Nonsteroidal progesterone receptor modulators
View Patent ↗This invention relates to nonsteroidal progesterone receptor modulators of general formula I, a process for their production, the use of progesterone receptor modulators for the production of pharmaceutical agents as well as pharmaceutical compositions that contain these compounds. The compounds according to the invention are suitable for therapy and prophylaxis of gynecological diseases, such as endometriosis, leiomyomas of the uterus, dysfunctional bleeding and dysmenorrhea, as well as for the therapy and prophylaxis of hormone-dependent tumors and for use for female birth control as well as for hormone replacement therapy.
1. A compound of formula I
in which
R 1 and R 2 , independently of one another, mean a hydrogen atom, a straight or nonstraight, branched or unbranched C 1 -C 5 -alkyl group, or together with the C atom of the chain forming a ring with a total of 3-7 members,
R 3 means a radical C≡C—R a , wherein
R a means a hydrogen or a C 1 -C 8 -alkyl, C 2 -C 8 -alkenyl, C 2 -C 8 -alkinyl, C 3 -C 10 -cycloalkyl, or heterocycloalkyl that optionally is substituted in one or more places, in the same way or differently, with K, or an aryl or heteroaryl that optionally is substituted in one or more places, in the same way or differently, with L,
K is a cyano, halogen, hydroxy, nitro, —C(O)R b , CO 2 R b , —O—R b , —S—R b , SO 2 NR c R d , —C(O)—NR c R d , —OC(O)—NR c R d , or —C═NOR b —NR c R d or a C 3 -C 10 -cycloalkyl that optionally is substituted in one or more places, in the same way or differently, with M, heterocycloalkyl, or aryl or heteroaryl that optionally is substituted in one or more places with L,
L means C 1 -C 8 -alkyl, C 2 -C 8 -alkenyl, C 2 -C 8 -alkinyl, C 1 -C 6 -perfluoroalkyl, C 1 -C 6 -perfluoroalkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkoxy, (CH 2 ) p —C 3 -C 10 -cycloalkyl, (CH 2 ) p -heterocycloalkyl, (CH 2 ) p CN, (CH 2 ) p Hal, (CH 2 ) p NO 2 , (CH 2 ) p —C 6 -C 12 -aryl, (CH 2 ) p -heteroaryl, —(CH 2 ) p PO 3 (R b ) 2 , —(CH 2 ) p NR c R d , —(CH 2 ) p NR e COR b , —(CH 2 ) p NR e CSR b , —(CH 2 ) p NR e S(O)R b , —(CH 2 ) p NR e S(O) 2 R b , —(CH 2 ) p NR e CONR c R d , —(CH 2 ) p NR e COOR b , —(CH 2 ) p NR e C(NH)NR c R d , —(CH 2 ) p NR e CSNR c R d , —(CH 2 ) p NR e S(O)NR c R d , —(CH 2 ) p NR e S(O) 2 NR c R d , —(CH 2 ) p COR b , —(CH 2 ) p CSR b , —(CH 2 ) p S(O)R b , —(CH 2 ) p S(O)(NH)R b , —(CH 2 ) p S(O) 2 R b , —(CH 2 ) p S(O) 2 NR c R d , —(CH 2 ) p SO 2 OR b , —(CH 2 ) p CO 2 R b , —(CH 2 ) p CONR c R d , —(CH 2 ) p CSNR c R d , —(CH 2 ) p OR b , —(CH 2 ) p SR b , —(CH 2 ) p CR b (OH)—R e , —(CH 2 ) p —C═NOR b , —O—(CH 2 ) n —O—, —O—(CH 2 ) n —CH 2 —, —O—CH═CH— or —(CH 2 ) n+2 —, wherein n=1 or 2, and the terminal oxygen atoms and/or carbon atoms are linked to directly adjacent ring-carbon atoms,
M means C 1 -C 6 -alkyl or a group —COR b , CO 2 R b , —O—R b , or —NR c R d , wherein
R b means a hydrogen or a C 1 -C 6 -alkyl, C 2 -C 8 -alkenyl, C 2 -C 8 -alkinyl, C 3 -C 10 -cycloalkyl, C 6 -C 12 -aryl or C 1 -C 3 -perfluoroalkyl and
R c and R d , independently of one another, mean a hydrogen, C 1 -C 6 -alkyl, C 2 -C 8 -alkenyl, C 2 -C 8 -alkinyl, C 3 -C 10 -cycloalkyl, C 6 -C 12 -aryl, C(O)R b or a hydroxy group,
wherein if
R c is a hydroxy group, R d can be only one hydrogen, a C 1 -C 6 -alkyl, C 2 -C 8 -alkenyl, C 2 -C 8 -alkinyl, C 3 -C 10 -cycloalkyl or C 6 -C 12 -aryl and vice versa, and
R e means a hydrogen, C 1 -C 6 -alkyl, C 2 -C 8 -alkenyl, C 2 -C 8 -alkinyl, C 3 -C 10 -cycloalkyl or C 6 -C 12 -aryl, and
p is a number from 0 to 6,
R 4a and R 4b , independently of one another, mean a hydrogen atom, a C 1 -C 4 -alkyl, a C 2 -C 4 -alkenyl or together with the ring-carbon atom forming a 3- to 6-membered ring,
A means a monocyclic or bicyclic, carbocyclic or heterocyclic aromatic ring, which is optionally substituted in one or more places with C 1 -C 8 -alkyl, C 2 -C 8 -alkenyl, C 2 -C 8 -alkinyl, C 1 -C 6 -perfluoroalkyl, C 1 -C 6 -perfluoroalkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy-C 1 -C 6 -alkoxy, (CH 2 ) p —C 3 -C 10 -cycloalkyl, (CH 2 ) p -heterocycloalkyl, (CH 2 ) p CN, (CH 2 ) p Hal, (CH 2 ) p NO 2 , (CH 2 ) p —C 6 -C 12 -aryl, (CH 2 ) p -heteroaryl, —(CH 2 ) p PO 3 (R b ) 2 , —(CH 2 ) p NR c R d , —(CH 2 ) p NR e COR b , —(CH 2 ) p NR e CSR b , —(CH 2 ) p NR e S(O)R b , —(CH 2 ) p NR e S(O) 2 R b , —(CH 2 ) p NR e CONR c R d , —(CH 2 ) p NR e COOR b , —(CH 2 ) p NR e C(NH)NR c R d , —(CH 2 ) p NR e CSNR c R d , —(CH 2 ) p NR e S(O)NR c R d , —(CH 2 ) p NR e S(O) 2 NR c R d , —(CH 2 ) p COR b , —(CH 2 ) p CSR b , —(CH 2 ) p S(O)R b , —(CH 2 ) p S(O)(NH)R b , —(CH 2 ) p S(O) 2 R b , —(CH 2 ) p S(O) 2 NR c R d , —(CH 2 ) p SO 2 OR b , —(CH 2 ) p CO 2 R b , —(CH 2 ) p CONR c R d , —(CH 2 ) p CSNR c R d , —(CH 2 ) p OR b , —(CH 2 ) p SR b , —(CH 2 ) p CR b (OH)—R d , —(CH 2 ) p —C═NOR b , —O—(CH 2 ) n —O—, —O—(CH 2 ) n —CH 2 —, —O—CH═CH— or —(CH 2 ) n+2 —, wherein n=1 or 2, and the terminal oxygen atoms and/or carbon atoms are linked to directly adjacent ring-carbon atoms, and
B means a carbonyl group, or a pharmaceutically acceptable salts thereof.
2. A compound according to claim 1 , in which R 1 and R 2 mean a hydrogen atom, a methyl group or an ethyl group.
3. A compound according to claim 1 , in which R 1 and R 2 together with the C atom of the chain form a ring with a total of 3 to 7 links.
4. A compound according to claim 1 , in which R 3 means alkinyl, arylalkinyl, heteroarylalkinyl, cycloalkylalkinyl, or heterocycloalkylalkinyl.
5. A compound according to claim 1 , in which R 3 means ethinyl, propinyl, butinyl, pentinyl, hexinyl, heptinyl, octinyl, hydroxypropinyl, hydroxybutinyl, 3-hydroxy-3-methylbutinyl, hydroxypentinyl, carboxypropinyl, t-butylcarboxypropinyl, phenylethinyl, (hydroxyphenyl)ethinyl, (methoxyphenyl)ethinyl, (dimethylaminophenyl)ethinyl, (methylphenyl)ethinyl, (cyanophenyl)ethinyl, (trifluoromethyl)ethinyl, (diphenyl)ethinyl, (nitrophenyl)ethinyl, (tert-butylphenyl)ethinyl, (acetylphenyl)ethinyl, (acetoxyphenyl)ethinyl, (carboxyphenyl)ethinyl or a benzylethinyl group.
6. A compound according to claim 1 , in which A is an aromatic ring.
7. A compound according to claim 1 , in which A is a phenyl or naphthyl radical.
8. A compound according to claim 7 , in which A is an unsubstituted phenyl radical or a phenyl radical that is substituted in one or more places.
9. A compound according to claim 8 , wherein the phenyl radical is substituted with one or two halogen atoms or a trifluoromethyl group.
10. A compound according to claim 9 , in which the one or two halogen atoms are chlorine and/or fluorine.
11. A compound according to claim 1 , in which A is an —O—(CH 2 ) n —O— or —O—(CH 2 ) n —CH 2 -substituted phenyl ring, wherein the respectively directly adjacent ring-carbon atoms are linked.
12. A compound according to claim 1 , in which R 4a and R 4b , independently of one another, in each case are a hydrogen atom.
13. A compound according to claim 1 , which is one of the following compounds
Racemic or
No.
Enantiomer
R3
1 2 3
rac+−
4 5 6
rac+−
7 8 9
rac+−
101112
rac+−
131415
rac+−
161718
rac+−
192021
rac+−
222324
rac+−
252627
rac+−
282930
rac+−
313233
rac+−
343536
rac+−
373839
rac+−
404142
rac+−
434445
rac+−
464748
rac+−
495051
rac+−
525354
rac+−
555657
rac+−
585960
rac+−
Racemic or
No.
Enantiomer
R3
616263
rac+−
646566
rac+−
676869
rac+−
707172
rac+−
737475
rac+−
767778
rac+−
798081
rac+−
828384
rac+−
858687
rac+−
888990
rac+−
919293
rac+−
949596
rac+−
979899
rac+−
100 101 102
rac+−
103 104 105
rac+−
106 107 108
rac+−
109 110 111
rac+−
112 113 114
rac+−
115 116 117
rac+−
118 119 120
rac+−
Racemic or
No.
Enantiomer
R3
121122123
rac+−
124125126
rac+−
127128129
rac+−
130131132
rac+−
133134135
rac+−
136137138
rac+−
139140141
rac+−
142143144
rac+−
145146147
rac+−
148149150
rac+−
151152153
rac+−
154155156
rac+−
157158159
rac+−
160161162
rac+−
163164165
rac+−
166167168
rac+−
169170171
rac+−
172173174
rac+−
175176177
rac+−
178179180
rac+−
Racemic or
No.
Enantiomer
R3
181182183
rac+−
184185186
rac+−
187188189
rac+−
190191192
rac+−
193194195
rac+−
196197198
rac+−
199200201
rac+−
202203204
rac+−
205206207
rac+−
208209210
rac+−
211212213
rac+−
214215216
rac+−
217218219
rac+−
220221222
rac+−
223224225
rac+−
226227228
rac+−
229230231
rac+−
232233234
rac+−
235236237
rac+−
238239240
rac+−
Racemic or
No.
Enantiomer
R3
241242243
rac+−
244245246
rac+−
247248249
rac+−
250251252
rac+−
253254255
rac+−
256257258
rac+−
259260261
rac+−
262263264
rac+−
265266267
rac+−
268269270
rac+−
271272273
rac+−
274275276
rac+−
277278279
rac+−
280281282
rac+−
283284285
rac+−
286287288
rac+−
289290291
rac+−
292293294
rac+−
295296297
rac+−
298299300
rac+−
Racemic or
No.
Enantiomer
R3
301302303
rac+−
304305306
rac+−
307308309
rac+−
310311312
rac+−
313314315
rac+−
316317318
rac+−
319320321
rac+−
322323324
rac+−
325326327
rac+−
328329330
rac+−
331332333
rac+−
334335336
rac+−
337338339
rac+−
340341342
rac+−
343344345
rac+−
346347348
rac+−
349350351
rac+−
352353354
rac+−
355356357
rac+−
358359360
rac+−
Racemic or
No.
Enantiomer
R3
361362363
rac+−
364365366
rac+−
367368369
rac+−
370371372
rac+−
373374375
rac+−
376377378
rac+−
379380381
rac+−
382383384
rac+−
385386387
rac+−
388389390
rac+−
391392393
rac+−
394395396
rac+−
397398399
rac+−
400401402
rac+−
403404405
rac+−
406407408
rac+−
409410411
rac+−
412413414
rac+−
415416417
rac+−
418419420
rac+−
Racemic or
No.
Enantiomer
R3
421422423
rac+−
424425426
rac+−
427428429
rac+−
430431432
rac+−
433434435
rac+−
436437438
rac+−
439440441
rac+−
442443444
rac+−
445446447
rac+−
448449450
rac+−
451452453
rac+−
454455456
rac+−
457458459
rac+−
460461462
rac+−
463464465
rac+−
466467468
rac+−
469470471
rac+−
472473474
rac+−
475476477
rac+−
478479480
rac+−
Racemic or
No.
Enantiomer
R3
481482483
rac+−
484485486
rac+−
487488489
rac+−
490491492
rac+−
493494495
rac+−
496497498
rac+−
499500501
rac+−
502503504
rac+−
505506507
rac+−
508509510
rac+−
511512513
rac+−
214515516
rac+−
517518519
rac+−
520521522
rac+−
523524525
rac+−
526227528
rac+−
529530531
rac+−
532533534
rac+−
535536537
rac+−
538539540
rac+−
Racemic or
No.
Enantiomer
R3
541542543
rac+−
544545546
rac+−
547548549
rac+−
550551552
rac+−
553554555
rac+−
556557558
rac+−
559560561
rac+−
562563564
rac+−
565566567
rac+−
568569570
rac+−
571572573
rac+−
574575576
rac+−
577578579
rac+−
580581582
rac+−
583584585
rac+−
586587588
rac+−
589590591
rac+−
592593594
rac+−
595596597
rac+−
598599600
rac+−
Racemic or
No.
Enantiomer
R3
601602603
rac+−
604605606
rac+−
607608609
rac+−
610611612
rac+−
613614615
rac+−
616617618
rac+−
619620621
rac+−
622623624
rac+−
625626627
rac+−
628629630
rac+−
631632633
rac+−
634635636
rac+−
637638639
rac+−
640641642
rac+−
643644645
rac+−
646647648
rac+−
649650651
rac+−
652653654
rac+−
655656657
rac+−
658659660
rac+−
Racemic or
No.
Enantiomer
R3
661662663
rac+−
664665666
rac+−
667668669
rac+−
670671672
rac+−
673674675
rac+−
676677678
rac+−
679680681
rac+−
682683684
rac+−
685686687
rac+−
688689690
rac+−
691692693
rac+−
694695696
rac+−
697698699
rac+−
700701702
rac+−
703704705
rac+−
706707708
rac+−
709710711
rac+−
712713714
rac+−
715716717
rac+−
718719720
rac+−
Racemic or
No.
Enantiomer
R3
721722723
rac+−
724725726
rac+−
727728729
rac+−
730731732
rac+−
733734735
rac+−
736737738
rac+−
739740741
rac+−
742743744
rac+−
745746747
rac+−
748749750
rac+−
751752753
rac+−
754755756
rac+−
757758759
rac+−
760761762
rac+−
763764765
rac+−
766767768
rac+−
769770771
rac+−
772773774
rac+−
775776777
rac+−
778779780
rac+−
Racemic or
No.
Enantiomer
R3
781782783
rac+−
784785786
rac+−
787788789
rac+−
790791792
rac+−
793794795
rac+−
796797798
rac+−
799800801
rac+−
802803804
rac+−
805806807
rac+−
808809810
rac+−
811812813
rac+−
814815816
rac+−
817818819
rac+−
820821822
rac+−
823824825
rac+−
826827828
rac+−
829830831
rac+−
832833834
rac+−
835836837
rac+−
838839840
rac+−
Racemic or
No.
Enantiomer
R3
841842843
rac+−
844845846
rac+−
847848849
rac+−
850851852
rac+−
853854855
rac+−
856857858
rac+−
859860861
rac+−
862863864
rac+−
865866867
rac+−
868869870
rac+−
871872873
rac+−
874875876
rac+−
877878879
rac+−
880881882
rac+−
883884885
rac+−
886887888
rac+−
889890891
rac+−
892893894
rac+−
895896897
rac+−
898899900
rac+−
Racemic or
No.
Enantiomer
R3
901902903
rac+−
904905906
rac+−
907908909
rac+−
910911912
rac+−
913914915
rac+−
916917918
rac+−
919920921
rac+−
922923924
rac+−
925926927
rac+−
928929930
rac+−
931932933
rac+−
934935936
rac+−
937938939
rac+−
940941942
rac+−
943944945
rac+−
946947948
rac+−
949950951
rac+−
952953954
rac+−
955956957
rac+−
958959960
rac+−
Racemic or
No.
Enantiomer
R3
961 962 963
rac+−
964 965 966
rac+−
967 968 969
rac+−
970 971 972
rac+−
973 974 975
rac+−
976 977 978
rac+−
979 980 981
rac+−
982 983 984
rac+−
985 986 987
rac+−
988 989 990
rac+−
991 992 993
rac+−
994 995 996
rac+−
997 998 999
rac+−
100010011002
rac+−
100310041005
rac+−
100610071008
rac+−
100910101011
rac+−
101210131014
rac+−
101510161017
rac+−
101810191020
rac+−
Racemic or
No.
Enantiomer
R3
102110221023
rac+−
102410251026
rac+−
102710281029
rac+−
103010311032
rac+−
103310341035
rac+−
103610371038
rac+−
103910401041
rac+−
104210431044
rac+−
104510461047
rac+−
104810491050
rac+−
105110521053
rac+−
105410551056
rac+−
105710581059
rac+−
106010611062
rac+−
106310641065
rac+−
106610671068
rac+−
106910701071
rac+−
107210731074
rac+−
107510761077
rac+−
107810791080
rac+−
Racemic or
No.
Enantiomer
R3
108110821083
rac+−
108410851086
rac+−
108710881089
rac+−
109010911092
rac+−
109310941095
rac+−
109610971098
rac+−
109911001101
rac+−
110211031104
rac+−
110511061107
rac+−
110811091110
rac+−
111111121113
rac+−
111411151116
rac+−
111711181119
rac+−
112011211122
rac+−
112311241125
rac+−
112611271128
rac+−
112911301131
rac+−
113211331134
rac+−
113511361137
rac+−
113811391140
rac+−
Racemic or
No.
Enantiomer
R3
114111421143
rac+−
114411451146
rac+−
114711481149
rac+−
115011511152
rac+−
115311541155
rac+−
115611571158
rac+−
115911601161
rac+−
116211631164
rac+−
116511661167
rac+−
116811691170
rac+−
117111721173
rac+−
117411751176
rac+−
117711781179
rac+−
118011811182
rac+−
118311841185
rac+−
118611871188
rac+−
118911901191
rac+−
119211931194
rac+−
119511961197
rac+−
119811991200
rac+−
Racemic or
No.
Enantiomer
R3
120112021203
rac+−
120412051206
rac+−
120712081209
rac+−
121012111212
rac+−
121312141215
rac+−
121612171218
rac+−
121912201221
rac+−
122212231224
rac+−
122512261227
rac+−
122812291230
rac+−
123112321233
rac+−
123412351236
rac+−
123712381239
rac+−
124012411242
rac+−
124312441245
rac+−
124612471248
rac+−
124912501251
rac+−
125212531254
rac+−
125512561257
rac+−
125812591260
rac+−
Racemic or
No.
Enantiomer
R3
126112621263
rac+−
126412651266
rac+−
126712681269
rac+−
127012711272
rac+−
127312741275
rac+−
127612771278
rac+−
127912801281
rac+−
128212831284
rac+−
128512861287
rac+−
128812891290
rac+−
129112921293
rac+−
129412951296
rac+−
129712981299
rac+−
130013011302
rac+−
130313041305
rac+−
130613071308
rac+−
130913101311
rac+−
131213131314
rac+−
131513161317
rac+−
131813191320
rac+−
Racemic or
No.
Enantiomer
R3
132113221323
rac+−
132413251326
rac+−
132713281329
rac+−
133013311332
rac+−
133313341335
rac+−
133613371338
rac+−
133913401341
rac+−
134213431344
rac+−
134513461347
rac+−
134813491350
rac+−
135113521353
rac+−
135413551356
rac+−
135713581359
rac+−
136013611362
rac+−
136313641365
rac+−
136613671368
rac+−
136913701371
rac+−
137213731374
rac+−
137513761377
rac+−
137813791380
rac+−
Racemic or
No.
Enantiomer
R3
138113821383
rac+−
138413851386
rac+−
138713881389
rac+−
139013911392
rac+−
139313941395
rac+−
139613971398
rac+−
139914001401
rac+−
140214031404
rac+−
140514061407
rac+−
140814091410
rac+−
141114121413
rac+−
141414151416
rac+−
141714181419
rac+−
142014211422
rac+−
142314241425
rac+−
142614271428
rac+−
142914301431
rac+−
143214331434
rac+−
143514361437
rac+−
143814391440
rac+−
Racemic or
No.
Enantiomer
R3
144114421443
rac+−
144414451446
rac+−
144714481449
rac+−
145014511452
rac+−
145314541455
rac+−
145614571458
rac+−
145914601461
rac+−
146214631464
rac+−
146514661467
rac+−
146814691470
rac+−
147114721473
rac+−
147414751476
rac+−
147714781479
rac+−
148014811482
rac+−
148314841485
rac+−
148614871488
rac+−
148914901491
rac+−
149214931494
rac+−
149514961497
rac+−
149814991500
rac+−
Racemic or
No.
Enantiomer
R3
150115021503
rac+−
150415051506
rac+−
150715081509
rac+−
151015111512
rac+−
151315141515
rac+−
151615171518
rac+−
151915201521
rac+−
152215231524
rac+−
152515261527
rac+−
152815291530
rac+−
153115321533
rac+−
153415351536
rac+−
153715381539
rac+−
154015411542
rac+−
154315441545
rac+−
154615471548
rac+−
154915501551
rac+−
155215531554
rac+−
155515561557
rac+−
155815591560
rac+−
Racemic or
No.
Enantiomer
R3
156115621563
rac+−
156415651566
rac+−
156715681569
rac+−
157015711572
rac+−
157315741575
rac+−
157615771578
rac+−
157915801581
rac+−
158215831584
rac+−
158515861587
rac+−
158815891590
rac+−
159115921593
rac+−
159415951596
rac+−
159715981599
rac+−
160016011602
rac+−
160316041605
rac+−
160616071608
rac+−
160916101611
rac+−
161216131614
rac+−
161516161617
rac+−
161816191620
rac+−
14. A compound according to claim 8 , in which A is an unsubstituted phenyl radical.
15. A pharmaceutical composition comprising a compound according to claim 1 and one or more pharmaceutically acceptable carriers, adjuvants and/or vehicles.
16. A pharmaceutical composition comprising a compound according to claim 13 and one or more pharmaceutically acceptable carriers, adjuvants and/or vehicles.
17. A compound according to claim 13 , which is one of the compounds from compounds numbers 1-120, 481-540, 961-1140, 1201-1260, 1321-1380, and 1561-1620.
18. A compound according to claim 13 , which is one of the compounds from compounds numbers 121-480, 541-720, 781-960 and 1261-1320.
19. A compound according to claim 13 , which is one of the compounds from compounds numbers 721-780.
20. A compound according to claim 13 , which is one of the compounds from compounds numbers 1141-1200.
21. A compound according to claim 13 , which is one of the compounds from compounds numbers 1381-1440.
22. A compound according to claim 13 , which is one of the compounds from compounds numbers 1441-1500.
23. A compound according to claim 13 , which is one of the compounds from compounds numbers 1501-1560.
24. A compound according to claim 13 , which is one of the compounds from compounds numbers 1-60.
25. A compound according to claim 13 , which is one of the compounds from compounds numbers 121-300.
26. A compound according to claim 13 , which is one of the compounds from compounds numbers 1441-1500.