U.S. patent application number 16/634337 was filed with the patent office on 2020-07-23 for preparation of substituted 3-aryl-5-trifluoromethyl-1,2,4-oxadiazoles.
The applicant listed for this patent is BASF SE. Invention is credited to Wassilios GRAMMENOS, Christopher KORADIN, Michael RACK, Violeta TERTERYAN-SEISER.
Application Number | 20200231556 16/634337 |
Document ID | / |
Family ID | 59485232 |
Filed Date | 2020-07-23 |
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United States Patent
Application |
20200231556 |
Kind Code |
A1 |
GRAMMENOS; Wassilios ; et
al. |
July 23, 2020 |
PREPARATION OF SUBSTITUTED
3-ARYL-5-TRIFLUOROMETHYL-1,2,4-OXADIAZOLES
Abstract
The present invention relates to a process for the preparation
of 3-aryl-5-trifluoromethyl-1,2,4-oxadiazoles, which are useful as
fungicidal compounds or as intermediates for the synthesis of
fungicidal oxaciazole compounds, using trifluoroacetyl halides.
##STR00001##
Inventors: |
GRAMMENOS; Wassilios;
(Ludwigshafen, DE) ; RACK; Michael; (Ludwigshafen,
DE) ; TERTERYAN-SEISER; Violeta; (Ludwigshafen,
DE) ; KORADIN; Christopher; (Ludwigshafen,
DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
BASF SE |
Ludwigshafen am Rhein |
|
DE |
|
|
Family ID: |
59485232 |
Appl. No.: |
16/634337 |
Filed: |
July 20, 2018 |
PCT Filed: |
July 20, 2018 |
PCT NO: |
PCT/EP2018/069712 |
371 Date: |
January 27, 2020 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 271/06
20130101 |
International
Class: |
C07D 271/06 20060101
C07D271/06 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 28, 2017 |
EP |
17183655.4 |
Claims
1.-15. (canceled)
16. A process for preparing compounds of formula I, ##STR00045##
wherein A.sup.1 is CH; A.sup.2 is N CH; R.sup.A is hydrogen or
fluorine; R is --COOH, --COOR.sup.1 or --C(.dbd.W)NR.sup.1R.sup.2;
W is O or S; R.sup.1 is C.sub.1-C.sub.6-alkyl,
C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl,
C.sub.1-C.sub.6-alkoxyimino-C.sub.1-C.sub.4-alkyl,
C.sub.3-C.sub.11-cycloalkyl, C.sub.3-C.sub.8-cycloalkenyl,
phenyl-C.sub.1-C.sub.4-alkyl, heteroaryl-C.sub.1-C.sub.4-alkyl,
phenyl or heteroaryl; and wherein the heteroaryl group is a 5- or
6-membered aromatic heterocycle, wherein the ring includes besides
carbon atoms 1, 2, 3 or 4 heteroatoms selected from the group
consisting of N, O and S as ring member atoms; and wherein any of
the aliphatic or cyclic groups are unsubstituted or substituted
with 1, 2, 3 or up to the maximum possible number of identical or
different radicals selected from the group consisting of halogen,
cyano, C.sub.1-C.sub.6-alkyl and C.sub.1-C.sub.6-alkoxy; R.sup.2 is
hydrogen, formyl, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy,
C.sub.2-C.sub.6-alkenyl, propargyl, C.sub.3-C.sub.8-cycloalkyl,
C.sub.3-C.sub.8-cycloalkenyl,
C.sub.3-C.sub.8-cycloalkyl-C.sub.1-C.sub.4-alkyl, phenyl,
C.sub.1-C.sub.6-alkylamino or diC.sub.1-C.sub.6-alkylamino; and
wherein any of the aliphatic or cyclic groups are unsubstituted or
substituted with 1, 2, 3, 4 or up to the maximum possible number of
identical or different radicals selected from the group consisting
of halogen, cyano, C.sub.1-C.sub.6-alkyl and
C.sub.1-C.sub.6-alkoxy; the process comprising: reacting a compound
of formula II, ##STR00046## wherein A.sup.1, A.sup.2, R.sup.A and R
is as defined above, with a trifluoroacetyl halide of formula IIa,
##STR00047## wherein Hal is chlorine or fluorine.
17. The process of claim 16, wherein the process is conducted in
the presence of an inert organic solvent.
18. The process of claim 16, wherein Hal in compound IIa is
chlorine.
19. The process of claim 16, wherein the process is conducted in
the presence of a base selected from trimethylamine, triethylamine,
tributylamine, diisopropylethylamine, pyridine, 2,4,6-collidine,
2,6-lutidine, 2-picoline, 3-picoline, 4-picoline,
5-ethyl-2-methyl-pyridine, sodium acetate, potassium acetate,
sodium carbonate, potassium carbonate and mixtures thereof.
20. The process of claim 16, wherein the process is conducted at a
pressure from 1 atm to 20 atm.
21. The process of claim 16, wherein the process is conducted at a
temperature from 0.degree. C. to 100.degree. C.
22. The process of claim 16, the process comprising two steps: i)
reacting a compound of formula V, ##STR00048## wherein R is as
defined in claim 16, with hydroxylamine or a salt thereof; ii)
reacting the product of step i), a compound of formula II,
##STR00049## wherein R is as defined above, with a trifluoroacetyl
halide according to the process as defined in claim 16.
23. The process of claim 16, further comprising the step of
reacting the compound of formula I to obtain a compound of formula
III ##STR00050##
24. The process of 23, further comprising the step of reacting the
compound of formula III with a compound of formula IV
R.sup.1--NH--R.sup.2 IV, wherein R.sup.1 and R.sup.2 in the
compound of formula IV is as defined in claim 16 to obtain a
compound of formula Ic ##STR00051##
25. The process of claim 24, further comprising the step of
reacting the compound of formula Ic to obtain a compound of formula
Id ##STR00052##
26. The process of claim 24, wherein R.sup.1 is methyl, ethyl,
n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, cyclopropyl,
2-methoxyiminoethyl, bicyclo[1.1.1]pentan-1-yl, or phenyl; and
wherein the phenyl group is unsubstituted or substituted with 1, 2,
3 or up to the maximum possible number of identical or different
radicals selected from the group consisting of fluorine, chlorine,
cyano, methyl, ethyl, methoxy, trifluoromethyl, trifluoromethoxy,
difluoromethyl, difluoromethoxy and cyclopropyl; R.sup.2 is
hydrogen, methyl or ethyl.
27. The process of claim 24, wherein R.sup.1 is methyl,
2-methoxyiminoethyl, bicyclo[1.1.1]pentan-1-yl, 2-fluoro-phenyl,
4-fluoro-phenyl or 2-difluoromethoxy-phenyl; R.sup.2 is hydrogen.
Description
[0001] The present invention relates to a process for the
preparation of substituted
3-aryl-5-trifluoromethyl-1,2,4-oxadiazoles (compounds I), which can
be obtained through reaction of hydroxyamidine type compounds of
formula II with trifluoroacetyl halides.
[0002] Certain 3-substituted 5-trifluoromethyl-1,2,4-oxadiazoles
are known as fungicides i.a. from EP 276432 A2, EP 3165093 A1, EP
3165094 A1, EP 3167716 A1, WO 2015/185485, WO 2017/055469, WO
2017/055473, WO 2017/076739, WO 2017/076740, WO 2017/076742, WO
2017/076757, WO 2017/076935, WO 2017/081309, WO 2017/081310, WO
2017081311, WO 2017081312, WO 2017/085098, WO 2017/085100,
WO2017/093019, WO2017/093348, WO 2017/085100, WO2017/093348,
WO2017/102006, WO2017/103219, WO2017/103223, WO2017/109044 and
WO2017/118689.
[0003] The formation of the 1,2,4-oxadiazole ring system in
3-aryl-5-trifluoromethyl-1,2,4-oxadiazoles, which are useful as
fungicidally active compounds or as intermediates in the synthesis
of fungicides, is described in the references cited above or in WO
2013/008162 by reacting amidoximes of type II with trifluoroacetic
anhydride (TFAA) in an organic solvent.
##STR00002##
[0004] One disadvantage of this reaction lies in the formation of
significant amounts of free trifluoroacetic acid (TFA) as a side
product. Regulatory restrictions oftentimes require very low
residue levels of TFA impurities in commercial agrochemical
pesticides. For the sake of receiving a market authorization it is
therefore crucial to control and minimize the amount of residual
TFA during the process of producing a pesticide.
[0005] In contrast to other acids it is particularly difficult to
remove free TFA from reaction mixtures, be it in solution or in
mixtures that are in a solid state. TFA has a tendency to form
cocrystals or clathrates with other solid reaction components. The
removal of TFA is oftentimes cumbersome and requires elaborate
additional purification steps (e. g. chromatography, distillation,
crystallization, etc.). Furthermore, TFA is very corrosive and
there is an interest to reduce the excess amounts of TFA furnished
during or after the ring closing reaction, for example during
workup. The reaction of compound II with TFAA produces one
equivalent TFA. In the course of the oxadiazole ring
closing/aromatisation reaction one equivalent of water is formed
per equivalent of compound II. The water immediately reacts with
another equivalent of TFAA, which in turn results in the formation
of two additional equivalents TFA. As a result, at least two
equivalents TFAA are necessary for a complete conversion of
compounds II and in total at least three equivalents TFA are formed
per equivalent of compounds II.
[0006] Reducing the number of equivalents of TFAA to the minimum
required by theory, i.e. to two equivalents based on the amounts of
compound II, does not always provide sufficient yield of the
desired product. Typically, an excess of TFAA is used to achieve
complete conversion of compounds II to compounds I. Hydrolyzation
of excess TFAA under aqueous workup conditions produces even more
TFA.
[0007] Thus, it was an object of the present invention to overcome
the disadvantages of the known processes and to provide an improved
and more economical and production plant friendly process.
[0008] It was now found that
3-aryl-5-trifluoromethyl-1,2,4-oxadiazoles can be obtained by the
use of trifluoroacetyl halides, in particular trifluoroacetyl
chloride (TFAC) or trifluoroacetyl fluoride (TFAF). The use of TFAC
or TFAF instead of TFAA has several surprising advantages in
relation to the preparation of the above-mentioned compounds.
[0009] The process of this invention does not require a large
excess of trifluoroacetyl halides in order to achieve high yields
of the desired oxadiazoles, which is desirable from both, an
economical and an ecological point of view. As a consequence, the
total organic carbon content in the production waste water is
reduced compared to the prior art processes, which makes the
process eco-friendly. Unlike the use of TFAA, the use of
trifluoroacetic halides results in the formation of a much smaller
amount of TFA, which makes such process more production plant
friendly and simplifies the workup procedure. As a result the
production costs are significantly lower. Furthermore, the process
of this invention provides the desired oxadiazoles in high yields
and with reduced amounts of undesired side products. The in-situ
preparation of compounds of type II enables a process, which
proceeds in a smooth and controlled manner, which is very safe,
simple, economical, user-friendly and commercially viable.
[0010] Accordingly, the present invention relates to a process for
preparing compounds of formula I,
##STR00003##
wherein [0011] A.sup.1 is N or CH; [0012] A.sup.2 is N or CH;
[0013] R.sup.A is hydrogen or halogen; [0014] R is methyl,
trichloromethyl, ethyl, iso-propyl, OH, SH, CN, halogen, CH.sub.2F,
CHF.sub.2, 2,2,2-trifluoroethyl, cyclopropyl, --COOH, --COOR.sup.1,
--C(.dbd.W)NR.sup.1R.sup.2, --CR.sup.3R.sup.4NR.sup.1R.sup.2,
--CR.sup.3R.sup.4OR.sup.1, --CR.sup.3(.dbd.NR.sup.1),
--CR.sup.3(.dbd.O), --CR.sup.3R.sup.4COOH,
--CR.sup.3R.sup.4COR.sup.1,
--CR.sup.3R.sup.4C(.dbd.W)NR.sup.1R.sup.2, --OCR.sup.3R.sup.4COOH,
--OCR.sup.3R.sup.4COR.sup.1,
--OCR.sup.3R.sup.4C(.dbd.W)NR.sup.1R.sup.2,
--CR.sup.3R.sup.4NR.sup.2C(.dbd.W)R.sup.1,
--CR.sup.3R.sup.4S(.dbd.O).sub.2R.sup.1, or
--CR.sup.3R.sup.4NR.sup.2S(.dbd.O).sub.2R.sup.1; [0015] W is O or
S; [0016] R.sup.2 is hydrogen, formyl, C.sub.1-C.sub.6-alkyl,
C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl,
C.sub.1-C.sub.6-alkoxy, C.sub.3-C.sub.11-cycloalkyl,
C.sub.3-C.sub.8-cycloalkenyl,
C.sub.3-C.sub.11-cycloalkyl-C.sub.1-C.sub.4-alkyl,
phenyl-C.sub.1-C.sub.4-alkyl, phenyl, pyridinyl,
--C(.dbd.O)--(C.sub.1-C.sub.6-alkyl),
--C(.dbd.O)--(C.sub.3-C.sub.11-cycloalkyl),
--C(.dbd.O)--(C.sub.1-C.sub.6-alkoxy) and --N(R.sup.2a).sub.2;
[0017] R.sup.2a is independently selected from the group consisting
of hydrogen, OH, C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl,
C.sub.2-C.sub.6-alkynyl, C.sub.3-C.sub.11-cycloalkyl,
C.sub.3-C.sub.8-cycloalkenyl, C.sub.1-C.sub.6-alkoxy,
C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkyl and
C.sub.1-C.sub.6-alkylthio; and wherein any of the aliphatic or
cyclic groups in R.sup.2 are unsubstituted or substituted with 1,
2, 3 or up to the maximum possible number of identical or different
radicals selected from the group consisting of halogen, hydroxy,
oxo, cyano, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy and
C.sub.3-C.sub.11-cycloalkyl; [0018] R.sup.1 is
C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy,
C.sub.3-C.sub.11-cycloalkyl, C.sub.3-C.sub.8-cycloalkenyl,
C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl,
C.sub.1-C.sub.6-alkoxyimino-C.sub.1-C.sub.4-alkyl,
C.sub.2-C.sub.6-alkenyloxyimino-C.sub.1-C.sub.4-alkyl,
C.sub.2-C.sub.6-alkynyloxyimino-C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.6-alkylamino, diC.sub.1-C.sub.6-alkylamino,
C(.dbd.O)--(C.sub.1-C.sub.6-alkyl),
C(.dbd.O)--(C.sub.1-C.sub.6-alkoxy), phenyl-C.sub.1-C.sub.4-alkyl,
phenyl-C.sub.1-C.sub.4-alkenyl, phenyl-C.sub.1-C.sub.4-alkynyl,
heteroaryl-C.sub.1-C.sub.4-alkyl, phenyl, naphthyl or a 3- to
10-membered saturated, partially unsaturated or aromatic mono- or
bicyclic heterocycle, wherein the ring member atoms of said mono-
or bicyclic heterocycle include besides carbon atoms further 1, 2,
3 or 4 heteroatoms selected from N, O and S as ring member atoms
with the provision that the heterocycle cannot contain 2 contiguous
atoms selected from O and S; and wherein the heteroaryl group in
the group heteroaryl-C.sub.1-C.sub.4-alkyl is a 5- or 6-membered
aromatic heterocycle, wherein the ring member atoms of the
heterocyclic ring include besides carbon atoms 1, 2, 3 or 4
heteroatoms selected from N, O and S as ring member atoms with the
provision that the heterocycle cannot contain 2 contiguous atoms
selected from O and S; and wherein any of the above-mentioned
aliphatic or cyclic groups are unsubstituted or substituted with 1,
2, 3 or up to the maximum possible number of identical or different
groups R.sup.1a; or [0019] R.sup.1 and R.sup.2, together with the
nitrogen atom to which R.sup.2 is attached, and together with
interjacent group --C(.dbd.W)--, if present, which is located
between said nitrogen atom and the group R.sup.1, form a saturated
or partially unsaturated mono- or bicyclic 3- to 10-membered
heterocycle, wherein the heterocycle includes beside one nitrogen
atom and one or more carbon atoms no further heteroatoms or 1, 2 or
3 further heteroatoms independently selected from N, O and S as
ring member atoms with the provision that the heterocycle cannot
contain 2 contiguous atoms selected from O and S; and wherein the
heterocycle is unsubstituted or substituted with 1, 2, 3, 4 or up
to the maximum possible number of identical or different groups
R.sup.1a; or [0020] if R.sup.2 is --N(R.sup.2a).sub.2, R.sup.1 and
one of the two groups R.sup.2a, together with the nitrogen atom to
which R.sup.2a is attached, and together with interjacent groups,
which are located between said nitrogen atom and the group R.sup.1,
form a saturated or partially unsaturated mono- or bicyclic 3- to
10-membered heterocycle, wherein the heterocycle includes beside
two nitrogen atoms and one or more carbon atoms no further
heteroatoms or 1, 2 or 3 further heteroatoms independently selected
from N, O and S as ring member atoms with the provision that the
heterocycle cannot contain 2 contiguous atoms selected from O and
S; and wherein the heterocycle is unsubstituted or substituted with
1, 2, 3, 4 or up to the maximum possible number of identical or
different groups R.sup.1a; [0021] R.sup.1a is halogen, oxo, cyano,
NO.sub.2, OH, SH, NH.sub.2, C.sub.1-C.sub.6-alkyl,
C.sub.1-C.sub.6-haloalkyl, C.sub.1-C.sub.6-alkoxy,
C.sub.1-C.sub.6-haloalkoxy, C.sub.1-C.sub.6-alkylthio,
C.sub.1-C.sub.6-haloalkylthio, C.sub.3-C.sub.8-cycloalkyl,
--NHSO.sub.2--C.sub.1-C.sub.4-alkyl,
(C.dbd.O)--C.sub.1-C.sub.4-alkyl,
C(.dbd.O)--C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.6-alkylsulfonyl,
hydroxyC.sub.1-C.sub.4-alkyl, C(.dbd.O)--NH.sub.2,
C(.dbd.O)--NH(C.sub.1-C.sub.4-alkyl),
C.sub.1-C.sub.4-alkylthio-C.sub.1-C.sub.4-alkyl,
aminoC.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-alkylamino-C.sub.1-C.sub.4-alkyl,
diC.sub.1-C.sub.4-alkylamino-C.sub.1-C.sub.4-alkyl,
aminocarbonyl-C.sub.1-C.sub.4-alkyl or
C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkyl; [0022] R.sup.3,
R.sup.4 independently of each other are selected from the group
consisting of hydrogen, halogen, cyano, C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-alkenyl, C.sub.1-C.sub.4-alkynyl,
C.sub.1-C.sub.4-haloalkyl and C.sub.1-C.sub.4-alkoxy; or [0023]
R.sup.3 and R.sup.4 together with the carbon atom to which they are
bound form a saturated 3- to 7-membered carbocycle or a saturated
3- to 6-membered heterocycle; wherein the saturated heterocycle
includes beside carbon atoms 1, 2 or 3 heteroatoms independently
selected from the group consisting of N, O and S as ring member
atoms with the provision that the heterocycle cannot contain 2
contiguous atoms selected from O and S; and wherein said N ring
member atom is substituted with the group R.sup.N; wherein [0024]
R.sup.N is hydrogen, C.sub.1-C.sub.6-alkyl or halogen; [0025] and
wherein said S ring member atom is unsubstituted or substituted
with 1 or 2 oxo radicals; and wherein one or two of the ring member
--CH.sub.2-- groups of said saturated carbocycle or of said
saturated heterocycle may be replaced by one or two groups
independently selected from --C(.dbd.O)-- and --C(.dbd.S)--; and
wherein the carbon ring member atoms of the saturated carbocycle or
of the saturated heterocycle are unsubstituted or substituted with
a total number of 1, 2, 3, 4 or up to the maximum possible number
of identical or different radicals selected from the group
consisting of halogen, cyano, C.sub.1-C.sub.6-alkyl,
C.sub.1-C.sub.6-alkoxy and C.sub.3-C.sub.8-cycloalkyl; the process
comprising: reacting a compound of formula II,
##STR00004##
[0025] wherein A.sup.1, A.sup.2, R.sup.A and R is as defined above,
with a compound of formula IIa,
##STR00005##
wherein Hal is chlorine or fluorine.
[0026] The amidoxime compounds II can be obtained from cyano
compounds V by treatment with hydroxylamine or a salt thereof, for
example the hydrochloride salt, in the presence of a base,
preferably triethylamine, in a suitable solvent, such as methanol,
at a temperature between 0.degree. C. and 100.degree. C. For
related examples see Kitamura, S. et al Chemi. Pharm. Bull. (2001),
49, 268 WO 2013/066838 or WO 2017/055473:
##STR00006##
[0027] Preferably, the formation of the amidoxime II and its
transformation to compounds I takes place in a two-step one-pot
reaction without any workup of the amidoxime II.
[0028] Compounds of formula III are either commercially available
or may be prepared using standard procedures known to a person
skilled in the art from readily available starting materials. Such
procedures are described in, for example, WO 2013/008162, EP 276432
A2, EP 3165093 A1, EP 3165094 A1, EP 3167716 A1, WO 2015/185485, WO
2017/055469, WO 2017/055473, WO 2017/076739, WO 2017/076740, WO
2017/076742, WO 2017/076757, WO 2017/076935, WO 2017/081309, WO
2017/081310, WO 2017081311, WO 2017081312, WO 2017/085098, WO
2017/085100, WO2017/093019, WO2017/093348, WO2017/102006,
WO2017/103219, WO2017/103223, WO2017/109044 and WO2017/118689.
[0029] According to a preferred embodiment, compound IIa is
trifluoacetyl chloride (TFAC).
[0030] In a preferred embodiment, the transformation of a compound
of formula II with compounds of formula IIa to produce compounds of
formula I is carried out in the presence of an inert organic
solvent, wherein the inert organic solvent is not identical with a
compound I, II, IIa, III or a base as defined herein.
[0031] In a preferred embodiment, said process is carried out in
the presence of a base, wherein the base is not identical with a
compound I, II, IIa, III or an inert organic solvent as defined
herein.
[0032] In another preferred embodiment, said process is carried out
in the presence of an inert organic solvent, wherein the inert
organic solvent is not identical with a compound I, II, IIa, III or
a base as defined herein; and in the absence of a base, wherein the
base is not identical with a compound I, II, IIa, III or an inert
organic solvent as defined herein.
[0033] In another preferred embodiment, said process is carried out
in the presence of a base, wherein the base is not identical with a
compound I, II, IIa, III or an inert organic solvent as defined
herein; and in the absence of an inert solvent, wherein the inert
organic solvent is not identical with a compound I, II, IIa, III or
a base as defined herein.
[0034] In another preferred embodiment, said process is carried out
in the presence of a base, wherein the base is not identical with a
compound I, II, IIa, III or a solvent as defined herein; and in the
presence of an inert solvent, wherein the inert organic solvent is
not identical with a compound I, II, IIa, III or a base as defined
herein.
[0035] By "inert organic solvent" is meant an organic solvent
which, under the reaction conditions of the process of this
invention, does not enter into any appreciable reaction with either
the reactants or the products.
[0036] In one embodiment, the inert organic solvent is selected
from non-halogenated inert organic solvents; preferably from
non-halogenated aliphatic hydrocarbons, non-halogenated
cycloaliphatic hydrocarbons, non-halogenated aromatic hydrocarbons,
halogenated aliphatic hydrocarbons, halogenated aromatic
hydrocarbons, amides, ethers, esters, ketones, nitriles and any
combination thereof.
[0037] Examples of suitable non-halogenated aliphatic hydrocarbons
include pentane, hexane, heptane, and the like. Preference is given
to saturated aliphatic hydrocarbons having from 5 to 10 carbon
atoms.
[0038] Examples of suitable non-halogenated cycloaliphatic
hydrocarbons include cyclopentane, cyclohexane, cycloheptane, and
the like. Preference is given to non-halogenated saturated
cycloaliphatic hydrocarbons having from 5 to 10 carbon atoms.
Cyclohexane is particularly preferred.
[0039] Examples of suitable a non-halogenated aromatic hydrocarbons
include toluene, o-xylene, m-xylene, p-xylene, ethylbenzene,
2-propylbenzene (cumene), 2-isopropyltoluene (o-cymol),
3-isopropyltoluene (m-cymol), 4-isopropyltoluene (p-cymol),
1,3,5-trimethylbenzene (mesitylene), and the like. Preference is
given to toluene, o-xylene, m-xylene, p-xylene, ethylbenzene,
1,3,5-trimethylbenzene (mesitylene), and any combination thereof.
Especially preferred among the non-halogenated aromatic
hydrocarbons are toluene, o-xylene, m-xylene, p-xylene, and any
combination thereof, with toluene being the most preferred.
[0040] Examples of suitable halogenated aliphatic hydrocarbons
include dichloromethane, chloroform, carbon tetrachloride,
1,2-dichloroethane, 1,1,1,2-tetrachloroethane,
1,1,2,2-tetrachloroethane, 1,1-dichloroethylene,
1,2-dichloroethylene, and the like. Preference is given to
dichloromethane and 1,2-dichloroethane and any combination
thereof.
[0041] Examples of suitable halogenated aromatic hydrocarbons
include chlorobenzene, bromobenzene, o-dichlorobenzene,
m-dichlorobenzene, .alpha.,.alpha.,.alpha.-trifluorotoluene
(benzotrifluoride) and the like and any combination thereof.
[0042] Examples of suitable amides include N,N-dimethylformamide,
N,N-dimethylacetamide, N,N-diethylacetamide, N-methyl-pyrrolidone,
and the like and any combination thereof.
[0043] Examples of suitable ethers include cyclic and acyclic
ethers such as diethyl ether, diisopropyl ether, n-butyl methyl
ether, isobutyl methyl ether, sec-butyl methyl ether, tert-butyl
methyl ether, cyclopentyl methyl ether, tetrahydrofuran,
1,4-dioxane, and the like and any combination thereof.
[0044] Examples of suitable esters include ethyl acetate,
n-propylacetate, isopropyl acetate, tert-butyl acetate, and the
like and any combination thereof.
[0045] Examples of suitable ketones include acetone, methyl ethyl
ketone, methyl isopropyl ketone, methyl isobutyl ketone,
cyclopropyl methyl ketone and the like, and any combination
thereof. Examples of suitable nitriles include acetonitrile,
benzonitrile, and the like and any combination thereof.
[0046] In a preferred embodiment, the inert organic solvent is
selected from non-halogenated aliphatic hydrocarbons,
non-halogenated cycloaliphatic hydrocarbons, non-halogenated
aromatic hydrocarbons, halogenated aliphatic hydrocarbons and any
combination thereof.
[0047] In a more preferred embodiment, the inert organic solvent is
selected from heptane, cyclohexane, cycloheptane, toluene,
o-xylene, m-xylene, p-xylene, ethylbenzene, 1,3,5-trimethylbenzene
(mesitylene), chlorobenzene, 1,2-dichloroethane, dichloromethane,
tetrahydrofuran, dioxane, ethyl acetate, methyl ethyl ketone and
benzotrifluoride and any combination thereof.
[0048] In an even more preferred embodiment, the inert organic
solvent is selected from heptane, cyclohexane, toluene,
dichloromethane and any combination thereof.
[0049] Still more preferably, the inert organic solvent is selected
from heptane, cyclohexane, toluene and any combination thereof.
[0050] Particularly preferred inert organic solvents are
non-halogenated aromatic hydrocarbons, especially non-halogenated
alkylbenzenes which are mono-, di-, or tri-alkylsubstituted with
each alkyl group containing 1 to 3 carbon atoms, and in particular
those selected from the group consisting of toluene, o-xylene,
m-xylene, p-xylene and any combination thereof. Most preferably,
the inert organic solvent is toluene.
[0051] The volume ratio of the inert organic solvent to the
hydroxyamidine II is generally from 0.01:1 to 20:1, preferably from
0.1:1 to 15:1, more preferably from 0.5:1 to 10:1, and most
preferably from 1:1 to 5:1.
[0052] In a preferred embodiment of the present invention, the
transformation of a compound of formula II with compounds of
formula IIa to produce compounds of formula I is carried out in the
presence of an organic base.
[0053] In one embodiment the base is selected from organic bases
such as, for example: tertiary amines, pyridine, substituted
pyridines, bicyclic amines and any mixture thereof. Preference is
given to tertiary amines, pyridine, substituted pyridines and any
mixture thereof. Particular preference is given to pyridine,
substituted pyridines and any mixture thereof. Pyridine is
especially preferred.
[0054] Examples of suitable tertiary amines are
tri-(C.sub.1-C.sub.6)-alkylamines such as trimethylamine,
triethylamine, tributylamine and diisopropylethylamine;
di-(C.sub.1-C.sub.6)-alkyl-phenylamines such as N,N-dimethylaniline
and N,N-diethylaniline; N-methyl imidazole,
N,N-dimethylaminopyridine and the like.
[0055] Examples of suitable substituted pyridines are collidine,
lutidines, 2-picoline, 3-picoline, 4-picoline,
N,N-dimethyl-4-aminopyridine, 5-ethyl-2-methyl-pyridine and the
like.
[0056] Examples of suitable bicyclic amines are
1,8-diazabicyclo[5.4.0]undec-7-en,
1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane and
the like.
[0057] In one embodiment the base is an organic base, which is
selected from trimethylamine, triethylamine, tributylamine,
diisopropylethylamine, N,N-dimethylaniline, N,N-diethylaniline,
N-methyl imidazole, pyridine, 2,4,6-collidine, 2,6-lutidine,
2-picoline, 3-picoline, 4-picoline, N,N-dimethyl-4-aminopyridine,
5-ethyl-2-methyl-pyridine,1,8-diazabicyclo[5.4.0]undec-7-en,
1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane and
mixtures thereof.
[0058] In another embodiment the base is an organic base, which is
selected from trimethylamine, triethylamine, diisopropylethylamine,
N,N-dimethylaniline, pyridine, 2,4,6-collidine, 2,6-lutidine,
2-picoline, 3-picoline, 4-picoline, 5-ethyl-2-methyl-pyridine,
N,N-dimethylaminopyridine and mixtures thereof.
[0059] More preferably the base is an organic base, which is
selected from trimethylamine, triethylamine, diisopropylethylamine,
pyridine, 2,4,6-collidine, 2,6-lutidine, 2-picoline, 3-picoline,
4-picoline, 5-ethyl-2-methyl-pyridine and mixtures thereof.
[0060] In another embodiment, the base is selected from alkali
metal and alkaline earth metal phosphates; alkali metal and
alkaline earth metal formats; alkali metal and alkaline earth metal
acetates; alkali metal and alkaline earth metal carbonates; alkali
metal and alkaline earth metal citrates; alkali metal and alkaline
earth metal sulfates and any combination thereof, even more
preferably selected from alkali metal and alkaline earth metal
phosphates; alkali metal and alkaline earth metal formats; alkali
metal and alkaline earth metal acetates; alkali metal and alkaline
earth metal carbonates; alkali metal and alkaline earth metal
citrates and any combination thereof, in particular selected from
alkali metal and alkaline earth metal phosphates; alkali metal and
alkaline earth metal acetates; particularly sodium acetate,
potassium acetate; alkali metal and alkaline earth metal carbonates
and any combination thereof, most preferably selected from alkali
metal and alkaline earth metal acetates; particularly preferred are
sodium carbonate and potassium carbonate.
[0061] In another embodiment the base is selected from
trimethylamine, triethylamine, tributylamine,
diisopropylethylamine, pyridine, 2,4,6-collidine, 2,6-lutidine,
2-picoline, 3-picoline, 4-picoline, 5-ethyl-2-methyl-pyridine,
sodium acetate, potassium acetate, sodium carbonate and potassium
carbonate and mixtures thereof.
[0062] The molar ratio of the base to hydroxyamidine II is
generally from 3:1 to 0.4:1 or from 1:1 to 0.2:1, preferably from
0.02:1 to 0.3:1, more preferably from 0.02:1 to 0.25:1, most
preferably from 0.02:1 to 0.2:1.
[0063] The process of the present invention can be carried out
under atmospheric pressure or under elevated or reduced pressure.
Typically, the atmospheric and elevated pressure is employed. In a
preferred embodiment the process of the present invention can be
carried out at pressure ranges typically from 0.8 atmospheres (atm)
to 80 atm, preferably form 1.0 atm to 20 atm, in particular from
1.0 to 7 atm.
[0064] The temperature used in the process of the present invention
can vary widely and is preferably from -30 to 150.degree. C., more
preferably from -10 to 120.degree. C. and even more preferably from
0 to 100.degree. C., 20 to 80.degree. C. or 40 to 70.degree. C.
[0065] Typical reaction times are in the range of from 1 to 20
hours, preferably from 2 to 15 hours and more preferably from 3 to
10 hours.
[0066] In one preferred embodiment, the transformation of a
compound of formula II with compounds of formula IIa to produce
compounds of formula I is carried out in the presence of an inert
organic solvent, wherein the inert organic solvent is selected from
trimethylamine, triethylamine, tributylamine,
diisopropylethylamine, pyridine, 2,4,6-collidine, 2,6-lutidine,
2-picoline, 3-picoline, 4-picoline, 5-ethyl-2-methyl-pyridine,
sodium acetate, potassium acetate, sodium carbonate and potassium
carbonate and mixtures thereof; and in the absence of a base,
wherein the base is not identical with a compound I, II, IIa, III
or an inert organic solvent as defined herein; and at a pressure
from 1 to 20 atm; and at a temperature from 0 to 100.degree. C.
[0067] In another preferred embodiment, said reaction is carried
out in the presence of an inert organic solvent, wherein the inert
organic solvent is selected from trimethylamine, triethylamine,
tributylamine, diisopropylethylamine, pyridine, 2,4,6-collidine,
2,6-lutidine, 2-picoline, 3-picoline, 4-picoline,
5-ethyl-2-methyl-pyridine, sodium acetate, potassium acetate,
sodium carbonate and potassium carbonate and mixtures thereof; and
in the absence of a base, wherein the base is not identical with a
compound I, II, IIa, III or an inert organic solvent as defined
herein; and at a pressure from 1 to 7 atm; and at a temperature
from 20 to 80.degree. C.
[0068] The process of the present invention may optionally be
carried out in the presence of at least one phase-transfer
catalyst.
[0069] Phase transfer catalysts suitable for use in the process of
this invention are those well known in the art such as, for
example, quaternary ammonium salts. Examples of suitable
phase-transfer catalysts are trimethyl(phenyl) ammonium chloride,
bromide, iodide or hydroxide and
tetra-n-C.sub.1-C.sub.12-alkyl-ammonium chlorides, bromides,
iodides or hydroxides, preferably
tetra-n-C.sub.1-C.sub.8-alkyl-ammonium chlorides, bromides, iodides
or hydroxides, e.g. tetramethylammonium chloride, bromide, iodide
or hydroxide, tetraethylammonium chloride, bromide, iodide or
hydroxide, tetra-n-propylammonium chloride, bromide, iodide or
hydroxide, tetra-n-butylammonium chloride, bromide, iodide or
hydroxide, tetra-n-pentylammonium chloride, bromide, iodide or
hydroxide, tetra-n-hexylammonium chloride, bromide, iodide or
hydroxide, tetra-n-heptylammonium chloride, bromide, iodide or
hydroxide, tetra-n-octylammonium chloride, bromide, iodide or
hydroxide, methyl-tri-n-butylammonium chloride, bromide, iodide or
hydroxide, ethyl-trimethylammonium chloride, bromide, iodide or
hydroxide, n-propyl-trimethyl ammonium chloride, bromide, iodide or
hydroxide, methyl-triethyl ammonium chloride, bromide, iodide or
hydroxide and n-butyl-triethylammonium chloride, bromide, iodide or
hydroxide. Of these, the use of
tetra-n-C.sub.1-C.sub.4-alkyl-ammonium chlorides, bromides, iodides
or hydroxides is preferred, in particular tetra-n-butylammonium
chloride, bromide, iodide or hydroxide and
methyl-tri-n-butylammonium chloride, bromide, iodide or
hydroxide.
[0070] The phase-transfer catalysts, which are usually solid in
pure form, can be used as such or, preferably, in dissolved form.
An effective amount of the phase-transfer catalyst may range from
0.001 to 0.5 molar equivalents, preferably 0.001 to 0.2 molar
equivalents relative to compound II.
[0071] According to one embodiment of said process, a mixture of
the E/Z-isomers of compounds of formula II is used, more preferably
said mixture comprises an E/Z-isomer ratio of from 0.1:1 to 10:1,
even more preferably of from 0.5:1 to 2:1.
[0072] According to another embodiment, the E-isomer of compounds
of formula II is used.
[0073] According to a further embodiment, the Z-isomer of compounds
of formula II is used.
[0074] The reaction mixture obtained is worked up and the compound
I can be isolated in a customary manner, e. g. by an aqueous,
extractive workup, in particular extraction with a basic or neutral
aqueous medium, and by removing the solvent, e. g. under reduced
pressure, or by a combination of these measures. Further
purification can be effected, for example, by crystallization,
thin-film-evaporation, rectification, sublimation, distillation or
by chromatography.
[0075] In a further embodiment, a compound of formula I, in which R
is methyl, is converted into valuable chemical products or
intermediates. Accordingly, compounds of formula I, wherein R is
methyl, can be further chlorinated to obtain a compound of formula
Ib
##STR00007##
wherein the variables A.sup.1, A.sup.2 and R.sup.A in compounds I
and Ib are as defined or preferably defined herein.
[0076] The chlorination of the methyl group R of compounds of
formula I can be achieved using suitable chlorinating agents, for
example molecular chlorine, N-chlorosuccinimide,
trichloroisocyanuric acid, sulfuryl chloride or phosphorus
pentachloride. The chlorination is conducted at temperatures
between 0.degree. C. and 200.degree. C., preferably between
60.degree. C. and 150.degree. C., under irradiation or in the
presence of radical starters, for example azobis(isobutyronitril)
or dibenzoyl peroxide. For reference, see J. Am. Chem. Soc. 1951,
73, 455.
[0077] In one embodiment, the chlorination is carried out in the
presence of at least one inert organic solvent, or mixtures of such
solvents. The term "inert organic solvent" means an organic
solvent, which does not enter into any appreciable reaction with
either the reactants or the products under the reaction conditions
of the process of this invention. The inert organic solvent used in
the process is preferably selected from halogenated aliphatic
hydrocarbons and halogenated aromatic hydrocarbons, such as
dichloromethane, tetrachloromethane, dichloroethane, chlorobenzene,
homologues of dichlorobenzenes or 1,2,4-trichlorobenzene.
[0078] In a particularly preferred embodiment the chlorination step
is conducted in substance, for example with the liquid reaction
product, which is directly obtained after the reaction of compounds
II and IIa and in the absence of a further solvent, as described
above.
[0079] The chlorination can be performed in the presence or absence
of TFA impurities originating from the previous reaction. TFA can
be removed during the chlorination process via distillation or
separately by distillation before carrying out the chlorination
step. After completion of the reaction the reaction mixture is
worked up in the usual manner or it can be used directly in the
next step.
[0080] In a further preferred embodiment, the compound of formula
Ib is hydrolyzed to obtain a compound of formula III
##STR00008##
wherein the variables A.sup.1, A.sup.2 and R.sup.A in compounds Ib
and III are as defined or preferably defined herein.
[0081] In one embodiment this transformation is carried out in the
presence of catalytic amounts of a lewis acid and water to obtain a
compound of formula III, as described in WO 2007/063028 A2 on pages
42-43. Preferably, the lewis acid is a metal salt, for example
aluminum(III) chloride or iron(III) chloride, particularly
iron(III) chloride. The lewis acid is used in sub-stoichiometric or
catalytic amounts, for example 0.001 to 0.5 molar equivalents,
preferably 0.002 to 0.2 molar equivalents, more preferably 0.005 to
0.1 molar equivalents, based on the amount of the compound of
formula Ib.
[0082] In one embodiment, the hydrolysis step is carried out in the
presence of at least one inert organic solvent, or mixtures of such
solvents. The inert organic solvent used in the process of this
invention is preferably selected from non-halogenated aliphatic
hydrocarbons, non-halogenated cycloaliphatic hydrocarbons,
halogenated aliphatic hydrocarbons, halogenated aromatic
hydrocarbons, amides, ethers, esters, ketones, nitriles.
[0083] In a preferred embodiment, the hydrolysis step is carried
out in the absence of a solvent, i.e. in substance. Under these
conditions the trichloromethyl compound Ib or the crude material
comprising Ib, which was obtained from the previous reaction step,
is heated to a temperature, where such material is a molten
mass.
[0084] The amount of water in the hydrolysis step is between 0.8 to
1.5 molar equivalents, preferably between 0.95 to 1.05 molar
equivalents, based on the amount of the compound Ib. The reaction
is carried out at temperatures between 20.degree. C. and
200.degree. C., preferably between 80.degree. C. and 130.degree. C.
After completion of the reaction the reaction mixture is worked up
in the usual manner or it can be used directly in the next
step.
[0085] In an especially preferred embodiment, the compound of
formula III is reacted with an amine of formula IV to obtain a
compound of formula Ic,
##STR00009##
wherein the variables A.sup.1, A.sup.2, R.sup.A, R.sup.1 and
R.sup.2 in compounds of formulae III and IV are as defined or
preferably defined herein.
[0086] A skilled person will recognize that oxadiazole compounds of
type Ic can be accessed by treating benzoic acid chloride of
formula III with an amine of formula IV. The reaction is preferably
carried out in a suitable inert organic solvent, such as
non-halogenated aliphatic hydrocarbons, non-halogenated
cycloaliphatic hydrocarbons, halogenated aliphatic hydrocarbons,
halogenated aromatic hydrocarbons, amides, ethers, esters, ketones,
nitriles; for example, N,N-dimethylformamide, dichloromethane or
tetrahydrofuran; preferably at a temperature between -20.degree. C.
and 200.degree. C., preferably between 0.degree. C. and 80.degree.
C., and optionally in the presence of a base such as pyridine,
triethylamine or N,N-diisopropylethylamine, or under conditions
described in the literature for an amide coupling. For examples,
see Valeur, E.; Bradley, M. Chem. Soc. Rev. 2009, 38, 606 and
Chinchilla, R., Najera, C. Chem. Soc. Rev. 2011, 40, 5084. After
completion of the reaction the reaction mixture is worked up in the
usual manner.
[0087] In another especially preferred embodiment, the compound of
formula Ic is used to obtain a compound of formula Id
##STR00010##
wherein the variables A.sup.1, A.sup.2, R.sup.A, R.sup.1 and
R.sup.2 in compounds of formulae Ic and Id are as defined or
preferably defined herein.
[0088] Compounds of formula Ib can be prepared from compounds of
formula Ic through treatment with Lawesson's reagent or phosphorus
pentasulfide in an inert organic solvent, such as non-halogenated
aliphatic hydrocarbons, non-halogenated cycloaliphatic
hydrocarbons, halogenated aliphatic hydrocarbons, halogenated
aromatic hydrocarbons, amides, ethers, esters, ketones, nitriles;
for example toluene, tetrahydrofuran, dioxane or ethyl acetate; at
a temperature between 0.degree. C. and 130.degree. C.,
preferentially between 60.degree. C. and 80.degree. C. For
examples, see Eur. J. Med. Chem. 2011, 46(9), 3917-3925; Synthesis
2003, 13, 1929-1958; WO 2006/0123242; WO 2010/086820; WO
2014/0151863. After completion of the reaction the reaction mixture
is worked up in the usual manner.
[0089] The terms "compounds I", "compounds II", "compounds IIa" and
"compounds III" refer to compounds of formulae I, II, IIa and III,
respectively. In the definitions of the variables given above,
collective terms are used which are generally representative for
the substituents in question.
[0090] The term "C.sub.n-C.sub.m" indicates the number of carbon
atoms possible in each case in the substituent or substituent
moiety in question.
[0091] The term "halogen" refers to fluorine, chlorine, bromine and
iodine.
[0092] The term "oxo" refers to an oxygen atom .dbd.O, which is
bound to a carbon atom or sulfur atom, thus forming, for example, a
ketonyl --C(.dbd.O)-- or sulfinyl --S(.dbd.O)-- group.
[0093] The term "formyl" refers to a group C(.dbd.O)H.
[0094] The term "C.sub.1-C.sub.6-alkyl" refers to a
straight-chained or branched saturated hydrocarbon group having 1
to 6 carbon atoms, for example methyl, ethyl, propyl,
1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, and
1,1-dimethylethyl.
[0095] The term "C.sub.2-C.sub.6-alkenyl" refers to a
straight-chain or branched unsaturated hydrocarbon radical having 2
to 6 carbon atoms and a double bond in any position, such as
ethenyl, 1-propenyl, 2-propenyl (allyl), 1-methylethenyl,
1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl,
2-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl.
[0096] The term "C.sub.2-C.sub.6-alkynyl" refers to a
straight-chain or branched unsaturated hydrocarbon radical having 2
to 6 carbon atoms and containing at least one triple bond, such as
ethynyl, 1-propynyl, 2-propynyl (propargyl), 1-butynyl, 2-butynyl,
3-butynyl, 1-methyl-2-propynyl.
[0097] The term "C.sub.1-C.sub.6-haloalkyl" refers to a
straight-chained or branched alkyl group having 1 to 6 carbon atoms
(as defined above), wherein some or all of the hydrogen atoms in
these groups may be replaced by halogen atoms as mentioned above,
for example chloromethyl, bromomethyl, dichloromethyl,
trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl,
chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl,
1-chloroethyl, 1-bromoethyl, 1-fluoroethyl, 2-fluoroethyl,
2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl,
2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl,
2,2,2-trichloroethyl and pentafluoroethyl, 2-fluoropropyl,
3-fluoropropyl, 2,2-difluoropropyl, 2,3-difluoropropyl,
2-chloropropyl, 3-chloropropyl, 2,3-dichloropropyl, 2-bromopropyl,
3-bromopropyl, 3,3,3-trifluoropropyl, 3,3,3-trichloropropyl,
CH.sub.2--C.sub.2F.sub.5, CF.sub.2--C.sub.2F.sub.5,
CF(CF.sub.3).sub.2, 1-(fluoromethyl)-2-fluoroethyl,
1-(chloromethyl)-2-chloroethyl, 1-(bromomethyl)-2-bromoethyl,
4-fluorobutyl, 4-chlorobutyl, 4-bromobutyl or nonafluorobutyl.
[0098] The term "C.sub.1-C.sub.6-alkoxy" refers to a straight-chain
or branched alkyl group having 1 to 6 carbon atoms (as defined
above) which is bonded via an oxygen, at any position in the alkyl
group, for example methoxy, ethoxy, n-propoxy, 1-methylethoxy,
butoxy, 1-methylpropoxy, 2-methylpropoxy or 1,1-dimethylethoxy.
[0099] The term "C.sub.1-C.sub.6-haloalkoxy" refers to a
C.sub.1-C.sub.6-alkoxy group as defined above, wherein some or all
of the hydrogen atoms may be replaced by halogen atoms as mentioned
above, for example, OCH.sub.2F, OCHF.sub.2, OCF.sub.3, OCH.sub.2Cl,
OCHCl.sub.2, OCCl.sub.3, chlorofluoromethoxy,
dichlorofluoromethoxy, chlorodifluoromethoxy, 2-fluoroethoxy,
2-chloroethoxy, 2-bromoethoxy, 2-iodoethoxy, 2,2-difluoroethoxy,
2,2,2-trifluoroethoxy, 2-chloro-2-fluoroethoxy,
2-chloro-2,2-difluoroethoxy, 2,2-dichloro-2-fluoroethoxy,
2,2,2-trichloroethoxy, OC.sub.2F.sub.5, 2-fluoropropoxy,
3-fluoropropoxy, 2,2-difluoropropoxy, 2,3-difluoropropoxy,
2-chloropropoxy, 3-chloropropoxy, 2,3-dichloropropoxy,
2-bromopropoxy, 3-bromopropoxy, 3,3,3-trifluoropropoxy,
3,3,3-trichloropropoxy, OCH.sub.2--C.sub.2F.sub.5,
OCF.sub.2--C.sub.2F.sub.5, 1-(CH.sub.2F)-2-fluoroethoxy,
1-(CH.sub.2Cl)-2-chloroethoxy, 1-(CH.sub.2Br)-2-bromoethoxy,
4-fluorobutoxy, 4-chlorobutoxy, 4-bromobutoxy or
nonafluorobutoxy.
[0100] The terms "phenyl-C.sub.1-C.sub.4-alkyl or
heteroaryl-C.sub.1-C.sub.4-alkyl" refer to alkyl having 1 to 4
carbon atoms (as defined above), wherein one hydrogen atom of the
alkyl radical is replaced by a phenyl or hetereoaryl radical
respectively.
[0101] The term "C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkyl"
refers to alkyl having 1 to 4 carbon atoms (as defined above),
wherein one hydrogen atom of the alkyl radical is replaced by a
C.sub.1-C.sub.4-alkoxy group (as defined above). Likewise, the term
"C.sub.1-C.sub.4-alkylthio-C.sub.1-C.sub.4-alkyl" refers to alkyl
having 1 to 4 carbon atoms (as defined above), wherein one hydrogen
atom of the alkyl radical is replaced by a
C.sub.1-C.sub.4-alkylthio group.
[0102] The term "C.sub.1-C.sub.6-alkylthio" as used herein refers
to straight-chain or branched alkyl groups having 1 to 6 carbon
atoms (as defined above) bonded via a sulfur atom. Accordingly, the
term "C.sub.1-C.sub.6-haloalkylthio" as used herein refers to
straight-chain or branched haloalkyl group having 1 to 6 carbon
atoms (as defined above) bonded through a sulfur atom, at any
position in the haloalkyl group.
[0103] The term "C.sub.1-C.sub.4-alkoxyimino" refers to a divalent
imino radical (C.sub.1-C.sub.4-alkyl-O--N.dbd.) carrying one
C.sub.1-C.sub.4-alkoxy group as substituent, e.g. methylimino,
ethylimino, propylimino, 1-methylethyl-imino, butylimino,
1-methylpropylimino, 2-methylpropylimino, 1,1-dimethylethylimino
and the like.
[0104] The term "C.sub.1-C.sub.6-alkoxyimino-C.sub.1-C.sub.4-alkyl"
refers to alkyl having 1 to 4 carbon atoms, wherein two hydrogen
atoms of one carbon atom of the alkyl radical are replaced by a
divalent C.sub.1-C.sub.6-alkoxyimino radical
(C.sub.1-C.sub.6-alkyl-O--N.dbd.) as defined above.
[0105] The term
"C.sub.2-C.sub.6-alkenyloxyimino-C.sub.1-C.sub.4-alkyl" refers to
alkyl having 1 to 4 carbon atoms, wherein two hydrogen atoms of one
carbon atom of the alkyl radical are replaced by a divalent
C.sub.2-C.sub.6-alkenyloxyimino radical
(C.sub.2-C.sub.6-alkenyl-O--N.dbd.).
[0106] The term
"C.sub.2-C.sub.6-alkynyloxyimino-C.sub.1-C.sub.4-alkyl" refers to
alkyl having 1 to 4 carbon atoms, wherein two hydrogen atoms of one
carbon atom of the alkyl radical are replaced by a divalent
C.sub.2-C.sub.6-alkynyloxyimino radical
(C.sub.2-C.sub.6-alkynyl-O--N.dbd.).
[0107] The term "hydroxyC.sub.1-C.sub.4-alkyl" refers to alkyl
having 1 to 4 carbon atoms, wherein one hydrogen atom of the alkyl
radical is replaced by a OH group.
[0108] The term "aminoC.sub.1-C.sub.4-alkyl" refers to alkyl having
1 to 4 carbon atoms, wherein one hydrogen atom of the alkyl radical
is replaced by a NH.sub.2 group.
[0109] The term "C.sub.1-C.sub.6-alkylamino" refers to an amino
group, which is substituted with one residue independently selected
from the group that is defined by the term C.sub.1-C.sub.6-alkyl.
Likewise the term "diC.sub.1-C.sub.6-alkylamino" refers to an amino
group, which is substituted with two residues independently
selected from the group that is defined by the term
C.sub.1-C.sub.6-alkyl.
[0110] The term "C.sub.1-C.sub.4-alkylamino-C.sub.1-C.sub.4-alkyl"
refers to refers to alkyl having 1 to 4 carbon atoms (as defined
above), wherein one hydrogen atom of the alkyl radical is replaced
by a C.sub.1-C.sub.4-alkyl-NH-group which is bound through the
nitrogen. Likewise the term
"diC.sub.1-C.sub.4-alkylamino-C.sub.1-C.sub.4-alkyl" refers to
refers to alkyl having 1 to 4 carbon atoms (as defined above),
wherein one hydrogen atom of the alkyl radical is replaced by a
(C.sub.1-C.sub.4-alkyl).sub.2N-group which is bound through the
nitrogen.
[0111] The term "aminocarbonyl-C.sub.1-C.sub.4-alkyl" refers to
alkyl having 1 to 4 carbon atoms, wherein one hydrogen atom of the
alkyl radical is replaced by a --(C.dbd.O)--NH.sub.2 group.
[0112] The term "C.sub.2-C.sub.6-alkenyl" refers to a
straight-chain or branched unsaturated hydrocarbon radical having 2
to 6 carbon atoms and a double bond in any position, such as
ethenyl, 1-propenyl, 2-propenyl (allyl), 1-methylethenyl,
1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl,
2-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl.
[0113] The term "C.sub.2-C.sub.6-alkynyl" refers to a
straight-chain or branched unsaturated hydrocarbon radical having 2
to 6 carbon atoms and containing at least one triple bond, such as
ethynyl, 1-propynyl, 2-propynyl (propargyl), 1-butynyl, 2-butynyl,
3-butynyl, 1-methyl-2-propynyl.
[0114] The term "C.sub.3-C.sub.11-cycloalkyl" refers to a
monocyclic, bicyclic or tricyclic saturated univalent hydrocarbon
radical having 3 to 11 carbon ring members that is connected
through one of the ring carbon atoms by substitution of one
hydrogen atom, such as cyclopropyl (C.sub.3H.sub.5), cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,
bicyclo[1.1.0]butyl, bicyclo[2.1.0]pentyl, bicyclo[1.1.1]pentyl,
bicyclo[3.1.0]hexyl, bicyclo[2.1.1]hexyl, norcaranyl
(bicyclo[4.1.0]heptyl) and norbornyl (bicyclo[2.2.1]heptyl).
Further examples of bicyclic or tricyclic cycloalkyl radicals are
found herein as examples R.sup.10.1 to R.sup.10.57.
[0115] The term "C.sub.3-C.sub.11-cycloalkyl" refers to a
monocyclic, bicyclic or tricyclic saturated univalent hydrocarbon
radical having 3 to 11 carbon ring members that is connected
through one of the ring carbon atoms by substitution of one
hydrogen atom, such as cyclopropyl (C.sub.3H.sub.5), cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,
bicyclo[1.1.0]butyl, bicyclo[2.1.0]pentyl, bicyclo[1.1.1]pentyl,
bicyclo[3.1.0]hexyl, bicyclo[2.1.1]hexyl, norcaranyl
(bicyclo[4.1.0]heptyl) and norbornyl (bicyclo[2.2.1]heptyl).
[0116] The term "C.sub.3-C.sub.11-cycloalkyl-C.sub.1-C.sub.6-alkyl"
refers to alkyl having 1 to 11 carbon atoms, wherein one hydrogen
atom of the alkyl radical is replaced by a
C.sub.3-C.sub.11-cycloalkyl group as defined above.
[0117] The term "C.sub.3-C.sub.11-cycloalkoxy" refers to a cyclic
univalent hydrocarbon radical having 3 to 11 carbon ring members
(as defined above) that is bonded via an oxygen, at any position in
the cycloalkyl group, for example cyclopropyloxy.
[0118] The terms "--C(.dbd.O)--C.sub.1-C.sub.4-alkyl",
"--C(.dbd.O)--C.sub.1-C.sub.4-alkoxy" and
"--C(.dbd.O)--C.sub.3-C.sub.11-cycloalkyl" refer to radicals which
are attached through the carbon atom of the --C(.dbd.O)--
group.
[0119] The term "aliphatic" refers to compounds or radicals
composed of carbon and hydrogen and which are non-aromatic
compounds. An "alicyclic" compound or radical is an organic
compound that is both aliphatic and cyclic. They contain one or
more all-carbon rings which may be either saturated or unsaturated,
but do not have aromatic character.
[0120] The terms "cyclic moiety" or "cyclic group" refer to a
radical which is an alicyclic ring or an aromatic ring, such as,
for example, phenyl or heteroaryl.
[0121] The term "and wherein any of the aliphatic or cyclic groups
are unsubstituted or substituted with . . . " refers to aliphatic
groups, cyclic groups and groups, which contain an aliphatic and a
cyclic moiety in one group, such as in, for example,
C.sub.3-C.sub.8-cycloalkyl-C.sub.1-C.sub.4-alkyl; therefore a group
which contains an aliphatic and a cyclic moiety both of these
moieties may be substituted or unsubstituted independently of each
other.
[0122] The term "phenyl" refers to an aromatic ring systems
including six carbon atoms (commonly referred to as benzene
ring.
[0123] The term "heteroaryl" refers to aromatic monocyclic or
polycyclic ring systems including besides carbon atoms, 1, 2, 3 or
4 heteroatoms independently selected from the group consisting of
N, O and S.
[0124] The term "saturated 3- to 7-membered carbocycle" is to be
understood as meaning monocyclic saturated carbocycles having 3, 4
or 5 carbon ring members. Examples include cyclopropyl,
cyclopentyl, cyclohexyl, cycloheptyl, and the like.
[0125] The term "3- to 10-membered saturated, partially unsaturated
or aromatic mono- or bicyclic heterocycle, wherein the ring member
atoms of said mono- or bicyclic heterocycle include besides carbon
atoms further 1, 2, 3 or 4 heteroatoms selected from N, O and S as
ring member atoms", is to be understood as meaning both, aromatic
mono- and bicyclic heteroaromatic ring systems, and also saturated
and partially unsaturated heterocycles, for example: a 3- or
4-membered saturated heterocycle which contains 1 or 2 heteroatoms
from the group consisting of N, O and S as ring members such as
oxirane, aziridine, thiirane, oxetane, azetidine, thiethane,
[1,2]dioxetane, [1,2]dithietane, [1,2]diazetidine;
[0126] and a 5- or 6-membered saturated or partially unsaturated
heterocycle which contains 1, 2 or 3 heteroatoms from the group
consisting of N, O and S as ring members such as
2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrothienyl,
3-tetrahydrothienyl, 2-pyrrolidinyl, 3-pyrrolidinyl,
3-isoxazolidinyl, 4-isoxazolidinyl, 5-isoxazolidinyl,
3-isothiazolidinyl, 4-isothiazolidinyl, 5-isothiazolidinyl,
3-pyrazolidinyl, 4-pyrazolidinyl, 5-pyrazolidinyl, 2-oxazolidinyl,
4-oxazolidinyl, 5-oxazolidinyl, 2-thiazolidinyl, 4-thiazolidinyl,
5-thiazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl,
1,2,4-oxadiazolidin-3-yl, 1,2,4-oxadiazolidin-5-yl,
1,2,4-thiadiazolidin-3-yl, 1,2,4-thiadiazolidin-5-yl,
1,2,4-triazolidin-3-yl, 1,3,4-oxadiazolidin-2-yl,
1,3,4-thiadiazolidin-2-yl, 1,3,4-triazolidin-2-yl,
2,3-dihydrofur-2-yl, 2,3-dihydrofur-3-yl, 2,4-dihydrofur-2-yl,
2,4-dihydrofur-3-yl, 2,3-dihydrothien-2-yl, 2,3-dihydrothien-3-yl,
2,4-dihydrothien-2-yl, 2,4-dihydrothien-3-yl, 2-pyrrolin-2-yl,
2-pyrrolin-3-yl, 3-pyrrolin-2-yl, 3-pyrrolin-3-yl,
2-isoxazolin-3-yl, 3-isoxazolin-3-yl, 4-isoxazolin-3-yl,
2-isoxazolin-4-yl, 3-isoxazolin-4-yl, 4-isoxazolin-4-yl,
2-isoxazolin-5-yl, 3-isoxazolin-5-yl, 4-isoxazolin-5-yl,
2-isothiazolin-3-yl, 3-isothiazolin-3-yl, 4-isothiazolin-3-yl,
2-isothiazolin-4-yl, 3-isothiazolin-4-yl, 4-isothiazolin-4-yl,
2-isothiazolin-5-yl, 3-isothiazolin-5-yl, 4-isothiazolin-5-yl,
2,3-dihydropyrazol-1-yl, 2,3-dihydropyrazol-2-yl,
2,3-dihydropyrazol-3-yl, 2,3-dihydropyrazol-4-yl,
2,3-dihydropyrazol-5-yl, 3,4-dihydropyrazol-1-yl,
3,4-dihydropyrazol-3-yl, 3,4-dihydropyrazol-4-yl,
3,4-dihydropyrazol-5-yl, 4,5-dihydropyrazol-1-yl,
4,5-dihydropyrazol-3-yl, 4,5-dihydropyrazol-4-yl,
4,5-dihydropyrazol-5-yl, 2,3-dihydrooxazol-2-yl,
2,3-dihydrooxazol-3-yl, 2,3-dihydrooxazol-4-yl,
2,3-dihydrooxazol-5-yl, 3,4-dihydrooxazol-2-yl,
3,4-dihydrooxazol-3-yl, 3,4-dihydrooxazol-4-yl,
3,4-dihydrooxazol-5-yl, 3,4-dihydrooxazol-2-yl,
3,4-dihydrooxazol-3-yl, 3,4-dihydrooxazol-4-yl, 2-piperidinyl,
3-piperidinyl, 4-piperidinyl, 1,3-dioxan-5-yl, 2-tetrahydropyranyl,
4-tetrahydropyranyl, 2-tetrahydrothienyl, 3-hexahydropyridazinyl,
4-hexahydropyridazinyl, 2-hexahydropyrimidinyl,
4-hexahydropyrimidinyl, 5-hexahydropyrimidinyl, 2-piperazinyl,
1,3,5-hexahydrotriazin-2-yl and 1,2,4-hexahydrotriazin-3-yl and
also the corresponding -ylidene radicals; and
[0127] a 7-membered saturated or partially unsaturated heterocycle
such as tetra- and hexahydroazepinyl, such as
2,3,4,5-tetrahydro[1H]azepin-1-,-2-,-3-,-4-,-5-,-6- or- 7-yl,
3,4,5,6-tetrahydro[2H]azepin-2-,-3-,-4-,-5-,-6- or- 7-yl,
2,3,4,7-tetrahydro[1H]azepin-1-,-2-,-3-,-4-,-5-,-6- or- 7-yl,
2,3,6,7-tetrahydro[1H]azepin-1-,-2-,-3-,-4-,-5-,-6- or- 7-yl,
hexahydroazepin-1-,-2-,-3- or- 4-yl, tetra- and hexahydrooxepinyl
such as 2,3,4,5-tetrahydro[1H]oxepin-2-,-3-,-4-,-5-,-6- or- 7-yl,
2,3,4,7-tetrahydro[1H]oxepin-2-,-3-,-4-,-5-,-6- or- 7-yl,
2,3,6,7-tetrahydro[1H]oxepin-2-,-3-,-4-,-5-,-6- or- 7-yl,
hexahydroazepin-1-,-2-,-3- or- 4-yl, tetra- and
hexahydro-1,3-diazepinyl, tetra- and hexahydro-1,4-diazepinyl,
tetra- and hexahydro-1,3-oxazepinyl, tetra- and
hexahydro-1,4-oxazepinyl, tetra- and hexahydro-1,3-dioxepinyl,
tetra- and hexahydro-1,4-dioxepinyl and the corresponding -ylidene
radicals.
[0128] The term "5- or 6-membered heteroaryl" or the term "5- or
6-membered aromatic heterocycle" refer to aromatic ring systems
including besides carbon atoms, 1, 2, 3 or 4 heteroatoms
independently selected from the group consisting of N, O and S, for
example, a 5-membered heteroaryl such as pyrrol-1-yl, pyrrol-2-yl,
pyrrol-3-yl, thien-2-yl, thien-3-yl, furan-2-yl, furan-3-yl,
pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl,
imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, imidazol-5-yl,
oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl,
isoxazol-4-yl, isoxazol-5-yl, thiazol-2-yl, thiazol-4-yl,
thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl,
1,2,4-triazolyl-1-yl, 1,2,4-triazol-3-yl 1,2,4-triazol-5-yl,
1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl and
1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl; or a 6-membered
heteroaryl, such as pyridin-2-yl, pyridin-3-yl, pyridin-4-yl,
pyridazin-3-yl, pyridazin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl,
pyrimidin-5-yl, pyrazin-2-yl and 1,3,5-triazin-2-yl and
1,2,4-triazin-3-yl.
[0129] In respect of the variables, the embodiments of the
intermediates correspond to the embodiments of the compounds I.
Preference is given to those compounds I and, where applicable,
also to compounds of all subformulae provided herein, e. g.
formulae I.1, I.2, II, Ia, III, wherein the variables have
independently of each other or more preferably in combination (any
possible combination of 2 or more substituents as defined herein)
the following meanings:
[0130] According to one embodiment of the invention in compounds of
formulae I, II, and III, R is methyl, ethyl, iso-propyl, CH.sub.2F,
CHF.sub.2, 2,2,2-trifluoroethyl or cyclopropyl.
[0131] According to a further embodiment in compounds of formulae
I, II, and III, R is CR.sup.3R.sup.4NR.sup.1R.sup.2, wherein
R.sup.3, R.sup.4 and R.sup.1 are as defined or preferably defined
herein and R.sup.2 is hydrogen. According to a further embodiment
in compounds of formulae I, II, and III, R is
C(.dbd.O)NR.sup.1R.sup.2, CR.sup.3R.sup.4C(.dbd.O)NR.sup.1R.sup.2
or CR.sup.3R.sup.4NR.sup.2C(.dbd.O)R.sup.1, wherein R.sup.3,
R.sup.4 and R.sup.1 are as defined or preferably defined herein and
R.sup.2 is hydrogen.
[0132] Further embodiments of the present invention relate to the
process for preparing compounds I, wherein group R is defined as
follows:
[0133] Embodiment R.1: R is COOH, --C(.dbd.W)NR.sup.1R.sup.2,
CR.sup.3R.sup.4COOH, CR.sup.3R.sup.4C(.dbd.W)NR.sup.1R.sup.2 or
CR.sup.3R.sup.4NR.sup.2C(.dbd.W)R.sup.1.
[0134] Embodiment R.2: R is COOH, --C(.dbd.O)NR.sup.1R.sup.2,
CR.sup.3R.sup.4COOH, CR.sup.3R.sup.4C(.dbd.O)NR.sup.1R.sup.2 or
CR.sup.3R.sup.4NR.sup.2C(.dbd.O)R.sup.1.
[0135] Embodiment R.3: R is COOH or CR.sup.3R.sup.4COOH.
[0136] Embodiment R.4: R is --C(.dbd.W)NR.sup.1R.sup.2,
CR.sup.3R.sup.4C(.dbd.W)NR.sup.1R.sup.2 or
CR.sup.3R.sup.4NR.sup.2C(.dbd.W)R.sup.1.
[0137] Embodiment R.5: R is --C(.dbd.O)NR.sup.1R.sup.2,
CR.sup.3R.sup.4C(.dbd.O)NR.sup.1R.sup.2 or
CR.sup.3R.sup.4NR.sup.2C(.dbd.O)R.sup.1.
[0138] Embodiment R.6: R is CR.sup.3R.sup.4NR.sup.2R.sup.1.
[0139] Embodiment R.7: R is
CR.sup.3R.sup.4NR.sup.2C(.dbd.O)R.sup.1.
[0140] Even more preferred embodiments of the present invention
relate to the process for preparing compounds I, wherein group R in
formulae of compounds I, II and III is defined as follows:
[0141] Embodiment R.8: R is CF.sub.2COOH or
CF.sub.2C(.dbd.O)NR.sup.1R.sup.2.
[0142] Embodiment R.9: R is CH.sub.2COOH or
CH.sub.2C(.dbd.O)NR.sup.1R.sup.2.
[0143] Embodiment R.10: R is --C(CH.sub.2--CH.sub.2)COOH or
--C(CH.sub.2--CH.sub.2)C(.dbd.O)NR.sup.1R.sup.2.
[0144] According to a further embodiment, W in compounds of
formulae I, II and III is O.
[0145] Further embodiments of the present invention relate to the
process for preparing compounds I, wherein group R.sup.1 in
formulae of compounds I, II and III is defined as follows:
Embodiment 1.1: R.sup.1 is C.sub.1-C.sub.6-alkyl,
C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl,
C.sub.3-C.sub.8-cycloalkyl, C.sub.3-C.sub.8-cycloalkenyl,
phenyl-C.sub.1-C.sub.4-alkyl, heteroaryl-C.sub.1-C.sub.4-alkyl,
phenyl or heteroaryl; and wherein the heteroaryl group is a 5- or
6-membered aromatic heterocycle, wherein the ring includes besides
carbon atoms 1, 2, 3 or 4 heteroatoms selected from N, O and S as
ring member atoms; and wherein any of the aliphatic or cyclic
groups are unsubstituted or substituted with 1, 2, 3 or up to the
maximum possible number of identical or different radicals R.sup.1a
as defined or preferably defined herein.
[0146] Embodiment 1.2: R.sup.1 is phenyl or heteroaryl; and wherein
the heteroaryl group is a 5- or 6-membered aromatic heterocycle,
wherein the ring includes besides carbon atoms 1, 2, 3 or 4
heteroatoms selected from N, O and S as ring member atoms; and
wherein any of the cyclic groups are unsubstituted or substituted
with 1, 2, 3 or up to the maximum possible number of identical or
different radicals R.sup.1a as defined or preferably defined
herein.
[0147] Embodiment 1.3: R.sup.1 is C.sub.3-C.sub.8-cycloalkyl or
C.sub.3-C.sub.8-cycloalkenyl; and wherein the cyclic group is
unsubstituted or substituted with 1, 2, 3 or up to the maximum
possible number of identical or different radicals R.sup.1a as
defined or preferably defined herein.
[0148] Embodiment 1.4: R.sup.1 is C.sub.1-C.sub.6-alkyl; and
wherein the alkyl group is unsubstituted or substituted with 1, 2,
3 or up to the maximum possible number of identical or different
radicals R.sup.1a as defined or preferably defined herein.
[0149] Embodiment 1.5: R.sup.1 is difluoromethyl, trifluoromethyl,
2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl,
2-chloro-2,2-difluoroethyl, 2,2,2-trichloroethyl and
pentafluoroethyl, 3,3,3-trifluoropropyl, CH.sub.2CF.sub.2CF.sub.3
or CF.sub.2CF.sub.2CF.sub.5, CH(CH.sub.3)CF.sub.3,
CH.sub.2CF.sub.2CH.sub.3, CH.sub.2C(CH.sub.3).sub.2F,
CH.sub.2CH(CH.sub.3)CF.sub.3 or
CH.sub.2C(CH.sub.3).sub.2CF.sub.3.
[0150] Embodiment 1.6: R.sup.1 is
C.sub.1-C.sub.6-alkoxyimino-C.sub.1-C.sub.4-alkyl,
C.sub.2-C.sub.6-alkenyloxyimino-C.sub.1-C.sub.4-alkyl or
C.sub.2-C.sub.6-alkynyloxyimino-C.sub.1-C.sub.4-alkyl.
[0151] Embodiment 1.7: R.sup.1 is a bicyclic or tricyclic
C.sub.4-C.sub.11-cycloalkyl which is unsubstituted or substituted
with 1, 2 or 3 radicals selected from the group consisting of oxo,
hydroxy, halogen and C.sub.1-C.sub.3-alkyl.
[0152] Embodiment 1.8: R.sup.1 is a bicyclic or tricyclic
carbocycle selected from the group consisting of radicals
R.sup.10.1 to R.sup.10.31 below; wherein each radical may be
connected to the remainder of the compounds of formula I through
one of the ring carbon atoms by substitution of one hydrogen atom;
and wherein R.sup.1 is unsubstituted or substituted with 1, 2 or 3
radicals selected from the group consisting of oxo, hydroxy,
halogen and C.sub.1-C.sub.3-alkyl.
##STR00011## ##STR00012## ##STR00013##
[0153] Embodiment 1.9: R.sup.1 is selected from the group
consisting of R.sup.10.32 to R.sup.10.57 below, particularly from
R.sup.10.32 to R.sup.10.49, which are further unsubstituted, and
wherein "# C" indicates the carbon atom, which is attached to the
remainder of the compounds of formula I.
##STR00014## ##STR00015## ##STR00016##
[0154] Further embodiments of the present invention relate to the
process for preparing compounds I, wherein group R.sup.1a is
defined as follows: In one embodiment R.sup.1a is selected from the
group consisting of halogen, cyano, C.sub.1-C.sub.6-alkyl,
C.sub.1-C.sub.6-haloalkyl, C.sub.1-C.sub.6-alkoxy,
C.sub.1-C.sub.6-haloalkoxy and C.sub.3-C.sub.8-cycloalkyl.
[0155] In another aspect of the invention R.sup.1a is selected from
the group consisting of fluorine, chlorine, cyano, methyl, ethyl,
methoxy, trifluoromethyl, trifluoromethoxy, difluoromethyl,
difluoromethoxy or cyclopropyl.
[0156] In another embodiment R.sup.1a is selected from the group
consisting of halogen, C.sub.1-C.sub.6-alkyl and
C.sub.3-C.sub.8-cycloalkyl; particularly from methyl, ethyl,
fluorine and chlorine; more particularly from fluorine and
chlorine.
[0157] According to a further embodiment in compounds of formulae
I, II, and III, R.sup.1 is C.sub.1-C.sub.6-alkyl,
C.sub.1-C.sub.6-alkoxy, C.sub.3-C.sub.6-cycloalkyl or a 4- to
5-membered saturated or partially unsaturated heterocycle, wherein
the ring member atoms of said heterocycle include besides carbon
atoms 1 or 2 heteroatoms selected from N and O as ring member
atoms; and wherein any of the above-mentioned aliphatic or cyclic
groups R.sup.1 are unsubstituted or substituted with 1, 2 or 3 of
identical or different groups R.sup.1a; wherein R.sup.1a is
halogen, oxo, cyano, NO.sub.2, OH, C.sub.1-C.sub.6-alkyl,
C.sub.1-C.sub.6-haloalkyl, C.sub.1-C.sub.6-alkoxy,
C.sub.1-C.sub.6-haloalkoxy or C.sub.3-C.sub.8-cycloalkyl.
[0158] In another embodiment R.sup.2 in formulae of compounds I, II
and III is hydrogen, formyl, C.sub.1-C.sub.6-alkyl,
C.sub.1-C.sub.6-alkoxy, C.sub.2-C.sub.6-alkenyl, propargyl,
C.sub.3-C.sub.8-cycloalkyl, C.sub.3-C.sub.8-cycloalkenyl,
C.sub.3-C.sub.8-cycloalkyl-C.sub.1-C.sub.4-alkyl, phenyl, pyridinyl
or --N(R.sup.2a).sub.2; and wherein any of the aliphatic or cyclic
groups are unsubstituted or substituted with 1, 2, 3, 4 or up to
the maximum possible number of identical or different radicals
selected from the group consisting of halogen, cyano,
C.sub.1-C.sub.6-alkyl and C.sub.1-C.sub.6-alkoxy; more preferably
from halogen, in particular the radical is fluorine; and wherein
R.sup.2a is independently selected from the group consisting of
hydrogen, OH, C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl,
C.sub.2-C.sub.6-alkynyl, C.sub.3-C.sub.8-cycloalkyl or
C.sub.1-C.sub.6-alkoxy.
[0159] Further embodiments of the present invention relate to the
process for preparing compounds I, wherein group R.sup.2 in
formulae of compounds I, II and III is defined as follows:
[0160] Embodiment 2.1: R.sup.2 independently of each other are
hydrogen, formyl, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy,
C.sub.2-C.sub.6-alkenyl, propargyl, C.sub.3-C.sub.8-cycloalkyl,
C.sub.3-C.sub.8-cycloalkenyl,
C.sub.3-C.sub.8-cycloalkyl-C.sub.1-C.sub.4-alkyl, phenyl,
C.sub.1-C.sub.6-alkylamino or diC.sub.1-C.sub.6-alkylamino; and
wherein any of the aliphatic or cyclic groups are unsubstituted or
substituted with 1, 2, 3, 4 or up to the maximum possible number of
identical or different radicals selected from the group consisting
of halogen, cyano, C.sub.1-C.sub.6-alkyl and
C.sub.1-C.sub.6-alkoxy.
[0161] Embodiment 2.2: R.sup.2 independently of each other are
hydrogen, formyl, methyl, ethyl, n-propyl, iso-propyl, methoxy,
ethyoxy, propyloxy, cyclopropyl, cyclopropyl-CH.sub.2--, allyl,
phenyl, 4-F-phenyl, 2-F-phenyl, C.sub.1-C.sub.6-alkylamino or
diC.sub.1-C.sub.6-alkylamino.
[0162] Embodiment 2.3: R.sup.2 independently of each other are
hydrogen, formyl, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy,
C.sub.2-C.sub.6-alkenyl, propargyl, C.sub.3-C.sub.8-cycloalkyl,
C.sub.1-C.sub.6-alkylamino or diC.sub.1-C.sub.6-alkylamino.
[0163] Embodiment 2.4: R.sup.2 independently of each other are
hydrogen, formyl, methyl, ethyl, n-propyl, iso-propyl, methoxy,
ethyoxy, propyloxy, cyclopropyl, cyclopropyl-CH.sub.2--, allyl,
C.sub.1-C.sub.6-alkylamino or diC.sub.1-C.sub.6-alkylamino.
[0164] Embodiment 2.5: R.sup.2 independently of each other are
hydrogen, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy,
C.sub.2-C.sub.6-alkenyl or propargyl, C.sub.1-C.sub.6-alkylamino or
diC.sub.1-C.sub.6-alkylamino.
[0165] Embodiment 2.6: R.sup.2 independently of each other are
hydrogen, methy, ethyl, methoxy, ethyoxy, propyloxy,
C.sub.1-C.sub.6-alkylamino or diC.sub.1-C.sub.6-alkylamino.
[0166] Embodiment 2.7: R.sup.2 is hydrogen.
[0167] According to a further embodiment in compounds of formulae
I, II, and III, R.sup.2 is C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.6-alkoxy or C.sub.3-C.sub.8-cycloalkyl, and wherein
any of the aliphatic or cyclic groups in R.sup.2 are unsubstituted
or substituted with 1, 2, 3 or up to the maximum possible number of
identical or different radicals selected from halogen.
[0168] In one embodiment R.sup.2 in formulae of compounds I, II and
III is hydrogen, formyl, C.sub.1-C.sub.6-alkyl,
C.sub.1-C.sub.6-alkoxy, C.sub.2-C.sub.6-alkenyl, propargyl,
C.sub.3-C.sub.8-cycloalkyl, C.sub.3-C.sub.8-cycloalkenyl,
C.sub.3-C.sub.8-cycloalkyl-C.sub.1-C.sub.4-alkyl, phenyl, pyridinyl
or --N(R.sup.2a).sub.2; and wherein any of the aliphatic or cyclic
groups are unsubstituted or substituted with 1, 2, 3, 4 or up to
the maximum possible number of identical or different radicals
selected from the group consisting of halogen, cyano,
C.sub.1-C.sub.6-alkyl and C.sub.1-C.sub.6-alkoxy; more preferably
from halogen, in particular the radical is fluorine; and wherein
R.sup.2a is independently selected from the group consisting of
hydrogen, OH, C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl,
C.sub.2-C.sub.6-alkynyl, C.sub.3-C.sub.8-cycloalkyl or
C.sub.1-C.sub.6-alkoxy; and R.sup.1 is C.sub.1-C.sub.6-alkyl,
C.sub.3-C.sub.8-cycloalkyl, C.sub.3-C.sub.8-cycloalkenyl,
C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl,
phenyl-C.sub.1-C.sub.4-alkyl, heteroaryl-C.sub.1-C.sub.4-alkyl,
phenyl or heteroaryl; and wherein the heteroaryl group is a 5- or
6-membered aromatic heterocycle, wherein the ring includes besides
carbon atoms 1, 2, 3 or 4 heteroatoms selected from N, O and S as
ring member atoms; and wherein any of the aliphatic or cyclic
groups in R.sup.1 are unsubstituted or substituted with 1, 2, 3, 4
or up to the maximum possible number of identical or different
radicals R.sup.1a as defined or preferably defined herein.
[0169] In another aspect R.sup.2 in formulae of compounds I, II and
III is hydrogen, formyl, C.sub.1-C.sub.6-alkyl,
C.sub.1-C.sub.6-alkoxy, C.sub.2-C.sub.6-alkenyl, propargyl,
C.sub.3-C.sub.8-cycloalkyl, C.sub.3-C.sub.8-cycloalkenyl,
C.sub.3-C.sub.8-cycloalkyl-C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.6-alkylamino or diC.sub.1-C.sub.6-alkylamino; and
R.sup.1 in formulae of compounds I, II and III is
C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.8-cycloalkyl,
C.sub.3-C.sub.8-cycloalkenyl, C.sub.2-C.sub.6-alkenyl,
C.sub.2-C.sub.6-alkynyl, phenyl-C.sub.1-C.sub.4-alkyl,
heteroaryl-C.sub.1-C.sub.4-alkyl, phenyl or heteroaryl; and wherein
the heteroaryl group is a 5- or 6-membered aromatic heterocycle,
wherein the ring includes besides carbon atoms 1, 2, 3 or 4
heteroatoms selected from N, O and S as ring member atoms; and
wherein any of the aliphatic or cyclic groups in R.sup.1 are
unsubstituted or substituted with 1, 2, 3, 4 or up to the maximum
possible number of identical or different radicals R.sup.1a as
defined or preferably defined herein.
[0170] In another aspect R.sup.2 in formulae of compounds I, II and
III is hydrogen, formyl, methyl, ethyl, n-propyl, iso-propyl,
methoxy, ethyoxy, propyloxy, cyclopropyl, cyclopropyl-CH.sub.2--,
allyl, C.sub.1-C.sub.6-alkylamino or diC.sub.1-C.sub.6-alkylamino;
and R.sup.1 in formulae of compounds I, II and III is
C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.8-cycloalkyl,
C.sub.3-C.sub.8-cycloalkenyl, C.sub.2-C.sub.6-alkenyl or
C.sub.2-C.sub.6-alkynyl; and wherein any of the aliphatic or cyclic
groups in R.sup.1 are unsubstituted or substituted with 1, 2, 3, 4
or up to the maximum possible number of identical or different
radicals selected from the group consisting of halogen or
C.sub.1-C.sub.6-alkyl.
[0171] Further embodiments of the present invention relate to the
process for preparing compounds I, wherein groups R.sup.3 and
R.sup.4 in formulae of compounds I, II and III, if present, are
defined as follows:
[0172] Embodiment 3.1: R.sup.3 and R.sup.4 independently of each
other are hydrogen, halogen, C.sub.1-C.sub.6-alkyl or
C.sub.1-C.sub.6-haloalkyl; or R.sup.3 and R.sup.4 together with the
carbon atom to which they are bound form a cyclopropyl ring,
wherein the cyclopropyl ring is unsubstituted.
[0173] Embodiment 3.2: R.sup.3 and R.sup.4 independently of each
other are hydrogen or C.sub.1-C.sub.4-alkyl; Embodiment 3.3:
R.sup.3 and R.sup.4 independently of each other are hydrogen,
methyl or ethyl.
[0174] Embodiment 3.4: R.sup.3 and R.sup.4 are independently of
each other hydrogen, fluorine, chlorine, methyl or trifluoromethyl;
or R.sup.3 and R.sup.4 together with the carbon atom to which they
are bound form a cyclopropyl ring, wherein the cyclopropyl ring is
unsubstituted.
[0175] Embodiment 3.5: R.sup.3 and R.sup.4 are both hydrogen.
[0176] Embodiment 3.6: R.sup.3 is hydrogen and R.sup.4 is
methyl.
[0177] Embodiment 3.7: R.sup.3 and R.sup.4 are both methyl.
[0178] Embodiment 3.8: R.sup.3 and R.sup.4 are both fluorine.
[0179] Embodiment 3.9: R.sup.3 and R.sup.4 are both
trifluoromethyl.
[0180] Embodiment 3.10: R.sup.3 and R.sup.4 together with the
carbon atom to which they are bound a saturated monocyclic 3- to
5-membered saturated heterocycle or saturated carbocycle; and
wherein the saturated heterocycle includes beside one or more
carbon atoms no heteroatoms or 1 or 2 heteroatoms independently
selected from N, O and S as ring member atoms; and wherein the
heterocycle or the carbocycle is unsubstituted or substituted 1, 2,
3, 4 or up to the maximum possible number of identical or different
radicals selected from the group consisting of halogen, cyano and
C.sub.1-C.sub.2-alkyl.
[0181] Embodiment 3.11: R.sup.3 and R.sup.4 together with the
carbon atom to which they are bound form a 3- or 4-membered
carbocylic ring; and wherein the carbocylic ring is
unsubstituted.
[0182] Embodiment 3.12: R.sup.3 and R.sup.4 together with the
carbon atom to which they are bound form a cyclopropyl ring,
wherein the cyclopropyl ring is unsubstituted.
[0183] Embodiment 3.13: R.sup.3 and R.sup.4 together with the
carbon atom to which they are bound form a saturated 3-membered
heterocycle; wherein the heterocycle includes beside two carbon
atoms one heteroatom selected from N, O and S as ring member atoms;
and wherein the heterocycle is unsubstituted or substituted 1, 2,
3, 4 or up to the maximum possible number of identical or different
radicals selected from the group consisting of halogen, cyano and
C.sub.1-C.sub.2-alkyl.
[0184] Embodiment 3.14: R.sup.3 is methyl and R.sup.4 is
fluorine.
[0185] Embodiment 3.15: R.sup.3 is hydrogen and R.sup.4 is
fluorine.
[0186] According to a further embodiment in compounds of formulae
I, II, and III, R is CR.sup.3R.sup.4NR.sup.2C(.dbd.O)R.sup.1,
wherein R.sup.3 and R.sup.4 are independently selected from
hydrogen and C.sub.1-C.sub.4-alkyl, in particular both are
hydrogen; and wherein R.sup.1 is C.sub.1-C.sub.6-alkyl,
C.sub.1-C.sub.6-alkoxy, C.sub.3-C.sub.6-cycloalkyl or a 4- to
5-membered saturated or partially unsaturated heterocycle, wherein
the ring member atoms of said heterocycle include besides carbon
atoms 1 or 2 heteroatoms selected from N and O as ring member
atoms; and wherein any of the above-mentioned aliphatic or cyclic
groups R.sup.1 are unsubstituted or substituted with 1, 2 or 3 of
identical or different groups R.sup.1a; wherein R.sup.1a is
halogen, oxo, cyano, NO.sub.2, OH, C.sub.1-C.sub.6-alkyl,
C.sub.1-C.sub.6-haloalkyl, C.sub.1-C.sub.6-alkoxy,
C.sub.1-C.sub.6-haloalkoxy or C.sub.3-C.sub.8-cycloalkyl; and
wherein R.sup.2 is hydrogen, C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.6-alkoxy or C.sub.3-C.sub.8-cycloalkyl, and wherein
any of the aliphatic or cyclic groups in R.sup.2 are unsubstituted
or substituted with 1, 2, 3 or up to the maximum possible number of
identical or different radicals selected from halogen.
[0187] According to a further embodiment in compounds of formulae
I, II, and III, R is CR.sup.3R.sup.4NR.sup.2C(.dbd.O)R.sup.1,
wherein R.sup.3 and R.sup.4 are both hydrogen; and wherein R.sup.1
is C.sub.3-C.sub.6-cycloalkyl or a 4- to 5-membered saturated or
partially unsaturated heterocycle, wherein the ring member atoms of
said heterocycle include besides carbon atoms 1 or 2 heteroatoms
selected from N and O as ring member atoms; and wherein any of the
above-mentioned aliphatic or cyclic groups R.sup.1 are
unsubstituted or substituted with 1, 2 or 3 of identical or
different groups R.sup.1a; wherein R.sup.1a is halogen, oxo, cyano,
NO.sub.2, OH, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl,
C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-haloalkoxy or
C.sub.3-C.sub.8-cycloalkyl; and wherein R.sup.2 is cyclopropyl.
[0188] Further embodiments with regard to the meaning of the
variables in compounds of formula I are as follows:
[0189] Embodiment E1: A.sup.1 and A.sup.2 are CH and R.sup.A is
hydrogen.
[0190] Embodiment E2: A.sup.1 and A.sup.2 are CH and R.sup.A is
fluorine.
[0191] Embodiment E3: A.sup.1 is N, A.sup.2 is CH and R.sup.A is
hydrogen.
[0192] Embodiment E4: A.sup.1 and A.sup.2 are CH, R.sup.A is
hydrogen, and R is methyl, trichloromethyl, --COOH, OH, SH, cyano,
chlorine or bromine.
[0193] Embodiment E5: A.sup.1 and A.sup.2 are CH, R.sup.A is
fluorine, and R is methyl, trichloromethyl, --COOH, OH, SH, cyano,
chlorine or bromine.
[0194] Embodiment E6: A.sup.1 is N, A.sup.2 is CH, R.sup.A is
hydrogen, and R is methyl, trichloromethyl, --COOH, OH, SH, cyano,
chlorine or bromine.
[0195] Embodiment E7: A.sup.1 and A.sup.2 are CH, R.sup.A is
hydrogen, and R is methyl, trichloromethyl, OH or SH; particularly
R is methyl.
[0196] Embodiment E8: A.sup.1 and A.sup.2 are CH, R.sup.A is
fluorine, and R is methyl, trichloromethyl, OH or SH; particularly
R is methyl.
[0197] Embodiment E9: A.sup.1 is N, A.sup.2 is CH, R.sup.A is
hydrogen, and R is methyl, trichloromethyl, OH or SH; particularly
R is methyl.
[0198] Embodiment E10: the combination of variables A.sup.1,
A.sup.2, R.sup.A corresponds to any one of the Embodiments E1, E2
or E3 defined above, and R is methyl.
[0199] In one embodiment the present invention relates to a process
for preparing compounds of formula I, wherein the combination of
variables A.sup.1, A.sup.2, R.sup.A corresponds to any one of the
Embodiments E1, E2 or E3 defined above; and [0200] R is methyl,
trichloromethyl, ethyl, iso-propyl, OH, SH, cyano, halogen,
CH.sub.2F, CHF.sub.2, 2,2,2-trifluoroethyl, cyclopropyl, --COOH,
--COOR.sup.1 or --C(.dbd.W)NR.sup.1R.sup.2; [0201] W is O or S;
[0202] R.sup.1 C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl,
C.sub.2-C.sub.6-alkynyl,
C.sub.1-C.sub.6-alkoxyimino-C.sub.1-C.sub.4-alkyl,
C.sub.3-C.sub.8-cycloalkyl, C.sub.3-C.sub.8-cycloalkenyl,
phenyl-C.sub.1-C.sub.4-alkyl, heteroaryl-C.sub.1-C.sub.4-alkyl,
phenyl or heteroaryl; and wherein the heteroaryl group is a 5- or
6-membered aromatic heterocycle, wherein the ring includes besides
carbon atoms 1, 2, 3 or 4 heteroatoms selected from N, O and S as
ring member atoms; and wherein any of the aliphatic or cyclic
groups are unsubstituted or substituted with 1, 2, 3 or up to the
maximum possible number of identical or different radicals selected
from the group consisting of halogen, cyano, C.sub.1-C.sub.6-alkyl
and C.sub.1-C.sub.6-alkoxy; [0203] R.sup.2 is hydrogen, formyl,
C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy,
C.sub.2-C.sub.6-alkenyl, propargyl, C.sub.3-C.sub.8-cycloalkyl,
C.sub.3-C.sub.8-cycloalkenyl,
C.sub.3-C.sub.8-cycloalkyl-C.sub.1-C.sub.4-alkyl, phenyl,
C.sub.1-C.sub.6-alkylamino or diC.sub.1-C.sub.6-alkylamino; and
wherein any of the aliphatic or cyclic groups are unsubstituted or
substituted with 1, 2, 3, 4 or up to the maximum possible number of
identical or different radicals selected from the group consisting
of halogen, cyano, C.sub.1-C.sub.6-alkyl and
C.sub.1-C.sub.6-alkoxy.
[0204] In one embodiment the present invention relates to a process
for preparing compounds of formula I, wherein the combination of
variables A.sup.1, A.sup.2, R.sup.A corresponds to any one of the
Embodiments E1, E2 or E3 defined above; and [0205] R is --COOH,
--COOR.sup.1 or --C(.dbd.W)NR.sup.1R.sup.2; [0206] W is O or S;
[0207] R.sup.1 is methyl, ethyl, n-propyl, iso-propyl, n-butyl,
sec-butyl, iso-butyl, 2-methoxyiminoethyl, cyclopropyl,
bicyclo[1.1.1]pentan-1-yl, or phenyl; and wherein the phenyl group
is unsubstituted or substituted with 1, 2, 3 or up to the maximum
possible number of identical or different radicals selected from
the group consisting of fluorine, chlorine, cyano, methyl, ethyl,
methoxy, trifluoromethyl, trifluoromethoxy, difluoromethyl,
difluoromethoxy and cyclopropyl. [0208] R.sup.2 is hydrogen, methyl
or ethyl.
[0209] In one embodiment the present invention relates to a process
for preparing compounds of formula I, wherein the combination of
variables A.sup.1, A.sup.2, R.sup.A corresponds to any one of the
Embodiments E1, E2 or E3 defined above; and [0210] R is --COOH,
--COOR.sup.1 or --C(.dbd.W)NR.sup.1R.sup.2; [0211] W is O or S;
[0212] R.sup.1 is methyl, ethyl, n-propyl, iso-propyl, n-butyl,
sec-butyl, iso-butyl, 2-methoxyiminoethyl, cyclopropyl,
bicyclo[1.1.1]pentan-1-yl, or phenyl; and wherein the phenyl group
is unsubstituted or substituted with 1 radical selected from the
group consisting of fluorine and 2-difluoromethoxy-phenyl; [0213]
R.sup.2 is hydrogen, methyl or ethyl.
[0214] In one embodiment the present invention relates to a process
for preparing compounds of formula I, wherein the combination of
variables A.sup.1, A.sup.2, R.sup.A corresponds to any one of the
Embodiments E1, E2 or E3 defined above; and [0215] R is
--C(.dbd.O)NR.sup.1R.sup.2; [0216] R.sup.1 is methyl,
2-methoxyiminoethyl, bicyclo[1.1.1]pentan-1-yl, 2-fluoro-phenyl,
4-fluoro-phenyl, or 2-difluoromethoxy-phenyl; [0217] R.sup.2 is
hydrogen.
[0218] In one embodiment the present invention relates to a process
for preparing compounds of formula I, wherein the combination of
variables A.sup.1, A.sup.2, R.sup.A corresponds to any one of the
Embodiments E1, E2 or E3 defined above; and [0219] R is
--C(.dbd.S)NR.sup.1R.sup.2; [0220] R.sup.1 is methyl,
2-methoxyiminoethyl, bicyclo[1.1.1]pentan-1-yl, 2-fluoro-phenyl,
4-fluoro-phenyl, or 2-difluoromethoxy-phenyl; [0221] R.sup.2 is
hydrogen.
[0222] In a further embodiment the present invention relates to a
process for preparing compounds of formula I, wherein [0223]
A.sup.1 and A.sup.2 are CH; [0224] R.sup.A is hydrogen; [0225] R is
--C(.dbd.O)NR.sup.1R.sup.2; [0226] R.sup.1 is methyl,
2-methoxyiminoethyl, bicyclo[1.1.1]pentan-1-yl, 2-fluoro-phenyl,
4-fluoro-phenyl, or 2-difluoromethoxy-phenyl; [0227] R.sup.2 is
hydrogen.
[0228] In a further embodiment the present invention relates to a
process for preparing compounds of formula I, wherein [0229]
A.sup.1 and A.sup.2 are CH; [0230] R.sup.A is hydrogen; [0231] R is
--C(.dbd.S)NR.sup.1R.sup.2; [0232] R.sup.1 is methyl,
2-methoxyiminoethyl, bicyclo[1.1.1]pentan-1-yl, 2-fluoro-phenyl,
4-fluoro-phenyl, or 2-difluoromethoxy-phenyl; [0233] R.sup.2 is
hydrogen.
[0234] In one embodiment the present invention relates to a process
for preparing compounds of formula I, wherein the combination of
variables A.sup.1, A.sup.2, R.sup.A corresponds to any one of the
Embodiments E1, E2 or E3 defined above; and [0235] R is
--CF.sub.2COOH, --CF.sub.2COR.sup.1 or
--CF.sub.2C(.dbd.O)NR.sup.1R.sup.2; [0236] R.sup.1
C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl,
C.sub.2-C.sub.6-alkynyl,
C.sub.1-C.sub.6-alkoxyimino-C.sub.1-C.sub.4-alkyl,
C.sub.3-C.sub.8-cycloalkyl, C.sub.3-C.sub.8-cycloalkenyl,
phenyl-C.sub.1-C.sub.4-alkyl, heteroaryl-C.sub.1-C.sub.4-alkyl,
phenyl or heteroaryl; and wherein the heteroaryl group is a 5- or
6-membered aromatic heterocycle, wherein the ring includes besides
carbon atoms 1, 2, 3 or 4 heteroatoms selected from N, O and S as
ring member atoms; and wherein any of the aliphatic or cyclic
groups are unsubstituted or substituted with 1, 2, 3 or up to the
maximum possible number of identical or different radicals selected
from the group consisting of halogen, cyano, C.sub.1-C.sub.6-alkyl
and C.sub.1-C.sub.6-alkoxy; [0237] R.sup.2 is hydrogen, formyl,
C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy,
C.sub.2-C.sub.6-alkenyl, propargyl, C.sub.3-C.sub.8-cycloalkyl,
C.sub.3-C.sub.8-cycloalkenyl,
C.sub.3-C.sub.8-cycloalkyl-C.sub.1-C.sub.4-alkyl, phenyl,
C.sub.1-C.sub.6-alkylamino or diC.sub.1-C.sub.6-alkylamino; and
wherein any of the aliphatic or cyclic groups are unsubstituted or
substituted with 1, 2, 3, 4 or up to the maximum possible number of
identical or different radicals selected from the group consisting
of halogen, cyano, C.sub.1-C.sub.6-alkyl and
C.sub.1-C.sub.6-alkoxy.
[0238] In one embodiment the present invention relates to a process
for preparing compounds of formula I, wherein the combination of
variables A.sup.1, A.sup.2, R.sup.A corresponds to any one of the
Embodiments E1, E2 or E3 defined above; and [0239] R is
--CF.sub.2COOH, --CF.sub.2COR.sup.1 or
--CF.sub.2C(.dbd.O)NR.sup.1R.sup.2; [0240] R.sup.1 is methyl,
ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl,
cyclopropyl, bicyclo[1.1.1]pentan-1-yl, or phenyl; and wherein the
phenyl group is unsubstituted or substituted with 1, 2, 3 or up to
the maximum possible number of identical or different radicals
selected from the group consisting of fluorine, chlorine, cyano,
methyl, ethyl, methoxy, trifluoromethyl, trifluoromethoxy,
difluoromethyl, difluoromethoxy and cyclopropyl. [0241] R.sup.2 is
hydrogen, methyl or ethyl.
[0242] In another embodiment the present invention relates to a
process for preparing compounds of formula I, wherein [0243]
A.sup.1 and A.sup.2 are CH; [0244] R.sup.A is hydrogen or fluorine;
[0245] R is --CF.sub.2COOH, --CF.sub.2COR.sup.1 or
--CF.sub.2C(.dbd.O)NR.sup.1R.sup.2; [0246] R.sup.1 is
1-methyl-cycloprop-1-yl or cyclobutyl; [0247] R.sup.2 is hydrogen,
methyl or ethyl.
[0248] In another embodiment the present invention relates to a
process for preparing compounds of formula I, wherein [0249]
A.sup.1 and A.sup.2 are CH; [0250] R.sup.A is hydrogen; [0251] R is
--CF.sub.2COOH, --CF.sub.2COR.sup.1 or
--CF.sub.2C(.dbd.O)NR.sup.1R.sup.2; [0252] R.sup.1 is
1-methyl-cycloprop-1-yl or cyclobutyl; [0253] R.sup.2 is
hydrogen.
[0254] In one embodiment the present invention relates to a process
for preparing compounds of formula I, wherein the combination of
variables A.sup.1, A.sup.2, R.sup.A corresponds to any one of the
Embodiments E1, E2 or E3 defined above; and [0255] R is
--OCF.sub.2COOH, --OCF.sub.2COR.sup.1 or
--OCF.sub.2C(.dbd.W)NR.sup.1R.sup.2; [0256] R.sup.1
C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl,
C.sub.2-C.sub.6-alkynyl,
C.sub.1-C.sub.6-alkoxyimino-C.sub.1-C.sub.4-alkyl,
C.sub.3-C.sub.8-cycloalkyl, C.sub.3-C.sub.8-cycloalkenyl,
phenyl-C.sub.1-C.sub.4-alkyl, heteroaryl-C.sub.1-C.sub.4-alkyl,
phenyl or heteroaryl; and wherein the heteroaryl group is a 5- or
6-membered aromatic heterocycle, wherein the ring includes besides
carbon atoms 1, 2, 3 or 4 heteroatoms selected from N, O and S as
ring member atoms; and wherein any of the aliphatic or cyclic
groups are unsubstituted or substituted with 1, 2, 3 or up to the
maximum possible number of identical or different radicals selected
from the group consisting of halogen, cyano, C.sub.1-C.sub.6-alkyl
and C.sub.1-C.sub.6-alkoxy; [0257] R.sup.2 is hydrogen, formyl,
C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy,
C.sub.2-C.sub.6-alkenyl, propargyl, C.sub.3-C.sub.8-cycloalkyl,
C.sub.3-C.sub.8-cycloalkenyl,
C.sub.3-C.sub.8-cycloalkyl-C.sub.1-C.sub.4-alkyl, phenyl,
C.sub.1-C.sub.6-alkylamino or diC.sub.1-C.sub.6-alkylamino; and
wherein any of the aliphatic or cyclic groups are unsubstituted or
substituted with 1, 2, 3, 4 or up to the maximum possible number of
identical or different radicals selected from the group consisting
of halogen, cyano, C.sub.1-C.sub.6-alkyl and
C.sub.1-C.sub.6-alkoxy.
[0258] In one embodiment the present invention relates to a process
for preparing compounds of formula I, wherein the combination of
variables A.sup.1, A.sup.2, R.sup.A corresponds to any one of the
Embodiments E1, E2 or E3 defined above; and [0259] R is
--OCF.sub.2COOH, --OCF.sub.2COR.sup.1 or
--OCF.sub.2C(.dbd.W)NR.sup.1R.sup.2; [0260] R.sup.1 is methyl,
ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl,
cyclopropyl, bicyclo[1.1.1]pentan-1-yl, or phenyl; and wherein the
phenyl group is unsubstituted or substituted with 1, 2, 3 or up to
the maximum possible number of identical or different radicals
selected from the group consisting of fluorine, chlorine, cyano,
methyl, ethyl, methoxy, trifluoromethyl, trifluoromethoxy,
difluoromethyl, difluoromethoxy and cyclopropyl. [0261] R.sup.2 is
hydrogen, methyl or ethyl.
[0262] In another embodiment the present invention relates to a
process for preparing compounds of formula I, wherein [0263]
A.sup.1 and A.sup.2 are CH; [0264] R.sup.A is hydrogen or fluorine;
[0265] R is --OCF.sub.2COOH, --OCF.sub.2COR.sup.1 or
--OCF.sub.2C(.dbd.W)NR.sup.1R.sup.2; [0266] R.sup.1 is methyl or
cyclopropyl; [0267] R.sup.2 is hydrogen, methyl or ethyl.
[0268] In another embodiment the present invention relates to a
process for preparing compounds of formula I, wherein [0269]
A.sup.1 and A.sup.2 are CH; [0270] R.sup.A is hydrogen; [0271] R is
--OCF.sub.2COOH, --OCF.sub.2COR.sup.1 or
--OCF.sub.2C(.dbd.W)NR.sup.1R.sup.2; [0272] R.sup.1 is methyl or
cyclopropyl; [0273] R.sup.2 is hydrogen.
[0274] In one embodiment the present invention relates to a process
for preparing compounds of formula I, wherein the combination of
variables A.sup.1, A.sup.2, R.sup.A corresponds to any one of the
Embodiments E1, E2 or E3 defined above; and [0275] R is
--CH.sub.2NR.sup.2C(.dbd.W)R.sup.1,
--CH.sub.2S(.dbd.O).sub.2R.sup.1 or
--CH.sub.2NR.sup.2S(.dbd.O).sub.2R.sup.1; [0276] W is O or S;
[0277] R.sup.1 is C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl,
C.sub.2-C.sub.6-alkynyl,
C.sub.1-C.sub.6-alkoxyimino-C.sub.1-C.sub.4-alkyl,
C.sub.3-C.sub.8-cycloalkyl, C.sub.3-C.sub.8-cycloalkenyl,
phenyl-C.sub.1-C.sub.4-alkyl, heteroaryl-C.sub.1-C.sub.4-alkyl,
phenyl or heteroaryl; and wherein the heteroaryl group is a 5- or
6-membered aromatic heterocycle, wherein the ring includes besides
carbon atoms 1, 2, 3 or 4 heteroatoms selected from N, O and S as
ring member atoms; and wherein any of the aliphatic or cyclic
groups are unsubstituted or substituted with 1, 2, 3 or up to the
maximum possible number of identical or different radicals selected
from the group consisting of halogen, cyano, C.sub.1-C.sub.6-alkyl
and C.sub.1-C.sub.6-alkoxy; [0278] R.sup.2 is hydrogen, formyl,
C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy,
C.sub.2-C.sub.6-alkenyl, propargyl, C.sub.3-C.sub.8-cycloalkyl,
C.sub.3-C.sub.8-cycloalkenyl,
C.sub.3-C.sub.8-cycloalkyl-C.sub.1-C.sub.4-alkyl, phenyl,
C.sub.1-C.sub.6-alkylamino or diC.sub.1-C.sub.6-alkylamino; and
wherein any of the aliphatic or cyclic groups are unsubstituted or
substituted with 1, 2, 3, 4 or up to the maximum possible number of
identical or different radicals selected from the group consisting
of halogen, cyano, C.sub.1-C.sub.6-alkyl and
C.sub.1-C.sub.6-alkoxy.
[0279] In one embodiment the present invention relates to a process
for preparing compounds of formula I, wherein the combination of
variables A.sup.1, A.sup.2, R.sup.A corresponds to any one of the
Embodiments E1, E2 or E3 defined above; and [0280] R is
--CH.sub.2NR.sup.2C(.dbd.W)R.sup.1,
--CH.sub.2S(.dbd.O).sub.2R.sup.1 or
--CH.sub.2NR.sup.2S(.dbd.O).sub.2R.sup.1; [0281] W is O or S;
[0282] R.sup.1 is methyl, ethyl, n-propyl, iso-propyl, n-butyl,
sec-butyl, iso-butyl, 2-methoxyiminoethyl, cyclopropyl,
bicyclo[1.1.1]pentan-1-yl, or phenyl; and wherein the phenyl group
is unsubstituted or substituted with 1, 2, 3 or up to the maximum
possible number of identical or different radicals selected from
the group consisting of fluorine, chlorine, cyano, methyl, ethyl,
methoxy, trifluoromethyl, trifluoromethoxy, difluoromethyl,
difluoromethoxy and cyclopropyl. [0283] R.sup.2 is hydrogen, methyl
or ethyl.
[0284] In another embodiment the present invention relates to a
process for preparing compounds of formula I, wherein [0285]
A.sup.1 and A.sup.2 are CH; [0286] R.sup.A is hydrogen or fluorine;
[0287] R is --CH.sub.2NR.sup.2C(.dbd.W)R.sup.1,
--CH.sub.2S(.dbd.O).sub.2R.sup.1 or
--CH.sub.2NR.sup.2S(.dbd.O).sub.2R.sup.1; [0288] W is O or S;
[0289] R.sup.1 is methyl, ethyl, n-propyl, iso-propyl, n-butyl,
sec-butyl, iso-butyl, 2-methoxyiminoethyl, cyclopropyl,
bicyclo[1.1.1]pentan-1-yl, or phenyl; and wherein the phenyl group
is unsubstituted or substituted with 1 radical selected from the
group consisting of fluorine and chlorine; [0290] R.sup.2 is
hydrogen, methyl or ethyl.
[0291] In another embodiment the present invention relates to a
process for preparing compounds of formula I, wherein [0292]
A.sup.1 and A.sup.2 are CH; [0293] R.sup.A is hydrogen or fluorine;
[0294] R is --CH.sub.2NR.sup.2C(.dbd.O)R.sup.1,
--CH.sub.2S(.dbd.O).sub.2R.sup.1 or
--CH.sub.2NR.sup.2S(.dbd.O).sub.2R.sup.1; [0295] R.sup.1 is methyl,
ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl,
2-methoxyiminoethyl, cyclopropyl or bicyclo[1.1.1]pentan-1-yl;
[0296] R.sup.2 is hydrogen.
[0297] In another embodiment the present invention relates to a
process for preparing compounds of formula I, wherein [0298]
A.sup.1 and A.sup.2 are CH; [0299] R.sup.A is hydrogen or fluorine;
[0300] R is --CH.sub.2NR.sup.2C(.dbd.O)R.sup.1 or
--CH.sub.2NR.sup.2S(.dbd.O).sub.2R.sup.1; [0301] R.sup.1 is methyl,
ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl,
2-methoxyiminoethyl, cyclopropyl or bicyclo[1.1.1]pentan-1-yl;
[0302] R.sup.2 is hydrogen.
[0303] In another embodiment the present invention relates to a
process for preparing compounds of formula I, wherein [0304]
A.sup.1 and A.sup.2 are CH; [0305] R.sup.A is hydrogen or fluorine;
[0306] R is --CH.sub.2S(.dbd.O).sub.2R.sup.1; [0307] R.sup.1 is
methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl,
2-methoxyiminoethyl, cyclopropyl or bicyclo[1.1.1]pentan-1-yl;
[0308] R.sup.2 is hydrogen.
[0309] In further aspects of the present invention the embodiments
E.1 to E.210 listed in Table E represent preferred combinations of
the embodiments, which are defined above for each of the variables
R, R.sup.1, R.sup.2, R.sup.3 and R.sup.4.
TABLE-US-00001 TABLE E Embodiment R R.sup.1 R.sup.2 R.sup.3,
R.sup.4 E.1 R.1 1.1 2.4 3.4 E.2 R.1 1.2 2.4 3.4 E.3 R.1 1.3 2.4 3.4
E.4 R.1 1.4 2.4 3.4 E.5 R.1 1.5 2.4 3.4 E.6 R.1 1.6 2.4 3.4 E.7 R.1
1.7 2.4 3.4 E.8 R.1 1.8 2.4 3.4 E.9 R.1 1.9 2.4 3.4 E.10 R.1 1.10
2.4 3.4 E.11 R.1 1.1 2.4 3.5 E.12 R.1 1.2 2.4 3.5 E.13 R.1 1.3 2.4
3.5 E.14 R.1 1.4 2.4 3.5 E.15 R.1 1.5 2.4 3.5 E.16 R.1 1.6 2.4 3.5
E.17 R.1 1.7 2.4 3.5 E.18 R.1 1.8 2.4 3.5 E.19 R.1 1.9 2.4 3.5 E.20
R.1 1.10 2.4 3.5 E.21 R.1 1.1 2.4 3.7 E.22 R.1 1.2 2.4 3.7 E.23 R.1
1.3 2.4 3.7 E.24 R.1 1.4 2.4 3.7 E.25 R.1 1.5 2.4 3.7 E.26 R.1 1.6
2.4 3.7 E.27 R.1 1.7 2.4 3.7 E.28 R.1 1.8 2.4 3.7 E.29 R.1 1.9 2.4
3.7 E.30 R.1 1.10 2.4 3.7 E.31 R.1 1.1 2.4 3.8 E.32 R.1 1.2 2.4 3.8
E.33 R.1 1.3 2.4 3.8 E.34 R.1 1.4 2.4 3.8 E.35 R.1 1.5 2.4 3.8 E.36
R.1 1.6 2.4 3.8 E.37 R.1 1.7 2.4 3.8 E.38 R.1 1.8 2.4 3.8 E.39 R.1
1.9 2.4 3.8 E.40 R.1 1.10 2.4 3.8 E.41 R.1 1.1 2.4 3.12 E.42 R.1
1.2 2.4 3.12 E.43 R.1 1.3 2.4 3.12 E.44 R.1 1.4 2.4 3.12 E.45 R.1
1.5 2.4 3.12 E.46 R.1 1.6 2.4 3.12 E.47 R.1 1.7 2.4 3.12 E.48 R.1
1.8 2.4 3.12 E.49 R.1 1.9 2.4 3.12 E.50 R.1 1.10 2.4 3.12 E.51 R.1
1.1 2.7 3.4 E.52 R.1 1.2 2.7 3.4 E.53 R.1 1.3 2.7 3.4 E.54 R.1 1.4
2.7 3.4 E.55 R.1 1.5 2.7 3.4 E.56 R.1 1.6 2.7 3.4 E.57 R.1 1.7 2.7
3.4 E.58 R.1 1.8 2.7 3.4 E.59 R.1 1.9 2.7 3.4 E.60 R.1 1.10 2.7 3.4
E.61 R.1 1.1 2.7 3.5 E.62 R.1 1.2 2.7 3.5 E.63 R.1 1.3 2.7 3.5 E.64
R.1 1.4 2.7 3.5 E.65 R.1 1.5 2.7 3.5 E.66 R.1 1.6 2.7 3.5 E.67 R.1
1.7 2.7 3.5 E.68 R.1 1.8 2.7 3.5 E.69 R.1 1.9 2.7 3.5 E.70 R.1 1.10
2.7 3.5 E.71 R.1 1.1 2.7 3.7 E.72 R.1 1.2 2.7 3.7 E.73 R.1 1.3 2.7
3.7 E.74 R.1 1.4 2.7 3.7 E.75 R.1 1.5 2.7 3.7 E.76 R.1 1.6 2.7 3.7
E.77 R.1 1.7 2.7 3.7 E.78 R.1 1.8 2.7 3.7 E.79 R.1 1.9 2.7 3.7 E.80
R.1 1.10 2.7 3.7 E.81 R.1 1.1 2.7 3.8 E.82 R.1 1.2 2.7 3.8 E.83 R.1
1.3 2.7 3.8 E.84 R.1 1.4 2.7 3.8 E.85 R.1 1.5 2.7 3.8 E.86 R.1 1.6
2.7 3.8 E.87 R.1 1.7 2.7 3.8 E.88 R.1 1.8 2.7 3.8 E.89 R.1 1.9 2.7
3.8 E.90 R.1 1.10 2.7 3.8 E.91 R.1 1.1 2.7 3.12 E.92 R.1 1.2 2.7
3.12 E.93 R.1 1.3 2.7 3.12 E.94 R.1 1.4 2.7 3.12 E.95 R.1 1.5 2.7
3.12 E.96 R.1 1.6 2.7 3.12 E.97 R.1 1.7 2.7 3.12 E.98 R.1 1.8 2.7
3.12 E.99 R.1 1.9 2.7 3.12 E.100 R.1 1.10 2.7 3.12 E.101 R.3 1.1
3.4 E.102 R.3 1.2 3.4 E.103 R.3 1.3 3.4 E.104 R.3 1.4 3.4 E.105 R.3
1.5 3.4 E.106 R.3 1.6 3.4 E.107 R.3 1.7 3.4 E.108 R.3 1.8 3.4 E.109
R.3 1.9 3.4 E.110 R.3 1.10 3.4 E.111 R.3 1.1 3.5 E.112 R.3 1.2 3.5
E.113 R.3 1.3 3.5 E.114 R.3 1.4 3.5 E.115 R.3 1.5 3.5 E.116 R.3 1.6
3.5 E.117 R.3 1.7 3.5 E.118 R.3 1.8 3.5 E.119 R.3 1.9 3.5 E.120 R.3
1.10 3.5 E.121 R.3 1.1 3.7 E.122 R.3 1.2 3.7 E.123 R.3 1.3 3.7
E.124 R.3 1.4 3.7 E.125 R.3 1.5 3.7 E.126 R.3 1.6 3.7 E.127 R.3 1.7
3.7 E.128 R.3 1.8 3.7 E.129 R.3 1.9 3.7 E.130 R.3 1.10 3.7 E.131
R.3 1.1 3.8 E.132 R.3 1.2 3.8 E.133 R.3 1.3 3.8 E.134 R.3 1.4 3.8
E.135 R.3 1.5 3.8 E.136 R.3 1.6 3.8 E.137 R.3 1.7 3.8 E.138 R.3 1.8
3.8 E.139 R.3 1.9 3.8 E.140 R.3 1.10 3.8 E.141 R.3 1.1 3.12 E.142
R.3 1.2 3.12 E.143 R.3 1.3 3.12 E.144 R.3 1.4 3.12 E.145 R.3 1.5
3.12 E.146 R.3 1.6 3.12 E.147 R.3 1.7 3.12 E.148 R.3 1.8 3.12 E.149
R.3 1.9 3.12 E.150 R.3 1.10 3.12 E.151 R.8 1.1 2.4 E.152 R.8 1.2
2.4 E.153 R.8 1.3 2.4 E.154 R.8 1.4 2.4 E.155 R.8 1.5 2.4 E.156 R.8
1.6 2.4 E.157 R.8 1.7 2.4 E.158 R.8 1.8 2.4 E.159 R.8 1.9 2.4 E.160
R.8 1.10 2.4 E.161 R.8 1.1 2.7 E.162 R.8 1.2 2.7 E.163 R.8 1.3 2.7
E.164 R.8 1.4 2.7 E.165 R.8 1.5 2.7 E.166 R.8 1.6 2.7 E.167 R.8 1.7
2.7 E.168 R.8 1.8 2.7 E.169 R.8 1.9 2.7 E.170 R.8 1.10 2.7 E.171
R.9 1.1 2.4 E.172 R.9 1.2 2.4 E.173 R.9 1.3 2.4 E.174 R.9 1.4 2.4
E.175 R.9 1.5 2.4 E.176 R.9 1.6 2.4 E.177 R.9 1.7 2.4 E.178 R.9 1.8
2.4 E.179 R.9 1.9 2.4 E.180 R.9 1.10 2.4 E.181 R.9 1.1 2.7 E.182
R.9 1.2 2.7 E.183 R.9 1.3 2.7 E.184 R.9 1.4 2.7 E.185 R.9 1.5 2.7
E.186 R.9 1.6 2.7 E.187 R.9 1.7 2.7 E.188 R.9 1.8 2.7 E.189 R.9 1.9
2.7 E.190 R.9 1.10 2.7 E.191 R.10 1.1 2.4 E.192 R.10 1.2 2.4 E.193
R.10 1.3 2.4 E.194 R.10 1.4 2.4 E.195 R.10 1.5 2.4 E.196 R.10 1.6
2.4 E.197 R.10 1.7 2.4 E.198 R.10 1.8 2.4 E.199 R.10 1.9 2.4 E.200
R.10 1.10 2.4 E.201 R.10 1.1 2.7 E.202 R.10 1.2 2.7 E.203 R.10 1.3
2.7 E.204 R.10 1.4 2.7 E.205 R.10 1.5 2.7 E.206 R.10 1.6 2.7 E.207
R.10 1.7 2.7 E.208 R.10 1.8 2.7 E.209 R.10 1.9 2.7 E.210 R.10 1.10
2.7
[0310] In one embodiment the present invention relates to compounds
of the formula II, namely compounds II.A-1 to II.A-315, wherein
A.sup.1 and A.sup.2 are CH, R.sup.A is hydrogen, and R in each of
the compounds II.A-1 to II.A-315 is defined as in one corresponding
line A-1 to A-315 in Table A below, and wherein # denotes the
position, which is bound to the phenyl moiety. This means, for
example, that a compound of formula II, wherein R is CO.sub.2H is
named II.A-43 in correspondence to the definition in line A-43 in
Table A.
TABLE-US-00002 TABLE A No R A-1 CH.sub.3 A-2 CCl.sub.3 A-3 OH A-4
SH A-5 cyano A-6 F A-7 Cl A-8 Br A-9 CH.sub.2CH.sub.3 A-10
CH(CH.sub.3).sub.2 A-11 CH.sub.2F A-12 CHF.sub.2 A-13
2,2,2-trifluoroethyl A-14 cyclopropyl A-15 CH.sub.2OH A-16
C(.dbd.O)CH.sub.3 A-17 CH.sub.2OCH.sub.3 A-18
CH.sub.2OCH.sub.2CH.sub.3 A-19 CH.sub.2OCH.sub.2CH.sub.2CH.sub.3
A-20 CH.sub.2OCH(CH.sub.3).sub.2 A-21 CH.sub.2OC(CH.sub.3).sub.3
A-22 CH.sub.2OCH.sub.2CH.dbd.CH.sub.2 A-23 CH.sub.2OC(phenyl).sub.3
A-24 CH.sub.2OSi(CH.sub.3).sub.3 A-25
CH.sub.2OSi(CH.sub.2phenyl).sub.3 A-26 CH.sub.2OC(.dbd.O)CH.sub.3
A-27 CH.sub.2OC(.dbd.O)CH.sub.2CH.sub.3 A-28
CH.sub.2OC(.dbd.O)CH.sub.2CH.sub.2CH.sub.3 A-29
CH.sub.2OC(.dbd.O)CH(CH.sub.3).sub.2 A-30
CH.sub.2OC(.dbd.O)C(CH.sub.3).sub.3 A-31
CH.sub.2OC(.dbd.O)CH.sub.2CH.dbd.CH.sub.2 A-32
CH.sub.2OC(.dbd.O)OCH.sub.3 A-33
CH.sub.2OC(.dbd.O)OCH.sub.2CH.sub.3 A-34
CH.sub.2OC(.dbd.O)OCH.sub.2CH.sub.2CH.sub.3 A-35
CH.sub.2OC(.dbd.O)OCH(CH.sub.3).sub.2 A-36
CH.sub.2OC(.dbd.O)OC(CH.sub.3).sub.3 A-37
CH.sub.2OC(.dbd.O)OCH.sub.2CH.dbd.CH.sub.2 A-38
CH.sub.2OCH.sub.2OCH.sub.3 A-39 CH.sub.2OCH.sub.2OCH.sub.2CH.sub.3
A-40 CH.sub.2OCH.sub.2OCH.sub.2CH.sub.2CH.sub.3 A-41
CH.sub.2OCH.sub.2OCH(CH.sub.3).sub.2 A-42
CH.sub.2OCH.sub.2O-tetrahydropyran-2-yl A-43 CO.sub.2H A-44
CO.sub.2CH.sub.3 A-45 CO.sub.2CH.sub.2CH.sub.3 A-46
CO.sub.2CH.sub.2CH.sub.2CH.sub.3 A-47 CO.sub.2CH(CH.sub.3).sub.2
A-48 CO.sub.2C(CH.sub.3).sub.3 A-49 CO.sub.2CH.sub.2CH.dbd.CH.sub.2
A-50 CH.sub.2CO.sub.2H A-51 CH.sub.2CO.sub.2CH.sub.3 A-52
CH.sub.2CO.sub.2CH.sub.2CH.sub.3 A-53
CH.sub.2CO.sub.2CH.sub.2CH.sub.2CH.sub.3 A-54
CH.sub.2CO.sub.2CH(CH.sub.3).sub.2 A-55
CH.sub.2CO.sub.2C(CH.sub.3).sub.3 A-56
CH.sub.2CO.sub.2CH.sub.2CH.dbd.CH.sub.2 A-57 CF.sub.2CO.sub.2H A-58
CF.sub.2CO.sub.2CH.sub.3 A-59 CF.sub.2CO.sub.2CH.sub.2CH.sub.3 A-60
CF.sub.2CO.sub.2CH.sub.2CH.sub.2CH.sub.3 A-61
CF.sub.2CO.sub.2CH(CH.sub.3).sub.2 A-62
CF.sub.2CO.sub.2C(CH.sub.3).sub.3 A-63
CF.sub.2CO.sub.2CH.sub.2CH.dbd.CH.sub.2 A-64
pyrrolidine-2-one-methyl A-65 CH.sub.2NH.sub.2 A-66
CH.sub.2NHNH.sub.2 A-67 CH.sub.2NH--N(CH.sub.3).sub.2 A-68
CH.sub.2NH--NH(CH.sub.3) A-69 CH.sub.2NH(CH.sub.3) A-70
CH.sub.2NH(CH.sub.2CH.sub.3) A-71
CH.sub.2NH(CH.sub.2CH.sub.2CH.sub.3) A-72
CH.sub.2NH(CH(CH.sub.3).sub.2) A-73 CH.sub.2NH(C(CH.sub.3).sub.3)
A-74 CH.sub.2NH(CH.sub.2CH.dbd.CH.sub.2) A-75 CH.sub.2NH(OCH.sub.3)
A-76 CH.sub.2NH(OCH.sub.2CH.sub.3) A-77
CH.sub.2NH(OCH.sub.2CH.sub.2CH.sub.3) A-78
CH.sub.2NH(OCH(CH.sub.3).sub.2) A-79
CH.sub.2NH(OCH.sub.2CH.dbd.CH.sub.2) A-80 CH.sub.2NH(cyclopropyl)
A-81 CH.sub.2NH(cyclobutyl) A-82 CH.sub.2NH(cyclopentyl) A-83
CH.sub.2NH(cyclohexyl) A-84 CH.sub.2N(CH.sub.3).sub.2 A-85
CH.sub.2N(CH.sub.3)(CH.sub.2CH.sub.3) A-86
CH.sub.2N(CH.sub.3)(CH.sub.2CH.sub.2CH.sub.3) A-87
CH.sub.2N(CH.sub.3)(CH(CH.sub.3).sub.2) A-88
CH.sub.2N(CH.sub.3)(C(CH.sub.3).sub.3) A-89
CH.sub.2N(CH.sub.3)(CH.sub.2CH.dbd.CH.sub.2) A-90
CH.sub.2N(CH.sub.3)(OCH.sub.3) A-91
CH.sub.2N(CH.sub.3)(OCH.sub.2CH.sub.3) A-92
CH.sub.2N(CH.sub.3)(OCH.sub.2CH.sub.2CH.sub.3) A-93
CH.sub.2N(CH.sub.3)(OCH.sub.2CH.dbd.CH.sub.2) A-94
CH.sub.2N(CH.sub.3)(cyclopropyl) A-95
CH.sub.2N(CH.sub.3)(cyclobutyl) A-96
CH.sub.2N(CH.sub.3)(cyclopentyl) A-97
CH.sub.2N(CH.sub.3)(cyclohexyl) A-98 CH.sub.2NH(C(.dbd.O)H) A-99
CH.sub.2NH(C(.dbd.O)CH.sub.3) A-100
CH.sub.2NH(C(.dbd.O)CH.sub.2CH.sub.3) A-101
CH.sub.2NH(C(.dbd.O)CH.sub.2CH.sub.2CH.sub.3) A-102
CH.sub.2NH(C(.dbd.O)CH(CH.sub.3).sub.2) A-103
CH.sub.2NH(C(.dbd.O)C(CH.sub.3).sub.3) A-104
CH.sub.2NH(C(.dbd.O)CH.sub.2CH.dbd.CH.sub.2) A-105
CH.sub.2NH(C(.dbd.O)OCH.sub.3) A-106
CH.sub.2NH(C(.dbd.O)OCH.sub.2CH.sub.3) A-107
CH.sub.2NH(C(.dbd.O)OCH.sub.2CH.sub.2CH.sub.3) A-108
CH.sub.2NH(C(.dbd.O)OCH.sub.2CH.dbd.CH.sub.2) A-109
CH.sub.2NH(C(.dbd.O)cyclopropyl) A-110
CH.sub.2NH(C(.dbd.O)cyclobutyl) A-111
CH.sub.2NH(C(.dbd.O)cyclopentyl) A-112
CH.sub.2NH(C(.dbd.O)cyclohexyl) A-113
CH.sub.2N(CH.sub.3)(C(.dbd.O)H) A-114
CH.sub.2N(CH.sub.3)(C(.dbd.O)CH.sub.3) A-115
CH.sub.2N(CH.sub.3)(C(.dbd.O)CH.sub.2CH.sub.3) A-116
CH.sub.2N(CH.sub.3)(C(.dbd.O)CH.sub.2CH.sub.2CH.sub.3) A-117
CH.sub.2N(CH.sub.3)(C(.dbd.O)CH(CH.sub.3).sub.2) A-118
CH.sub.2N(CH.sub.3)(C(.dbd.O)C(CH.sub.3).sub.3) A-119
CH.sub.2N(CH.sub.3)(C(.dbd.O)CH.sub.2CH.dbd.CH.sub.2) A-120
CH.sub.2N(CH.sub.3)(C(.dbd.O)OCH.sub.3) A-121
CH.sub.2N(CH.sub.3)(C(.dbd.O)OCH.sub.2CH.sub.3) A-122
CH.sub.2N(CH.sub.3)(C(.dbd.O)OCH.sub.2CH.sub.2CH.sub.3) A-123
CH.sub.2N(CH.sub.3)(C(.dbd.O)OCH.sub.2CH.dbd.CH.sub.2) A-124
CH.sub.2N(CH.sub.3)(C(.dbd.O)cyclopropyl) A-125
CH.sub.2N(CH.sub.3)(C(.dbd.O)cyclobutyl) A-126
CH.sub.2N(CH.sub.3)(C(.dbd.O)cyclopentyl) A-127
CH.sub.2N(CH.sub.3)(C(.dbd.O)cyclohexyl) A-128
CH.sub.2N(CH.sub.2CH.sub.3)(C(.dbd.O)H) A-129
CH.sub.2N(CH.sub.2CH.sub.3)(C(.dbd.O)CH.sub.3) A-130
CH.sub.2N(CH.sub.2CH.sub.3)(C(.dbd.O)CH.sub.2CH.sub.3) A-131
CH.sub.2N(CH.sub.2CH.sub.3)(C(.dbd.O)--CH.sub.2CH.sub.2CH.sub.3)
A-132 CH.sub.2N(CH.sub.2CH.sub.3)(C(.dbd.O)CH(CH.sub.3).sub.2)
A-133 CH.sub.2N(CH.sub.2CH.sub.3)(C(.dbd.O)C(CH.sub.3).sub.3) A-134
CH.sub.2N(CH.sub.2CH.sub.3)(C(.dbd.O)--CH.sub.2CH.dbd.CH.sub.2)
A-135 CH.sub.2N(CH.sub.2CH.sub.3)(C(.dbd.O)OCH.sub.3) A-136
CH.sub.2N(CH.sub.2CH.sub.3)(C(.dbd.O)OCH.sub.2CH.sub.3) A-137
CH.sub.2N(CH.sub.2CH.sub.3)(C(.dbd.O)--OCH.sub.2CH.sub.2CH.sub.3)
A-138
CH.sub.2N(CH.sub.2CH.sub.3)(C(.dbd.O)--OCH.sub.2CH.dbd.CH.sub.2)
A-139 CH.sub.2N(CH.sub.2CH.sub.3)(C(.dbd.O)cyclopropyl) A-140
CH.sub.2N(CH.sub.2CH.sub.3)(C(.dbd.O)cyclobutyl) A-141
CH.sub.2N(CH.sub.2CH.sub.3)(C(.dbd.O)cyclopentyl) A-142
CH.sub.2N(CH.sub.2CH.sub.3)(C(.dbd.O)cyclohexyl) A-143
CH.sub.2N(CH.sub.2CH.sub.2CH.sub.3)(C(.dbd.O)H) A-144
CH.sub.2N(CH.sub.2CH.sub.2CH.sub.3)(C(.dbd.O)CH.sub.3) A-145
CH.sub.2N(CH.sub.2CH.sub.2CH.sub.3)(C(.dbd.O)--CH.sub.2CH.sub.3)
A-146
CH.sub.2N(CH.sub.2CH.sub.2CH.sub.3)(C(.dbd.O)--CH.sub.2CH.sub.2CH.s-
ub.3) A-147
CH.sub.2N(CH.sub.2CH.sub.2CH.sub.3)(C(.dbd.O)--CH(CH.sub.3).sub.2)
A-148
CH.sub.2N(CH.sub.2CH.sub.2CH.sub.3)(C(.dbd.O)--C(CH.sub.3).sub.3)
A-149
CH.sub.2N(CH.sub.2CH.sub.2CH.sub.3)(C(.dbd.O)--CH.sub.2CH.dbd.CH.su-
b.2) A-150 CH.sub.2N(CH.sub.2CH.sub.2CH.sub.3)(C(.dbd.O)OCH.sub.3)
A-151
CH.sub.2N(CH.sub.2CH.sub.2CH.sub.3)(C(.dbd.O)--OCH.sub.2CH.sub.3)
A-152
CH.sub.2N(CH.sub.2CH.sub.2CH.sub.3)(C(.dbd.O)--OCH.sub.2CH.sub.2CH.-
sub.3) A-153
CH.sub.2N(CH.sub.2CH.sub.2CH.sub.3)(C(.dbd.O)--OCH.sub.2CH.dbd.CH.s-
ub.2) A-154
CH.sub.2N(CH.sub.2CH.sub.2CH.sub.3)(C(.dbd.O)--cyclopropyl) A-155
CH.sub.2N(CH.sub.2CH.sub.2CH.sub.3)(C(.dbd.O)--cyclobutyl) A-156
CH.sub.2N(CH.sub.2CH.sub.2CH.sub.3)(C(.dbd.O)--cyclopentyl) A-157
CH.sub.2N(CH.sub.2CH.sub.2CH.sub.3)(C(.dbd.O)--cyclohexyl) A-158
CH.sub.2N(CH(CH.sub.3).sub.2)(C(.dbd.O)H) A-159
CH.sub.2N(CH(CH.sub.3).sub.2)(C(.dbd.O)CH.sub.3) A-160
CH.sub.2N(CH(CH.sub.3).sub.2)(C(.dbd.O)CH.sub.2CH.sub.3) A-161
CH.sub.2N(CH(CH.sub.3).sub.2)(C(.dbd.O)--CH.sub.2CH.sub.2CH.sub.3)
A-162 CH.sub.2N(CH(CH.sub.3).sub.2)(C(.dbd.O)CH(CH.sub.3).sub.2)
A-163 CH.sub.2N(CH(CH.sub.3).sub.2)(C(.dbd.O)C(CH.sub.3).sub.3)
A-164
CH.sub.2N(CH(CH.sub.3).sub.2)(C(.dbd.O)--CH.sub.2CH.dbd.CH.sub.2)
A-165 CH.sub.2N(CH(CH.sub.3).sub.2)(C(.dbd.O)OCH.sub.3) A-166
CH.sub.2N(CH(CH.sub.3).sub.2)(C(.dbd.O)OCH.sub.2CH.sub.3) A-167
CH.sub.2N(CH(CH.sub.3).sub.2)(C(.dbd.O)--OCH.sub.2CH.sub.2CH.sub.3)
A-168
CH.sub.2N(CH(CH.sub.3).sub.2)(C(.dbd.O)--OCH.sub.2CH.dbd.CH.sub.2)
A-169 CH.sub.2N(CH(CH.sub.3).sub.2)(C(.dbd.O)--cyclopropyl) A-170
CH.sub.2N(CH(CH.sub.3).sub.2)(C(.dbd.O)cyclobutyl) A-171
CH.sub.2N(CH(CH.sub.3).sub.2)(C(.dbd.O)--cyclopentyl) A-172
CH.sub.2N(CH(CH.sub.3).sub.2)(C(.dbd.O)cyclohexyl) A-173
CH.sub.2N(OCH.sub.3)(C(.dbd.O)H) A-174
CH.sub.2N(OCH.sub.3)(C(.dbd.O)CH.sub.3) A-175
CH.sub.2N(OCH.sub.3)(C(.dbd.O)CH.sub.2CH.sub.3) A-176
CH.sub.2N(OCH.sub.3)(C(.dbd.O)CH.sub.2CH.sub.2CH.sub.3) A-177
CH.sub.2N(OCH.sub.3)(C(.dbd.O)CH(CH.sub.3).sub.2) A-178
CH.sub.2N(OCH.sub.3)(C(.dbd.O)C(CH.sub.3).sub.3) A-179
CH.sub.2N(OCH.sub.3)(C(.dbd.O)CH.sub.2CH.dbd.CH.sub.2) A-180
CH.sub.2N(OCH.sub.3)(C(.dbd.O)OCH.sub.3) A-181
CH.sub.2N(OCH.sub.3)(C(.dbd.O)OCH.sub.2CH.sub.3) A-182
CH.sub.2N(OCH.sub.3)(C(.dbd.O)OCH.sub.2CH.sub.2CH.sub.3) A-183
CH.sub.2N(OCH.sub.3)(C(.dbd.O)--OCH.sub.2CH.dbd.CH.sub.2) A-184
CH.sub.2N(OCH.sub.3)(C(.dbd.O)cyclopropyl) A-185
CH.sub.2N(OCH.sub.3)(C(.dbd.O)cyclobutyl) A-186
CH.sub.2N(OCH.sub.3)(C(.dbd.O)cyclopentyl) A-187
CH.sub.2N(OCH.sub.3)(C(.dbd.O)cyclohexyl) A-188
CH.sub.2N(OCH.sub.2CH.sub.3)(C(.dbd.O)H) A-189
CH.sub.2N(OCH.sub.2CH.sub.3)(C(.dbd.O)CH.sub.3) A-190
CH.sub.2N(OCH.sub.2CH.sub.3)(C(.dbd.O)CH.sub.2CH.sub.3) A-191
CH.sub.2N(OCH.sub.2CH.sub.3)(C(.dbd.O)--CH.sub.2CH.sub.2CH.sub.3)
A-192 CH.sub.2N(OCH.sub.2CH.sub.3)(C(.dbd.O)CH(CH.sub.3).sub.2)
A-193 CH.sub.2N(OCH.sub.2CH.sub.3)(C(.dbd.O)C(CH.sub.3).sub.3)
A-194
CH.sub.2N(OCH.sub.2CH.sub.3)(C(.dbd.O)--CH.sub.2CH.dbd.CH.sub.2)
A-195 CH.sub.2N(OCH.sub.2CH.sub.3)(C(.dbd.O)OCH.sub.3) A-196
CH.sub.2N(OCH.sub.2CH.sub.3)(C(.dbd.O)OCH.sub.2CH.sub.3) A-197
CH.sub.2N(OCH.sub.2CH.sub.3)(C(.dbd.O)--OCH.sub.2CH.sub.2CH.sub.3)
A-198
CH.sub.2N(OCH.sub.2CH.sub.3)(C(.dbd.O)--OCH.sub.2CH.dbd.CH.sub.2)
A-199 CH.sub.2N(OCH.sub.2CH.sub.3)(C(.dbd.O)--cyclopropyl) A-200
CH.sub.2N(OCH.sub.2CH.sub.3)(C(.dbd.O)cyclobutyl) A-201
CH.sub.2N(OCH.sub.2CH.sub.3)(C(.dbd.O)--cyclopentyl) A-202
CH.sub.2N(OCH.sub.2CH.sub.3)(C(.dbd.O)--cyclohexyl) A-203
CH.sub.2N(OCH.sub.2CH.sub.2CH.sub.3)(C(.dbd.O)H) A-204
CH.sub.2N(OCH.sub.2CH.sub.2CH.sub.3)(C(.dbd.O)CH.sub.3) A-205
CH.sub.2N(OCH.sub.2CH.sub.2CH.sub.3)(C(.dbd.O)--CH.sub.2CH.sub.3)
A-206
CH.sub.2N(OCH.sub.2CH.sub.2CH.sub.3)(C(.dbd.O)--CH.sub.2CH.sub.2CH.-
sub.3) A-207
CH.sub.2N(OCH.sub.2CH.sub.2CH.sub.3)(C(.dbd.O)--CH(CH.sub.3).sub.2)
A-208
CH.sub.2N(OCH.sub.2CH.sub.2CH.sub.3)(C(.dbd.O)--C(CH.sub.3).sub.3)
A-209
CH.sub.2N(OCH.sub.2CH.sub.2CH.sub.3)(C(.dbd.O)--CH.sub.2CH.dbd.CH.s-
ub.2) A-210
CH.sub.2N(OCH.sub.2CH.sub.2CH.sub.3)(C(.dbd.O)OCH.sub.3) A-211
CH.sub.2N(OCH.sub.2CH.sub.2CH.sub.3)(C(.dbd.O)--OCH.sub.2CH.sub.3)
A-212
CH.sub.2N(OCH.sub.2CH.sub.2CH.sub.3)(C(.dbd.O)OCH.sub.2CH.sub.2CH.s-
ub.3) A-213
CH.sub.2N(OCH.sub.2CH.sub.2CH.sub.3)(C(.dbd.O)--OCH.sub.2CH.dbd.CH.-
sub.2) A-214
CH.sub.2N(OCH.sub.2CH.sub.2CH.sub.3)(C(.dbd.O)--cyclopropyl) A-215
CH.sub.2N(OCH.sub.2CH.sub.2CH.sub.3)(C(.dbd.O)--cyclobutyl) A-216
CH.sub.2N(OCH.sub.2CH.sub.2CH.sub.3)(C(.dbd.O)--cyclopentyl) A-217
CH.sub.2N(OCH.sub.2CH.sub.2CH.sub.3)(C(.dbd.O)--cyclohexyl) A-218
CH.sub.2NHC(.dbd.O)NH(CH.sub.3) A-219
CH.sub.2NHC(.dbd.O)NH(CH.sub.2CH.sub.3) A-220
CH.sub.2NHC(.dbd.O)NH(CH.sub.2CH.sub.2CH.sub.3) A-221
CH.sub.2NHC(.dbd.O)NH(CH(CH.sub.3).sub.2) A-222
CH.sub.2NHC(.dbd.O)NH(C(CH.sub.3).sub.3) A-223
CH.sub.2NHC(.dbd.O)NH(CH.sub.2CH.dbd.CH.sub.2) A-224
CH.sub.2NHC(.dbd.O)NH(OCH.sub.3)) A-225
CH.sub.2NHC(.dbd.O)NH(OCH.sub.2CH.sub.3) A-226
CH.sub.2NHC(.dbd.O)NH(OCH.sub.2CH.sub.2CH.sub.3) A-227
CH.sub.2NHC(.dbd.O)NH(OCH.sub.2CH.dbd.CH.sub.2) A-228
CH.sub.2NHC(.dbd.O)NHcyclopropyl A-229
CH.sub.2NHC(.dbd.O)NHcyclobutyl A-230
CH.sub.2NHC(.dbd.O)NHcyclopentyl A-231
CH.sub.2NHC(.dbd.O)NHcyclohexyl A-232 C(.dbd.O)NH.sub.2 A-233
C(.dbd.O)NH(CH.sub.3) A-234 C(.dbd.O)NH(CH.sub.2CH.sub.3) A-235
C(.dbd.O)NH(CH.sub.2CH.sub.2CH.sub.3) A-236
C(.dbd.O)NH(CH(CH.sub.3).sub.2)
A-237 C(.dbd.O)NH(C(CH.sub.3).sub.3) A-238
C(.dbd.O)NH(CH.sub.2CH.dbd.CH.sub.2) A-239 C(.dbd.O)NH(OCH.sub.3)
A-240 C(.dbd.O)NH(OCH.sub.2CH.sub.3) A-241
C(.dbd.O)NH(OCH.sub.2CH.sub.2CH.sub.3) A-242
C(.dbd.O)NH(OCH.sub.2CH.dbd.CH.sub.2) A-243 C(.dbd.O)NHcyclopropyl
A-244 C(.dbd.O)NHcyclobutyl A-245 C(.dbd.O)NHcyclopentyl A-246
C(.dbd.O)NHcyclohexyl A-247 C(.dbd.S)NH.sub.2 A-248
C(.dbd.S)NH(CH.sub.3) A-249 C(.dbd.S)NH(CH.sub.2CH.sub.3) A-250
C(.dbd.S)NH(CH.sub.2CH.sub.2CH.sub.3) A-251
C(.dbd.S)NH(CH(CH.sub.3).sub.2) A-252
C(.dbd.S)NH(C(CH.sub.3).sub.3) A-253
C(.dbd.S)NH(CH.sub.2CH.dbd.CH.sub.2) A-254 C(.dbd.S)NH(OCH.sub.3)
A-255 C(.dbd.S)NH(OCH.sub.2CH.sub.3) A-256
C(.dbd.S)NH(OCH.sub.2CH.sub.2CH.sub.3) A-257
C(.dbd.S)NH(OCH.sub.2CH.dbd.CH.sub.2) A-258
C(.dbd.S)NH(cyclopropyl) A-259 C(.dbd.S)NH(cyclobutyl) A-260
C(.dbd.S)NH(cyclopentyl) A-261 C(.dbd.S)NH(cyclohexyl) A-262
C(.dbd.O)N(CH.sub.3).sub.2 A-263
C(.dbd.O)N(CH.sub.3)(CH.sub.2CH.sub.3) A-264
C(.dbd.O)N(CH.sub.3)(CH.sub.2CH.sub.2CH.sub.3) A-265
C(.dbd.O)N(CH.sub.3)(CH(CH.sub.3).sub.2) A-266
C(.dbd.O)N(CH.sub.3)(C(CH.sub.3).sub.3) A-267
C(.dbd.O)N(CH.sub.3)(OCH.sub.3) A-268
C(.dbd.O)N(CH.sub.3)(OCH.sub.2CH.sub.3) A-269
C(.dbd.O)N(CH.sub.3)(OCH.sub.2CH.sub.2CH.sub.3) A-270
C(.dbd.O)N(CH.sub.3)(OCH.sub.2CH.dbd.CH.sub.2) A-271
C(.dbd.O)N(CH.sub.3)(cyclopropyl) A-272
C(.dbd.O)N(CH.sub.3)(cyclobutyl) A-273
C(.dbd.O)N(CH.sub.3)(cyclopentyl) A-274
C(.dbd.O)N(CH.sub.3)(cyclohexyl) A-275 C(.dbd.S)N(CH.sub.3).sub.2
A-276 C(.dbd.S)N(CH.sub.3)(CH.sub.2CH.sub.3) A-277
C(.dbd.S)N(CH.sub.3)(CH.sub.2CH.sub.2CH.sub.3) A-278
C(.dbd.S)N(CH.sub.3)(CH(CH.sub.3).sub.2) A-279
C(.dbd.S)N(CH.sub.3)(C(CH.sub.3).sub.3) A-280
C(.dbd.S)N(CH.sub.3)(OCH.sub.3) A-281
C(.dbd.S)N(CH.sub.3)(OCH.sub.2CH.sub.3) A-282
C(.dbd.S)N(CH.sub.3)(OCH.sub.2CH.sub.2CH.sub.3) A-283
C(.dbd.S)N(CH.sub.3)(OCH.sub.2CH.dbd.CH.sub.2) A-284
C(.dbd.S)N(CH.sub.3)(cyclopropyl) A-285
C(.dbd.S)N(CH.sub.3)(cyclobutyl) A-286
C(.dbd.S)N(CH.sub.3)(cyclopentyl) A-287
C(.dbd.S)N(CH.sub.3)(cyclohexyl) A-288 ##STR00017## A-289
##STR00018## A-290 ##STR00019## A-291 ##STR00020## A-292
##STR00021## A-293 ##STR00022## A-294 ##STR00023## A-295
##STR00024## A-296 ##STR00025## A-297 ##STR00026## A-298
##STR00027## A-299 ##STR00028## A-300 ##STR00029## A-301
##STR00030## A-302 ##STR00031## A-303 ##STR00032## A-304
##STR00033## A-305 ##STR00034## A-306 ##STR00035## A-307
##STR00036## A-308 ##STR00037## A-309 ##STR00038## A-310
##STR00039## A-311 ##STR00040## A-312 ##STR00041## A-313
##STR00042## A-314 ##STR00043## A-315 ##STR00044##
[0311] In preferred embodiments the present invention relates to
the transformation of a compound of formula II with compounds of
formula IIa to give compounds of formula I as described herein; and
wherein the specific combination of reaction conditions is as
defined in embodiments B-1 to B-32 in Table B below. All reactions
defined by embodiments B1 to B-32 are carried out with 2
equivalents of trifluoroacetic acid chloride, based on the amount
of compound II, with a molar ratio of the base to compound II of
1:1, at atmospheric pressure and whereas the other expressions in
embodiments B-1 to B-32 have the following meaning:
[0312] Acylating agent IIa: 2 equivalents of trifluoroacetic acid
chloride, based on the amount of compound II (ac1), 2 equivalents
of trifluoroacetic acid fluoride, based on the amount of compound
II (ac2).
[0313] Base: pyridine (b1), 2,4,6-collidine (b2), 2,6-lutidine
(b3), trimethylamine (b4), triethylamin (b5), diisopropylethylamine
(b6), sodium acetate (b7), potassium actetate (b8), tributylamine
(b9), 2-picoline (b10), 3-picoline (b11), 4-picoline (b12),
5-ethyl-2-methyl-pyridine (b13), sodium carbonate (b14), potassium
carbonate (b15).
[0314] Molar ratio of base to compound II: 3:1 (ba1), 1:1 (ba2),
1:50 (ba2).
[0315] Solvents: heptane (s1), cyclohexane (s2), toluene (s3),
xylene (s4), dichloromethane (s5), 1,2-dichlorobenzene (s6),
chlorobenzene (s7), 1,3,5-trimethylbenzene (s8), ethylbenzene (s9),
tetrahydrofurane (s10), dioxane (s11), ethyl acetate (s12), methyl
ethylketone (s13), benzotrifluoride (s14).
[0316] Volume ratio of solvent to compound II: 1:2 (sa1), 1:1
(sa2), 5:1 (sa2).
[0317] Pressure: 1 atmosphere (p1), 3 atm (p2), 8 atm (p3), 50 atm
(p4).
[0318] Temperature: -10.degree. C. (t1), 0.degree. C. (t2),
50.degree. C. (t3), 100.degree. C. (t4).
[0319] This means, for example, that a reaction, in which the
acylating agent IIa is 2 equivalents of TFAC based on the amount of
compound II, in the presence of pyridine as a base in a molar ratio
of 1:1 based on the amount of compound II, in toluene as solvent
and with a volume ratio of toluene to compound II of 1:1, at
atmospheric pressure and a temperature of 50.degree. C., is
identified as embodiment B-2.
TABLE-US-00003 TABLE B B-1: b1, s3, t2; B-2: b1, s3, t3; B-3: b1,
s5, t2; B-4: b1, s5, t3; B-5: b1, s10, t2; B-6: b1, s10, t3; B-7:
b1, s12, t2; B-8: b1, s12, t3; B-9: b4, s3, t2; B-10: b4, s3, t3;
B-11: b4, s5, t2; B-12: b4, s5, t3; B-13: b4, s10, t2; B-14: b4,
s10, t3; B-15: b4, s12, t2; B-16: b4, s12, t3; B-17: b5, s3, t2;
B-18: b5, s3, t3; B-19: b5, s5, t2; B-20: b5, s5, t3; B-21: b5,
s10, t2; B-22: b5, s10, t3; B-23: b5, s12, t2; B-24: b5, s12, t3;
B-25: no base, s3, t2; B-26: no base, s3, t3; B-27: no base, s5,
t2; B-28: no base, s5, t3; B-29: no base, s10, t2; B-30: no base,
s10, t3; B-31: no base, s12, t2; B-32: no base, s12, t3.
[0320] In further preferred embodiments D-1 to D-32, which are
summarized in table D below, the present invention relates to the
transformation of a compound selected from the group of compounds
II.A-1 to II.A-315 with TFAC to give compounds of formula I; and
wherein the specific combination of the reaction conditions in each
case is as defined in embodiments B-1 to B-32 of Table B. This
means, for example, that a reaction, in which any of compounds
II.A-1 to II.A-315 is reacted with TFAC under the conditions as
defined in Table B, embodiment B-2, is described in embodiment
D-2.
TABLE-US-00004 TABLE D D-1: B-1 & II.A-1 to II-A-315; D-2: B-2
& II.A-1 to II-A-315; D-3: B-3 & II.A-1 to II-A-315; D-4:
B-4 & II.A-1 to II-A-315; D-5: B-5 & II.A-1 to II-A-315;
D-6: B-6 & II.A-1 to II-A-315; D-7: B-7 & II.A-1 to
II-A-315; D-8: B-8 & II.A-1 to II-A-315; D-9: B-9 & II.A-1
to II-A-315; D-10: B-10 & II.A-1 to II- A-315; D-11: B-11 &
II.A-1 to II-A-315; D-12: B-12 & II.A-1 to II-A-315; D-13: B-13
& II.A-1 to II- A-315; D-14: B-14 & II.A-1 to II-A-315;
D-15: B-15 & II.A-1 to II-A-315; D-16: B-16 & II.A-1 to II-
A-315; D-17: B-17 & II.A-1 to II-A-315; D-18: B-18 & II.A-1
to II-A-315; D-19: B-19 & II.A-1 to II- A-315; D-20: B-20 &
II.A-1 to II-A-315; D-21: B-21 & II.A-1 to II-A-315; D-22: B-22
& II.A-1 to II- A-315; D-23: B-23 & II.A-1 to II-A-315;
D-24: B-24 & II.A-1 to II-A-315; D-25: B-25 & II.A-1 to II-
A-315; D-26: B-26 & II.A-1 to II-A-315; D-27: B-27 & II.A-1
to II-A-315; D-28: B-28 & II.A-1 to II- A-315; D-29: B-29 &
II.A-1 to II-A-315; D-30: B-30 & II.A-1 to II-A-315; D-31: B-31
& II.A-1 to II- A-315; D-32: B-32 & II.A-1 to II-A-315.
[0321] The invention is illustrated by the following examples:
EXAMPLE 1: PREPARATION OF
N-methyl-N-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]cy-
clopropanecarboxamide
[0322] 5.0 g (17.6 mmol)
N-[[4-[(Z)-N'-hydroxycarbamimidoyl]phenyl]methyl]-N-methyl-cyclopropaneca-
rboxamide and 25 g (271 mmol) toluene were placed in a glass
reactor and cooled to -22.degree. C. After that 4.6 g (35 mmol)
trifluoroacetyl chloride was dosed continuously under vigorous
stirring over 10 minutes at -22.degree. C. to the reaction mixture.
The reaction mixture was stirred for further 45 minutes at
-15.degree. C. to -13.degree. C. Then the reaction mixture was
heated up to 25.degree. C. 25 g water was added to the reaction
mixture. After phase separation the organic phase was extracted
with 20 g water. The solvent of the organic phase was distilled off
under reduced pressure (40.degree. C.; 2 kPa). Residue: 3.1 g;
HPLC-purity of 76.6%; Yield: 42%.
EXAMPLE 2: PREPARATION OF
2,2-difluoro-N-methyl-2-[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phen-
yl]acetamide
[0323] 20.0 g (78 mmol)
2,2-difluoro-2-[4-[(Z)-N'-hydroxycarbamimidoyl]phenyl]-N-methyl-acetamide
and 200 mL dichloromethane were placed in a pressure reactor and
cooled to -10.degree. C. Then 21.5 g (162 mmol) trifluoroacetyl
chloride was dosed continuously under vigorous stirring over 10
minutes at -10.degree. C. to the reaction mixture. The reaction
mixture was stirred for 4 hours at 100.degree. C. and 990 kPa.
Then, after the reactor was cooled down to 25.degree. C., the
pressure of the reactor was released and 200 g water was added to
the reaction mixture. After phase separation the organic phase was
extracted once with 200 g of an aqueous solution of sodium
hydroxide (5% by weight) and once with 100 g water. The organic
phase was dried over magnesium sulfate. The solvent was the removed
under reduced pressure (40.degree. C.; 2 kPa). Residue: 17.5 g;
HPLC gave a purity of 76.3%; Yield: 66.3%.
EXAMPLE 3: PREPARATION OF
3-(p-tolyl)-5-(trifluoromethyl)-1,2,4-oxadiazole
[0324] 100 g (0.67 mol) N'-hydroxy-4-methyl-benzamidine were
suspended in 450 g (5.22 mol) tetrahydro-2-methylfuran (Me-THF). In
total, 203 g (1.53 mol) trifluoroacetyl chloride were dosed in
between 0.degree. C. and 25.degree. C. in 5 hours. Then, the
volatiles were removed in vacuo (60.degree. C., 250 to 5 mbar) to
yield 138 g (>99% HPLC purity, 91% yield)
3-(p-tolyl)-5-(trifluoromethyl)-1,2,4-oxadiazole.
EXAMPLE 4: PREPARATION OF
3-(p-tolyl)-5-(trifluoromethyl)-1,2,4-oxadiazole
[0325] 100 g (0.67 mol) N'-hydroxy-4-methyl-benzamidine were
suspended in 450 g (5.22 mol) Me-THF. In total, 203 g (1.53 mol)
trifluoroacetylchloride were dosed 40.degree. C. in 3 hours. The
volatiles were removed in vacuo (60.degree. C., 10 to 0.5 kPa) to
yield 137 g (>98% HPLC purity, 90% yield)
3-(p-tolyl)-5-(trifluoromethyl)-1,2,4-oxadiazole.
EXAMPLE 5: PREPARATION OF
N-methyl-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzamide--Solvent
Screening
[0326] 0.1 g (0.517 mmol) N'-hydroxy-4-methyl-benzamidine were
suspended in 5 g solvent. Then, 1.13-1.26 g (0.0566 mol) ca. 10-12%
solution of trifluoroacetyl chloride in Me-THF or ethyl acetate
were added at room temperature and stirred for 1 hour. The table
below shows the HPLC % of
N-methyl-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzamide
following this procedure and in the presence of several different
organic solvents.
TABLE-US-00005 Solvent HPLC % N,N-dimethylformamide 85 NMP 50
Tetrahydro-2-methylfuran 96 Acetonitrile 87 Tetrahydrofurane 92
Methyl tert-butylether 35 Ethyl acetate 85 Me-Imidazolin 99 Acetone
44 Dioxane 73 DME 96 Dichloromethane 41
EXAMPLE 6: PREPARATION OF
N-methyl-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzamide
[0327] 5 g (0.026 mol) N'-hydroxy-4-methyl-benzamidine were
suspended in 20 g (0.232 mol) in Me-THF. 62 g (0.0566 mol) ca. 12%
solution of trifluoroacetyl chloride in Me-THF were added at room
temperature and stirred for 102 hours. After addition of 140 g of a
4% sodium bicarbonate-solution, phases were separated. The organic
phase was washed with water and all volatiles were removed in vacuo
(up to 80.degree. C. and 0.5 kPa) to yield 6.6 g (>98% HPLC
purity, 93% yield)
N-methyl-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzamide.
EXAMPLE 7: PREPARATION OF
N-(2-fluorophenyl)-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzamide
[0328] N-(2-fluorophenyl)-4-[(Z)-N'-hydroxycarbamimidoyl]benzamide
(1000 mg, 3.65 mmol) was suspended in Me-THF (10 mL) and
trifluoroacetyl chloride (12% solution in Me-THF; 1.9 g, 14.63
mmol) was added dropwise at room temperature and stirred for 10
hours at 60.degree. C. The reaction mass was quenched with water
following by adjusting pH to 8 with a 4% sodium bicarbonate
solution. The organic phase was separated, washed with water and
all volatiles were removed in vacuo (up to 80.degree. C. and 0.5
kPa) to yield 955 mg of the title product.
EXAMPLE 8: PREPARATION OF
4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzoic acid
[0329] 4-[(Z)-N'-hydroxycarbamimidoyl]benzoic acid (500 mg, 3 mmol)
was suspended in Me-THF (2 mL) and trifluoroacetyl chloride (12%
solution in Me-THF; 6.2 g, 6 mmol) was added dropwise at room
temperature and stirred for 20 hours. The reaction mass was
quenched with water following by adjusting pH to 8 with a 4% sodium
bicarbonate solution. The organic phase was separated, washed with
water and all volatiles were removed in vacuo (up to 80.degree. C.
and 0.5 kPa) to yield the title product.
EXAMPLE 9: PREPARATION OF
N-methyl-L[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]met-
hanesulfonamide
[0330]
N'-hydroxy-4-[[methyl(methylsulfonyl)amino]methyl]benzamidine (500
mg, 2 mmol) was suspended Me-THF (2 mL) and trifluoroacetyl
chloride (12% solution in Me-THF; 16.2 g, 14.63 mmol) was added
dropwise at room temperature and stirred for 10 hours at 60.degree.
C. The reaction mass was quenched with water following by adjusting
pH to 8 with a 4% sodium bicarbonate solution. The organic phase
was separated, washed with water and all volatiles were removed in
vacuo (up to 80.degree. C. and 0.5 kPa) to yie