CA2611897A1 - Non-steroidal progesterone receptor modulators - Google Patents

Abstract

The present invention relates to non-steroidal progesterone receptor modulators of the general formula (I), a process for their preparation, the use of the progesterone receptor modulators for producing medicaments, and pharmaceutical compositions comprising these compounds. The compounds according to the invention are suitable for the therapy and prophylaxis of gynaecological disorders such as endometriosis, leiomyomas of the uterus, dysfunctional (bleeding )and dysmenorrhoea, and for the therapy and prophylaxis of hormone-dependent tumours and for use for female fertility control and for hormone replacement therapy.

Description

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 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 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

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, -(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 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.

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).

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 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

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 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:

No. Racemic or R3 enantiomer I rac R' OH
2 - /~ /-0 3 + d H
0 N "
4 rac + o ~ 0 7 rac /-, 8 +

rac 11 +

13 rac 14 +
- r~
16 rac rF17 + ~
18 - -~~
19 rac + //\~, 22 rac 23 +
24 - ~
rac 26 +

28 rac F, 29 + ~
31 rac 32 +
33 - ' 34 rac +
36 - ~ ' 37 rac 38 +
39 - -~
rac %N
+

42 - ~
43 rac 44 +
46 rac NO, 47 +
48 - -~

49 rac OH
50 1+

No. Racemic or R3 enantiomer R' OH
52 rac ci 53 - /~ N
54 + .~ ~ - N
55 rac o o 56 + F 0 58 rac H
59 +

61 rac ~
62 +
63 - -~~
64 rac 65 +
66 - /' 67 rac CF, 68 +

70 rac 71 +

73 rac 0 74 +
75 - r%
76 rac 77 +
78 - -~' 79 rac 80 +

82 rac 83 +

85 rac 86 +

88 rac 89 +
90 - -~' 91 rac 92 +

94 rac 95 +
96 - -~

97 rac Ng 98 +
99 - '~
100 rac H
191 +
102 - ~
103 rac "
104 +

No. Racemic or R3 enantiomer R' OH
106 rac 107 - /~ N
108 + N
109 rac o o 110 + 0 112 rac -, 113 +

115 rac ~
116 + ~ I

118 rac 119 +
120 - r ~
121 rac cf122 + ~

124 rac 125 +
126 - -~
127 rac 128 +
129 - -~~
130 rac ~
131 +

133 rac CF>
134 +

136 rac \ N
137 +

139 rac 140 + ~

142 rac 143 +
144 - -~

145 rac N
146 + -148 rac 149 + ~-150 - -~~
151 rac 152 + 153 154 rac 155 +
156 - -'~ \
157 rac CF
158 +
159 - -~ ~
160 rac 161 + ~
162 - "~
163 rac 164 + f/\

166 rac , oN
167 + .
168 - '' No. Racemic or R3 enantiomer R OH
169 rac 170 - /~ N
171 + N
172 rac o o 173 + o 175 rac 176 +

178 rac 179 +

181 rac 182 +
183 - '' 184 rac 185 + CF

187 rac i 188 +

190 rac 0 191 +
192 - -~

193 rac 194 +
195 - 196 rac 197 +

199 rac 200 +
201 - -~
202 rac 203 +

205 rac 206 +
207 - -~
208 rac N
209 +

211 rac 212 +

214 rac No, 215 + .~
216 - '' 217 rac 218 +

220 rac CF
221 +
222 - -~
223 rac 224 +
225 - -~ lo 226 rac 227 +

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 +

238 rac 239 + "

241 rac 242 +
-244 rac 245 +
246 - -~
247 rac 248 + 'F' 250 rac 251 +
252 - ,-o ' 253 rac 0 254 +

256 rac 257 +

259 rac 260 +
261 - -' 262 rac õ
263 +

265 rac 266 +

268 rac oll 269 +
270 - '~
271 rac "
272 +

274 rac 275 +
276 - -'~
277 rac 278 + "O' 279 - -~
280 rac 281 +

283 rac CF, 284 + .

286 rac 287 +

289 rac 290 + /~

292 rac O, 293 +

No. Racemic or R3 R3 OH
enantiomer H
295 rac N ~ N
296 o ~~ o 297 +
298 rac F o 299 +

301 rac 302 + "
303 - ~
304 rac 305 +

307 rac 308 +
309 - '' 310 rac 311 +

313 rac i 314 +

316 rac 0 317 +

319 rac 320 +
321 - -~~
322 rac ~
323 + ' 325 rac 326 +

328 rac 329 +

331 rac a 333 - '' 334 rac N
335 +
336 - -~
337 rac 338 +
339 - -~' 340 rac 341 + NO' 342 - -~
343 rac 344 +
- -~o 346 rac 347 +
348 - "~
349 rac ~
350 + ~ ~ -351 - '' 352 rac 353 + ri 355 rac OH
356 +

No. Racemic or R3 enantiomer R3 358 rac OH

360 + N
361 rac ~ o ~ o 362 + 51~ o 364 rac 365 +

367 rac 368 +
369 - -~
370 rac 371 +
372 - -~' 373 rac U, 374 +
375 - ~
376 rac 377 + _ 379 rac o 380 +

382 rac 383 +
384 - -~
385 rac 386 +

388 rac V
389 +

391 rac 0 392 +

394 rac 395 + ' '~

397 rac N
398 +
399 - ~' 400 rac 401 +

403 rac No, 404 +
405 - -'' 406 rac 407 +

409 rac CF4410 +
411 - -'' 412 rac 413 +
414 - l 415 rac 416 +
417 - -' ~
418 rac OH
419 +

No. Racemic or R3 enantiomer 421 rac R3 423 + "
424 rac " r, 425 + o o 427 rac 428 + "
429 - '~
430 rac 431 +
432 - -~' 433 rac 434 + I
435 - .~

436 rac CF, 437 +
438 - -~' 439 rac 440 +
441 - ' 442 rac 443 +

445 rac 446 +
447 - -~
448 rac ~
449 +

451 rac 452 +
453 - ~
454 rac 455 + oz 457 rac 458 + .
459 - -~' 460 rac N
461 +
462 - '~
463 rac ~
464 +

466 rac 467 + NO, 469 rac 470 + - ~

472 rac F, 473 +
474 - -'' 475 rac 476 +
477 - -'' 478 rac 479 +

481 rac "
482 +

No. Racemic or R3 enantiomer R' OH
484 rac 486 + N 'N
487 rac o o 489 - f 490 rac 491 +

493 rac 494 +
495 - -~
496 rac 497 +

499 rac CF500 + - ~

502 rac 503 +

505 rac 506 +
507 - -' 508 rac 509 +

511 rac CF>
512 +

514 rac 515 + ~

517 rac 518 +

520 rac 521 +
522 - -~' 523 rac N
524 + . ~
525 - '' 526 rac 527 +

529 rac NO, 530 +
531 - '~
532 rac 533 +

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 +

556 rac 557 +
558 - '~
559 rac 560 +
561 - '' 562 rac 563 + CF

565 rac 566 + N

568 rac 0 569 +
570 - -~' 571 rac 572 +
573 - %
574 rac F.
575 +
576 - %
577 rac \ N
578 + ' 580 rac 581 + ~~i 582 - ' 583 rac 584 +
585 - -' 586 rac 587 +
588 - 589 rac 590 +

592 rac No, 593 +

595 rac 596 +

598 rac 599 + c~
600 - r %
601 rac 602 + ' i 604 rac 605 +
606 - -~
607 rac OH
608 +

No. Racemic or R3 enantiomer 610 rac R3 OH

612 + N
613 rac 614 + F o o o 616 rac 617 + "
618 - f 619 rac 620 +

622 rac 623 +

625 rac CF
626 + ~
627 .~ ~
628 rac 629 +
630 - -~ ~

631 rac 632 +

634 rac 635 +

637 rac 638 +
639 - -~' 640 rac 641 +

643 rac 644 +
645 - --~
646 rac 647 + ll 649 rac N
650 +
651 - -'' 652 rac 653 + ~
654 - %
655 rac 656 + "

658 rac 659 +

661 rac CF, 662 +
663 - -~
664 rac 665 +

667 rac 668 + ri 670 rac H
671 +

No. Racemic or R3 enantiomer R' 673 rac oH
674 - /~ F H
675 + N
676 rac O o 677 + CF 3 679 rac H
680 + .~ ~

682 rac 683 +

685 rac 686 +

688 rac CF689 + - ~
690 - -~
691 rac 692 +

694 rac o 695 +
696 - -~
697 rac 698 +
699 - ' 700 rac 701 +

703 rac \N/
704 +
705 - -~~
706 rac 707 +
708 - ~ ' 709 rac 710 + oll 712 rac 713 +
714 - -'~
715 rac 716 +

718 rac "o, 719 + .
720 - '' 721 rac 722 +

724 rac ~, 725 +
726 - -~
727 rac 728 +

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 +

745 rac 746 +

748 rac 749 +
750 - f 751 rac 752 + CF' 754 rac 755 +

757 rac 0 758 +

760 rac 761 +
762 - %
763 rac F
764 +
765 - -~' 766 rac 767 +

769 rac 770 +

772 rac oll 773 +
774 - '~
775 rac 776 + /N

778 rac 779 +
780 - -~
781 rac 782 + "0' 783 - -~~
784 rac 785 +

787 rac CF. , 788 +

790 rac 791 + .~

793 rac 794 +
795 - -~
796 rac O, 797 +
798 - -~~

No. Racemic or R3 , enantiomer R OH
799 rac -o H

801 + /~ \ \ \
f I / O / O
802 rac ci 803 + o 805 rac 806 +

808 rac 809 +
810 - % ~
811 rac ~
812 +
813 - '' 814 rac ~, 815 +

817 rac 818 + "
819 820 rac 821 +
822 - '~
823 rac 824 +

826 rac 827 +

829 rac N, 830 +
831 - 832 rac 833 +

835 rac o'~
836 +
837 - '' 838 rac N
839 +
840 - -~
841 rac 842 +
843 - -~' 844 rac No, 845 +

847 rac 848 +
849 - -~~
850 rac 851 + CF 852 853 rac 854 +

856 rac 857 +
858 - -~
859 rac om 860 + /.~
861 - f No. Racemic or R3 enantiomer R' OH
862 rac 864 + N N
865 rac 866 + f~ F 0 868 rac 869 + H

871 rac 872 +

874 rac 875 +
876 - -~' 877 rac 878 +
879 - r 880 rac 881 +

883 rac 0 884 +

886 rac 887 +
888 - -~
889 rac ', 890 +

892 rac 893 +
894 - ~
895 rac 896 +

898 rac o, 899 +
900 - "~
901 rac 902 +
903 - -~
904 rac 905 +

907 rac NO, 908 +

910 rac 911 +

913 rac CF
914 +
915 - -~~
916 rac 917 +
918 - "~
919 rac 920 +
921 - -~ ~
922 rac OH
923 +
924 - ~

No. Racemic or R3 R OH
enantiomer 0 H
925 rac N N
926 o 927 +
928 rac F 0 929 +

931 rac H
932 +

934 rac 935 +

937 rac 938 +
939 - -~' 940 rac CF, 941 +
942 - ~
943 rac 944 +

946 rac 947 +

949 rac 950 +
951 - -~
952 rac 953 +

955 rac V
956 +

958 rac 959 +

961 rac 962 +
963 - '~
964 rac 965 +
966 - -~
967 rac 968 +
969 - ~
970 rac NO
971 +

973 rac 974 +

976 rac CF977 +
978 - -~
979 rac 980 + ~

982 rac 983 +

985 rac 986 +

No. Racemic or R3 , enantiomer R OH
988 rac ar H

990 +
991 rac 992 + f/ F o 994 rac 995 +

997 rac 998 +

1000 rac 1001 +
1002 - -~' 1003 rac CF, 1004 +

1006 rac 1007 + N' 1009 rac o 1010 +

1012 rac 1013 +
1014 - -~' 1015 rac 1016 +
1017 - -~~
1018 rac 1019 +

1021 rac 1022 +
1023 - .-%
1024 rac o', 1025 +
1026 - "~
1027. rac N
1028 +
1029 - -~' 1030 rac 1031 +
1032 - 1033 rac No 1034 +

1036 rac 1037 +
1038 - -'' 1039 rac 1040 +
1041 - -~~
1042 rac 1043 +

1045 rac 1046 +

1048 rac OH
1049 +

No. Racemic or R3 enantiomer R3 1051 rac OH
1052 - /~ H
1053 + .~ ~ N N
1054 rac 0 o 1055 + -.5 ~, cF ' o 1057 rac 1058 +

1060 rac 1061 +

1063 rac 1064 +
1065 - -~' 1066 rac CF1 1067 +
1068 - ~' 1069 rac 1070 +

1072 rac o 1073 +

1075 rac 1076 +
1077 - -~' 1078 rac 1079 +

1081 rac N
1082 +

1084 rac 0 1085 +

1087 rac 1088 +
1089 - "~
1090 rac N

1092 - -~' 1093 rac 1094 +
1095 - -~' 1096 rac 1097 +

1099 rac 1100 +
1101 - -'' 1102 rac CF, 1103 +
1104 - -~~
1105 rac 1106 + ~
1107 - '~
1108 rac 1109 + ri 1111 rac OH
1112 +
1113 - ~' No. Racemic or R3 enantiomer R, 1114 rac OH
1115 - / cF3 H
1116 + " "
1117 r a c o o 1118 + F 0 1120 rac H
1121 +

1123 rac 1124 +
1125 - '~
1126 rac ~
1127 + ~I
1128 - -~~
1129 rac CF3 1130 +
1131 - ~
1132 rac õ' 1133 +

1135 rac O
1136 +

1138 rac 1139 +
1140 - -~
1141 rac F, 1142 +
1143 - -~
1144 rac \N/
1145 +

1147 rac o 1148 +

1150 rac o 1151 +
1152 - "~
1153 rac N
1154 +
1155 - -~~
1156 rac 1157 +
1158 - ' 1159 rac NO
1160 +

1162 rac 1163 +
1164 - -~' 1165 rac CF11166 +
1167 - -~
1168 rac 1169 +

1171 rac 1172 + ri 1174 rac 1175 +

No. Racemic or R3 enantiomer R3 1177 rac OH

1179 + N N
1180 rac o o 1181 + o 1183 rac 1184 +

1186 rac 1187 +
1188 - ~
1189 rac 1190 +
1191 - -~
1192 rac CF, 1193 +
1194 - -' 1195 rac 1196 + "_ 1198 rac 0 1199 +

1202 rac 1202 +
1203 - -~' 1204 rac 1205 +

1207 rac N~
1208 +

1210 rac 1211 +

1213 rac O~, 1214 + -1215 - ' 1216 rac N
1217 +
1218 - -~~
1219 rac 1220 +
1221 - ' 1222 rac NO
1223 + a' 1225 rac 1226 +
1227 - -' 1228 rac ~
1229 +

1231 rac 1232 +

1234 rac 1235 + r i 1237 rac OH
1238 +

No. Racemic or R3 enantiomer R3 1240 rac OH

1242 + N N
1243 rac o o 1244 + F
f~ o 1246 rac 1247 + "

1249 rac 1250 +

1252 rac 1253 +
1254 - -~
1255 rac CF3 1256 +
1257 - ~ ~
1258 rac 1259 + // N-1260 - ' 1261 rac 1262 +

1264 rac 1265 +
1266 - -~~
1267 rac "1268 +
1269 - -~
1270 rac 1271 +

1273 rac 1274 +

1276 rac O~
1277 +
1278 - '~
1279 rac N
1280 +
1281 -~
1282 rac 1283 +

1285 rac NO
1286 +

1288 rac 1289 + / ~

1291 rac CF
1292 + ~ i 1293 - -~
1294 rac 1295 +

1297 rac 1298 +
1299 - / ~
1300 rac 1302 - -~' No. Racemic or R3 enantiomer R3 1303 rac OH
1304 - / ci H
1305 + 4NLN
1306 rac o o 1307 + 151::~ F 0 1309 rac 1310 +

1312 rac 1313 +

1315 rac 1316 +
1317 - -~' 1318 rac CF3 1319 + ~ -1320 - ~
1321 rac 1322 +

1324 rac 1325 +

1327 rac 1328 +
1329 - -~
1330 rac '~
1331 +
1332 - -~~
1333 rac õ/
1334 +

1336 rac 1337 + -1338 - % 1339 rac O~
1340 +
1341 - "~
1342 rac 1343 +
1344 - -~
1345 rac 1346 +

1348 rac NO
1349 +

1351 rac 1352 +
1353 - '' 1354 rac CF
1355 +
1356 - -~
1357 rac 1358 +

1360 rac 1361 + ri 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 1372 rac 1373 +

1375 rac 1376 +
1377 - 1378 rac 1379 +
1380 - -~
1381 rac CF, 1382 +
1383 - ~
1384 rac 1385 +

1387 rac o 1388 +

1390 rac 1391 +
1392 - -~' 1393 rac ", 1394 +

1396 rac 1397 +

1399 rac 1400 +

1402 rac o', 1403 +
1404 - f 1405 rac N
1406 +
1407 - -~' 1408 rac 1409 +

1410 - 1411 rac No 1412 +

1414 rac 1415 +

1417 rac CF, 1418 +

1420 rac 1421 +

1423 rac 1424 +
1425 - -~
1426 rac OH
1427 +

No. Racemic or R3 enantiomer R 3 1429 rac OH
1430 cF3 H
1431 + N N
1432 rac 0 o 1433 + 0 1435 rac 1436 +

1438 rac 1439 +

1441 rac 1442 +
1443 - -~ ~
1444 rac CF, 1445 +

1447 rac 1448 + -1450 rac o 1453 rac 1454 +
1455 - -~~

1456 rac 1457 +
1458 - -~
1459 rac 1460 +

1462 rac 1463 +

1465 rac o', 1466 +
1467 - ' 1468 rac N
1469 +
1470 - -~
1471 rac 1472 +
1473 - 1474 rac 1475 + f/ ~No, 1477 rac 1478 +
1479 - '~
1480 rac CF
1481 +
1482 - -~
1483 rac 1484 +

1486 rac 1487 +

1489 rac OH
1490 +

No. Racemic or R3 enantiomer R3 1492 rac OH
1493 - / ci H
1494 + 54NLN
1495 rac o o 1496 + o 1498 rac 1499 +

1501 rac 1502 +

1504 rac 1505 +
1506 - -~' 1507 rac CF, 1508 +
1509 - ~
1510 rac 1511 +

1513 rac 1514 +

1516 rac 1517 +
1518 - -~' 1519 rac , 1520 +

1522 rac õ
1523 +

1525 rac 1526 +

1528 rac o'~
1529 +
1530 - ' 1531 rac "
1532 +
1533 - -~' 1534 rac 1535 + ~ i 1537 rac "o 1538 +

1540 rac 1541 +
1542 - -'' 1543 rac CF, 1544 +
1545 -~
1546 rac 1547 +
1548 - "~
1549 rac 1550 +
1551 - ~~
1552 rac "
1553 +

No. Racemic or R3 R' OH
enantiomer oder ci Enantiomer "
1555 rac N "
1556 - ~ o o 1557 + o 1558 rac 1559 +

1561 rac 1562 +

1564 rac 1565 +
1566 - 1567 rac 1568 +
1569 - -~
1570 rac CF, 1571 +
1572 - '' 1573 rac 1574 + "\

1576 rac 0 1577 +

1579 rac 1580 +
1581 - -~~
1582 rac ', 1583 +
1584 - -~
1585 rac 1586 +

1588 rac 1589 +

1591 rac 1592 +
1593 - '~
1594 rac 1595 +
1596 - -~
1597 rac 1598 +
1599 - -~
1600 rac "O
1601 + flo 1603 rac 1604 +
1605 - -'' 1606 rac ~
1607 +

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 1624 rac 1625 +

1627 rac 1628 +

1630 rac 1631 +
1632 - -~ ~
1633 rac CF, 1634 +
1635 - ~' 1636 rac 1637 + /~ ~ \

1639 rac 0 1640 +

1642 rac 1643 +
1644 - -~' 1645 rac CF
1646 +
1647 - .~
1648 rac 1649 +
1650 - .-~

1651 rac 1652 +

1654 rac o 1655 +
1656 - "~
1657 rac N
1658 +
1659 - -~
1660 rac 1661 +
1662 - 1663 rac õo 1664 + ~

1666 rac 1667 +

1669 rac 1670 +
1671 - -~~
1672 rac 1673 +

1675 rac 1676 + r j 1678 rac OH
1679 +

No. Racemic or R3 enantiomer 1681 rac R3 OH

1683 + ~ r"v ~
1684 rac o 1685 + o I~ f~ I

1687 rac 1688 +

1690 rac 1691 +

1693 rac 1694 +
1695 - -~' 1696 rac 1697 + ~ I
1698 - ~' 1699 rac 1700 + -1701 - % ' 1702 rac ~
1703 + ' i 1705 rac 1706 +
1707 - -~' 1708 rac 1709 +
1710 - -~~
1711 rac 1712 +

1714 rac 1715 +

1717 rac 1718 +
1719 - ' 1720 rac N
1721 +
1722 - -~' 1723 rac 1724 +
1725 - 1726 rac NO
1727 +

1729 rac 1730 +
1731 - '' 1732 rac CF1733 +
1734 - -~~
1735 rac 1736 +

1738 rac 1739 + ri 1741 rac OH
1742 +
1743 - "~

No. Racemic or R3 enantiomer R, 1744 rac ~ 1745 - 1746 + 1747 rac JJ>OH

0 o 1748 +

1750 rac 1751 +

1753 rac 1754 +
1755 - ' 1756 rac 1757 +
1758 - -~' 1759 rac CF, 1760 +
1761 - -~
1762 rac 1763 +
1764 - ' 1765 rac o 1766 +

1768 rac 1769 +
1770 - -~' 1771 rac CF, 1772 +

1774 rac \ N
1775 +
1776 - ",-6 1777 rac o 1778 +

1780 rac 1781 +
1782 - ' 1783 rac "
1784 +
1785 - -~
1786 rac 1787 +
1788 - ~ ' 1789 rac 1790 + "~

1792 rac 1793 +
1794 - -'' 1795 rac 1796 +

1798 rac 1799 + ~

1801 rac 1802 +

1804 rac 1805 +
1806 - -'' 1807 rac 1808 +

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 1819 rac 1820 +

1822 rac 1823 +
1824 - '' 1825 rac 1826 +

1828 rac CF
1829 +
1830 - ~' 1831 rac 1832 +

1834 rac 1835 +

1837 rac 1838 +
1839 - -~' 1840 rac ' , 1841 +

1843 rac 1844 +

1846 rac 1847 + -1848 - % ~ ~
1849 rac o 1850 +
1851 - ' 1852 rac N
1853 +
1854 - -~
1855 rac 1856 +
1857 - 1858 rac No 1859 + ,~ 2 1861 rac 1862 +

1864 rac CF
1865 +

1867 rac , i 1868 +

1870 rac 1871 + / i 1873 rac aõ
1874 + .
1875 - '' No. Racemic or R3 enantiomer R3 1876 rac OH

1878 + N \ N
1879 rac o o 1880 + 0 1882 rac 1883 + f/H

1885 rac 1886 + ~ I

1888 rac 1889 +
1890 - -~

1891 rac Cf, 1892 + -1893 - ~
1894 rac 1895 +

1897 rac 1898 +

1900 rac 1901 +
1902 - -~
1903 rac 1904 +
1905 - -~
1906 rac õ
1907 +

1909 rac 1910 + ~
1911 - %
1912 rac o', 1913 +
1914 - ' 1915 rac N
1916 +
1917 - -~~
1918 rac 1919 +

1921 rac NO
1922 +

1924 rac 1925 +

1927 rac CF
1928 +
1929 - -~
1930 rac , 1931 +

1933 rac 1934 + ~
1935 - '' 1936 rac "
1937 +

No. Racemic or R3 enantiomer R3 1939 rac o"
1940 - /~ o o H
1941 + d ~ N N
1942 rac 1943 + o 1945 rac 1946 + f/H

1948 rac 1949 +
1950 - ~
1951 rac 1952 +
1953 - -~
1954 rac CF
1955 +
1956 - ~
1957 rac 1958 +

1960 rac 0 1961 +

1963 rac 1964 +
1965 - -~
1966 rac "
1967 +
1968 - -~
1969 rac V
1970 +

1972 rac 0 1973 +

1975 rac o', 1976 +
1977 - "' 1978 rac "
1979 +
1980 - -~' 1981 rac 1982 +
1983 - ' 1984 rac 1985 + "~

1987 rac i 1988 +
1989 - -~' 1990 rac CF
1991 +
1992 - -~ 1993 rac 1994 +
1995 - '~
1996 rac 1997 + /~

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 2008 rac 2009 +

2011 rac 2012 +
2013 - '~
2014 rac 2015 +
2016 - -~
2017 rac rF, 2018 +
2019 - ~
2020 rac 2021 +
2022 - -~~
2023 rac o 2024 +

2026 rac 2027 +
2028 - -~' 2029 rac "2030 +

2032 rac õ
2033 +
2034 - ~
2035 rac 2036 +
2037 % z 2038 rac O', 2039 +
2040 - "' 2041 rac N
2042 +
2043 - -~' 2044 rac 2045 +
2046 - 2047 rac NO
2048 + /~ ~

2050 rac 2051 +
2052 - ' 2053 rac CF
2054 +
2055 - -~ ~
2056 rac , i 2057 + ~

2059 rac 2060 + r 2062 rac OH
2063 +

No. Racemic or R3 enantiomer R3 2065 rac OH
2066 - / ci H
2067 + N N
2068 rac o o 2069 + o 2071 rac 2072 + f /H

2074 rac 2075 +

2077 rac 2078 +

2080 rac CF, 2081 +
2082 - ~' 2083 rac 2084 +

2086 rac 0 2087 +

2089 rac 2090 +
2091 - -'~
2092 rac 2093 +
2094 - -~
2095 rac 2096 +

2098 rac 2099 +

2101 rac 2102 +
2103 - '~
2104 rac 2105 +
2106 - -~
2107 rac 2108 +
2109 - -'~
2110 rac No, 2111 +

2113 rac 2114 +

2116 rac CF
2117 +
2118 - -~~
2119 rac 2120 +

2122 rac 2123 +

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 2134 rac H
2135 +

2137 rac 2138 +

2140 rac 2141 +
2142 - -~
2143 rac U, 2144 +
2145 - ~' 2146 rac 2147 +

2149 rac o 2150 +

2152 rac 2153 +
2154 - -~' 2155 rac 2156 +

2158 rac õ
2159 +

2161 rac 2163 +

2164 rac a,~
2165 +
2166 - "' 2167 rac 2168 +
2169 - -~' 2170 rac 2171 +
2172 - ' 2173 rac 2174 +

2176 rac 2177 + / ~i 2179 rac CF, 2180 +

2182 rac , 2183 + ~~
2184 - "~

2185 rac 2186 + ri 2188 rac OH
2189 +

No. Racemic or R3 enantiomer R3 2191 rac OH
2192 - / CFa H
2193 + N ~ ~N
2194 rac o ~ ~ o 2195 + F 0 2197 rac H
2198 +

2200 rac 2201 +

2203 rac 2204 +
2205 - -~
2206 rac CF3 2207 +
2208 - -~
2209 rac 2210 + N' 2212 rac o 2213 +

2215 rac 2216 +
2217 - -~~
2218 rac 'F, 2219 +
2220 - -~~
2221 rac 2222 +

2224 rac 2225 +

2227 rac o'~
2228 +
2229 - ' 2230 rac N
2231 +
2232 - -~~

2233 rac 2234 +
2235 - ' 2236 rac No, 2237 +

2239 rac 2240 +
2241 - -~' 2242 rac CF, 2243 +
2244 - -~
2245 rac 2246 +

2248 rac 2249 +

2251 rac OH
2252 +

No. Racemic or R3 enantiomer R3 2254 rac o"
2255 - /~ c H
2256 + ! \ N ' N
2257 rac o o 2258 + o 2260 rac 2261 +

2263 rac 2264 +

2266 rac 2267 +
2268 - -~' 2269 rac CF, 2270 +
2271 - ~' 2272 rac 2273 +

2273 rac o 2276 +

2278 rac 2279 +
2280 - -~' 2281 rac F3I
2282 +
2283 - -~~
2284 rac 2285 +

2287 rac 2288 +

2290 rac o'~
2291 +

2293 rac N
2294 +
2295 - -~' 2296 rac 2297 +
2298 - -~~
2299 rac 2300 +

2302 rac 2303 +

2305 rac ~
2306 +
2307 - -~
2308 rac 2309 +
2310 - "~
2311 rac 2312 +

2314 rac OH
2315 +

No. Racemic or R3 enantiomer R3 2317 rac OH
2318 - /~ H
2319 + r ~ " C
'" 2320 rac o o 2321 + o 2323 rac 2324 + "

2326 rac 2327 + .

2329 rac 2330 +
2331 - -~' 2332 rac 'F
2333 + r 2335 rac 2336 + "
2337 \
2338 rac 2339 +

2341 rac 2342 +
2343 - -'~
2344 rac F
2345 +

2347 rac V
2348 +

2350 rac 2351 +

2353 rac o, 2354 +

2356 rac "
2357 +
2358 - -~~
2359 rac 2360 +

2362 rac "O, 2363 +

2365 rac 2366 +

2368 rac CF
2369 +
2370 - -~~
2371 rac 2372 +

2374 rac 2375 +
2376 - -~ ~
2377 rac OH
2378 +
2379 - '~

No. Racemic or R3 enantiomer R, 2380 rac OH
2381 - /~ o H
2382 + d \ N N
2383 rac o o 2384 + o 2386 rac 2387 + f/H

2389 rac 2390 +
2391 - ' 2392 rac 2393 +
2394 - -~' 2395 rac 2396 +
2397 - -' 2398 rac 2399 + "' 2400 - ' 2401 rac O
2402 +

2404 rac 2405 +
2406 - ' 2407 rac 2408 +

2410 rac \ N.
2411 +

2413 rac 0 2414 + -2416 rac O', 2417 +
2418 - ' 2419 rac 2420 +
2421 - -~
2422 rac 2423 +
2424 - ~ ' 2425 rac NO
2426 + ~_ 2428 rac 2429 +
2430 - -'' 2431 rac Cf, 2432 +

2434 rac , i 2435 +

2437 rac 2438 + r i 2440 rac aõ
2441 +
2442 - '~
No. Racemic or Structure enantiomer 2443 rac 2445 +
2446 rac 2447 +

2449 rac 2450 +
2451 - ~t 2452 rac 2453 +

2455 rac 2456 +

2458 rac 2459 +
2460 - b 2461 rac 2462 +

2464 rac 2465 +

2467 rac 2468 +

2470 rac 2471 +

2473 rac 2474 +

2476 rac 2477 +

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.

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 16 0,7 82 0,5 13 17b 0,03 88 n. b. 7 18 0,2 89 n. b. 8 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 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

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 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-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 preparations which may also be mentioned are for example suppositories and compositions for vaginal use.

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-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 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}-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:

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+].

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 -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%.

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, 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

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);

(527.0): LC-MS: m/z = 527 [M + H+].

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

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'].

rac-6-{4-(2-Chloro-4-fluorophenyl)-2-hydroxy-4-methyl-2-vinyl-pentanoylamino}-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 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 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

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).

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).

(+)-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

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) 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

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) 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 o 1 H-NMR (ppm, CDCI3, 400 MHz): 1.50 (3H), 1.68 (3H), 2.58 (3H), 2.64-2.81 (3H), 7.18 (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), 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

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 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 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 HO // H
N -N
~ O

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

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]-methyl-2,3-benzoxazin-l-one 30a and (-)-6-[2-[(4-Acetylphenyl)ethynyl]-2-hydroxy-4-methyl-4-phenylpentanoylamino]-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) 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

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) 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

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 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).

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 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

/
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 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).

(+)-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 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.

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 &HO O

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

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:

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 HO

HO

O

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).

Claims (26)

1 Compounds of the general formula I

R1 and R2 are independently of one another a hydrogen atom, a linear or nonlinear, branched or unbranched C1-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.ident.C-R a, where R a is a hydrogen or a C1-C8-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, C3-C10-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)R b, CO2R b, -O-R b, -S-R b, SO2NR c R d, -C(O)-NR c R d, -OC(O)-NR c R d, -C=NOR b -NR c R d or C3-C10-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 C1-C8-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, C1-C6-perfluoroalkyl, C1-C6-perfluoroalkoxy, C1-C6-alkoxy-C1-C6-alkoxy, (CH2)P C3-C10-cycloalkyl, (CH2)p-heterocycloalkyl, (CH2)p CN, (CH2)p Hal, (CH2)p NO2, (CH2)p-C6-C12-aryl, (CH2)p- heteroaryl, -(CH2)p PO3(R b)2, -(CH2)p NR c R d, -(CH2)p NR e COR b, -(CH2)p NR e CSR b, -(CH2)p NR e S(O)R b, -(CH2)p NR e S(O)2R b, -(CH2)p NR e CONR c R d, -(CH2)p NR e COOR b, -(CH2)p NR e C(NH)NR c R d, -(CH2)p NR e CSNR c R d, -(CH2)p NR e S(O)NR c R d, -(CH2)p NR e S(O)2NR c R d, -(CH2)p COR b, -(CH2)p CSR b, -(CH2)p S(O)R b, -(CH2)p S(O)(NH)R b, -(CH2)p S(O)2R b, -(CH2)p S(O)2NR c R d, -(CH2)p SO2OR b, -(CH2)p CO2R b, -(CH2)p CONR c R d, -(CH2)p CSNR c R d, -(CH2)p OR b, -(CH2)p SR b, -(CH2)p CR b(OH)-R e, -(CH2)p-C=NOR b, -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 C1-C6-alkyl or a group -COR b, CO2R b, -O-R b, or -NR c R d, where R b is a hydrogen or a C1-C6-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, C3-C10-cycloalkyl, C6-C12-aryl or C1-C3-perfluoroalkyl and R c and R d are independently of one another a hydrogen, C1-C6-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, C3-C10-cycloalkyl, C6-C12-aryl, C(O)R b or a hydroxy group, where if R c is a hydroxy group, then R d can only be a hydrogen, a C1-C6-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, C3-C10-cycloalkyl or C6-C12-aryl and vice versa, and R e is a hydrogen, C1-C6-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, C3-C10-cyclo-alkyl or C6-C12-aryl, and p can be a number from 0-6, or R3 is a radical C=C-R g R h, where R g and R h are independently of one another a hydrogen or a C1-C8-alkyl, C2-C8-alkenyl or C2-C8-alkynyl optionally substituted one or more times, identically or differently, by X, in which X is a cyano, halogen, hydroxy, nitro, -C(O)R b, CO2R b, -O-R b, -C(O)-NR c R d, -NR c R d with the meanings already mentioned before for R b, R c and R d, and R4 is a hydrogen atom, a methyl or an ethyl group or a partly or completely fluorinated C1-C3 alkyl group, A is a mono- or bicyclic carbocyclic or heterocyclic aromatic ring which may optionally be substituted one or more times by C1-C8-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, C1-C6-perfluoroalkyl, C1-C6-perfluoroalkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkoxy, (CH2)p-C3-C10-cycloalkyl, (CH2)p-heterocycloalkyl, (CH2)p CN, (CH2)p Hal, (CH2)p NO2, (CH2)p-C6-C12-aryl, (CH2)p-heteroaryl, -(CH2)p PO3(R b)2, -(CH2)p NR c R d, -(CH2)p NR e COR b, -(CH2)p NR e CSR b, -(CH2)p NR e S(O)R b, -(CH2)p NR e S(O)2R b, -(CH2)p NR e CONR c R d, -(CH2)p NR e COOR b, -(CH2)p NR e C(NH)NR c R d, -(CH2)p NR e CSNR c R d, -(CH2)p NR e S(O)NR c R d, -(CH2)p NR e S(O)2NR c R d, -(CH2)p COR b, -(CH2)p CSR b, -(CH2)p S(O)R b, -(CH2)p S(O)(NH)R b, -(CH2)p S(O)2R b, -(CH2)p S(O)2NR c R d, -(CH2)p SO2OR b, -(CH2)p CO2R b, -(CH2)p CONR c R d, -(CH2)p CSNR c R d, -(CH2)p OR b, -(CH2)p SR b, -(CH2)p CR b(OH)-R d, -(CH2)p -C=NOR b, -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 -CO2R b, C(O)NR c R d, COR b, or A is an alkenyl group -CR5=CR6R7, where R5, R6 and R7 are identical or different and are independently of one another hydrogen atoms, halogen atoms, aryl radicals or an unsubstituted or partly or completely fluorinated C1-C5 alkyl group, or A is an alkynyl group -C.ident.CR5, with the meaning stated above for R5, and B is a carbonyl or a CH2 group and their pharmaceutically acceptable salts.

2. Compounds according to Claim 1, in which R1 and R2 are preferably a hydrogen atom, a methyl or ethyl group.

3. Compounds according to Claim 1, in which R1 and R2 preferably form together with the C atom of the chain a ring having a total of 3-7 members.

4. Compounds according to Claim 1 to 3, in which R3 is preferably alkenyl, alkynyl, arylalkynyl, heteroarylalkynyl, cycloalkylalkynyl, heterocycloalkylalkynyl.

5. Compounds according to any of the preceding claims, in which R3 is preferably a vinyl, ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, hydroxypropynyl, hydroxybutynyl, 3-hydroxy-3-methylbutynyl, hydroxypentynyl, carboxypropynyl, t-butylcarboxypropynyl, phenylethynyl, (hydroxyphenyl)ethynyl, (methoxyphenyl)ethynyl, (dimethylaminophenyl)ethynyl, (methylphenyl)ethynyl, (cyanophenyl)ethynyl, (trifluoromethyl)ethynyl, (diphenyl)ethynyl, (nitrophenyl)ethynyl, (tert-butylphenyl)ethynyl, (acetylphenyl)ethynyl, (acetoxyphenyl)ethynyl, (carboxyphenyl)ethynyl or a benzylethynyl group.

6. Compounds according to any of the preceding claims, in which A is preferably an aromatic ring.

7. Compounds according to any of the preceding claims, in which A is preferably a phenyl or naphthyl radical.

8. Compounds according to Claim 7, in which A is preferably an unsubstituted or optionally mono- or polysubstituted phenyl radical.

9. Compounds according to Claim 8, where the phenyl radical is preferably substituted by one or two halogen atoms or one trifluoromethyl group.

10. Compounds according to Claim 9, in which the halogen atoms are preferably chlorine and/or fluorine.

11. Compounds according to Claims 1-8, in which A is preferably a phenyl ring substituted by -O-(CH2)r,-O- or -O-(CH2),-CH2-, where the respectively directly adjacent ring carbon atoms are linked.

12. Compounds according to any of the preceding claims, in which R4 is a hydrogen atom, a methyl or a trifluoromethyl radical.

13. Compounds according to Claim 1 to 5, namely ~

~

~

14. Pharmaceutical composition comprising at least one compound of the general formula I according to any of Claims 1 to 13 and, where appropriate, at least one further active ingredient together with pharmaceutically suitable excipients and/or carriers.

15. Pharmaceutical composition according to Claim 14, where the further active ingredient is a SERM (selective estrogen receptor modulator), an aromatase inhibitor, an antiestrogen or a prostaglandin.

16. Pharmaceutical composition according to Claim 14, where the active ingredient may be tamoxifen, 5-(4-{5-[(RS)-(4,4,5,5,5-pentafluoropentyl)sulphinyl]pentyloxy}phenyl)-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol, ICI 182 780 (7alpha-[9-(4,4,5,5-pentafluoropentylsulphinyl)nonyl]estra-1,3,5(10)-triene-3,17beta-diol), 11beta-fluoro-7alpha-[5-(methyl{3-[(4,4,5,5,5-pentafluoropentyl)sulphanyl]-propyl}amino)pentyl]estra-1,3,5(10)-triene-3,17beta-diol, 11beta-fluoro-7alpha-{5-[methyl(7,7,8,8,9,9,10,10,10-nonafluorodecyl)amino]pentyl}estra-1,3,5(10)-triene-3,17beta-diol, 11beta-fluoro-17alpha-methyl-7alpha-{5-[methyl(8,8,9,9,9-pentafluorononyl)amino]pentyl}estra-1,3,5(10)-triene-3,17beta-diol, clomifen, raloxifen, fadrozole, formestane, letrozole, anastrozole or atamestane.

17. Use of compounds according to any of Claims 1 to 13 for producing a medicament.

18. Use of compounds according to Claim 17 for producing a medicament for the therapy and prophylaxis of gynaecological disorders such as endometriosis, leiomyomas of the uterus, dysfunctional bleeding and dysmenorrhoea.

19. Use of compounds according to Claim 17 for producing a medicament for the therapy and prophylaxis of hormone-dependent tumours.

20. Use of compounds according to Claim 17 for producing a medicament for the therapy and prophylaxis of breast carcinomas.

21. Use of compounds according to Claim 17 for producing a medicament for the therapy and prophylaxis of endometrial carcinoma.

22. Use of compounds according to Claim 17 for producing a medicament for the therapy and prophylaxis of ovarian carcinomas.

23. Use of compounds according to Claim 17 for producing a medicament for the therapy and prophylaxis of prostate carcinomas.

24. Use of compounds according to Claim 17 for producing a medicament for female hormone replacement therapy.

25. Use of compounds according to Claim 17 for female fertility control.

26. Process for the selective addition of lithium alkynyl and magnesium haloalkynyl compounds onto a keto amide.