Note: Descriptions are shown in the official language in which they were submitted.
CA 02611897 2007-12-11
WO 2006/136461 PCT/EP2006/006531
Non-steroidal progesterone receptor modulators
The present invention relates to non-steroidal progesterone receptor
modulators, to a
process for their preparation, to the use of the progesterone receptor
modulators for
producing medicaments, and to pharmaceutical compositions which comprise these
compounds.
The steroid hormone progesterone controls in a decisive manner the
reproductive
process in the female body. Progesterone is secreted in large quantities
during the
cycle and pregnancy respectively by the ovary and the placenta. Progesterone
in
cooperation with oestrogens brings about cyclic changes in the uterine mucosa
(endometrium) during the menstrual cycle. Elevated progesterone levels after
ovulation
influence the uterine mucosa to convert it into a state permitting nidation of
an embryo
(blastocyst). During pregnancy, progesterone controls the relaxation of the
myometrium
and maintains the function of the decidual tissue.
It is further known that progesterone inhibits endometrial proliferation by
suppressing
oestrogen-mediated mitosis in uterine tissue (K. Chwalisz, R.M. Brenner, U.
Fuhrmann,
H. Hess-Stumpp, W. Elger, Steroids 65, 2000, 741-751).
Progesterone and progesterone receptors are also known to play a significant
part in
pathophysiological processes. Progesterone receptors have been detected in the
foci of
endometriosis, but also in tumours of the uterus, of the breast and of the
CNS. It is
further known that uterine leiomyomas grow progesterone-dependently.
The effects of progesterone in the tissues of the genital organs and in other
tissues
occur through interactions with progesterone receptors which are responsible
for the
cellular effects.
Progesterone receptor modulators are either pure agonists or inhibit the
effect of
progesterone partly or completely. Accordingly, substances are defined as pure
agonists, partial agonists (SPRMs) and pure antagonists.
In accordance with ability of progesterone receptor modulators to influence
the effect of
the progesterone receptor, these compounds have a considerable potential as
CA 02611897 2007-12-11
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therapeutic agents for gynaecological and oncological indications and for
obstetrics and
fertility control.
Pure progesterone receptor antagonists completely inhibit the effect of
progesterone on
the progesterone receptor. They have anti-ovulatory properties and the ability
to inhibit
oestrogen effects in the endometrium, as far as complete atrophy. They are
therefore
particularly suitable for intervening in the female reproductive process, e.g.
post-
ovulation, in order to prevent nidation, during pregnancy in order to increase
the
reactivity of the uterus to prostaglandins or oxytocin, or in order to achieve
opening and
softening ("ripening") of the cervix, and to induce a great readiness of
myometrium to
contract.
A beneficial effect on the pathological event is expected in foci of
endometriosis and in
tumour tissues which are equipped with progesterone receptors after
administration of
pure progesterone receptor antagonists. There might be particular advantages
for
influencing pathological states such as endometriosis or uterine leiomyomas if
ovulation
inhibition can additionally be achieved by the progesterone receptor
antagonists.
Ovulation inhibition also dispenses with some of the ovarian hormone
production and
thus the stimulating effect, deriving from this proportion, on the
pathologically altered
tissue.
The first progesterone receptor antagonist described, RU 486 (also
mifepristone), was
followed by a large number of analogues with progesterone receptor-
antagonistic
activity of varying strength. Whereas RU 486 shows an antiglucocorticoid
effect in
addition to the progesterone receptor-antagonistic effect, compounds
synthesized later
are notable in particular for a more selective effect as progesterone receptor
antagonists.
Besides steroidal compounds such as onapristone or lilopristone, which are
notable by
comparison with RU 486 for a better dissociation of the progesterone receptor-
antagonistic effect and the antiglucocorticoid effect, also known from the
literature are
various non-steroidal structures whose antagonistic effect on the progesterone
receptor
is being investigated [see, for example, S. A. Leonhardt and D. P. Edwards,
Exp. Biol.
Med. 227: 969-980 (2002) and R. Winneker, A. Fensome, J. E. Wrobel, Z. Zhang,
P.
Zhang, Seminars in Reproductive Medicine, Volume 23: 46-57 (2005)]. However,
compounds disclosed to date have only moderate antagonistic activity compared
with
the known steroidal structures. The most effective non-steroidal compounds are
2
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WO 2006/136461 PCT/EP2006/006531
reported to have in vitro activities which are 10% of the activity of RU 486.
The antiglucocorticoid activity is disadvantageous for therapeutic use, where
the
inhibition of progesterone receptors is at the forefront of the therapy. An
antiglucocorticoid activity causes unwanted side effects at the dosages
necessary for
therapy. This may prevent administration of a therapeutically worthwhile dose
or lead to
discontinuation of the treatment.
Partial or complete reduction of the antiglucocorticoid properties is
therefore an
important precondition for therapy with progesterone receptor antagonists,
especially for
those indications requiring treatment lasting weeks or months.
In contrast to the pure antagonists, partial progesterone receptor agonists
(SPRMs)
show a residual agonistic property which may vary in strength. This leads to
these
substances showing potentially agonistic effects on the progesterone receptor
in certain
organ systems (D. DeManno, W. Elger, R. Garg, R. Lee, B. Schneider, H. Hess-
Stumpp, G. Schuber, K. Chwalisz, Steroids 68, 2003, 1019-1032). Such an organ-
specific and dissociated effect may be of therapeutic benefit for the
described
indications.
It is therefore an object of the present invention to provide further non-
steroidal
progesterone receptor modulators. These compounds are intended to have a
reduced
antiglucocorticoid effect and therefore be suitable for the therapy and
prophylaxis of
gynaecological disorders such as endometriosis, leiomyomas of the uterus,
dysfunctional bleeding and dysmenorrhoea. The compounds according to the
invention
are additionally intended to be suitable for the therapy and prophylaxis of
hormone-
dependent tumours, for example of breast, endometrial, ovarian and prostate
carcinomas. The compounds are intended furthermore to be suitable for use in
female
fertility control and for female hormone replacement therapy.
The object is achieved according to the present invention by the provision of
non-
steroidal compounds of the general formula I
R' 2 H R4
A R3 B~N N
O
0
3
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WO 2006/136461 PCT/EP2006/006531
in which
R' and R2 are independently of one another a hydrogen atom, a linear or
nonlinear, branched or unbranched C,-C5-alkyl group, further forming
together with the C atom of the chain a ring having a total of 3-7
members,
R3 is a radical C=C-Ra, where
Ra is a hydrogen or a C,-C8-alkyl, CZ-CB-alkenyl, C2-C8-
alkynyl, C3-C,o-cycloalkyl, heterocycloalkyl optionally
substituted one or more times, identically or differently, by
K, or an aryl or heteroaryl optionally substituted one or
more times, identically or differently by L,
K is a cyano, halogen, hydroxy, nitro, -C(O)Rb,
CO2Rb, -0-R , -S-Rb, SO2NRcRd, -C(O)-NR Rd,
-OC(O)-NR Rd, -C=NORb -NRcRd or C3-C,o-cyclo-
alkyl, heterocycloalkyl optionally substituted one or
more times, identically or differently, by M, or aryl
or heteroaryl optionally substituted one or more
times by L,
L is C,-C8-alkyl, C2-CB-alkenyl, C2-C8-alkynyl, C,-Cs-
perfluoroalkyl, C,-C6-perfluoroalkoxy, C,-C6-alkoxy-
Cl-Cs-alkoxy, (CH2)P C3-Clo-cycloalkyl, (CH2)p
heterocycloalkyl, (CH2)PCN, (CH2)PHal, (CH2)PNO2,
(CHZ)P C6-C12-aryl, (CH2)p heteroaryl,
-(CH2)PP03(Rb)2,
-(CH2)PNR Rd, -(CH2)PNReCORb,
-(CH2)PNReCSRb, -(CH2)PNReS(O)Rb,
-(CH2)PNReS(O)2Rb, -(CH2)PNReCONR Rd,
-(CH2)PNReCOORb, -(CH2)PNReC(NH)NR'Rd,
-(CH2)PNReCSNRcRd, -(CH2)PNReS(O)NR Rd,
-(CH2)PNReS(O)2NR Rd, -(CH2)PCORb,
-(CH2)PCSR , -(CH2)PS(O)Rb,
-(CHZ)PS(O)(NH)Rb, -(CH2)PS(O)2Rb,
-(CH2)PS(O)2NR Rd, -(CHZ)PSO2ORb335 -(CH2)PCOZRb, -(CH2)PCONRcRd,
-(CH2)PCSNR Rd, -(CH2)PORb, -(CH2)PSRb,
4
CA 02611897 2007-12-11
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-(CH2)pCR (OH)-Re, -(CH2)P C=NORb,
-O-(CH2)n-O-, -O-(CH2)n-CH2-, -O-CH=CH- or
-(CH2)n+2-, where n is 1 or 2, and the terminal
oxygen atoms and/or carbon atoms are linked
to directly adjacent ring carbon atoms,
M is C,-C6-alkyl or a group -CORb, CO2Rb, -O-Rb,
or -NR'Rd, where
Rb is a hydrogen or a C,-C6-alkyl, C2-C8-
alkenyl, C2-C8-alkynyl, C3-C,o-
cycloalkyl, C6-C12-aryl or C,-C3-
perfluoroalkyl and
Rc and Rd are independently of one another a
hydrogen, C,-C6-alkyl, C2-C8-alkenyl,
C2-C8-alkynyl, C3-C,o-cycloalkyl,
C6-C12-aryl, C(O)Rb or a hydroxy
group, where if
Rc is a hydroxy group, then Rd can only
be a hydrogen, a C,-Cs-alkyl, C2-Ce-
alkenyl, C2-C8-alkynyl, C3-C,o-
cycloalkyl or C6-C12-aryl and vice
versa, and
Re is a hydrogen, C,-C6-alkyl, C2-C8-
alkenyl, C2-C$-alkynyl, C3-C,o-cyclo-
alkyl or C6-C12-aryl, and
p can be a number from 0-6,
or
R3 is a radical C=C-R9Rh, where
R9 and Rh are independently of one another a hydrogen or a
C,-CB-alkyl, C2-C8-alkenyl or CZ-CB-alkynyl
optionally substituted one or more times, identically
or differently, by X, in which
X is a cyano, halogen, hydroxy, nitro,
-C(O)Rb, CO2Rb, -0-R , -C(O)-NR Rd,
-NR Rd with the meanings already
5
CA 02611897 2007-12-11
WO 2006/136461 PCT/EP2006/006531
mentioned before for Rb, Rc and Rd, and
R4 is a hydrogen atom, a methyl or an ethyl group or a partly or
completely fluorinated C,-C3 alkyl group,
A is a mono- or bicyclic carbocyclic or heterocyclic aromatic ring which
may optionally be substituted one or more times by C,-Cg-alkyl, C2-CB-
alkenyl, C2-C8-alkynyl, C,-Cs-perfluoroalkyl, C,-Cs-perfluoroalkoxy,
C,-C6-alkoxy-C,-C6-alkyl, C,-C6-alkoxy-C,-C6-alkoxy, (CH2)P C3-C,o-
cycloalkyl, (CH2)P heterocycloalkyl, (CHZ)PCN, (CH2)pHal, (CH2)PNO2,
(CH2)p C6-C12-aryl, (CH2)p heteroaryl,
-(CH2)PPO3(Rb)2, -(CH2)pNR Rd, -(CH2)pNReCORb, -(CH2)PNReCSRb,
-(CH2)PNReS(O)Rb, -(CH2)PNReS(O)2Rb, -(CH2)PNReCONRcRd,
-(CHZ)PNReCOORb, -(CH2)PNReC(NH)NR Rd, -(CH2)PNReCSNR Rd,
-(CHZ)pNReS(O)NRcRd, -(CH2)pNReS(O)2NR Rd, -(CH2)pCORb,
-(CH2)pCSRb, -(CH2)P S(O)Rb, -(CH2)PS(O)(NH)Rb, -(CH2)pS(0)2Rb
-(CH2)pS(O)2NR Rd, -(CH2)PSO2ORb, -(CH2)PCOZRb, -(CH2)pCONR Rd,
-(CH2)PCSNR Rd, -(CH2)PORb, -(CH2)pSRb, -(CH2)PCR (OH)-Rd,
-(CHZ)p C=NORb, -O-(CH2)n-O-, -O-(CH2)n-CH2-, -O-CH=CH- or
-(CH2)n+2-, where n is 1 or 2, and the terminal oxygen atoms and/or
carbon atoms are linked to directly adjacent ring carbon atoms, or
A is a radical -CO2Rb, C(O)NR Rd, CORb,
or
A is an alkenyl group -CR5=CR6R7, where
R , R are identical or different and are independently of
56 and R'
one another hydrogen atoms, halogen atoms, aryl
radicals or an unsubstituted or partly or completely
fluorinated C,-CS alkyl group, or
A is an alkynyl group -C=CR5, with the meaning stated above for R5, and
B is a carbonyl or a CH2 group,
and their pharmaceutically acceptable salts.
6
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WO 2006/136461 PCT/EP2006/006531
The compounds according to the invention of the general formula I may, owing
to the
presence of centres of asymmetry, exist as different stereoisomers. Both the
racemates
and the separate stereoisomers belong to the subject matter of the present
invention.
.5 The present invention further includes the novel compounds as active
pharmaceutical
ingredients, the preparation thereof, their therapeutic use and pharmaceutical
dosage
forms which comprise the novel substances.
The compounds according to the invention of the general formula (I) or their
pharmaceutically acceptable salts can be used to produce a medicament, in
particular
for the treatment and prophylaxis of gynaecological disorders such as
endometriosis,
leiomyomas of the uterus, dysfunctional bleeding and dysmenorrhoea. The
compounds
according to the invention may further be used for the treatment and
prophylaxis of
hormone-dependent tumours such as, for example, for breast, prostate and
endometrial
carcinoma.
The compounds according to the invention of the general formula (I) or their
pharmaceutically acceptable salts are suitable for use for female fertility
control or for
female hormone replacement therapy.
The present invention additionally relates to a process for preparing the
compounds of
the general formula (I). The substituent R3 is introduced by selective
addition reaction of
organometallic compounds such as lithium alkynyls or magnesium haloalkynyls
onto a
keto group. This leads either directly or after carrying out further
modificiations to the
compounds according to the invention of the general formula (I).
4
R 2 H R3-Li or R3-MgHal R~ R2 H H Ra
~y~
=N N \x~/!~ , N k
A B O A R3 g N
O
O O
The compounds according to the invention are prepared by selective addition of
organometallic compounds onto keto amides which have been described for
example in
the published specifications US 2002/0077356, US 6,323,199B1, WO 200375915 and
WO 9854159. The organometallic compounds may be for example lithium alkynyl or
magnesium haloalkynyl compounds. These are generated for example by reacting
the
appropriate alkynes with butyllithium or Grignard compounds. The corresponding
7
CA 02611897 2007-12-11
WO 2006/136461 PCT/EP2006/006531
organometallic alkenyl compounds can also be prepared in analogy thereto. The
reactivity of the keto groups is in this case distinctly higher by comparison
with the
amide carbonyl and with the benzoxazinone, so that a selective addition is
achieved on
suitable choice of the reaction conditions. Alternatively, the alkynyl or
alkenyl radicals
introduced as R3 can also be further modified later. Reactions suitable for
these
modifications are those known to the skilled person, such as oxidation,
reduction,
substitution, alkylation, palladium-catalysed reaction. Any protective groups
present are
eliminated at a suitable time.
The non-steroidal compounds according to the invention of the general formula
I have
strong antagonistic or strong partial agonistic effects on the progesterone
receptor.
They show a strong dissociation of effects in relation to their strength of
binding to the
progesterone receptor and to the glucocorticoid receptor. Whereas known
progesterone
receptor antagonists such as mifepristone (RU 486) show, besides the desired
high
binding affinity for the progesterone receptor, likewise a high affinity for
the
glucocorticoid receptor, the compounds according to the invention are notable
for a very
low glucocorticoid receptor binding with simultaneously a high progesterone
receptor
affinity.
The substituents, defined as groups, of the compounds according to the
invention of the
general formula I may in each case have the following meanings:
C1-C5-, C1-C6- and C,-C$-alkyl group means linear or nonlinear, branched or
unbranched alkyl radicals. Examples thereof are a methyl, ethyl, n-propyl,
isopropyl, n-,
iso-, tert-butyl, an n-pentyl, 2,2-dimethylpropyl, 3-methylbutyl, hexyl,
heptyl or octyl
group.
Preferred in the meaning of Ra in this connection are the methyl, ethyl, n-
propyl or
n-butyl group and an n-pentyl group.
Preferred in the meaning of R' and R2 are methyl or ethyl.
Alkenyl means linear or nonlinear, branched or unbranched alkenyl radicals.
Examples
of the meaning of a CZ-CB-alkenyl group in the context of the invention are
the following:
vinyl, allyl, 3-buten-1-yl or 2,3-dimethyl-2-propenyl. If the aromatic system
A is
substituted by a C2-C8-alkenyl radical, it is preferably a vinyl group.
Alkynyl means linear or nonlinear, branched or unbranched alkynyl radicals. A
C2-CB-
8
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WO 2006/136461 PCT/EP2006/006531
alkynyl radical is intended to be for example an ethynyl, propynyl, butynyl,
pentynyl,
hexynyl and octynyl group, preferably an ethynyl or propynyl group.
Examples which may be mentioned of C3-C,o-cycloalkyl are cyclopropyl,
cyclobutyl,
cyclopentyl and cyclohexyl. Cyclopropyl, cyclopentyl and cyclohexyl are
preferred.
Heterocycloalkyl in the meaning of Ra, K and L means 3-8-membered
heterocycloalkyl
radicals. Examples of heterocycloalkyl are morpholinyl, tetrahydrofuranyl,
pyranyl,
piperazinyl, piperidinyl, pyrrolidinyl, oxiranyl, oxetanyl, aziridinyl,
dioxolanyl and
dioxanyl. In this connection, the position of the heteroatom in relation to
the point of
linkage can be any chemically possible position.
Possible examples of C,-C6-alkoxyl-C,-C6-alkoxy group are methoxymethoxy,
ethoxymethoxy or 2-methoxyethoxy.
A radical ORb in the context of the invention, is a hydroxy, methoxy, ethoxy,
n-propoxy,
isopropoxy, n-, iso-, tert-butoxy or n-pentoxy, 2,2-dimethylpropoxy or 3-
methylbutoxy
group. Hydroxy, methoxy and ethoxy are preferred.
Suitable for a partly or completely fluorinated C,-C5-alkyl group are the
perfluorinated
alkyl groups above. Of these, preference is given in particular to the
trifluoromethyl or
pentafluoroethyl group and, partly fluorinated alkyl groups, for example the
5,5,5,4,4-
pentafluoropentyl or 5,5,5,4,4,3,3-heptafluoropentyl group.
A halogen atom may be a fluorine, chlorine, bromine or iodine atom. Fluorine,
chlorine
or bromine is preferred here.
If R' and R2 form together with the C atom of the chain a 3-7 membered ring,
this is for
example a cyclopropyl, -butyl, -pentyl or -hexyl ring. The cyclopropyl and the
cyclopentyl
ring are preferred.
The mono- or bicyclic carbocyclic aromatic ring A, which may be substituted
more than
once, is a carbocyclic or heterocyclic aryl radical.
In the former case it is for example a phenyl or naphthyl radical, preferably
a phenyl
radical.
It is possible to use as heterocyclic radical for example a monocyclic
heterocyclic
9
CA 02611897 2007-12-11
WO 2006/136461 PCT/EP2006/006531
radical, for example the thienyl, furyl, pyranyl, pyrrolyl, imidazolyl,
pyrazolyl, pyridyl,
pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, oxazolyl, furazanyl,
pyrrolinyl, imidazolinyl,
pyrazolinyl, thiazolinyl, triazolyl, tetrazolyl radical, in particular all the
possible isomers in
relation to the positions of the heteroatoms.
R3 means in the case of an aryl radical an optionally substituted phenyl, 1-
or 2-naphthyl
radical, with preference for the phenyl radical. Examples of a heteroaryl
radical are the
2-, 3- or 4-pyridinyl, the 2- or 3-furyl, the 2- or 3-thienyl, the 2- or 3-
pyrrolyl, the 2-, 4- or
5-imidazolyl, the pyrazinyl, the 2-, 4- or 5-pyrimidinyl or 3- or 4-
pyridazinyl radical.
The number p for a(CH2)P radical may be a number from 0 to 6, preferably 0 to
2.
"Radical" means according to the invention all functional groups stated in
connection
with (CH2)P.
In the case where the compounds of the general formula I (B = -CH2-) are in
the form of
salts, this is possible for example in the form of the hydrochloride,
sulphate, nitrate,
tartrate, citrate, fumarate, succinate or benzoate.
If the compounds according to the invention are in the form of racemic
mixtures, they
can be fractionated by methods of racemate resolution familiar to the skilled
person into
the pure optically active forms. For example, the racemic mixtures can be
separated
into the pure isomers by chromatography on a support material which is itself
optically
active (CHIRALPAK AD ). It is also possible to esterify the free hydroxy group
in a
racemic compound of the general formula I with an optically active acid, and
to separate
the resulting diastereoisomeric esters by fractional crystallization or
chromatography
and to hydrolyse the separated esters in each case to the optically pure
isomers. It is
possible to use as optically active acid for example mandelic acid,
camphorsulphonic
acid or tartaric acid.
The compounds specified below, and the use thereof, are preferred according to
the
invention:
CA 02611897 2007-12-11
WO 2006/136461 PCT/EP2006/006531
No. Racemic or R3
enantiomer
I rac R' OH
2 - /~ /-0
3 + d H
0 N "
4 rac
+ o ~ 0
6 - 0
7 rac /-,
8 +
9 -
rac
11 +
12
13 rac
14 +
- r~
16 rac rF17 + ~
18 - -~~
19 rac
+ //\~,
21 -
22 rac
23 +
24 - ~
rac
26 +
27
28 rac F,
29 + ~
31 rac
32 +
33 - '
34 rac
+
36 - ~ '
37 rac
38 +
39 - -~
rac %N
+
41
42 - ~
43 rac
44 +
46 rac
NO,
47 +
48 - -~
11
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WO 2006/136461 PCT/EP2006/006531
49 rac OH
50 1+
51 -
No. Racemic or R3
enantiomer R' OH
52 rac
ci
53 - /~ N
54 + .~ ~ - N
55 rac o o
56 + F 0
57 -
58 rac
H
59 +
60 -
61 rac ~
62 +
63 - -~~
64 rac
65 +
66 - /'
67 rac CF,
68 +
69 -
70 rac
71 +
72
73 rac 0
74 +
75 - r%
76 rac
77 +
78 - -~'
79 rac
80 +
81 -
82 rac
83 +
84
85 rac
86 +
87
88 rac
89 +
90 - -~'
91 rac
92 +
93
94 rac
95 +
96 - -~
12
CA 02611897 2007-12-11
WO 2006/136461 PCT/EP2006/006531
97 rac Ng
98 +
99 - '~
100 rac H
191 +
102 - ~
103 rac "
104 +
105 -
No. Racemic or R3
enantiomer R' OH
106 rac
107 - /~ N
108 + N
109 rac o o
110 + 0
111 -
112 rac -,
113 +
114 -
115 rac ~
116 + ~ I
117
118 rac
119 +
120 - r ~
121 rac cf122 + ~
123
124 rac
125 +
126 - -~
127 rac
128 +
129 - -~~
130 rac ~
131 +
132
133 rac CF>
134 +
135
136 rac \ N
137 +
138 -
139 rac
140 + ~
141
142 rac
143 +
144 - -~
13
CA 02611897 2007-12-11
WO 2006/136461 PCT/EP2006/006531
145 rac N
146 + -
147
148 rac
149 + ~-
150 - -~~
151 rac
152 + 153
153 -
154 rac
155 +
156 - -'~ \
157 rac CF
158 +
159 - -~ ~
160 rac
161 + ~
162 - "~
163 rac
164 + f/\
165 -
166 rac , oN
167 + .
168 - ''
No. Racemic or R3
enantiomer R OH
169 rac
170 - /~ N
171 + N
172 rac o o
173 + o
174 -
175 rac
176 +
177 -
178 rac
179 +
180 -
181 rac
182 +
183 - ''
184 rac
185 + CF
186
187 rac i
188 +
189
190 rac 0
191 +
192 - -~
14
CA 02611897 2007-12-11
WO 2006/136461 PCT/EP2006/006531
193 rac
194 +
195 - 196 rac
197 +
198
199 rac
200 +
201 - -~
202 rac
203 +
204
205 rac
206 +
207 - -~
208 rac N
209 +
210
211 rac
212 +
213
214 rac No,
215 + .~
216 - ''
217 rac
218 +
219
220 rac CF
221 +
222 - -~
223 rac
224 +
225 - -~ lo
226 rac
227 +
228
229 rac oõ
230 + -
231 - ''
No. Racemic or R3 R' oH
enantiomer
232 rac H CF3
233 - ~ N 'N
234 + o o
235 rac o
236 +
237 - /
238 rac
239 + "
240 - /
CA 02611897 2007-12-11
WO 2006/136461 PCT/EP2006/006531
241 rac
242 +
-
243
244 rac
245 +
246 - -~
247 rac
248 + 'F'
249
250 rac
251 +
252 - ,-o '
253 rac 0
254 +
255
256 rac
257 +
258
259 rac
260 +
261 - -'
262 rac õ
263 +
264
265 rac
266 +
267
268 rac oll
269 +
270 - '~
271 rac
"
272 +
273
274 rac
275 +
276 - -'~
277 rac
278 + "O'
279 - -~
280 rac
281 +
282
283 rac CF,
284 + .
285 -
286 rac
287 +
288 -
289 rac
290 + /~
291 -
16
CA 02611897 2007-12-11
WO 2006/136461 PCT/EP2006/006531
292 rac O,
293 +
294
No. Racemic or R3 R3 OH
enantiomer H
295 rac N ~ N
296 o ~~ o
297 +
298 rac F o
299 +
300 -
301 rac
302 + "
303 - ~
304 rac
305 +
306 -
307 rac
308 +
309 - ''
310 rac
311 +
312
313 rac i
314 +
315
316 rac 0
317 +
317
319 rac
320 +
321 - -~~
322 rac ~
323 + '
324
325 rac
326 +
327
328 rac
329 +
330
331 rac a
332
333 - ''
334 rac N
335 +
336 - -~
337 rac
338 +
339 - -~'
17
CA 02611897 2007-12-11
WO 2006/136461 PCT/EP2006/006531
340 rac
341 + NO'
342 - -~
343 rac
344 +
- -~o
345
346 rac
347 +
348 - "~
349 rac ~
350 + ~ ~ -
351 - ''
352 rac
353 + ri
354 -
355 rac OH
356 +
357 -
No. Racemic or R3
enantiomer R3
358 rac OH
359 - // N
360 + N
361 rac ~ o ~ o
362 + 51~ o
363 -
364 rac
365 +
366 -
367 rac
368 +
369 - -~
370 rac
371 +
372 - -~'
373 rac U,
374 +
375 - ~
376 rac
377 + _
378 -
379 rac o
380 +
381
382 rac
383 +
384 - -~
385 rac
386 +
387
18
CA 02611897 2007-12-11
WO 2006/136461 PCT/EP2006/006531
388 rac V
389 +
390
391 rac 0
392 +
393
394 rac
395 + ' '~
396
397 rac N
398 +
399 - ~'
400 rac
401 +
402
403 rac No,
404 +
405 - -''
406 rac
407 +
408
409 rac CF4410 +
411 - -''
412 rac
413 +
414 - l
415 rac
416 +
417 - -' ~
418 rac OH
419 +
420 -
No. Racemic or R3
enantiomer
421 rac R3
422 - OH
423 + "
424 rac " r,
425 + o o
426 - 0
427 rac
428 + "
429 - '~
430 rac
431 +
432 - -~'
433 rac
434 + I
435 - .~
19
CA 02611897 2007-12-11
WO 2006/136461 PCT/EP2006/006531
436 rac CF,
437 +
438 - -~'
439 rac
440 +
441 - '
442 rac
443 +
444
445 rac
446 +
447 - -~
448 rac ~
449 +
450
451 rac
452 +
453 - ~
454 rac
455 + oz
456 -
457 rac
458 + .
459 - -~'
460 rac N
461 +
462 - '~
463 rac ~
464 +
465
466 rac
467 + NO,
468
469 rac
470 + - ~
471
472 rac F,
473 +
474 - -''
475 rac
476 +
477 - -''
478 rac
479 +
480 -
481 rac "
482 +
483 -
CA 02611897 2007-12-11
WO 2006/136461 PCT/EP2006/006531
No. Racemic or R3
enantiomer R' OH
484 rac
485 H
486 + N 'N
487 rac o o
488 F 0
489 - f
490 rac
491 +
492 -
493 rac
494 +
495 - -~
496 rac
497 +
498
499 rac CF500 + - ~
501
502 rac
503 +
504
505 rac
506 +
507 - -'
508 rac
509 +
510
511 rac CF>
512 +
513
514 rac
515 + ~
516
517 rac
518 +
519 -
520 rac
521 +
522 - -~'
523 rac N
524 + . ~
525 - ''
526 rac
527 +
528
529 rac NO,
530 +
531 - '~
532 rac
533 +
534
21
CA 02611897 2007-12-11
WO 2006/136461 PCT/EP2006/006531
535 rac
536 +
537 - ''
538 rac
539 +
540 - -~'
541 rac
542 +
543 - -~ i
544 rac aõ
545 +
546 - '~
No. Racemic or R3
enantiomer R3 OH
547 rac
548_ - // H
549 + d C F N N
550 rac o o
551 + o
552 - f
553 rac õ
554 +
555 -
556 rac
557 +
558 - '~
559 rac
560 +
561 - ''
562 rac
563 + CF
564
565 rac
566 + N
567
568 rac 0
569 +
570 - -~'
571 rac
572 +
573 - %
574 rac F.
575 +
576 - %
577 rac \ N
578 + '
579
580 rac
581 + ~~i
582 - '
22
CA 02611897 2007-12-11
WO 2006/136461 PCT/EP2006/006531
583 rac
584 +
585 - -'
586 rac
587 +
588 - 589 rac
590 +
591
592 rac No,
593 +
594 -
595 rac
596 +
597 -
598 rac
599 + c~
600 - r %
601 rac
602 + ' i
603
604 rac
605 +
606 - -~
607 rac OH
608 +
609 -
No. Racemic or R3
enantiomer
610 rac R3 OH
611
612 + N
613 rac
614 + F o o
o
615 - CF3
616 rac
617 + "
618 - f
619 rac
620 +
621
622 rac
623 +
624
625 rac CF
626 + ~
627 .~ ~
628 rac
629 +
630 - -~ ~
23
CA 02611897 2007-12-11
WO 2006/136461 PCT/EP2006/006531
631 rac
632 +
633
634 rac
635 +
636
637 rac
638 +
639 - -~'
640 rac
641 +
642
643 rac
644 +
645 - --~
646 rac
647 + ll
648
649 rac N
650 +
651 - -''
652 rac
653 + ~
654 - %
655 rac
656 + "
657
658 rac
659 +
660 -
661 rac
CF,
662 +
663 - -~
664 rac
665 +
666 -
667 rac
668 + ri
669 -
670 rac H
671 +
672 -
No. Racemic or R3
enantiomer R'
673 rac oH
674 - /~ F H
675 + N
676 rac O o
0
677 + CF 3
678 -
24
CA 02611897 2007-12-11
WO 2006/136461 PCT/EP2006/006531
679 rac H
680 + .~ ~
681 -
682 rac
683 +
684
685 rac
686 +
687
688 rac CF689 + - ~
690 - -~
691 rac
692 +
693
694 rac o
695 +
696 - -~
697 rac
698 +
699 - '
700 rac
701 +
702
703 rac \N/
704 +
705 - -~~
706 rac
707 +
708 - ~ '
709 rac
710 + oll
711
712 rac
713 +
714 - -'~
715 rac
716 +
717
718 rac "o,
719 + .
720 - ''
721 rac
722 +
723
724 rac ~,
725 +
726 - -~
727 rac
728 +
729
CA 02611897 2007-12-11
WO 2006/136461 PCT/EP2006/006531
730 rac
731 +
732 - -~
733 rac
734 +
735 - -~~
No. Racemic or R3
enantiomer R' H
736 rac
737 - /~ N
738 + ~ ~ N
739 rac o ~ o
740 + 0
741 - ~
742 rac H
743 +
744 -
745 rac
746 +
747 -
748 rac
749 +
750 - f
751 rac
752 + CF'
753
754 rac
755 +
756
757 rac 0
758 +
759
760 rac
761 +
762 - %
763 rac F
764 +
765 - -~'
766 rac
767 +
768
769 rac
770 +
771
772 rac oll
773 +
774 - '~
775 rac
776 + /N
777
26
CA 02611897 2007-12-11
WO 2006/136461 PCT/EP2006/006531
778 rac
779 +
780 - -~
781 rac
782 + "0'
783 - -~~
784 rac
785 +
786
787 rac CF. ,
788 +
789 -
790 rac
791 + .~
792 -
793 rac
794 +
795 - -~
796 rac O,
797 +
798 - -~~
No. Racemic or R3 ,
enantiomer R OH
799 rac -o
H
800 N N
801 + /~ \ \ \
f I / O / O
802 rac ci
803 + o
804 -
805 rac
806 +
807 -
808 rac
809 +
810 - % ~
811 rac ~
812 +
813 - ''
814 rac ~,
815 +
816 -
817 rac
818 + "
819 820 rac
821 +
822 - '~
823 rac
824 +
825
27
CA 02611897 2007-12-11
WO 2006/136461 PCT/EP2006/006531
826 rac
827 +
828
829 rac N,
830 +
831 - 832 rac
833 +
834
835 rac o'~
836 +
837 - ''
838 rac N
839 +
840 - -~
841 rac
842 +
843 - -~'
844 rac
No,
845 +
846 -
847 rac
848 +
849 - -~~
850 rac
851 + CF 852
853 rac
854 +
855
856 rac
857 +
858 - -~
859 rac
om
860 + /.~
861 - f
No. Racemic or R3
enantiomer R' OH
862 rac
863 - H
864 + N N
865 rac
866 + f~ F 0
867 -
868 rac
869 + H
870 -
871 rac
872 +
873
28
CA 02611897 2007-12-11
WO 2006/136461 PCT/EP2006/006531
874 rac
875 +
876 - -~'
877 rac
878 +
879 - r
880 rac
881 +
882
883 rac 0
884 +
885
886 rac
887 +
888 - -~
889 rac ',
890 +
891
892 rac
893 +
894 - ~
895 rac
896 +
897
898 rac o,
899 +
900 - "~
901 rac
902 +
903 - -~
904 rac
905 +
906 -
907 rac
NO,
908 +
909 -
910 rac
911 +
912 -
913 rac CF
914 +
915 - -~~
916 rac
917 +
918 - "~
919 rac
920 +
921 - -~ ~
922 rac OH
923 +
924 - ~
29
CA 02611897 2007-12-11
WO 2006/136461 PCT/EP2006/006531
No. Racemic or R3 R OH
enantiomer 0 H
925 rac N N
926 o
927 +
928 rac F 0
929 +
930 -
931 rac
H
932 +
933 -
934 rac
935 +
936
937 rac
938 +
939 - -~'
940 rac CF,
941 +
942 - ~
943 rac
944 +
945
946 rac
947 +
948
949 rac
950 +
951 - -~
952 rac 953 +
954
955 rac V
956 +
957
958 rac
959 +
960 -
961 rac
962 +
963 - '~
964 rac
965 +
966 - -~
967 rac
968 +
969 - ~
970 rac
NO
971 +
972 -
CA 02611897 2007-12-11
WO 2006/136461 PCT/EP2006/006531
973 rac
974 +
975 -
976 rac
CF977 +
978 - -~
979 rac
980 + ~
981 -
982 rac
983 +
984 -
985 rac 986 +
987 -
No. Racemic or R3 ,
enantiomer R OH
988 rac ar H
989 N N
990 +
991 rac
992 + f/ F o
993 -
994 rac
995 +
996 -
997 rac
998 +
999
1000 rac
1001 +
1002 - -~'
1003 rac CF,
1004 +
1005
1006 rac
1007 + N'
1008
1009 rac o
1010 +
1011
1012 rac
1013 +
1014 - -~'
1015 rac
1016 +
1017 - -~~
1018 rac
1019 +
1020
31
CA 02611897 2007-12-11
WO 2006/136461 PCT/EP2006/006531
1021 rac
1022 +
1023 - .-%
1024 rac o',
1025 +
1026 - "~
1027. rac N
1028 +
1029 - -~'
1030 rac
1031 +
1032 - 1033 rac
No
1034 +
1035 -
1036 rac
1037 +
1038 - -''
1039 rac
1040 +
1041 - -~~
1042 rac
1043 +
1044 -
1045 rac
1046 +
1047 -
1048 rac OH
1049 +
1050
No. Racemic or R3
enantiomer R3
1051 rac OH
1052 - /~ H
1053 + .~ ~ N N
1054 rac 0 o
1055 + -.5 ~, cF ' o
1056 -
1057 rac
1058 +
1059 -
1060 rac
1061 +
1062
1063 rac
1064 +
1065 - -~'
1066 rac CF1
1067 +
1068 - ~'
32
CA 02611897 2007-12-11
WO 2006/136461 PCT/EP2006/006531
1069 rac
1070 +
1071
1072 rac o
1073 +
1074
1075 rac
1076 +
1077 - -~'
1078 rac
1079 +
1080
1081 rac N
1082 +
1083
1084 rac 0
1085 +
1086
1087 rac
1088 +
1089 - "~
1090 rac N
1091
1092 - -~'
1093 rac
1094 +
1095 - -~'
1096 rac
1097 +
1098 -
1099 rac
1100 +
1101 - -''
1102 rac CF,
1103 +
1104 - -~~
1105 rac
1106 + ~
1107 - '~
1108 rac
1109 + ri
1110 -
1111 rac OH
1112 +
1113 - ~'
33
CA 02611897 2007-12-11
WO 2006/136461 PCT/EP2006/006531
No. Racemic or R3
enantiomer R,
1114 rac OH
1115 - / cF3 H
1116 + " "
1117 r a c o o
1118 + F 0
1119 -
1120 rac
H
1121 +
1122
1123 rac
1124 +
1125 - '~
1126 rac ~
1127 + ~I
1128 - -~~
1129 rac CF3
1130 +
1131 - ~
1132 rac õ'
1133 +
1134 -
1135 rac O
1136 +
1137
1138 rac
1139 +
1140 - -~
1141 rac F,
1142 +
1143 - -~
1144 rac \N/
1145 +
1146
1147 rac o
1148 +
1149
1150 rac o
1151 +
1152 - "~
1153 rac N
1154 +
1155 - -~~
1156 rac
1157 +
1158 - '
1159 rac
NO
1160 +
1161 -
1162 rac
1163 +
1164 - -~'
34
CA 02611897 2007-12-11
WO 2006/136461 PCT/EP2006/006531
1165 rac CF11166 +
1167 - -~
1168 rac
1169 +
1170 -
1171 rac
1172 + ri
1173 -
1174 rac 1175 +
1176 -
No. Racemic or R3
enantiomer R3
1177 rac OH
1178 - / CF3 H
1179 + N N
1180 rac o o
1181 + o
1182 -
1183 rac
1184 +
1185 -
1186 rac
1187 +
1188 - ~
1189 rac
1190 +
1191 - -~
1192 rac CF,
1193 +
1194 - -'
1195 rac
1196 + "_
1197
1198 rac 0
1199 +
1200
1202 rac
1202 +
1203 - -~'
1204 rac
1205 +
1206
1207 rac N~
1208 +
1209
1210 rac
1211 +
1212
CA 02611897 2007-12-11
WO 2006/136461 PCT/EP2006/006531
1213 rac O~,
1214 + -
1215 - '
1216 rac N
1217 +
1218 - -~~
1219 rac
1220 +
1221 - '
1222 rac
NO
1223 + a'
1224 -
1225 rac
1226 +
1227 - -'
1228 rac ~
1229 +
1230
1231 rac
1232 +
1233 -
1234 rac
1235 + r i
1236 -
1237 rac OH
1238 +
1239 -
No. Racemic or R3
enantiomer R3
1240 rac OH
1241 - / CF3 H
1242 + N N
1243 rac o o
1244 + F
f~ o
1245 -
1246 rac
1247 + "
1248 -
1249 rac
1250 +
1251
1252 rac
1253 +
1254 - -~
1255 rac CF3
1256 +
1257 - ~ ~
1258 rac
1259 + // N-
1260 - '
36
CA 02611897 2007-12-11
WO 2006/136461 PCT/EP2006/006531
1261 rac
1262 +
1263
1264 rac
1265 +
1266 - -~~
1267 rac "1268 +
1269 - -~
1270 rac
1271 +
1272
1273 rac
1274 +
1275
1276 rac O~
1277 +
1278 - '~
1279 rac N
1280 +
1281 -~
1282 rac
1283 +
1284
1285 rac
NO
1286 +
1287 -
1288 rac
1289 + / ~
1290 -
1291 rac CF
1292 + ~ i
1293 - -~
1294 rac
1295 +
1296 -
1297 rac
1298 +
1299 - / ~
1300 rac
1301
1302 - -~'
No. Racemic or R3
enantiomer R3
1303 rac OH
1304 - / ci H
1305 + 4NLN
1306 rac o o
1307 + 151::~ F 0
1308 -
37
CA 02611897 2007-12-11
WO 2006/136461 PCT/EP2006/006531
1309 rac
1310 +
1311 -
1312 rac
1313 +
1314
1315 rac
1316 +
1317 - -~'
1318 rac CF3
1319 + ~ -
1320 - ~
1321 rac
1322 +
1323
1324 rac
1325 +
1326
1327 rac
1328 +
1329 - -~
1330 rac '~
1331 +
1332 - -~~
1333 rac õ/
1334 +
1335
1336 rac
1337 + -
1338 - % 1339 rac O~
1340 +
1341 - "~
1342 rac
1343 +
1344 - -~
1345 rac
1346 +
1347 -
1348 rac
NO
1349 +
1350 -
1351 rac
1352 +
1353 - ''
1354 rac CF
1355 +
1356 - -~
1357 rac
1358 +
1359 -
38
CA 02611897 2007-12-11
WO 2006/136461 PCT/EP2006/006531
1360 rac
1361 + ri
1362 -
1362 rac OH
1364 +
1365 - ''
No. Racemic or R3
enantiomer R3
1366 rac OH
1367 - /~ F H
1368 + f ~ 4NLN
~ 1369 rac o ~ ~ o
1370 + F 0
1371 -
1372 rac
1373 +
1374 -
1375 rac
1376 +
1377 - 1378 rac
1379 +
1380 - -~
1381 rac CF,
1382 +
1383 - ~
1384 rac
1385 +
1386
1387 rac o
1388 +
1389
1390 rac
1391 +
1392 - -~'
1393 rac ",
1394 +
1395
1396 rac
1397 +
1398
1399 rac 1400 +
1401
1402 rac o',
1403 +
1404 - f
1405 rac N
1406 +
1407 - -~'
39
CA 02611897 2007-12-11
WO 2006/136461 PCT/EP2006/006531
1408 rac
1409 +
1410 - 1411 rac No
1412 +
1413 -
1414 rac
1415 +
1416 -
1417 rac CF,
1418 +
1419 -
1420 rac
1421 +
1422 -
1423 rac
1424 +
1425 - -~
1426 rac
OH
1427 +
1428 -
No. Racemic or R3
enantiomer R 3
1429 rac OH
1430 cF3 H
1431 + N N
1432 rac 0 o
1433 + 0
1434 -
1435 rac
1436 +
1437 -
1438 rac
1439 +
1440
1441 rac
1442 +
1443 - -~ ~
1444 rac CF,
1445 +
1446 -
1447 rac
1448 + -
1449 -
1450 rac o
1451
1452
1453 rac
1454 +
1455 - -~~
CA 02611897 2007-12-11
WO 2006/136461 PCT/EP2006/006531
1456 rac 1457 +
1458 - -~
1459 rac
1460 +
1461
1462 rac
1463 +
1464
1465 rac o',
1466 +
1467 - '
1468 rac N
1469 +
1470 - -~
1471 rac
1472 +
1473 - 1474 rac
1475 + f/ ~No,
1476 -
1477 rac
1478 +
1479 - '~
1480 rac CF
1481 +
1482 - -~
1483 rac
1484 +
1485 -
1486 rac
1487 +
1488 -
1489 rac OH
1490 +
1491 -
No. Racemic or R3
enantiomer R3
1492 rac OH
1493 - / ci H
1494 + 54NLN
1495 rac o o
1496 + o
1497 -
1498 rac
1499 +
1500 -
1501 rac
1502 +
1503
41
CA 02611897 2007-12-11
WO 2006/136461 PCT/EP2006/006531
1504 rac
1505 +
1506 - -~'
1507 rac CF,
1508 +
1509 - ~
1510 rac
1511 +
1512
1513 rac
1514 +
1515
1516 rac
1517 +
1518 - -~'
1519 rac ,
1520 +
1521
1522 rac õ
1523 +
1524
1525 rac
1526 +
1527
1528 rac o'~
1529 +
1530 - '
1531 rac "
1532 +
1533 - -~'
1534 rac
1535 + ~ i
1536 -
1537 rac "o
1538 +
1539 -
1540 rac
1541 +
1542 - -''
1543 rac CF,
1544 +
1545 -~
1546 rac
1547 +
1548 - "~
1549 rac
1550 +
1551 - ~~
1552 rac "
1553 +
1554 -
42
CA 02611897 2007-12-11
WO 2006/136461 PCT/EP2006/006531
No. Racemic or R3 R' OH
enantiomer oder ci
Enantiomer "
1555 rac N "
1556 - ~ o o
1557 + o
1558 rac
1559 +
1560 -
1561 rac
1562 +
1563 -
1564 rac
1565 +
1566 - 1567 rac
1568 +
1569 - -~
1570 rac CF,
1571 +
1572 - ''
1573 rac
1574 + "\
1575
1576 rac 0
1577 +
1578
1579 rac
1580 +
1581 - -~~
1582 rac ',
1583 +
1584 - -~
1585 rac
1586 +
1587
1588 rac
1589 +
1590
1591 rac
1592 +
1593 - '~
1594 rac
1595 +
1596 - -~
1597 rac
1598 +
1599 - -~
1600 rac
"O
1601 + flo
1602 -
43
CA 02611897 2007-12-11
WO 2006/136461 PCT/EP2006/006531
1603 rac
1604 +
1605 - -''
1606 rac ~
1607 +
1608
1609. rac
1610 +
1611 - ~
1612 rac
1613 +
1614 - ''
1615 rac O,
1616 +
1617 - -~'
No. Racemic or R3
enantiomer R3
1618 rac OH
1619 - / cF3 H
1620 + f/ \ N N
1621 rac o o
1622 + F 0
1623 -
1624 rac
1625 +
1626 -
1627 rac
1628 +
1629
1630 rac
1631 +
1632 - -~ ~
1633 rac CF,
1634 +
1635 - ~'
1636 rac
1637 + /~ ~ \
1638 -
1639 rac 0
1640 +
1641
1642 rac
1643 +
1644 - -~'
1645 rac CF
1646 +
1647 - .~
1648 rac
1649 +
1650 - .-~
44
CA 02611897 2007-12-11
WO 2006/136461 PCT/EP2006/006531
1651 rac
1652 +
1653
1654 rac o
1655 +
1656 - "~
1657 rac N
1658 +
1659 - -~
1660 rac
1661 +
1662 - 1663 rac õo
1664 + ~
1665 -
1666 rac
1667 +
1668 -
1669 rac
1670 +
1671 - -~~
1672 rac
1673 +
1674 -
1675 rac
1676 + r j
1677 -
1678 rac OH
1679 +
1680 -
No. Racemic or R3
enantiomer
1681 rac R3 OH
1682 -
1683 + ~ r"v ~
1684 rac o
1685 + o I~ f~ I
1686 -
1687 rac
1688 +
1689 -
1690 rac
1691 +
1692
1693 rac
1694 +
1695 - -~'
1696 rac
1697 + ~ I
1698 - ~'
CA 02611897 2007-12-11
WO 2006/136461 PCT/EP2006/006531
1699 rac
1700 + -
1701 - % '
1702 rac ~
1703 + ' i
1704
1705 rac
1706 +
1707 - -~'
1708 rac 1709 +
1710 - -~~
1711 rac
1712 +
1713
1714 rac 1715 +
1716
1717 rac
1718 +
1719 - '
1720 rac N
1721 +
1722 - -~'
1723 rac
1724 +
1725 - 1726 rac
NO
1727 +
1728 -
1729 rac
1730 +
1731 - ''
1732 rac
CF1733 +
1734 - -~~
1735 rac
1736 +
1737 -
1738 rac
1739 + ri
1740 -
1741 rac OH
1742 +
1743 - "~
46
CA 02611897 2007-12-11
WO 2006/136461 PCT/EP2006/006531
No. Racemic or R3
enantiomer R,
1744 rac ~ 1745 - 1746 + 1747 rac JJ>OH
0 o
1748 +
1749 -
1750 rac
1751 +
1752 -
1753 rac
1754 +
1755 - '
1756 rac
1757 +
1758 - -~'
1759 rac CF,
1760 +
1761 - -~
1762 rac
1763 +
1764 - '
1765 rac o
1766 +
1767
1768 rac
1769 +
1770 - -~'
1771 rac CF,
1772 +
1773
1774 rac \ N
1775 +
1776 - ",-6
1777 rac o
1778 +
1779
1780 rac
1781 +
1782 - '
1783 rac "
1784 +
1785 - -~
1786 rac
1787 +
1788 - ~ '
1789 rac
1790 + "~
1791 -
1792 rac
1793 +
1794 - -''
47
CA 02611897 2007-12-11
WO 2006/136461 PCT/EP2006/006531
1795 rac
1796 +
1797
1798 rac
1799 + ~
1800 -
1801 rac
1802 +
1803
1804 rac
1805 +
1806 - -''
1807 rac
1808 +
1809 -
1810 rac
1811 +
1812 - f
No. Racemic or R3
enantiomer R3
1813 rac OH
1814 o H
1815 + N N
1816 rac o o
1817 + o
1818 -
1819 rac
1820 +
1821 -
1822 rac
1823 +
1824 - ''
1825 rac
1826 +
1827
1828 rac CF
1829 +
1830 - ~'
1831 rac
1832 +
1833
1834 rac
1835 +
1836
1837 rac
1838 +
1839 - -~'
1840 rac ' ,
1841 +
1842
48
CA 02611897 2007-12-11
WO 2006/136461 PCT/EP2006/006531
1843 rac
1844 +
1845
1846 rac
1847 + -
1848 - % ~ ~
1849 rac o
1850 +
1851 - '
1852 rac N
1853 +
1854 - -~
1855 rac
1856 +
1857 - 1858 rac No
1859 + ,~ 2
1860 -
1861 rac
1862 +
1863 -
1864 rac CF
1865 +
1866
1867 rac , i
1868 +
1869 -
1870 rac
1871 + / i
1872 -
1873 rac aõ
1874 + .
1875 - ''
No. Racemic or R3
enantiomer R3
1876 rac OH
1877 - / CI H
1878 + N \ N
1879 rac o o
1880 + 0
1881 -
1882 rac
1883 + f/H
1884 -
1885 rac
1886 + ~ I
1887
1888 rac
1889 +
1890 - -~
49
CA 02611897 2007-12-11
WO 2006/136461 PCT/EP2006/006531
1891 rac Cf,
1892 + -
1893 - ~
1894 rac
1895 +
1896
1897 rac
1898 +
1899
1900 rac
1901 +
1902 - -~
1903 rac 1904 +
1905 - -~
1906 rac õ
1907 +
1908
1909 rac
1910 + ~
1911 - %
1912 rac o',
1913 +
1914 - '
1915 rac N
1916 +
1917 - -~~
1918 rac
1919 +
1920
1921 rac
NO
1922 +
1923 -
1924 rac
1925 +
1926 -
1927 rac CF
1928 +
1929 - -~
1930 rac ,
1931 +
1932 -
1933 rac
1934 + ~
1935 - ''
1936 rac "
1937 +
1938 -
CA 02611897 2007-12-11
WO 2006/136461 PCT/EP2006/006531
No. Racemic or R3
enantiomer R3
1939 rac o"
1940 - /~ o o H
1941 + d ~ N N
1942 rac
1943 + o
1944 -
1945 rac
1946 + f/H
1947 -
1948 rac
1949 +
1950 - ~
1951 rac
1952 +
1953 - -~
1954 rac CF
1955 +
1956 - ~
1957 rac
1958 +
1959
1960 rac 0
1961 +
1962
1963 rac
1964 +
1965 - -~
1966 rac "
1967 +
1968 - -~
1969 rac V
1970 +
1971
1972 rac 0
1973 +
1974
1975 rac o',
1976 +
1977 - "'
1978 rac "
1979 +
1980 - -~'
1981 rac
1982 +
1983 - '
1984 rac
1985 + "~
1986 -
1987 rac i
1988 +
1989 - -~'
51
CA 02611897 2007-12-11
WO 2006/136461 PCT/EP2006/006531
1990 rac CF
1991 +
1992 - -~ 1993 rac
1994 +
1995 - '~
1996 rac
1997 + /~
1998 -
1999 rac
2000 +
2001 - "~
No. Racemic or R3
enantiomer R3
2002 rac OH
2003 - / ci H
2004 + d \ N N
2005 rac o o
2006 + 0
2007 -
2008 rac
2009 +
2010 -
2011 rac
2012 +
2013 - '~
2014 rac
2015 +
2016 - -~
2017 rac rF,
2018 +
2019 - ~
2020 rac
2021 +
2022 - -~~
2023 rac o
2024 +
2025
2026 rac
2027 +
2028 - -~'
2029 rac "2030 +
2031
2032 rac õ
2033 +
2034 - ~
2035 rac
2036 +
2037 % z
52
CA 02611897 2007-12-11
WO 2006/136461 PCT/EP2006/006531
2038 rac O',
2039 +
2040 - "'
2041 rac N
2042 +
2043 - -~'
2044 rac
2045 +
2046 - 2047 rac
NO
2048 + /~ ~
2049 -
2050 rac
2051 +
2052 - '
2053 rac CF
2054 +
2055 - -~ ~
2056 rac , i
2057 + ~
2058 -
2059 rac
2060 + r
2061 -
2062 rac OH
2063 +
2064 -
No. Racemic or R3
enantiomer R3
2065 rac OH
2066 - / ci H
2067 + N N
2068 rac o o
2069 + o
2070 -
2071 rac
2072 + f /H
2073 -
2074 rac
2075 +
2076
2077 rac
2078 +
2079 - /
2080 rac CF,
2081 +
2082 - ~'
2083 rac
2084 +
2085
53
CA 02611897 2007-12-11
WO 2006/136461 PCT/EP2006/006531
2086 rac 0
2087 +
2088
2089 rac
2090 +
2091 - -'~
2092 rac
2093 +
2094 - -~
2095 rac
2096 +
2097
2098 rac
2099 +
2100
2101 rac
2102 +
2103 - '~
2104 rac
2105 +
2106 - -~
2107 rac
2108 +
2109 - -'~
2110 rac
No,
2111 +
2112 -
2113 rac
2114 +
2115 -
2116 rac CF
2117 +
2118 - -~~
2119 rac
2120 +
2121 -
2122 rac
2123 +
2124 -
2125 rac oõ
2126 +
2127 - ''
No. Racemic or R3
enantiomer R3
2128 rac o"
2129 - / ci H
2130 + N ~N
2131 rac o o
2132 + o
2133 -
54
CA 02611897 2007-12-11
WO 2006/136461 PCT/EP2006/006531
2134 rac
H
2135 +
2136 -
2137 rac
2138 +
2139
2140 rac
2141 +
2142 - -~
2143 rac U,
2144 +
2145 - ~'
2146 rac
2147 +
2148
2149 rac o
2150 +
2151
2152 rac
2153 +
2154 - -~'
2155 rac
2156 +
2157
2158 rac õ
2159 +
2160
2161 rac
2163 +
2163
2164 rac a,~
2165 +
2166 - "'
2167 rac
2168 +
2169 - -~'
2170 rac
2171 +
2172 - '
2173 rac
2174 +
2175 -
2176 rac
2177 + / ~i
2178 -
2179 rac
CF,
2180 +
2181
2182 rac ,
2183 + ~~
2184 - "~
CA 02611897 2007-12-11
WO 2006/136461 PCT/EP2006/006531
2185 rac
2186 + ri
2187 -
2188 rac OH
2189 +
2190 -
No. Racemic or R3
enantiomer R3
2191 rac OH
2192 - / CFa H
2193 + N ~ ~N
2194 rac o ~ ~ o
2195 + F 0
2196 -
2197 rac
H
2198 +
2199 -
2200 rac
2201 +
2202
2203 rac
2204 +
2205 - -~
2206 rac CF3
2207 +
2208 - -~
2209 rac
2210 + N'
2211
2212 rac o
2213 +
2214
2215 rac
2216 +
2217 - -~~
2218 rac 'F,
2219 +
2220 - -~~
2221 rac
2222 +
2223
2224 rac
2225 +
2226
2227 rac o'~
2228 +
2229 - '
2230 rac N
2231 +
2232 - -~~
56
CA 02611897 2007-12-11
WO 2006/136461 PCT/EP2006/006531
2233 rac
2234 +
2235 - '
2236 rac
No,
2237 +
2238 -
2239 rac
2240 +
2241 - -~'
2242 rac CF,
2243 +
2244 - -~
2245 rac
2246 +
2247 -
2248 rac
2249 +
2250 -
2251 rac OH
2252 +
2253 -
No. Racemic or R3
enantiomer R3
2254 rac o"
2255 - /~ c H
2256 + ! \ N ' N
2257 rac o o
2258 + o
2259 -
2260 rac
2261 +
2262 -
2263 rac
2264 +
2265 -
2266 rac
2267 +
2268 - -~'
2269 rac CF,
2270 +
2271 - ~'
2272 rac
2273 +
2274
2273 rac o
2276 +
2277
2278 rac
2279 +
2280 - -~'
57
CA 02611897 2007-12-11
WO 2006/136461 PCT/EP2006/006531
2281 rac F3I
2282 +
2283 - -~~
2284 rac
2285 +
2286 -
2287 rac
2288 +
2289 -
2290 rac o'~
2291 +
2292 -
2293 rac N
2294 +
2295 - -~'
2296 rac
2297 +
2298 - -~~
2299 rac
2300 +
2301 -
2302 rac
2303 +
2304
2305 rac ~
2306 +
2307 - -~
2308 rac
2309 +
2310 - "~
2311 rac
2312 +
2313 -
2314 rac OH
2315 +
2316 -
No. Racemic or R3
enantiomer R3
2317 rac OH
2318 - /~ H
2319 + r ~ " C
'" 2320 rac o o
2321 + o
2322 -
2323 rac
2324 + "
2325 -
2326 rac
2327 + .
2328 -
58
CA 02611897 2007-12-11
WO 2006/136461 PCT/EP2006/006531
2329 rac
2330 +
2331 - -~'
2332 rac 'F
2333 + r
2334 -
2335 rac
2336 + "
2337 \
2338 rac
2339 +
2340
2341 rac
2342 +
2343 - -'~
2344 rac F
2345 +
2346
2347 rac V
2348 +
2349
2350 rac
2351 +
2652
2353 rac o,
2354 +
2355 -
2356 rac "
2357 +
2358 - -~~
2359 rac
2360 +
2361 -
2362 rac
"O,
2363 +
2364 -
2365 rac
2366 +
2367 -
2368 rac CF
2369 +
2370 - -~~
2371 rac
2372 +
2373 -
2374 rac
2375 +
2376 - -~ ~
2377 rac OH
2378 +
2379 - '~
59
CA 02611897 2007-12-11
WO 2006/136461 PCT/EP2006/006531
No. Racemic or R3
enantiomer R,
2380 rac OH
2381 - /~ o H
2382 + d \ N N
2383 rac o o
2384 + o
2385 -
2386 rac
2387 + f/H
2388 -
2389 rac
2390 +
2391 - '
2392 rac
2393 +
2394 - -~'
2395 rac
2396 +
2397 - -'
2398 rac
2399 + "'
2400 - '
2401 rac O
2402 +
2403
2404 rac
2405 +
2406 - '
2407 rac
2408 +
2409
2410 rac \ N.
2411 +
2412
2413 rac 0
2414 + -
2415
2416 rac O',
2417 +
2418 - '
2419 rac
2420 +
2421 - -~
2422 rac
2423 +
2424 - ~ '
2425 rac
NO
2426 + ~_
2427 -
2428 rac
2429 +
2430 - -''
CA 02611897 2007-12-11
WO 2006/136461 PCT/EP2006/006531
2431 rac Cf,
2432 +
2433
2434 rac , i
2435 +
2436 -
2437 rac
2438 + r i
2439 -
2440 rac aõ
2441 +
2442 - '~
No. Racemic or Structure
enantiomer
2443 rac
2444
2445 +
2446 rac
2447 +
2448 -
2449 rac
2450 +
2451 - ~t
2452 rac
2453 +
2454 -
2455 rac
2456 +
2457 -
2458 rac
2459 +
2460 - b
2461 rac
2462 +
2463 -
2464 rac
2465 +
2466 -
2467 rac
2468 +
2469 -
2470 rac
2471 +
2472 -
2473 rac
2474 +
2475 - 61
CA 02611897 2007-12-11
WO 2006/136461 PCT/EP2006/006531
2476 rac
2477 +
2478
62
CA 02611897 2007-12-11
WO 2006/136461 PCT/EP2006/006531
Biological characterization of the compounds according to the invention
Progesterone receptor modulators can be identified with the aid of simple
methods, test
programmes known to the skilled person. It is possible for this purpose for
example to
incubate a compound to be tested together with a progestogen in a test system
for
progesterone receptors and to check whether the effect mediated by
progesterone is
altered in the presence of the modulator in this test system.
The substances according to the invention of the general formula I were tested
in the
following models:
Progesterone receptor-binding assay
Measurement of the receptor binding affinity:
The receptor binding affinity was determined by competitive binding of a
specifically
binding 3H-labelled hormone (tracer) and of the compound to be tested on
receptors in
the cytosol from animal target organs. The aim in this case was receptor
saturation and
reaction equilibrium.
The tracer and increasing concentrations of the compound to be tested
(competitor)
were coincubated at 0-4 C for 18 h with the receptor-containing cytosol
fraction. After
removal of unbound tracer with carbon-dextran suspension, the receptor-bound
tracer
content was measured for each concentration, and the IC50 was determined from
the
concentration series. The relative molar binding affinity (RBA) was calculated
as ratio of
the IC50 values for reference substance and compound to be tested (x 100%)
(RBA of
the reference substance = 100%).
The following incubation conditions were chosen for the receptor types:
Progesterone receptor:
Uterus cytosol of the estradiol-primed rabbit, homogenized in TED buffer
(20 mMTris/HCI, pH 7.4; 1 mM ethylenediaminetetraacetate, 2 mM dithiothreitol)
with
250 mM sucrose; stored at -30 C. Tracer: 3H-ORG 2058, 5 nM; reference
substance:
progesterone.
Glucocorticoid receptor:
Thymus cytosol from the adrenalectomized rat, thymi stored at -30 C; buffer:
TED.
Tracer: 3H-dexamethasone, 20 nM; reference substance: dexamethasone.
63
CA 02611897 2007-12-11
WO 2006/136461 PCT/EP2006/006531
The relative receptor binding affinities (RBA values) for the compounds
according to the
invention of the general formula (I) on the progesterone receptor are between
3 and
100% relative to progesterone. The RBA values at the glucocorticoid receptor
are in the
range from 3 to 30% relative to dexamethasone.
The compounds according to the invention accordingly have a high affinity for
the
progesterone receptor, but only a low affinity for the glucocorticoid
receptor.
Antagonism at the PR-B progesterone receptor
The transactivation assay is carried out as described in WO 02/054064.
Agonism on the PR-B progesterone receptor
The transactivation assay is carried out as described in Fuhrmann et al.
(Fuhrmann U.,
Hess-Stump H., Cleve A., Neef G., Schwede W., Hoffmann J., Fritzemeier K.-H.,
Chwalisz K., Journal of Medicinal Chem, 43, 26, 2000, 5010-5016).
No. Antagonistic Activity Agonistic Acticity
IC50 [nM] Efficacy [%] EC50 [nM] Efficacy [%]
5 0,2 86 0,2 10
14 6 53 7 35
16 0,7 82 0,5 13
17b 0,03 88 n. b. 7
18 0,2 89 n. b. 8
24 2 100 0
35 2 100 0
Dosage
The progesterone receptor modulators can be administered orally, enterally,
parenterally or transdermally for the use according to the invention.
Satisfactory results are generally to be expected in the treatment of the
indications
mentioned hereinbefore when the daily doses cover a range from 1 g to 500 mg
of the
compound according to the invention.
Suitable dosages of the compounds according to the invention in humans for the
treatment of endometriosis, of leiomyomas of the uterus and dysfunctional
bleeding and
for use in fertility control and for hormone replacement therapy are from 50
pg to
64
CA 02611897 2007-12-11
WO 2006/136461 PCT/EP2006/006531
500 mg per day, depending on the age and constitution of the patient, it being
possible
to administer the necessary daily dose by single or multiple administration.
The dosage range for the compounds according to the invention for the
treatment of
breast carcinomas is 10 mg to 1000 mg per day.
The pharmaceutical products based on the novel compounds are formulated in a
manner known per se by processing the active ingredient with the carrier
substances,
fillers, substances influencing disintegration, binders, humectants,
lubricants,
absorbents, diluents, masking flavours, colorants, etc. which are used in
pharmaceutical
technology, and converting into the desired administration form. Reference
should be
made in this connection to Remington's Pharmaceutical Sciences, 15th ed. Mack
Publishing Company, Easton, Pennsylvania (1980).
Suitable for oral administration are in particular tablets, film-coated
tablets, sugar-coated
tablets, capsules, pills, powders, granules, pastilles, suspensions, emulsions
or
solutions.
Preparations for injection and infusion are possible for parenteral
administration.
Appropriately prepared crystal suspensions can be used for intraarticular
injection.
Aqueous and oily solutions for injection or suspensions and corresponding
depot
preparations can be used for intramuscular injection.
For rectal administration, the novel compounds can be used in the form of
suppositories, capsules, solutions (e.g. in the form of enemas) and ointments,
both for
systemic and for local therapy.
Furthermore, compositions for vaginal use may also be mentioned as
preparation.
For pulmonary administration of the novel compounds, they can be used in the
form of
aerosols and inhalants.
Patches are possible for transdermal administration, and formulations in gels,
ointments, fatty ointments, creams, pastes, dusting powders, milk and
tinctures are
possible for topical application. The dosage of the compounds of the general
formula I
CA 02611897 2007-12-11
WO 2006/136461 PCT/EP2006/006531
in these preparations should be 0:01 %- 20% in order to achieve an adequate
pharmacological effect.
Corresponding tablets can be obtained for example by mixing active ingredient
with
known excipients, for example inert diluents such as dextrose, sugar,
sorbitol, mannitol,
polyvinylpyrrolidone, disintegrants such as maize starch or alginic acid,
binders such as
starch or gelatin, lubricants such as magnesium stearate or talc and/or means
to
achieve a depot effect such as carboxypolymethylene, carboxymethylcellulose,
cellulose acetate phthalate or polyvinyl acetate. The tablets may also consist
of a
plurality of layers.
Correspondingly, coated tablets can be produced by coating cores produced in
analogy
to the tablets with compositions normally used in tablet coatings, for example
polyvinylpyrrolidone or shellac, gum arabic, talc, titanium oxide or sugar.
The tablet
covering may in this case also consist of a plurality of layers, it being
possible to use the
excipients mentioned above for tablets.
Solutions or suspensions of the compounds according to the invention of the
general
formula I may additionally comprise taste-improving agents such as saccharin,
cyclamate or sugar, and, for example, flavourings such as vanillin or orange
extract.
They may additionally comprise suspending excipients such as sodium
carboxymethylcellulose or preservatives such as p-hydroxybenzoates.
Capsules comprising the compounds of the general formula I can be produced for
example by mixing the compound(s) of the general formula I with an inert
carrier such
as lactose or sorbitol and encapsulating it in gelatin capsules.
Suitable suppositories can be produced for example by mixing with carriers
intended for
this purpose, such as neutral fats or polyethylene glycol or derivatives.
The compounds according to the invention of the general formula (I) or their
pharmaceutically acceptable salts can be used, because of their antagonistic
or partial
agonistic activity, for producing a medicament, in particular for the
treatment and
prophylaxis of gynaecological disorders such as endometriosis, leiomyomas of
the
uterus, dysfunctional bleeding and dysmenorrhoea. They can furthermore be
employed
to counteract hormonal irregularities, for inducing menstruation and alone or
in
66
CA 02611897 2007-12-11
WO 2006/136461 PCT/EP2006/006531
combination with prostaglandins and/or oxytocin to-induce labour.
The compounds according to the invention of the general formula (I) or their
pharmaceutically acceptable salts are furthermore suitable for producing
products for
female contraception (see also WO 93/23020, WO 93/21927).
The compounds according to the invention or their pharmaceutically acceptable
salts
can additionally be employed alone or in combination with a selective estrogen
receptor
modulator (SERM) for female hormone replacement therapy.
In addition, the said compounds have an antiproliferative effect in hormone-
dependent
tumours. They are therefore suitable for the therapy of hormone-dependent
carcinomas
such as, for example, for breast, prostate and endometrial carcinomas.
The compounds according to the invention or their pharmaceutically acceptable
salts
can be employed for the treatment of hormone-dependent carcinomas both in
first-line
therapy and in second-line therapy, especially after tamoxifen failure.
The compounds according to the invention, having antagonistic or partially
agonistic
activity, of the general formula (I) or their pharmaceutically acceptable
salts can also be
used in combination with compounds having antiestrogenic activity (estrogen
receptor
antagonists or aromatase inhibitors) or selective estrogen receptor modulators
(SERM)
for producing pharmaceutical products for the treatment of hormone-dependent
tumours. The compounds according to the invention can likewise be used in
combination with SERMs or an antiestrogen (estrogen receptor antagonist or
aromatase inhibitor) for the treatment of endometriosis or of leiomyomas of
the uterus.
In the treatment of hormone-dependent tumours the progesterone receptor
modulator
and the antiestrogen (estrogen receptor antagonists or aromatase inhibitors)
or the
SERM can be provided for simultaneous or else for sequential administration.
In the
sequential administration, preferably the antiestrogen (estrogen receptor
antagonists or
aromatase inhibitors) or SERM is administered first and subsequently the
progesterone
receptor modulator is administered.
Suitable for combination with the non-steroidal progesterone receptor
modulators
according to the invention in this connection are for example the following
antiestrogens
(estrogen receptor antagonists or aromatase inhibitors) or SERMs:
tamoxifen, 5-(4-{5-((RS)-(4,4,5,5,5-
pentafluoropentyl)sulphinyl]pentyloxy}phenyl)-6-
67
CA 02611897 2007-12-11
WO 2006/136461 PCT/EP2006/006531
phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol (WO 00/03979), ICI 182 780 (7alpha-
[9-
(4,4,5,5-pentafluoropentylsulphinyl)nonyl]estra-1,3,5(10)-triene-3,17beta-
diol), 11 beta-
fluoro-7alpha-[5-(methyl{3-[(4,4,5,5,5-
pentafluoropentyl)sulphanyl]propyl}amino)pentyl]-
estra-1,3,5(10)-triene- 3,17beta-diol (W098/07740), 11 beta-fluoro-7alpha-(5-
[methyl(7,7,8,8,9,9,10,10,10-nonafluorodecyl)amino]pentyl}estra-1,3,5(10)-
triene-3,17-
beta-diol (WO 99/33855), 11 beta-fluoro-17alpha-methyl-7alpha-{5-
[methyl(8,8,9,9,9-
pentafluorononyl)amino]pentyl}estra-1,3,5(10)-triene-3,17beta-diol (WO
03/045972),
clomifen, raloxifen, and further compounds having antiestrogenic activity, and
aromatase inhibitors such as, for example, fadrozole, formestane, letrozole,
anastrozole
or atamestane.
Finally, the present invention also relates to the use of the compounds of the
general
formula I, where appropriate together with an antiestrogen or SERM, for
producing a
medicament.
The present invention further relates to pharmaceutical compositions which
comprise at
least one compound according to the invention, where appropriate in the form
of a
pharmaceutically/pharmacologically acceptable salt, without or together with
pharmaceutically acceptable excipients and/or carriers.
These pharmaceutical compositions and medicaments may be intended for oral,
rectal,
vaginal, subcutaneous, percutaneous, intravenous or intramuscular
administration.
Besides conventional carriers and/or diluents, they comprise at least one
compound
according to the invention.
The medicaments of the invention are produced with the conventional solid or
liquid
carriers or diluents and the excipients normally used in pharmaceutical
technology
appropriate for the desired mode of administration with a suitable dosage in a
known
manner. The preferred preparations consist of a dosage suitable for oral
administration.
Examples of such dosage forms are tablets, film-coated tablets, sugar-coated
tablets,
capsules, pills, powders, solutions or suspensions or else depot forms.
The pharmaceutical compositions comprising at least one of the compounds
according
to the invention are preferably administered orally.
Also suitable are parenteral preparations such as solutions for injection.
Further
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preparations which may also be mentioned are for example suppositories and
compositions for vaginal use.
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The following examples serve to illustrate the subject-matter of the invention
in more
detail without wishing to restrict it thereto.
Preparation of the starting compounds 6-[4-(2-chloro-5-fluorophenyl)-4-methyl-
2-
oxovaleroylamino]-4-methyl-2,3-benzoxazin-1 -one, 6-[4-(2-chloro-4-
fluorophenyl)-4-
methyl-2-oxovaleroylamino]-4-methyl-2,3-benzoxazin-1-one and 6-{3-[1-(2-chloro-
phenyl)cyclopentyl]-2-oxopropionylamino}-4-methyl-2,3-benzoxazin-1-one has
been
described in the patent US 2002/0077356, the compound 6-[4-(2,3-dihydro-7-
benzofuranyl)-4-methyl-2-oxopentanoylamino]-4-methyl-2,3-benzoxazinone in US
patent 6,323,199B1 (example 87 therein), the compound 6-(4-methyl-4-phenyl-2-
oxovaleroylamino)-4-methyl-2,3-benzoxazin-1-one in the patent WO 199854159 and
the compound 6-[3-[1-(2-fluoro-5-trifluoromethylphenyl)cyclopropyl]-2-
oxopropionyl-
amino]-4-methyl-2,3-benzoxazin-1-one in the patent WO 200375915.
General methods
1-(Benzo(1, 3]dioxol-4-yl)-1-methylethanol
57.2 ml of methyl magnesium chloride solution (3M in THF) were added to 25.5 g
of
4-acetylbenzo[1,3]dioxole in 375 ml of THF at RT under argon. The mixture was
stirred
at RT for 16 h and added to ice/2N hydrochloric acid. It was then extracted
with ethyl
acetate, and the organic phase was washed with water and brine and dried
(Na2SO4).
27.89 g of 1-[benzo(1,3)dioxol-4-yl]-1-methylethanol were obtained as a brown
oil.
'H-NMR (CDCI3, ppm) = 1.6 (s, 6H), 5.95 (s, 2H), 6.76 (dd, 1H), 6.82 (t, 1H),
6.91 (dd,
1 H)
4-(Benzo[1,3]dioxol-4-yl)-4-methyl-2-oxopentanoic acid
47 ml of tin(IV) chloride were added to 9.5 g of 1-(benzo[1,3]dioxol-4-yl)-1-
methylethanol and 14.2 g of ethyl 2-trimethylsilyloxyacrylate in 200 ml of
dichloromethane at -70 C. After 15 minutes, the solution was added to
potassium
carbonate solution. After extraction with diethyl ether, the organic phase was
washed
with water, dried and evaporated.
14.4 g of the ethyl 4-(benzo[1,3]dioxol-4-yl)-4-methyl-2-oxopentanoate
obtained in this
way were stirred with 150 ml of 1 M sodium hydroxide and 300 *ml of methanol
at RT for
10 hours. The methanol was then removed in vacuo, and the remaining solution
was
extracted with diethyl ether. The aqueous phase was acidified with 1 M
hydrochloric
acid and extracted with diethyl ether. Drying and evaporation resulted in 11.1
g of
CA 02611897 2007-12-11
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4-(benzo[1,3]dioxol-4-yl)-4-methyl-2-oxopentanoic acid as yellowish oil.
MS (ei) m/e: M+ = 251
6-(4-(Benzo[1, 3]dioxol-4-yl)-4-methyl-2-oxovaleroylamino]-4-methyl-2, 3-
benzoxazin-l-
one
g of 4-(benzo[1,3]dioxol-4-yl)-4-methyl-2-oxopentanoic acid were dissolved in
125 ml
of dimethylacetamide and, at -0 C under argon, 3.5 ml of thionyl chloride were
added.
After stirring at -3 to +3 C for 20 minutes, 7.6 g of 6-amino-4-methyl-2,3-
benzoxazin-l-
one (WO 00/32584) were added. The mixture was stirred at room temperature for
10 96 hours and, after addition of water, extracted with ethyl acetate, the
organic phase
was washed with water and dried (Na2SO4), and evaporation of the solvent and
chromatography of the crude product on silica gel with hexane/ethyl acetate
(100:0 ->
60:40) resulted in 6.56 g of 6-[4-(benzo[1,3]dioxol-4-yl)-4-methyl-2-
oxovaleroylamino]-4-
methyl-2,3-benzoxazin-1-one as a beige solid.
m.p. = 165-166 C, MS (ei) m/e: M+ = 409
Synthesis examples
(-)-6-{2-[2-(2,3-(Methylenedioxy)phenyl)-2-methylpropyl]-2-hydroxyoct-3-ynoyl}-
4-
methyl-2,3-benzoxazin-l-one 1 and (+)-6-{2-[2-(2,3-(methylenedioxy)phenyl)-2-
methylpropyl]-2-hydroxyoct-3-ynoyl}-4-methyl-2,3-benzoxazin-1-one 2
l-O O H II OH
I
N ~ \ N 0 O N
O I / O C N
O
O
O
O
nBuLi (0.7 ml, 1.6M in hexane) was added to a solution of 1-hexyne (0.5 ml) in
THF
(4 ml) at -78 C. The mixture was stirred at -78 C for 20 min, 6-[4-
(benzo[1,3]dioxol-4-
yl)-4-methyl-2-oxovaleroylamino]-4-methyl-2,3-benzoxazin-1-one (192 mg) was
added,
and the mixture was stirred at -78 C for 4 h. Water was then added and the
mixture was
allowed to reach room temp. Extraction with ethyl acetate, washing with
saturated
sodium chloride solution, drying over sodium sulphate and purification by
column
chromatography on silica gel resulted in 82 mg of a white foam which was then
converted by preparative chiral HPLC (Chiralpak AD 250 x 10 mm, eluent:
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acetonitrile/water 55/45 v/v, flow rate 4.7 mI/min, temperature 40 C,
retention times:
12.2 min (+)-enantiomer, 15.7 min (-)-enantiomer) into the compounds (-)-6-{2-
[2-(2,3-
(methylenedioxy) phenyl)-2-methylpropyl]-2-hydroxyoct-3-ynoyl}-4-methyl-2, 3-
benzoxazin-l-one (Example 1) and (+)-6-{2-[2-(2,3-(methylenedioxy)phenyl)-2-
methylpropyl]-2-hydroxyoct-3-ynoyl}-4-methyl-2,3-benzoxazin-1-one (Example 2).
1H-NMR (ppm, CDCI3i 400 MHz): 0.91 (t, J = 7.2 Hz, 3H, CH3), 1.32 - 1.49 (m,
4H),
1.55 (s, 3H), 1.58 (s, 3H), 2.17 (t, J = 7.2 Hz, 2H), 2.56 (s, 3H, CH3), 2.59
(d, J = 14.4
Hz, 1 H), 2.74 (d, J = 14.8 Hz, 1 H), 2.80 (s, 1 H, OH), 5.94 - 5.96 (m, 2H),
6.46 - 6.49
(m, 1 H), 6.64 (t, J = 7.8 Hz, 1 H), 7.47 - 7.49 (m, 1 H), 8.25 - 8.28 (m, 1
H), 8.76 (s, 1 H,
NH). C28H3oN206 (490.6):
rac-6-{2-[2-(2-Chloro-5-fluorophenyl)-2-methylpropyl]-2,7-dihydroxyhept-3-
ynoyl}-
4-methyl-2,3-benzoxazin-l-one 3
OH
cl I I
H
N N
OHO I / O
F
Stage A: Reaction of 5-(tert-butyidimethylsilyloxy)pent-1-yne (531 mg), nBuLi
(0.7 ml,
1.6 M in hexane) and 6-[4-(2-chloro-5-fluorophenyl)-4-methyl-2-
oxovaleroylamino]-4-
methyl-2,3-benzoxazin-l-one (207 mg) at -78 C as described for Example 1 gave,
after
column chromatography on silica gel, a colouriess oil (86 mg).
Stage B: The resulting oil was stirred in THF (3 ml) at room temp. under argon
(3 h).
Addition of water, extraction with ethyl acetate and washing with saturated
brine were
followed by drying with sodium sulphate. Purification by column chromatography
on
silica gel led to the title compound as a white foam (43 mg).
1 H-NMR (ppm, CDCI3, 400 MHz): 1.58 (s, 3H, Me), 1.59 (s, 3H, Me), 1.71 - 1.74
(m,
2H, CH2), 2.2 - 2.3 (m, 2H), 2.56 (s, 3H, CH3), 2.75 (d, J = 15.2 Hz, 1 H,
CH), 2.92 (d, J
= 14.8 Hz, 1 H, CH), 3.26 (s, 1 H, OH), 3.74 - 3.78 (m, 2H), 6.67 - 6.78 (m, 1
H), 7.09 -
7.19 (m, 2H), 7.66 - 7.69 (m, 2H), 8.20 - 8.21 (m, 1 H), 8.27 - 8.29 (m, 1 H),
8.99 (s, 1 H,
NH). C26H26CIFN205 (501.0): LC-MS: m/z = 501 [M + H+].
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rac-6-{2-[2-(2-Chloro-5-fluorophenyl)-2-methylpropyl]-2-hydroxyoct-3-ynoyl}-4-
methyl-2,3-benzoxazin-1-one 4
ci HO
~~ N
O I / O
F O
Reaction of 1-hexyne (0.6 ml), nBuLi (0.7 ml, 1.6 M in hexane) and 6-[4-(2-
chloro-5-
fluorophenyl)-4-methyl-2-oxovaleroylamino]-4-methyl-2,3-benzoxazin-1-one (207
mg) at
-78 C as described for Example 1 gave, after column chromatography on silica
gel and
preparative thin-layer chromatography a viscous oil (12 mg).
1 H-NMR (ppm, CDCI3r 400 MHz): 0.90 (t, J = 7.2 Hz, 3H, Me), 1.32 - 1.47 (m,
4H), 1.57
(s, 3H, Me), 1.62 (s, 3H, Me), 2.13 (t, J = 7.2 Hz, CH2C=C), 2.56 (s, 3H, Me),
2.81 -
2.95 (m, 3H), 6.68 - 6.71 (m, 1 H), 7.11 - 7.17 (m, 2H), 7.56 - 7.58 (m, 1 H),
8.21 (d, J =
2.0 Hz, 1 H), 8.29 (d, J = 12.6 Hz, 1 H), 8.73 (br. s., 1H, NH). C27H28CIFN204
(499.0): LC-
MS: m/z = 499 [M + H+].
rac-6-{2-[(2-Chlorophenyl)cyclopentyl]methyl-2-hydroxy-4-phenylbut-3-ynoyl-
amino}-4-methyl-2,3-benzoxazin-l-one 5
Q
ci I
H
N
N
oH
o
Lithiumphenylacetylide (0.65 ml, 1M in THF) was added to 6-{3-[1-(2-
chlorophenyl)-
cyclopentyl]-2-oxopropionylamino}-4-methyl-2,3-benzoxazin-1-one (110 mg) at -
78 C
and allowed to reach room temperature under argon during the night. Working up
as
described for Example 1 and column chromatography on silica gel resulted in
the title
compound as a foam (54 mg) after oil-pump drying. 1 H-NMR (ppm, CDCI3, 400
MHz):
1.59 - 1.85 (m, 5H), 2.18 - 2.35 (m, 3H), 2.54 (s, 3H, Me), 2.7 - 3.09 (3H),
6.94 - 7.58
(m, 10H), 8.18 (d, J = 1.1 Hz), 8.25 (d, J = 8.6 Hz, 1 H), 8.81 (br. s., 1H,
NH).
C31H27CIN204 (526.0): HPLCMS: m/z = 526 [M], purity 97%.
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6-{2-[2-( 2, 3-D i hyd ro-7-be nzof u ra ny l)-2-m ethy l p ro py l] -2-hyd
roxy-3-
octynoylamino}-4-methyl-2,3-benzoxazin-1-one 6
O HO
H
N
O
O
Reaction of 1-hexyne (0.4 ml), nBuLi (0.7 ml, 1.6 M in hexane) and 6-[4-(2,3-
dihydro-7-
benzofuranyl)-4-methyl-2-oxopentanoylamino]-4-methyl-2,3-benzoxazin-1-one
(99.5 mg) at -78 C in THF (3 ml) as described for Example 1 gave, after column
chromatography on silica gel and drying in vacuo, a solidified colourless oil
(42 mg).
1 H NMR (ppm, CDCI3, 400 MHz): 0.89 (t, J =7.2 Hz, 3H, Me), 1.35 - 1.56 (m,
10H),
2.14 - 2.18 (m, 2H), 2.56 (s, 3H, Me), 2.66 (d, J =14.8 Hz, 1H), 2.73 (d, J =
14.8 Hz,
1 H), 3.0 -3.2 (m, 2H), 3.27 (s, 1 H), 4.57 (t, J = 9.3 Hz, 2H), 6.75 (t, J =
7.5 Hz, 1 H),
6.95 (d, J = 6.3 Hz, 1 H), 7.05 (d, J = 7.8 Hz, 1 H), 7.50 - 7.52 (m, 1 H),
8.23 - 8.29 (m,
2H), 8.78 (br. s., NH). C29H32CIN205 (488): LC-MS: m/z = 489 [M + H+].
rac-6-{4-(2-Chloro-4-fluorophenyl)-2-hydroxy-2-[(4-hydroxyphenyl)ethynyl]-4-
methylpentanoylamino}-4-methyl-2,3-benzoxazin-l-one 7
OH
~
CI HO //
H
I \ N \
F / O \ ~
O
Stage A: a suspension of the compound of Example 10 (57.8 mg),
triphenylphosphine
(6.8 mg), copper iodide (5 mg), 4-iodophenyl acetate (51 mg), 5 mg of
palladium
acetate in THF (1 ml) and triethylamine (3 mi) was reacted in an ultrasonic
bath under
argon for 1 h. Addition of saturated aqueous ammonium chloride solution was
followed
by extraction with ethyl acetate and washing with water and brine. Drying with
sodium
sulphate was followed by concentration and purification by column
chromatography on
silica gel. A white solid (46.7 mg) was obtained. Stage B: A suspension of the
compound from stage A (46.7 mg) and sodium bicarbonate (128 mg) in methanol
was
stirred at room temperature under argon for 6 h. A spatula tip of sodium
bicarbonate
was then added, and the mixture was stirred overnight. It was diluted with
ethyl acetate,
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water was added, and separation of the phases was followed by extraction with
ethyl
acetate. Washing of the combined organic phases with brine, drying over sodium
sulphate, concentration and column chromatography on silica gel resulted in
the title
compound as a viscous oil (29 mg).
1 H-NMR (ppm, CDCI3, 400 MHz): 1.63 (s, 3H, Me), 1.69 (s, 3H, Me), 2.56 (s,
3H, Me),
2.94 - 3.01 (m, 3H), 5.48 (br. s, 1 H, OH), 6.74 - 6.77 (m, 2H), 6.84 - 6.93
(m, 2H), 7.21
- 7.25 (m, 2H), 7.43 (dd, J 9.0, 6.1 Hz, 1 H), 7.57 - 7.59 (dd, J = 8.6, 2.3
Hz, 1 H), 8.22
- 8.23 (m, 1 H), 8.31 (d, J 8.6 Hz, 1 H), 8.80 (br. s, 1 H, NH). C29H24CIFN2O5
(534.98):
LC-MS: m/z = 535 [M + H+].
rac-6-{2-[2-(2-Chloro-4-fluorophenyl)-2-methylpropyl]-2-hydroxydec-3-ynoyl-
amino}-4-methyl-2,3-benzoxazin-1-one 8
CI HO //
H
I \ N \N
F / 0 0
0
Reaction of 1-octyne (0.4 ml), nBuLi (0.6 ml, 1.6 M in hexane) and 6-[4-(2-
chloro-4-
fluorophenyl)-4-methyl-2-oxovaleroylamino]-4-methyl-2,3-benzoxazin-1-one (110
mg) in
THF (3 ml) at -78 C as described for Example 1 gave, after column
chromatography on
silica gel, a white solid (25 mg).
1 H-NMR (ppm, CDCI3, 400 MHz): 0.87 (t, J = 7.0 Hz, 3H), 1.26 - 1.46 (m, 8H),
1.58 (s,
3H, Me), 1.63 (s, 3H, Me), 2.12 (t, J = 7.0 Hz, CH2C=C), 2.56 (s, 3H, Me)2.79 -
2.91 (m,
3H), 6.92 - 6.95 (m, 2H), 7.40 (dd, J = 8.9, 6.3 Hz, 1 H), 7.53 (dd, J= 8.6,
1.9 Hz, 1 H),
8.21 (d, J = 1.9 Hz, 1H), 8.30 (d, J = 8.6 Hz, 1H), 8.71 (br. s., 1 H, NH);
C29H32CIFN204
(527.0): LC-MS: m/z = 527 [M + H+].
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rac-6-{2-[2-(2-Chloro-4-fluorophenyl)-2-methylpropyl]-2-hydroxy-5-phenylpent-3-
ynoylamino}-4-methyl-2,3-benzoxazin-l-one 9
cl HO
H
~ N N
~ ~ O 0
F
0
Reaction of 3-phenyl-l-propyne (0.17 ml), nBuLi (0.51 ml, 1.6 M in hexane) and
6-[4-(2-
chloro-4-fluorophenyl)-4-methyl-2-oxovaleroylamino]-4-methyl-2,3-benzoxazin-1-
one
(140 mg) in THF (3 ml) at -78 C as described for Example 1 gave, after column
chromatography on silica gel and drying in vacuo, a white foam (116 mg).
1 H-NMR (ppm, CDCI3i 400 MHz): 1.59 (s, 3H, Me), 1.61 (s, 3H, Me), 2.55 (s,
3H, Me),
2.79 - 2.95 (m, 3H), 3.4 - 3.6 (m, 2H, CH2C=C), 6.8 - 6.93 (m, 2H), 7.23 -
7.42 (m,
7H), 8.15 (d, J = 2.3 Hz, IH), 8.27 (d, J = 8.6 Hz, 1 H), 8.64 (br. s., 1 H,
NH).
C30H26CIFN204 (533.0): LC-MS: m/z = 533 [M + H+].
rac-6-{4-(2-Chloro-4-fluorophenyl)-2-ethynyl-2-hydroxy-4-methylpentanoylamino}-
4-methyl-2,3-benzoxazin-l-one 10
cl HO // N -
I
~ O
FI O
/ _ O
Ethynylmagnesium bromide (2.2 ml, 0.5 M in THF) was added to an ice-cold
solution of
6-[4-(2-chloro-4-fluorophenyl)-4-methyl-2-oxovaleroylamino]-4-methyl-2,3-
benzoxazin-
1-one (208 mg) in THF (4 ml). Under argon, the reaction solution was allowed
to reach
room temperature over the course of 3 h. Working up as described in Example 1
and
column chromatography on silica gel resulted in the title compound as a foam
(84 mg)
after oil-pump drying. 1 H-NMR (ppm, CDCI3, 400 MHz): 0.8 - 0.9 (m, 1 H), 1-58
(s, 3H,
Me), 1.65 (s, 3H, Me), 2.56 - 2.96 (6H), 6.86 - 6.94 (m, 2H), 7.41 (dd, J 9.0,
6.2 Hz,
1 H), 7.56 (dd, J = 8.6, 1.9 Hz, 1 H), 8.19 (d, J = 1.9 Hz, 1 H), 8.31 (d, J
8.6 Hz, 1 H),
8.63 (br. s., 1 H, NH).
C23H2OCIFN204 (542.9): LC-MS: m/z = 543 [M + H'].
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rac-6-{4-(2-Chloro-4-fluorophenyl)-2-hydroxy-4-methyl-2-vinyl-pentanoylamino}-
4-
methyl-2,3-benzoxazin-l-one 11
CI HO\ p ~ / ~ 'N
I O
F O
A vinylmagnesium bromide solution (0.5 ml, 1M in THF) was injected into 6-[4-
(2-chloro-
4-fluorophenyl)-4-methyl-2-oxovaleroylamino]-4-methyl-2,3-benzoxazin-1-one
(103 mg)
in THF (3 ml) at -78 C, and the mixture was allowed to reach room temp. under
argon
overnight. Addition of aqueous ammonium chloride solution was followed by
extraction
with ethyl acetate and washing with sat. sodium chloride solution. Drying with
sodium
sulphate was followed by concentration in a rotary evaporator and purification
by
column chromatography on silica gel to result in the title compound as
solidified oil
(18 mg). 1 H-NMR (ppm, CDCI3i 400 MHz, selected signals): 1.53 (s, 3H, Me),
1.57 (s,
3H, Me), 2.35 (s, 1 H), 2.56 (s, 3H, Me), 2.74 (d, J = 15.3 Hz, 1 H), 2.89 (d,
J = 15.3 Hz,
1 H), 5.15 (d, J = 10.5 Hz, 1 H), 5.27 (d, J = 17.6 Hz, 1 H), 6.10 (dd, J =
17.2, 10.6 Hz,
1 H), 6.81 - 6.86 (m, 1 H),
rac-6-{4-(2-Chloro-4-fluorophenyl)-2-hydroxy-2-[(4-methoxyphenyl)ethynyl]-4-
methylpentanoylamino}-4-methyl-2,3-benzoxazin-l-one 12
0
CI HO N -N
O
O
F O
Reaction of 4-methoxyphenylacetylene (0.4 ml), nBuLi (0.6 ml, 1.6 M in hexane)
and
6-[4-(2-chloro-4-fluorophenyl)-4-methyl-2-oxovaleroylamino]-4-methyl-2,3-
benzoxazin-
1-one (110 mg) at -78 C as described for Example 1 gave, after column
chromatography on silica gel, the title compound as a white solid (44 mg).
1 H-NMR (ppm, CDCI3i 400 MHz): 1.63 (s, 3H, Me), 1.69 (s, 3H, Me), 2.91 - 3.01
(m,
3H), 3.81 (s, 3H, Me), 6.81 - 6.94 (m, 3H), 7.25 - 7.29 (m, 3H), 7.43 (dd, J =
8.4, 6.3
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Hz, 1H), 7.58 (dd, J = 8.6, 2.3 Hz, 1H), 8.24 (d, J = 1.9 Hz, 1H), 8.31 (d, J
8.6 Hz,
1 H), 8.79 (br. s., 1 H, NH). C30H26CIFN205 (549.0): LC-MS: m/z = 549 [M +
H+].
rac-6-{4-(2-Chloro-4-fluorophenyl)-2-hydroxy-4-methyl-2-(phenylethynyl)-
pentanoylamino}-4-methyl-2,3-benzoxazin-l-one 13
cl HO N \N
I
O
F O
Lithium phenylacetylide (0.65 ml, 1 M in THF) was added to 6-[4-(2-chloro-4-
fluorophenyl)-4-methyl-2-oxovaleroylamino]-4-methyl-2,3-benzoxazin-1-one (136
mg) at
-78 C and the mixture was stirred at -78 C under argon for 2.5 h. Working up
as
described for Example 1 and column chromatography on silica gel resulted in
the title
compound as a white foam (102 mg) after oil-pump drying.
1 H-NMR (ppm, CDCI3, 400 MHz): 1.64 (s, 3H, Me), 1.70 (s, 3H, Me), 2.57 (s,
3H, Me),
2.92 - 3.03 (m, 3H), 6.82 - 6.86 (m, 1 H), 6.91 - 6.93 (m, 1 H), 7.30 - 7.36
(m, 5H), 7.44
(dd, J = 9.0, 6.2 Hz, 1 H), 7.59 (dd, J = 8.6, 2.0 Hz, 1 H), 8.23 (d, J = 2.0
Hz, 1 H), 8.31
(d, J = 8.2 Hz, 1H), 8.79 (br. s., NH); C29H24CIFN204 (519.0): HPLC-MS: m/z =
518 [M].
The compounds 14 and 15 were prepared in analogy to Example 10 from 6-(4-
methyl-
4-phenyl-2-oxovaleroylamino)-4-methyl-2,3-benzoxazin-1-one and the alkynyl-
magnesium halide:
rac-6-[2-Ethynyl-2-hydroxy-4-methyl-4-phenylpentanoylamino]-4-methyl-2,3-
benzoxazin-l-one 14
HO N -N
I
0
0
O
1H-NMR (ppm, CDCI3, 400 MHz): 1.42 (3H), 1.59 (3H), 2.57 (3H), 2.64 (4H), 7.15
(1 H),
7.31 (2H), 7.46 (2H), 7.58 (1 H), 8.25 (1 H), 8.30 (1 H), 8.81 (1 H).
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rac-6-[2-Hydroxy-4-methyl-4-phenyl-2-propynylpentanoylamino]-4-methyl-2,3-
benzoxazin-l-one 15
HO // H
N -N
I \ I ~ O
O
O
1 H-NMR (ppm, CDCI3, 400 MHz): 1.42 (3H), 1.59 (3H), 2.50-2.65 (6H), 7.11 (1
H), 7.30
(2H), 7.43 (2H), 7.58 (1 H), 8.29 (2H), 8.85 (1 H).
The compounds 15-28 were prepared in analogy to Example 1 from 6-(4-methyl-4-
phenyl-2-oxovaleroylamino)-4-methyl-2,3-benzoxazin-1-one and the respective
lithium
arylacetylide:
rac-6-[2-Hydroxy-4-methyl-4-phenyl-2-(phenylethynyl)pentanoylamino]-4-methyl-
2,3-benzoxazin-l-one 16
Q
HO N -N
I \ ~ / O
O
O
1 H-NMR (ppm, CDCI3, 300 MHz): 1.47 (3H), 1.65 (3H), 2.57 (3H), 2.62-2.78
(3H), 7.15
(1 H), 7.27-7.37 (5H), 7.40 (2H), 7.50 (2H), 7.59 (1 H), 8.29 (2H), 8.90 (1
H).
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(+)-6-[2-Hydroxy-4-methyl-2-[(4-methylphenyl)ethynyl]-4-phenylpentanoylamino]-
4-methyl-2,3-benzoxazin-l-one 17a and
(-)-6-[2-Hydroxy-4-methyl-2-[(4-methylphenyl)ethynyl]-4-phenylpentanoylamino]-
4-methyl-2,3-benzoxazin-l-one 17b
HO H
N -i
I \ ~ ~ O
O
1 H-NMR (ppm, CDCI3i 300 MHz): 1.48 (3H), 1.64 (3H), 2.36 (3H), 2.57 (3H),
2.60-2.80
(3H), 7.08-7.20 (3H), 7.30 (4H), 7.49 (2H), 7.60 (1 H), 8.29 (2H), 8.90 (1 H).
16a: [a] 2o: +28.4 (CHCI3, 1.03 g/100 ml; X=589 nm)
16b: [a] 20: -28.6 (CHCI3, 1.01 g/100 ml; X=589 nm)
rac-6-[2-Hydroxy-2-[(4-methoxyphenyl)ethynyl]-4-methyl-4-phenylpentanoyl-
amino]-4-methyl-2,3-benzoxazin-l-one 18
o-
HO N \N
I
O
O
0
1 H-NMR (ppm, CDCI3, 300 MHz): 1.47 (3H), 1.63 (3H), 2.56 (3H), 2.60-2.78
(3H), 3.80
(3H), 6.81 (2H), 7.13 (1 H), 7.25-7.38 (4H), 7.48 (2H), 7.60 (1 H), 8.28 (2H),
8.89 (1 H).
(+)-6-[2-Hydroxy-2-[(4-methoxyphenyl)ethynyl]-4-methyl-4-
phenylpentanoylamino]-4-methyl-2,3-benzoxazin-l-one 18a and
(-)-6-[2-Hydroxy-2-[(4-methoxyphenyl)ethynyl]-4-methyl-4-
phenylpentanoylamino]-4-methyl-2,3-benzoxazin-l-one 18b
The racemic mixture which was described in example 18 was separated by
preparative
chiral HPLC (column Chiralpak AD 250x10 mm) into the enantiomers 18a and 18b.
18a :[a] 2o: + 29.3 (CHCI3, 1.12 g/100 ml; ?~=589 nM)
18b :[a] zo: - 30.0 (CHCI3i 1.14 g/100 ml; X=589 nM)
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rac-6-[2-Hydroxy-2-[(4-(N,N-dimethylamino)phenyl)ethynyl]-4-methyl-4-phenyl-
pentanoylamino]-4-methyl-2,3-benzoxazin-l-one 19
N,
/ ~ .
HO N
I \N
O
0
O
1 H-NMR (ppm, CDCI3i 400 MHz): 1.48 (3H), 1.62 (3H), 2.57 (3H), 2.60-2.75
(3H), 2.98
(6H), 6.58 (2H), 7.12 (1 H), 7.23-7.38 (4H), 7.48 (2H); 7.57 (1 H), 8.28 (2H),
8.90 (1 H).
rac-6-[2-Hydroxy-4-methyl-4-phenyl-2-[(4-trifluoromethylphenyl)ethynyl]-
pentanoylamino]-4-methyl-2,3-benzoxazin-1-one 20
F F
F
HO N
D
\
O N
I O
O
1H-NMR (ppm, CDCI3, 400 MHz): 1.48 (3H), 1.63 (3H), 2.57 (3H), 2.64-2.80 (3H),
7.17
(1 H), 7.33 (2H), 7.48 (4H), 7.56 (2H), 7.61 (1 H), 8.30 (2H), 8.92 (1 H).
(+)-6-[2-Hydroxy-4-methyl-4-phenyl-2-[(4-trifluormethylphenyl)ethynyl]-
pentanoylamino]-4-methyl-2,3-benzoxazin-1-one 20a and
(-)-6-[2-Hydroxy-4-methyl-4-phenyl-2-[(4-trifluormethylphenyl)ethynyl]-
pentanoylamino]-4-methyl-2,3-benzoxazin-l-one 20b
The racemic mixture which was described in example 20 was separated by
preparative
chiral HPLC (column Chiralpak AD 250x10 mm) into the enantiomers 20a and 20b.
20a :[a] 20: + 19.9 (CHCI3, 1.05 g/100 ml; X=589 nM)
20b :[a] 20: - 20.4 (CHCI3, 1.01 g/100 ml; X=589 nM)
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rac-6-[2-[(4-Cyanophenyl)ethynyl]-2-hydroxy-4-methyl-4-phenylpentanoylamino]-
4-methyl-2,3-benzoxazin-1-one 21
%eHO
N -N
//O H
O
O
1 H-NMR (ppm, CDCI3, 400 MHz): 1.50 (3H), 1.62 (3H), 2.57 (3H), 2.63-2.82
(3H), 7.18
(1 H), 7.35 (2H), 7.48 (4H), 7.55-7.68 (2H), 7.62 (1 H), 8.30 (2H), 8.94 (1
H).
(+)-6-[2-[(4-Cyanophenyl)ethynyl]-2-hydroxy-4-methyl-4-phenylpentanoylamino]-
4-methyl-2,3-benzoxazin-l-one 21 a and
(-)-6-[2-[(4-Cyanophenyl)ethynyl]-2-hydroxy-4-methyl-4-phenylpentanoylamino]-4-
methyl-2,3-benzoxazin-l-one 21b
The racemic mixture which was described in example 21 was separated by
preparative
chiral HPLC (column Chiralpak AD 250x10 mm) into the enantiomers 21 a and 21
b.
21a :[a] 20: + 26.60 (CHCI3, 1.12 g/100 ml; X=589 nM)
21 b:[a] 20: - 26.80 (CHCI3, 1.02 g/100 ml; X=589 nM)
rac-6-[2-Hydroxy-4-methyl-4-phenyl-2-[(4-phenylphenyl)ethynyl]pentanoylamino]-
4-methyl-2,3-benzoxazin-l-one 22
/ ~
,
/ ~
HO // H
N -N
I~ o
0
o
1 H-NMR (ppm, CDCI3, 400 MHz): 1.50 (3H), 1.68 (3H), 2.58 (3H), 2.64-2.81
(3H), 7.18
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(1 H), 7.30-7.40 (3H), 7.41-7.61 (11 H), 8.30 (2H), 8.92 (1 H).
(+)-6-[2-Hydroxy-4-methyl-4-phenyl-2-[(4-phenylphenyl)ethynyl]pentanoylamino]-
4-methyl-2,3-benzoxazin-l-one 22a and
(-)-6-[2-Hydroxy-4-methyl-4-phenyl-2-[(4-phenylphenyl)ethynyl]pentanoylamino]-
4-methyl-2,3-benzoxazin-l-one 22b
The racemic mixture which was described in example 22 was separated by
preparative
chiral HPLC (column Chiralpak AD 250x10 mm) into the enantiomers 22a and 22b.
22a :[a] 20: + 38.4 (CHCI3i 1.06 g/100 ml; X=589 nM)
22b :[a] 20: - 30.6 (CHCI3, 1.12 g/100 ml; X=589 nM)
rac-6-[2-Hydroxy-4-methyl-4-phenyl-2-[(3-trifluoromethylphenyl)ethynyl]-
pentanoylamino]-4-methyl-2,3-benzoxazin-l-one 23
F
F
F
HO // N I
N
\
O
O
O
1 H-NMR (ppm, CDCI3, 300 MHz): 1.52 (3H), 1.68 (3H), 2.60 (3H), 2.65-2.88
(3H), 7.21
(1 H), 7.49 (2H), 7.42-7.70 (7H), 8.34 (2H), 8.96 (1 H).
rac-6-[2-Hydroxy-4-methyl-4-phenyl-2-[(2-trifluoromethylphenyl)ethynyl]-
pentanoylamino]-4-methyl-2,3-benzoxazin-l-one 24
F
F i
F
HO H
-i
Nz~ O
O
O
1 H-NMR (ppm, CDCI3, 600 MHz): 1.52 (3H), 1.65 (3H), 2.62 (3H), 2.69 (1 H),
2.78 (1 H),
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2.91 (1 H), 7.11 (1H), 7.32 (3H), 7.51 (3H), 7.57 (2H), 7.70 (1 H), 8.20 (1H),
8.45 (1H),
8.75 (1 H).
(+)-6-[2-Hydroxy-4-methyl-4-phenyl-2-[(2-trifluormethylphenyl)ethynyl]-
pentanoylamino]-4-methyl-2,3-benzoxazin-l-one 24a and
(-)-6-[2-Hydroxy-4-methyl-4-phenyl-2-[(2-trifluormethylphenyl)ethynyl]-
pentanoylamino]-4-methyl-2,3-benzoxazin-l-one 24b
The racemic mixture which was described in example 24 was separated by
preparative
chiral HPLC (column Chiralpak AD 250x10 mm) into the enantiomers 24a and 24b.
24a :[a] 20: + 21.30 (CHCI3i 1.00 g/100 ml; X=589 nM)
24b :[a] 20: - 19.4 (CHCI3i 1.00 g/100 ml; X=589 nM)
rac-6-[2-Hydroxy-4-methyl-2-[(4-nitrophenyl)ethynyl]-4-phenylpentanoylamino]-4-
methyl-2,3-benzoxazin-l-one 25
NO~i2
HO // H
N -N
O
I
O
O
1 H-NMR (ppm, CDCI3, 600 MHz): 1.47 (3H), 1.62 (3H), 2.55 (3H), 2.79 (1 H),
2.81 (2H),
7.18 (1 H), 7.34 (2H), 7.50 (4H), 7.63 (1 H), 8.17 (2H), 8.80 (2H), 8.94 (1
H).
rac-6-[2-[[4-(1,1-Dimethylethyl)phenyl]ethynyl]-2-hydroxy-4-methyl-
4-phenylpentanoylamino]-4-methyl-2,3-benzoxazin-l-one 26
JOHO//H
~N 0
O
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1 H-NMR (ppm, CDCI3, 300 MHz): 1.32 (9H), 1.51 (3H), 1.68 (3H),.2.62 (3H),
2.65-2.82
(3H), 7.18 (1 H), 7.30-7.40 (6H), 7.52 (2H), 7.63 (1 H), 8.32 (2H), 8.93 (1
H).
rac-6-[2-Hydroxy-4-methyl-2-[(3-methylphenyl)ethynyl]-4-phenylpentanoylamino]-
4-methyl-2,3-benzoxazin-l-one 27
HO H
N -i
I \ ~ / 0
0
0
1 H-NMR (ppm, CDCI3, 400 MHz): 1.47 (3H), 1.63 (3H), 2.30 (3H), 2.58 (3H),
2.62-2.80
(3H), 7.12-7.26 (5H), 7.32 (2H), 7.50 (2H), 7.60 (1 H), 8.30 (2H), 8.90 (1 H).
rac-6-[2-Hydroxy-4-methyl-2-[(2-methylphenyl)ethynyl]-4-phenylpentanoylamino]-
4-methyl-2,3-benzoxazin-l-one 28
HO H
N -i
\ I / 0
0
0
1 H-NMR (ppm, CDCI3, 300 MHz): 1.47 (3H), 1.65 (3H), 2.38 (3H), 2.58 (3H),
2.62-2.80
(3H), 7.08-7.42 (7H), 7.49 (2H), 7.60 (1H), 8.22-8.36 (2H), 8.90 (1H).
rac-6-[2-(3,3-Dimethylbutynyl)-2-hydroxy-4-methyl-4-phenylpentanoylamino]-4-
methyl-2,3-benzoxazin-l-one 29
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HO // H
N -N
~ O
0
0
1 H-NMR (ppm, CDCI3i 300 MHz): 1.20 (9H), 1.43 (3H), 1.60 (3H), 2.46 (1 H),
2.50-2.63
(5H), 7.11 (1 H), 7.28 (2H), 7.43 (2H), 7.54 (1 H), 8.22 (1 H), 8.29 (1 H),
8.32 (1 H).
The following compound was prepared in analogy to Example 7 from the compound
described in Example 13 and 4'-iodoacetophenone:
rac-6-[2-[(4-Acetylphenyl)ethynyl]-2-hydroxy-4-methyl-4-phenylpentanoylamino]-
4-methyl-2,3-benzoxazin-l-one 30
O
HO H
N -i
O
0
O
1 H-NMR (ppm, CDC13r 300 MHz): 1.48 (3H), 1.63 (3H), 2.56 (3H), 2.60 (3H),
2.63-2.82
(3H), 7.18 (1 H), 7.33 (2H), 7.40-7.56 (4H), 7.62 (1 H), 7.90 (2H), 8.30 (2H),
8.93 (1 H).
(+)-6-[2-[(4-Acetylphenyl)ethynyl]-2-hydroxy-4-methyl-4-phenylpentanoylamino]-
4-
methyl-2,3-benzoxazin-l-one 30a and
(-)-6-[2-[(4-Acetylphenyl)ethynyl]-2-hydroxy-4-methyl-4-phenylpentanoylamino]-
4-
methyl-2,3-benzoxazin-l-one 30b
The racemic mixture which was described in example 30 was separated by
preparative
chiral HPLC (column Chiralpak AD 250x10 mm) into the enantiomers 30a and 30b.
30a :[a] 20: + 31.30 (CHCI3, 1.09 g/100 ml; X=589 nM)
30b :[a] 2o: - 28.4 (CHCI3, 1.09 g/100 ml; X=589 nM)
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The compounds 30 and 31 were prepared in analogy to Example 1 from 6-[3-[1-(2-
fluoro-5-trifluoromethylphenyl)cyclopropyl]-2-oxopropionylamino]-4-methyl-2,3-
benzoxazin-1-one
rac-6-[2-[(2-Fluoro-5-trifluoromethylphenyl)cyclopropylmethyl]-2-hydroxy-4-(4-
trifluoromethylphenyl)but-3-inoylamino]-4-methyl-2,3-benzoxazin-l-one 31
F F
F
F HO N \N
0
o
o
F F
F
1 H-NMR (ppm, CDCI3, 400 MHz): 0.90 (1 H), 1.00-1.15 (3H), 2.51 (1 H), 2.55
(3H), 2.68
(1H), 3.18 (1 H), 7.01 (1 H), 7.30 (1 H), 7.41 (2H), 7.56 (2H), 7.63 (1H),
7.68 (1 H), 8.19
(1 H), 8.31 (1 H), 8.98 (1 H).
(+)-6-[2-[(2-Fluor-5-trifluormethylphenyl)cyclopropylmethyl]-2-hydroxy-4-(4-
trifluormethylphenyl)but-3-inoylamino]-4-methyl-2,3-benzoxazin-l-one 31a and
(-)-6-[2-[(2-Fluor-5-trifluormethylphenyl)cyclopropylmethyl]-2-hydroxy-4-(4-
trifluormethylphenyl)but-3-inoylamino]-4-methyl-2,3-benzoxazin-l-one 31 b
The racemic mixture which was described in example 31 was separated by
preparative
chiral HPLC (column Chiralpak AD 250x10 mm) into the enantiomers 31 a and 31
b.
31a :[a] 2o: + 2.3 (CHCI3, 1.00 g/100 ml; X=589 nM)
31 b:[a] 20: - 1.90 (CHCI3, 1.00 g/100 ml; X=589 nM)
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rac-6-[2-[(2-Fluoro-5-trifluoromethylphenyl)cyclopropylmethyl]-2-hydroxy-4-(4-
methylphenyl)but-3-ynoylamino]-4-methyl-2,3-benzoxazin-1-one 32
F HO
I \ I ~ O
0
0
F F
F
1 H-NMR (ppm, CDCI3i 400 MHz): 0.88 (1 H), 0.98-1.13 (3H), 2.34 (3H), 2.44 (1
H), 2.55
(3H), 2.70 (1 H), 3.02 (1 H), 7.01 (1 H), 7.10 (2H), 7.22 (2H), 7.30 (1 H),
7.64 (2H), 8.19
(1 H), 8.31 (1 H), 8.98 (1 H).
(+)-6-[2-[(2-Fluor-5-trifluormethylphenyl)cyclopropylmethyl]-2-hydroxy-4-(4-
methylphenyl)but-3-inoylamino]-4-methyl-2,3-benzoxazin-1-one 32a and
(-)-6-[2-[(2-Fluor-5-trifluormethylphenyl)cyclopropylmethyl]-2-hydroxy-4-(4-
methylphenyl)but-3-inoylamino]-4-methyl-2,3-benzoxazin-1-one 32b
The racemic mixture which was described in example 32 was separated by
preparative
chiral HPLC (column Chiralpak AD 250x10 mm) into the enantiomers 32a and 32b.
32a :[a] 20: + 8.6 (CHCI3, 1.00 g/100 mi; X=589 nM)
32b :[a] 2o: - 8.7 (CHCI3, 1.00 g/100 mi; X=589 nM)
The following compound was prepared in analogy to example 7 from compound
which
was described in example 14 and 3'-Iodacetophenon:
rac-6-[2-[(3-Acetylphenyl)ethynyl]-2-hydroxy-4-methyl-4-phenylpentanoylamino]-
4-methyl-2,3-benzoxazin-1-one 33
0
HO // H
N -N
I \ I / O
O
O
1 H-NMR (ppm, CDCI3, 300 MHz): 1.49 (3H), 1.63 (3H), 2.57 (6H), 2.62-2.81
(3H), 7.16
81 H), 7.28-7.70 (7H), 7.90-8.00 (2H), 8.30 (2H), 8.94 (1 H).
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Compounds 34 and 35 were prepared in analogy to example 1 from 6-(4-Methyl-4-
phenyl-2-oxovaleroylamino)-4-methyl-2,3-benzoxazin-1-one and the according
Lithium
arylacetylide.
rac-6-[2-[(2,5-Dimethylphenyl)ethynyl]-2-hydroxy-4-methyl-4-
phenylpentanoylamino]-4-methyl-2,3-benzoxazin-1-one 34
/ ~
HO // N
~N
I
~ O
O
O
1 H-NMR (ppm, CDCI3i 400 MHz): 1.49 (3H), 1.62 (3H), 2.27 (3H), 2.33 (3H),
2.57 (3H),
2.65-2.78 (3H), 7.03 (2H), 7.13 (2H), 7.30 (2H), 7.50 (2H), 7.61 (1 H), 8.22
(1H), 8.30
(1 H), 8.89 (1 H).
rac-6-[2-[(2,4,5-Trimethylphenyl)ethynyl]-2-hydroxy-4-methyl-4-
phenylpentanoylamino]-4-methyl-2,3-benzoxazin-l-one 35
HO H
N -i
\ I~ O
O
O
1 H-NMR (ppm, CDCI3i 400 MHz): 1.47 (3H), 1.64 (3H), 2.18 (3H), 2.21 (3H),
2.30 (3H),
2.56 (3H), 2.65-2.77 (3H), 6.93 (1H), 7.12 (2H), 7.30 (2H), 7.48 (2H), 7.59
(1H), 8.22
(1 H), 8.29 (1 H), 8.90 (1 H).
(+)-6-[2-[(2,4,5-Trimethylphenyl)ethynyl]-2-hydroxy-4-methyl-4-
phenylpentanoylamino]-4-methyl-2,3-benzoxazin-1-one 35a and
(-)-6-[2-[(2,4,5-Trimethylphenyl)ethynyl]-2-hydroxy-4-methyl-4-
phenylpentanoylamino]-4-methyl-2,3-benzoxazin-1-one 35b
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The racemic mixture which was described in example 35 was separated by
preparative
chiral HPLC (column Chiralpak AD 250x10 mm) into the enantiomers 35a and 35b.
35a :[a] zo: + 30.6 (CHCI3, 0.97 g/100 ml; X=589 nM)
35b :[a] 20: - 28.0 (CHCI3i 0.96 g/100 ml; X=589 nM)
The following compound was prepared in analogy to example 9 from 3-Phenyl-l-
propine, nBuLi and 6-(4-Methyl-4-phenyl-2-oxovaleroylamino)-4-methyl-2,3-
benzoxazin-
1-one:
rac-6-{2-(2-phenyl)-2-methylpropyl]-2-hydroxy-5-phenylpent-3-inoylamino}-4-
methyl-2,3-benzoxazin-l-one 36
\ /
HO //
H
N ~ -N
0
/
I /
O
1H-NMR (ppm, CDCI3, 400 MHz): 1.42 (3H), 1.53 (3H), 2.55-2.70 (6H), 3.58 (2H),
7.11
(1 H), 7.20-7.35 (7H), 7.41 (2H), 7.48 (1 H), 8.20 (1 H), 8.28 (1 H), 8.80 (1
H).
Compounds 37 and 38 were prepared in analogy to example 1 from 6-(4-Methyl-4-
(2-
chlor-6-fluorphenyl)-2-oxovaleroylamino)-4-methyl-2,3-benzoxazin-1-one and the
according Lithium arylacetylide.
rac-6-[2-Hydroxy-4-methyl-4-(2-chlor-6-fluorphenyl)-2-(4-methylphenyl-
ethinyl)pentanoylamino]-4-methyl-2,3-benzoxazin-1-one 37
6FCA HO //0 N N
I
o
O
1H-NMR (ppm, CDCI3, 300 MHz): 1.73 (3H), 1.82 (3H), 2.33 (3H), 2.57 (3H), 2.88-
3.02
(3H), 6.75-6.96 (2H), 7.01 (1H), 7.09 (2H), 7.27 (2H), 7.60 (1 H), 8.22-8.35
(2H), 8.96
(1 H).
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(+)-6-[2-Hydroxy-4-methyl-4-(2-chlor-6-fluorphenyl)-2-(4-methylphenyl-
ethynyl)pentanoylamino]-4-methyl-2,3-benzoxazin-l-one 37a and
(-)-6-[2-Hydroxy-4-methyl-4-(2-chlor-6-fluorphenyl)-2-(4-methylphenyl-
ethynyl)pentanoylamino]-4-methyl-2,3-benzoxazin-l-one 37b
The racemic mixture which was described in example 37 was separated by
preparative
chiral HPLC (column Chiralpak AD 250x10 mm) into the enantiomers 37a and 37b.
37a :[a] 2o: + 21.5 (CHCI3, 1.00 g/100 ml; X=589 nM)
37b :[a] ZO: - 21.0 (CHCI3, 1.04 g/100 ml; X=589 nM)
rac-6-[2-Hydroxy-4-methyl-4-(2-chlor-6-fluorphenyl)-2-(4-
(trifluormethyl)phenyl-
ethynyl)pentanoylamino]-4-methyl-2,3-benzoxazin-1-one 38
CF3
G Ho
F o
1 H-NMR (ppm, CDCI3, 400 MHz): 1.60 (3H), 1.93 (3H), 2.36 (1 H), 2.56-2.72
(5H), 7.04
(1H), 7.14 (2H), 7.45 (2H), 7.53 (2H), 7.80 (1H), 8.35-8.45 (2H), 8.90 (1H).
(+)-6-[2-Hydroxy-4-methyl-4-(2-chlor-6-fluorphenyl)-2-(4-
(trifluormethyl)phenyl-
ethynyl)pentanoylamino]-4-methyl-2,3-benzoxazin-l-one 38a and
(-)-6-[2-Hydroxy-4-methyl-4-(2-chlor-6-fluorphenyl)-2-(4-(trifl
uormethyl)phenyl-
ethynyl)pentanoylamino]-4-methyl-2,3-benzoxazin-l-one 38b
The racemic mixture which was described in example 38 was separated by
preparative
chiral HPLC (column Chiralpak AD 250x10 mm) into the enantiomers 38a and 38b.
38a :[a] 20: + 143.2 (CHCI3, 1.05 g/100 ml; X=589 nM)
38b :[a] 20: - 137.8 (CHCI3, 1.12 g/100 ml; X=589 nM)
Compounds 39 and 40 were prepared in analogy to example 1 from 6-(4-Methyl-4-
(2-
chlorphenyl)-2-oxovaleroylamino)-4-methyl-2,3-benzoxazin-1-one and the
according
Lithium arylacetylide.
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rac-6-[2-(2-Chlorphenyl)cyclopropylmethyl]-2-hydroxy-4-(4-methylphenyl)but-3-
inoylamino]-4-methyl-2,3-benzoxazin-l-one 39
HO N
I
\N
\ I , 0
O
1 H-NMR (ppm, CDCI3, 400 MHz): 0.84 (1 H), 1.00 (1 H), 1.08-1.22 (2H), 2.36
(3H), 2.53
(3H), 2.90 (1 H), 7.03-7.18 (4H), 7.23-7.38 (3H), 7.50 (1 H), 7.60 (1 H), 8.22
(1 H), 8.29
(1H), 8.91 (1H).
(+)-6-[2-(2-Chlorphenyl)cyclopropylmethyl]-2-hydroxy-4-(4-methylphenyl)but-3-
inoylamino]-4-methyl-2,3-benzoxazin-1-one 39a and
(-)-6-[2-(2-Chlorphenyl)cyclopropylmethyl]-2-hydroxy-4-(4-methylphenyl)but-3-
inoylamino]-4-methyl-2,3-benzoxazin-l-one 39b
The racemic mixture which was described in example 39 was separated by
preparative
chiral HPLC (column Chiralpak AD 250x10 mm) into the enantiomers 39a and 39b.
39a :[a] 20: + 30.8 (CHCI3, 1.00 g/100 ml; X=589 nM)
39b :[a] zo: - 28.3 (CHCI3r 1.00 g/100 ml; X=589 nM)
rac-6-[2-(2-Chlorphenyl)cyclopropylmethyl]-2-hydroxy-4-(4-trifluor-
methylphenyl)but-3-inoylamino]-4-methyl-2,3-benzoxazin-1-one 40
CF3
&HO O
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1 H-NMR (ppm, CDCI3, 300 MHz): 0.91 (1 H), 1.02 (1 H), 1.08-1.25 (2H), 2.53
(3H), 3.00
(1 H), 7.02-7.18 (2H), 7.28 (1 H), 7.42-7.54 (3H), 7.55-7.67 (3H), 8.22 (1 H),
8.32 (1 H),
8.91 (1 H).
(+)-6-[2-(2-Chlorphenyl)cyclopropylmethyl]-2-hydroxy-4-(4-trifluor-
methylphenyl)but-3-inoylamino]-4-methyl-2,3-benzoxazin-1-one 40a and
(-)-6-[2-(2-Chiorphenyl)cyclopropylmethyl]-2-hydroxy-4-(4-trifluor-
methylphenyl)but-3-inoylamino]-4-methyl-2,3-benzoxazin-l-one 40b
The racemic mixture which was described in example 40 was separated by
preparative
chiral HPLC (column Chiralpak AD 250x10 mm) into the enantiomers 40a and 40b.
40a :[a] 2o: + 20.9 (CHCI3i 1.06 g/100 ml; X=589 nM)
40b :[a] 20: - 20.6 (CHCI3, 1.05 g/100 ml; X=589 nM)
rac-6-[2-[[3-(1-Hydroxy-1-methylethyl)phenyl]ethynyl]-2-hydroxy-4-methyl-
4-phenylpentanoylamino]-4-methyl-2,3-benzoxazin-l-one 41
OH
HO // H
a', O
N -i
O
0
59 NI of 3 molar solution of Methylmagnesium chloride was diluted with 1 ml of
pure
Tetrahydrofurane. The solution was cooled to -70 C and a solution of 30 mg of
the
compound which was described in example 33 in 0,5 ml of pure Tetrahydrofurane
was
added. After stirring for 2,5 hours at -70 C the mixture was given to a
saturated solution
of ammonium chloride. After extracting the mixture with Ethyl acetate the
combined
organic phases were washed with saturated sodium chloride and dried over
sodium
sulphate. After column chromatography 16 mg of the product was obtained.
'H-NMR (ppm, CDCI3, 400 MHz): 1.46 (3H), 1.53 (6H), 1.62 (3H), 1.80 (1H), 2.55
(3H),
2.65-2.90 (3H), 7.12 (1H), 7.30 (3H), 7.40-7.52 (3H), 7.53 (1H), 7.60 (1 H),
8.27 (2H),
8.95 (1 H).
The following compound was prepared in analogy to example 7 from the compound
which was described in example 14 and 4-lodobenzylalcohol:
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rac-6-[2-[[4-(Hydroxymethyl)phenyl]ethynyl]-2-hydroxy-4-methyl-
4-phenylpentanoylamino]-4-methyl-2,3-benzoxazin-1-one 42
OH
HO//
O
O
1 H-NMR (ppm, CDCI3, 300 MHz): 1.47 (3H), 1.60 (3H), 1.80 (1 H), 2.57 (3H),
2.62-2.83
(3H), 4.68 (2H), 7.13 (1H), 7.25-7.43 (6H), 7.48 (2H), 7.59 (1H), 8.25-8.32
(2H), 8.91
(1 H).
The following compound was prepared in analogy to example 7 from the compound
which was described in example 14 and 4-lodobenzylalcohol:
rac-6-[2-[[3-(Hydroxymethyl)phenyl]ethinyl]-2-hydroxy-4-methyl-
4-phenylpentanoylamino]-4-methyl-2,3-benzoxazin-l-one 43
HO
HO H
N -;i
O
O
O
1 H-NMR (ppm, CDCI3, 400 MHz): 1.48 (3H), 1.62 (3H), 1.79 (1 H), 2.57 (3H),
2.62-2.80
(3H), 4.68 (2H), 7.15 (1H), 7.25-7.39 (5H), 7.40 (1H), 7.49 (2H), 7.60 (1H),
8.29 (2H),
8.91 (1 H).
The following compound was prepared in analogy to example 41 from the compound
which was described in example 30 and a solution of Methyl magnesium chloride:
rac-6-[2-[[4-(1-Hydroxy-l-methylethyl)phenyl]ethynyl]-2-hydroxy-4-methyl-
4-phenylpentanoylamino]-4-methyl-2,3-benzoxazin-1-one 44
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HO
HO
O
0
1H-NMR (ppm, CDCI3, 400 MHz): 1.47 (3H), 1.55 (6H), 1.62 (3H), 1.70 (1 H),
2.55 (3H),
2.60-2.80 (3H), 7.14 (1 H), 7.28-7.40 (4H), 7.41 (2H), 7.48 (2H), 7.60 (1 H),
8.25-8.32
(2H), 8.90 (1 H).
15
95
