O O
.[.I-277.]..Iadd.I-83.Iaddend. OH Phenyl Methyl
.[.OMe.]..Iadd.OCH.sub.3.I- addend. CF.sub.3 CH O O
.[.I-278.]..Iadd.I-84.Iaddend. OH Phenyl Methyl
.[.OMe.]..Iadd.OCH.sub.3.I- addend. CF.sub.3 N O O
.[.I-279.]..Iadd.I-85.Iaddend. OH 3,4-Dimethoxyphenyl Benzyl
Me.Iadd.thyl.- Iaddend. Me.Iadd.thyl.Iaddend. O O
.[.I-280.]..Iadd.I-86.Iaddend. OH 3,4-Dimethoxyphenyl Methyl
.[.OMe.]..Iad- d.OCH.sub.3.Iaddend. O--CH.sub.2CH.sub.2--C O O
.[.I-281.]..Iadd.I-87.Iaddend. OH Phenyl Methyl
.[.OMe.]..Iadd.OCH.sub.3.I- addend. O--CH.sub.2--CH.sub.2--C O O
126 (decomp.) .[.I-282.]..Iadd.I-88.Iaddend. OH Phenyl Methyl
.[.OMe.]..Iadd.OCH.sub.3.I- addend. O--CH(CH.sub.3)--CH.sub.2--C O
O .[.I-283.]..Iadd.I-89.Iaddend. OH Phenyl Methyl
.[.OMe.]..Iadd.OCH.sub.3.I- addend. N(CH.sub.3)--CH.dbd.CH--C O O
118 .[.I-284.]..Iadd.I-90.Iaddend. OH Phenyl Methyl
.[.OMe.]..Iadd.OCH.sub.3.I- addend.
S--C(CH.sub.3).dbd.C(CH.sub.3)--C O O
.[.I-285.]..Iadd.I-91.Iaddend. OH Phenyl Methyl
.[.OMe.]..Iadd.OCH.sub.3.I- addend. O--C(CH.sub.3).dbd.CH--C O O
.[.I-286.]..Iadd.I-92.Iaddend. OH Phenyl Methyl
Me.Iadd.thyl.Iaddend. O--C- (CH.sub.3).dbd.CH--C O O
.[.I-287.]..Iadd.I-93.Iaddend. OH Phenyl Methyl
Me.Iadd.thyl.Iaddend. O--C- H.dbd.CH--C O O
.[.I-288.]..Iadd.I-94.Iaddend. OH 4-F--Phenyl Methyl
Me.Iadd.thyl.Iaddend.- S--CH.dbd.CH--C O O
.[.I-289.]..Iadd.I-95.Iaddend. OH 4-F--Phenyl H
.[.OMe.]..Iadd.OCH.sub.3.I- addend.
.[.OMe.]..Iadd.OCH.sub.3.Iaddend. CH O S
.[.I-290.]..Iadd.I-96.Iaddend. OH Phenyl Methyl
.[.OMe.]..Iadd.OCH.sub.3.I- addend. CH.sub.2--CH.sub.2--CH.sub.2--C
O O 149-151 (decomp.) .[.I-291.]..Iadd.I-97.Iaddend. OH Phenyl
Methyl Methyl CH.sub.2--CH.sub.2-- -CH.sub.2--C O O 157 (decomp.)
.[.I-292.]..Iadd.I-98.Iaddend. OH Phenyl Methyl Ethyl
CH.sub.2--CH.sub.2--- CH.sub.2--CH.sub.2--C O O
.[.I-293.]..Iadd.I-99.Iaddend. OH Phenyl Methyl
.[.OMe.]..Iadd.OCH.sub.3.I- addend.
CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--C O O
.[.I-294.]..Iadd.I-100.Iaddend. OH Phenyl Methyl
Me.Iadd.thyl.Iaddend. Me.- Iadd.thyl.Iaddend. CH O O
.[.I-295.]..Iadd.I-101.Iaddend. OH Phenyl Methyl
Et.Iadd.hyl.Iaddend. Et.I-
add.hyl.Iaddend. CH O O .[.I-296.]..Iadd.I-102.Iaddend. OH Phenyl
Methyl Me.Iadd.thyl.Iaddend. Me.- Iadd.thyl.Iaddend. C--CH.sub.3 O
O .[.I-297.]..Iadd.I-103.Iaddend. OH Phenyl Methyl
.[.OMe.]..Iadd.OCH.sub.3.- Iaddend. .[.Me.]..Iadd.CH.sub.3.Iaddend.
CH O O .[.I-298.]..Iadd.I-104.Iaddend. OH Cyclohexyl Methyl
.[.OMe.]..Iadd.OCH.su- b.3.Iaddend.
.[.OMe.]..Iadd.OCH.sub.3.Iaddend. CH O O
.[.I-299.]..Iadd.I-105.Iaddend. OH Cyclohexyl Methyl
.[.OMe.]..Iadd.OCH.su- b.3.Iaddend. CH.sub.2--CH.sub.2--CH.sub.2--C
O O .[.I-300.]..Iadd.I-106.Iaddend. OH Phenyl Methyl OCH.sub.3
OCH.sub.3 CH S - S .[.I-301.]..Iadd.I-107.Iaddend. OH Phenyl Methyl
OCH.sub.3 OCH.sub.3 CH O - S 134 .[.I-302.]..Iadd.I-108.Iaddend.
OCH.sub.3 Phenyl Methyl OCH.sub.3 OCH.sub.- 3 CH S S
.[.I-303.]..Iadd.I-109.Iaddend. OH Phenyl Methyl OCH.sub.3
OCH.sub.3 CH O - O .[.I-304.]..Iadd.I-110.Iaddend. OCH.sub.3
2-Fluorophenyl Methyl OCH.sub.3 - OCH.sub.3 CH O O
.[.I-305.]..Iadd.I-111.Iaddend. OC.sub.2H.sub.5 3-Chlorophenyl
Methyl OCH.- sub.3 OCH.sub.3 N O O .[.I-306.]..Iadd.I-112.Iaddend.
ON(CH.sub.3).sub.2 4-Bromophenyl Methyl CF- .sub.3 CF.sub.3 CH S O
.[.I-307.]..Iadd.I-113.Iaddend. O--CH.sub.2-- Phenyl Ethyl
OCH.sub.3 CF.su- b.3 CH O O C.dbd.CH
.[.I-308.]..Iadd.I-114.Iaddend. OH Phenyl Propyl OCH.sub.3
OCF.sub.3 CH O - S .[.I-309.]..Iadd.I-115.Iaddend. OCH.sub.3 Phenyl
i-Propyl OCH.sub.3 CH.sub- .3 CH O O
.[.I-310.]..Iadd.I-116.Iaddend. OC.sub.2H.sub.5 Phenyl s-Butyl
OCH.sub.3 C- l CH S O .[.I-311.]..Iadd.I-117.Iaddend.
ON(CH.sub.3).sub.2 2-Methylphenyl Methyl O- CH.sub.3 OCH.sub.3 CH O
O .[.I-312.]..Iadd.I-118.Iaddend. ON(CH.sub.3).sub.2
3-Methoxyphenyl Methyl - OCH.sub.3 OCH.sub.3 CH O O
.[.I-313.]..Iadd.I-119.Iaddend. ON.dbd.C(CH.sub.3).sub.2
4-Nitrophenyl Met- hyl OCH.sub.3 OCH.sub.3 CH O O
.[.I-314.]..Iadd.I-120.Iaddend. ON(CH.sub.3).sub.2 Phenyl
1-Phenylpropyn-3- -yl OCH.sub.3 OCF.sub.3 N O S
.[.I-315.]..Iadd.I-121.Iaddend. ON.dbd.C(CH.sub.3).sub.2
2-Hydroxyphenyl M- ethyl OCH.sub.3 CH.sub.3 N O O
.[.I-316.]..Iadd.I-122.Iaddend. ONSO.sub.2(C.sub.6H.sub.5
3-Trifluoromethy- l- Methyl OCH.sub.3 Cl N O O phenyl
.[.I-317.]..Iadd.I-123.Iaddend. NH.[.Phenyl.].-- 4-Dimethyl- Methyl
OCH.su- b.3 OCH.sub.3 CH S O .Iadd.phenyl.Iaddend. aminophenyl
.[.I-318.]..Iadd.I-124.Iaddend. OC.sub.2H.sub.5 Phenyl
Trifluoromethyl CH.- sub.3 CH.sub.3 CH O O
.[.I-319.]..Iadd.I-125.Iaddend. ON(CH.sub.3).sub.2 Phenyl Benzyl Cl
Cl CH - O O .[.I-320.]..Iadd.I-126.Iaddend. ON(CH.sub.3).sub.2
Phenyl 2-Methoxyethyl O- CH.sub.3 --O--CH.sub.2--CH.sub.2-- S O
.[.I-321.]..Iadd.I-127.Iaddend. OH Phenyl Phenyl OCH.sub.3
OCH.sub.3 CH O - O .[.I-322.]..Iadd.I-128.Iaddend. OH Phenyl Phenyl
OCH.sub.3 --O--CH.sub.2--- CH.sub.2-- O O
.[.I-323.]..Iadd.I-129.Iaddend. OH Phenyl Phenyl OCH.sub.3
OCH.sub.3 N O O- .[.I-324.]..Iadd.I-130.Iaddend. OH Phenyl Phenyl
OCH.sub.3 OCH.sub.3 CH S - O .[.I-325.]..Iadd.I-131.Iaddend. OH
Phenyl Phenyl OCH.sub.3 OCH.sub.3 CH S - S
.[.I-326.]..Iadd.I-132.Iaddend. OH Phenyl Phenyl OCH.sub.3
OCH.sub.3 CH O - S .[.I-327.]..Iadd.I-133.Iaddend. OH Phenyl Phenyl
OCH.sub.3 OCH.sub.3 CH O - O .[.I-328.]..Iadd.I-134.Iaddend. OH
Phenyl Phenyl OCH.sub.3 OCH.sub.3 CH O - O
.[.I-329.]..Iadd.I-135.Iaddend. OH --(CH.sub.2).sub.5-- Phenyl
Phenyl OCH.- sub.3 CH O O .[.I-330.]..Iadd.I-136.Iaddend. OH Phenyl
.[.2-thiozolyl.]..Iadd.2-.Iadden- d. OCH.sub.3 OCH.sub.3 CH O O
.Iadd.thiazolyl.Iaddend. .[.I-331.]..Iadd.I-137.Iaddend. OCH.sub.3
2-Fluorophenyl Phenyl OCH.sub.3 - OCH.sub.3 CH O O
.[.I-332.]..Iadd.I-138.Iaddend. OC.sub.2H.sub.5 3-Chlorophenyl
Phenyl OCH.- sub.3 OCH.sub.3 N O O .[.I-333.]..Iadd.I-139.Iaddend.
ON(CH.sub.3).sub.2 4-Bromophenyl Phenyl CF- .sub.3 CF.sub.3 CH O O
.[.I-334.]..Iadd.I-140.Iaddend. .[.OCH2CH.]. Phenyl 2-Fluorophenyl
OCH.sub- .3 CF.sub.3 CH O O .Iadd.OCH2.dbd.CH.Iaddend.
.[.I-335.]..Iadd.I-141.Iaddend. OH Phenyl 3-Chlorophenyl OCH.sub.3
OCF.sub- .3 CH O S .[.I-336.]..Iadd.I-142.Iaddend. OCH.sub.3 Phenyl
4-Bromophenyl OCH.sub.3 C- H.sub.3 CH O O
.[.I-337.]..Iadd.I-143.Iaddend. OC.sub.2H.sub.5 Phenyl 4-Thiazolyl
OCH.sub- .3 Cl CH S O .[.I-338.]..Iadd.I-144.Iaddend.
ON(CH.sub.3).sub.2 2-Methylphenyl Phenyl O- CH.sub.3 OCH.sub.3 CH O
O .[.I-339.]..Iadd.I-145.Iaddend. ON.dbd.C(CH.sub.3).sub.2
2-Methoxyphenyl P- henyl OCH.sub.3 OCH.sub.3 CH O O
.[.I-340.]..Iadd.I-146.Iaddend. OH Phenyl Methyl OCH.sub.3
--CH.sub.2--CH.- sub.2--CH.sub.2--C O O
.[.I-341.]..Iadd.I-147.Iaddend. OH 4-Fluorophenyl Methyl OCH.sub.3
OCH.sub- .3 CH O O 168 (decomp.) .[.I-342.]..Iadd.I-148.Iaddend. OH
4-Fluorophenyl Methyl OCH.sub.3 --CH.su- b.2--CH.sub.2--CH.sub.2--C
O O .[.I-343.]..Iadd.I-149.Iaddend. NH--SO--C.sub.6H.sub.5
4-Nitrophenyl Pheny- l OCH.sub.3 OCH.sub.3 CH O O
.[.I-344.]..Iadd.I-150.Iaddend. OCH.sub.3 Phenyl 3-Imidazolyl
OCH.sub.3 --- O--CH.sub.2--CH.sub.2 O O
.[.I-345.]..Iadd.I-151.Iaddend. OC.sub.2H.sub.5 Phenyl 4-Imidazolyl
OCH.su- b.3 CF.sub.3 N S O .[.I-346.]..Iadd.I-152.Iaddend.
ON(CH.sub.3).sub.2 Phenyl 2-Pyrazolyl OCH.- sub.3 OCF.sub.3 N O S
.[.I-347.]..Iadd.I-153.Iaddend. ON.dbd.C(CH.sub.3).sub.2
2-Hydroxyphenyl P- henyl OCH.sub.3 CH.sub.3 N O O
.[.I-348.]..Iadd.I-154.Iaddend. NH--SO.sub.2--C.sub.6H.sub.5
3-Trifluorome- thyl- Phenyl OCH.sub.3 Cl N O O phenyl
.[.I-349.]..Iadd.I-155.Iaddend. NH.[.Phenyl.].-- 4-Dimethylamino-
Phenyl O- CH.sub.3 OCH.sub.3 CH S O .Iadd.phenyl.Iaddend. phenyl
.[.I-350.]..Iadd.I-156.Iaddend. ONa Phenyl Phenyl OCH.sub.3
OCH.sub.3 CH S- S .[.I-351.]..Iadd.I-157.Iaddend.
O--CH.sub.2--C.ident.C Phenyl Phenyl OCH.s- ub.3 OCH.sub.3 N S S
.[.I-352.]..Iadd.I-158.Iaddend. OH Phenyl Phenyl CF.sub.3 CF.sub.3
CH O S - .[.I-353.]..Iadd.I-159.Iaddend. OCH.sub.3 Phenyl Phenyl
OCF.sub.3 OCF.sub.- 3 CH O O .[.I-354.]..Iadd.I-160.Iaddend.
OC.sub.2H.sub.5 Phenyl 2-Dimethylamino- CH- .sub.3 CH.sub.3 CH O O
phenyl .[.I-355.]..Iadd.I-161.Iaddend. ONC(CH.sub.3).sub.2 Phenyl
3-Hydroxyphenyl- Cl Cl CH O O .[.I-356.]..Iadd.I-162.Iaddend.
ON.dbd.C(CH.sub.3).sub.2 Phenyl 4-Trifluor- omethyl- OCH.sub.3
--O--CH.sub.2--CH.sub.2-- S O phenyl
.[.I-357.]..Iadd.I-163.Iaddend. NH--SO.sub.2--C.sub.6H.sub.5 Phenyl
2-Oxaz- olyl OCH.sub.3 CF.sub.3 N S S
.[.I-358.]..Iadd.I-164.Iaddend. OH Phenyl Methyl CH.sub.3 CH.sub.3
CH O O - .[.I-359.]..Iadd.I-165.Iaddend. OH Cyclohexyl Methyl
OCH.sub.3 OCH.sub.3 C- H O O .[.I-360.]..Iadd.I-166.Iaddend. OH
Cyclohexyl Methyl OCH.sub.3 CH.sub.2--C- H.sub.2--CH--C O O
.[.I-361.]..Iadd.I-167.Iaddend. OH Phenyl Methyl N(CH.sub.3).sub.2
N(CH.su- b.3).sub.2 CH O O .[.I-362.]..Iadd.I-168.Iaddend. OH
Phenyl Methyl OCH.sub.3 OCH.sub.3 CH O - SO.sub.2
.[.I-363.]..Iadd.I-169.Iaddend. OH Phenyl Methyl OCH.sub.3
OCH.sub.3 CH O - SO.sub.2 .[.I-364.]..Iadd.I-170.Iaddend. OH
3-F--Phenyl Me.Iadd.thyl.Iaddend. .[.OM-
e.]..Iadd.OCH.sub.3.Iaddend. .[.OMe.]..Iadd.OCH.sub.3.Iaddend. CH O
O .[.I-365.]..Iadd.I-171.Iaddend. OH 3-F--Phenyl
Me.Iadd.thyl.Iaddend. .[.OM- e.]..Iadd.OCH.sub.3.Iaddend.
CH.sub.2--CH.sub.2--CH.sub.2--C O O .[.I-366.]..Iadd.I-172.Iaddend.
OH 4-F--Phenyl Me.Iadd.thyl.Iaddend. .[.OM-
e.]..Iadd.OCH.sub.3.Iaddend. CH.sub.2--CH.sub.2CH.sub.2--C O O
142-143 191.degree. C. .[.I-367.]..Iadd.I-173.Iaddend. OH
3-Me.Iadd.thyl.Iaddend.--O--Phenyl Me.I- add.thyl.Iaddend.
.[.OMe.]..Iadd.OCH.sub.3.Iaddend. CH.sub.2--CH.sub.2--CH- .sub.2--C
O O 158-161 (decomp.) .[.I-368.]..Iadd.I-174.Iaddend. OH
3-Me.Iadd.thyl.Iaddend.--O--Phenyl Me.I- add.thyl.Iaddend.
.[.OMe.]..Iadd.OCH.sub.3.Iaddend. .[.OMe.]..Iadd.OCH.sub-
.3.Iaddend. CH O O .[.I-369.]..Iadd.I-175.Iaddend. OH
3-Me.Iadd.thyl.Iaddend.--O--Phenyl Et.I- add.hyl.Iaddend.
.[.OMe.]..Iadd.OCH.sub.3.Iaddend. CH.sub.2--CH.sub.2--CH.- sub.2--C
O O .[.I-370.]..Iadd.I-176.Iaddend. OH Phenyl
HO--CH.sub.2--CH.sub.2 .[.OMe.].- .Iadd.OCH.sub.3.Iaddend.
CH.sub.2--CH.sub.2--CH.sub.2--C O O .[.I-371.]..Iadd.I-177.Iaddend.
OH Phenyl Me.Iadd.thyl.Iaddend. .[.NMe.sub- .2.]. .[.NMe.sub.2.]. N
O O 181 .Iadd.N(CH.sub.3).sub.2.Iaddend.
.Iadd.N(CH.sub.3).sub.2.Iaddend. .[.I-372.]..Iadd.I-178.Iaddend. OH
Phenyl Me.Iadd.thyl.Iaddend. .[.OMe.]..- Iadd.OCH.sub.3.Iaddend.
.[.OMe.]..Iadd.OCH.sub.3.Iaddend. N O O
.[.I-323.]..Iadd.I-179.Iaddend. OH .Iadd.3-F--Phenyl.Iaddend.
.Iadd.Methyl- .Iaddend. .Iadd.OCH.sub.3.Iaddend.
.Iadd.CH.sub.3.Iaddend. .Iadd.CH.Iadden- d. .Iadd.O.Iaddend.
.Iadd.O.Iaddend. .[.I-374.]..Iadd.I-180.Iaddend. NH--SO.sub.2--
Phenyl Me.Iadd.thyl.Iaddend- . .[.OMe.]..Iadd.OCH.sub.3.Iaddend.
.[.OMe.]..Iadd.OCH.sub.3.Iaddend. CH O- O Phenyl
.[.I-375.]..Iadd.I-181.Iaddend. NH--SO.sub.2--.[.Me.]. Phenyl
Me.Iadd.thyl- .Iaddend. .[.OMe.]..Iadd.OCH.sub.3.Iaddend.
.[.OMe.]..Iadd.OCH.sub.3.Iadde- nd. CH O O .Iadd.CH.sub.3.Iaddend.
.[.I-376.]..Iadd.I-182.Iaddend. CH.sub.2--SO.sub.2-- Phenyl
Me.Iadd.thyl.I- addend. .[.OMe.]..Iadd.OCH.sub.3.Iaddend.
.[.OMe.]..Iadd.OCH.sub.3.Iaddend- . CH O O Phenyl
.[.I-377.]..Iadd.I-183.Iaddend. NH--SO.sub.2--.[.Me.]. Phenyl
Me.Iadd.thyl- .Iaddend. .[.OMe.]..Iadd.OCH.sub.3.Iaddend.
.[.OMe.]..Iadd.OCH.sub.3.Iadde- nd. CH O O .Iadd.CH.sub.3.Iaddend.
.[.I-378.]..Iadd.I-184.Iaddend. --CN Phenyl Me.Iadd.thyl.Iaddend.
.[.OMe.]- ..Iadd.OCH.sub.3.Iaddend.
.[.OMe.]..Iadd.OCH.sub.3.Iaddend. CH O O
.[.I-379.]..Iadd.I-185.Iaddend. Tetrazole.[.[sic].]. Phenyl
Me.Iadd.thyl.I- addend. .[.OMe.]..Iadd.OCH.sub.3.Iaddend.
.[.OMe.]..Iadd.OCH.sub.3.Iaddend- . CH O O
.[.I-380.]..Iadd.I-186.Iaddend. NH--SO.sub.2-- Phenyl
Me.Iadd.thyl.Iaddend- . .[.OMe.]..Iadd.OCH.sub.3.Iaddend.
.[.OMe.]..Iadd.OCH.sub.3.Iaddend. CH O- O 167 Phenyl
.[.I-381.]..Iadd.I-187.Iaddend. N--Methyltetra- Phenyl
Me.Iadd.thyl.Iadden- d. .[.OMe.]..Iadd.OCH.sub.3.Iaddend.
.[.OMe.]..Iadd.OCH.sub.3.Iaddend. CH - O O zole.[.[sic].].
.[.I-382.]..Iadd.I-188.Iaddend. ONa Phenyl Me.Iadd.thyl.Iaddend.
.[.OMe.].- .Iadd.OCH.sub.3.Iaddend. --O--CH.sub.2--CH.sub.2--C-- O
O 122-139 .Iadd.(decomp.).Iaddend. .[.(zers.).].
.[.I-383.]..Iadd.I-189.Iaddend. OH o-F--Phenyl
Me.Iadd.thyl.Iaddend. .[.OM- e.]..Iadd.OCH.sub.3.Iaddend.
--O--CH.sub.2--CH.sub.2--C-- O O 140-144 (decomp.)
.[.I-384.]..Iadd.I-190.Iaddend. OH m-Me.Iadd.thyl.Iaddend.-Phenyl
Me.Iadd.- thyl.Iaddend. .[.OMe.]..Iadd.OCH.sub.3.Iaddend.
.[.OMe.]..Iadd.OCH.sub.3.I- addend. CH O O 169-177
.[.I-385.]..Iadd.I-191.Iaddend. OH m-Me.Iadd.thyl.Iaddend.-Phenyl
Me.Iadd.- thyl.Iaddend. .[.OMe.]..Iadd.OCH.sub.3.Iaddend.
--O--CH.sub.2--CH.sub.2--C- -- O O 119-135 (decomp.)
.[.I-386.]..Iadd.I-192.Iaddend. OH p-F--Phenyl
Me.Iadd.thyl.Iaddend. .[.OM- e.]..Iadd.OCH.sub.3.Iaddend.
.[.Me.]..Iadd.CH.sub.3.Iaddend. CH O O 137-14- 0 (decomp.)
.[.I-387.]..Iadd.I-193.Iaddend. OH m-F--Phenyl
Me.Iadd.thyl.Iaddend. Me.Ia- dd.thyl.Iaddend.
--O--CH.sub.2--CH.sub.2--C-- O O 150-152
.[.I-388.]..Iadd.I-194.Iaddend. OH p-F--Phenyl
Me.Iadd.thyl.Iaddend. Me.Ia- dd.thyl.Iaddend.
--O--CH.sub.2--CH.sub.2--C-- O O 169-170
TABLE-US-00002 TABLE II ##STR00015## m.p. No. R.sup.1 A R.sup.6
R.sup.2 R.sup.3 X Y Z [.degree. C.] II-1 OH Bond Methyl
OMe.Iadd.thyl.Iaddend. OMe.Iadd.thyl.Iaddend. CH O O 9- 6-98 II-2
OH CH.sub.2 Methyl OMe.Iadd.thyl.Iaddend. OMe.Iadd.thyl.Iaddend. CH
O- O II-3 OH CH.sub.2--CH.sub.2 Methyl OMe.Iadd.thyl.Iaddend.
OMe.Iadd.thyl.Iad- dend. CH O O II-4 OH CH.dbd.CH Methyl
OMe.Iadd.thyl.Iaddend. OMe.Iadd.thyl.Iaddend. CH - O O II-5 OH O
Methyl OMe.Iadd.thyl.Iaddend. OMe.Iadd.thyl.Iaddend. CH O O II-6 OH
S Methyl OMe.Iadd.thyl.Iaddend. OMe.Iadd.thyl.Iaddend. CH O O II-7
OH NH(CH.sub.3) Methyl OMe.Iadd.thyl.Iaddend.
OMe.Iadd.thyl.Iaddend. - CH O O II-8 OH Bond Isopropyl
OMe.Iadd.thyl.Iaddend. OMe.Iadd.thyl.Iaddend. CH O - O 137-139 II-9
OH Bond p-Isopropylphenyl OMe.Iadd.thyl.Iaddend.
OMe.Iadd.thyl.Iadden- d. CH O O II-10 OH Bond Benzyl
OMe.Iadd.thyl.Iaddend. OMe.Iadd.thyl.Iaddend. CH O O - II-11 OH
CH.dbd.CH Ethyl OMe.Iadd.thyl.Iaddend. OMe.Iadd.thyl.Iaddend. CH -
O O II-12 OH CH.dbd.CH (CH.sub.3).sub.2--CH.sub.2--CH.sub.2
OMe.Iadd.thyl.Iadd- end. OMe.Iadd.thyl.Iaddend. CH O O II-13 OH
CH.dbd.CH Cyclopropylmethyl OMe.Iadd.thyl.Iaddend. OMe.Iadd.thyl.-
Iaddend. CH O O .[.ene.]..[.[sic].]. II-14 OH CH.dbd.CH Methyl
OMe.Iadd.thyl.Iaddend. O--CH.sub.2--CH.sub.2--C - O O II-15 OH
CH.sub.2--CH.sub.2 Ethyl OMe.Iadd.thyl.Iaddend. O--CH.dbd.CH--C O-
O II-16 OH .[.CH.sub.2.dbd.CH.sub.2.]. Methyl
OMe.Iadd.thyl.Iaddend. CH.sub.- 2--CH.sub.2--CH.sub.2--C O O
.Iadd.CH.sub.2--CH.sub.2.Iaddend. II-17 OH Bond Methyl
OMe.Iadd.thyl.Iaddend. CH.sub.2--CH.sub.2--CH.sub.2--- C O O
147
Example 35
Receptor binding data were measured by the binding assay described
above for the compounds listed below. The results are shown in
Table 2 .[.[sic].]..
TABLE-US-00003 TABLE 2 Receptor binding data (K.sub.i values)
Compound ET.sub.A [nM] ET.sub.B [nM] I-2 6 34 I-29 86 180 I-5 12
160 I-4 7 2500 I-87 1 57 I.89 86 9300 I-103 0.4 29 I-107 3 485 I-12
19 1700 I-26 23 2000 I-23 209 1100 I-47 150 1500 I-60 33 970 I-96
0.6 56 II-3 107 7300 II-1 28 2300
* * * * *