CA2241623A1 - Use of 3,4-diphenyl chromans for the manufacture of a pharmaceutical composition for the treatment or prophylaxis of menopausal symptoms - Google Patents
Use of 3,4-diphenyl chromans for the manufacture of a pharmaceutical composition for the treatment or prophylaxis of menopausal symptoms Download PDFInfo
- Publication number
- CA2241623A1 CA2241623A1 CA002241623A CA2241623A CA2241623A1 CA 2241623 A1 CA2241623 A1 CA 2241623A1 CA 002241623 A CA002241623 A CA 002241623A CA 2241623 A CA2241623 A CA 2241623A CA 2241623 A1 CA2241623 A1 CA 2241623A1
- Authority
- CA
- Canada
- Prior art keywords
- use according
- compound
- phenyl
- treatment
- menopausal symptoms
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 206010027304 Menopausal symptoms Diseases 0.000 title claims abstract description 16
- 238000011282 treatment Methods 0.000 title claims abstract description 16
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 9
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 5
- 238000011321 prophylaxis Methods 0.000 title claims abstract description 4
- 239000004305 biphenyl Substances 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 42
- 150000003839 salts Chemical class 0.000 claims abstract description 21
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 10
- 239000001257 hydrogen Substances 0.000 claims abstract description 10
- 125000001302 tertiary amino group Chemical group 0.000 claims abstract description 9
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims abstract description 7
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 4
- 150000002367 halogens Chemical class 0.000 claims abstract description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 3
- 239000003937 drug carrier Substances 0.000 claims abstract description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract 5
- 150000002431 hydrogen Chemical class 0.000 claims abstract 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract 2
- 239000000203 mixture Substances 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 8
- XZEUAXYWNKYKPL-URLMMPGGSA-N ormeloxifene Chemical compound C1([C@@H]2[C@H](C3=CC=C(C=C3OC2(C)C)OC)C=2C=CC(OCCN3CCCC3)=CC=2)=CC=CC=C1 XZEUAXYWNKYKPL-URLMMPGGSA-N 0.000 claims description 8
- 229960003327 ormeloxifene Drugs 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 230000002265 prevention Effects 0.000 claims description 4
- 230000002500 effect on skin Effects 0.000 claims description 3
- 239000007943 implant Substances 0.000 claims description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- -1 n-amyl Chemical group 0.000 description 13
- 239000000262 estrogen Substances 0.000 description 8
- 229940011871 estrogen Drugs 0.000 description 8
- 125000003545 alkoxy group Chemical group 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 208000024891 symptom Diseases 0.000 description 5
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- 230000000740 bleeding effect Effects 0.000 description 3
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 3
- 238000013270 controlled release Methods 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 229940093915 gynecological organic acid Drugs 0.000 description 3
- 230000009245 menopause Effects 0.000 description 3
- 230000002175 menstrual effect Effects 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- 235000005985 organic acids Nutrition 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 239000005711 Benzoic acid Substances 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical class C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- 235000011054 acetic acid Nutrition 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 235000010233 benzoic acid Nutrition 0.000 description 2
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 2
- 235000015165 citric acid Nutrition 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 239000001530 fumaric acid Substances 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 239000004310 lactic acid Substances 0.000 description 2
- 235000014655 lactic acid Nutrition 0.000 description 2
- XZEUAXYWNKYKPL-WDYNHAJCSA-N levormeloxifene Chemical compound C1([C@H]2[C@@H](C3=CC=C(C=C3OC2(C)C)OC)C=2C=CC(OCCN3CCCC3)=CC=2)=CC=CC=C1 XZEUAXYWNKYKPL-WDYNHAJCSA-N 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 235000011007 phosphoric acid Nutrition 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 239000000583 progesterone congener Substances 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 230000001850 reproductive effect Effects 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 1
- 125000006176 2-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 206010002942 Apathy Diseases 0.000 description 1
- 208000006820 Arthralgia Diseases 0.000 description 1
- 208000004746 Atrophic Vaginitis Diseases 0.000 description 1
- 206010003693 Atrophic vulvovaginitis Diseases 0.000 description 1
- 206010065687 Bone loss Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 241001677188 Coccus viridis Species 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- 206010014733 Endometrial cancer Diseases 0.000 description 1
- 206010014759 Endometrial neoplasm Diseases 0.000 description 1
- 201000009273 Endometriosis Diseases 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- 208000033830 Hot Flashes Diseases 0.000 description 1
- 206010060800 Hot flush Diseases 0.000 description 1
- 206010022998 Irritability Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 208000010428 Muscle Weakness Diseases 0.000 description 1
- 206010028372 Muscular weakness Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 206010033557 Palpitations Diseases 0.000 description 1
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 206010046798 Uterine leiomyoma Diseases 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000001833 anti-estrogenic effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 229940107161 cholesterol Drugs 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 230000002301 combined effect Effects 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 208000002173 dizziness Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000002124 endocrine Effects 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 206010016256 fatigue Diseases 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 235000011167 hydrochloric acid Nutrition 0.000 description 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229910052500 inorganic mineral Chemical class 0.000 description 1
- 206010022437 insomnia Diseases 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 201000010260 leiomyoma Diseases 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000011707 mineral Chemical class 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 230000036651 mood Effects 0.000 description 1
- 210000000663 muscle cell Anatomy 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 229940127234 oral contraceptive Drugs 0.000 description 1
- 239000003539 oral contraceptive agent Substances 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- 230000002611 ovarian Effects 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 201000010808 postmenopausal atrophic vaginitis Diseases 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 230000036299 sexual function Effects 0.000 description 1
- 230000000392 somatic effect Effects 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 210000004243 sweat Anatomy 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 208000010579 uterine corpus leiomyoma Diseases 0.000 description 1
- 201000007954 uterine fibroid Diseases 0.000 description 1
- 230000001457 vasomotor Effects 0.000 description 1
- 230000004584 weight gain Effects 0.000 description 1
- 235000019786 weight gain Nutrition 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/12—Drugs for genital or sexual disorders; Contraceptives for climacteric disorders
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyrane Compounds (AREA)
Abstract
The present invention provides novel uses of compounds of general formula (I) wherein R1, R4, and R5 are individually hydrogen, hydroxy, halogen, trifluoro-methyl, C1-6 alkyl, C1-6 alkoxy or (tertiary amino)(C1-6 alkoxy); and R2 and R3 are individually hydrogen or C1-6 alkyl, or as a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable carrier for the manufacture of a pharmaceutical composition for the treatment or prophylaxis of menopausal symptoms.
Description
CA 02241623 1998-06-2~
Use of 3,4-diphenyl chromans for the manufacture of a pharmaceutical composi-tion for the treatment or prophylaxis of menopausal symptoms FIFLD OF THIS INVENTION
The present invention relates to the use of compounds of the general formula I
for the prevention and treatment of menopausal symptoms. The present inventi-on also embraces pharmaceutical compositions comprising these compounds and methods of using the compounds and their pharmaceutical compositions.
RACKGROUND OF THIS INVENTION
The menopause is defined as the final episode of menstrual bleeding in women.
However, the term is used commonly to refer to the period of the female climac-15 teric that encompasses the transitional period between the reproductive years upto and beyond the last episode of menstrual bleeding. This period is also referred to as the peri-menopause or the climacterium. During this period there is a gra-dual but progressive loss of ovarian function and a variety of endocrine, somatic and psycological changes. The median age of the women at the time of cessati-20 on of menstrual bleeding is 50 to 51 years. Since the life expectancy of womenin developed countries is now close to 80 years, approximately one-third of a woman's life-span occurs after cessation of reproductive function.
The symptoms associated with declining estrogen levels in the perimenopause 25 include hot flashes and sweats, atrophic vaginitis, headache, dizziness, joint pain, sleeplessness, apathy, lassitude, muscular weakness, palpitations and psy-chological symptoms such as changes in mood, depression, memory and conceri-tration deficits, irritability and problems related to sexual functioning. All of these symptoms are a direct consequence of the declining estrogen production.
.
CA 02241623 1998-06-2~
Currently the treatment of these disorders involves different regimens of estro-gen administration with or without concomitant progestin administration. Estro-gen alone and in different combinations is often associated with unacceptable side effects. The effects of progestin are often poorly tolerated causing depressi-5 on and may even in some tissues negate the positive results of estrogen. Thehormone replacement theraphy often causes unpleasant effects such as water retention, frequently weight gain and prolonged therapy is associated with an in-creased risk of endometrial cancer. Thus there is a need for a new compound, which ameliorates the symptoms of the menopause, but which is safe and cau-10 ses less side effects, and preferably brings the woman into a stable post-menopausal state in a reduced period of time than known compounds.
Centchroman is a non-steroidal compound known to have antiestrogenic activity.
It is in use in India as an oral contraceptive ~see, for example, Salman et al., U.S.
Patent Specification No. 4,447,622; Singh et al., e~ Fndocrina~ (Copenh) 126 (1992), 444 - 450; Grubb, Curr Opin Obstet Gynecol 3 (1991), 491 - 495; San-karan et al., Contraception 9 (1974), 279 - 289; Indian Patent Specification No.129187). Centchroman has also been investigated as an anti-cancer agent for treatment of advanced breast cancer (Misra et al., Int J Cancer 43 (1989), 781 -20 783. Recently, centchroman as a racemate has been found as a potent choleste-rol lowering pharmaceutical expressed by a significant decrease of the serum concentrations (S.D. Bain et al., J Min ~Qn Res 9 (1994), S 394).
U.S. patent 5,453,442 describes methods of lowering serum cholesterol and in-25 hibiting smoother muscle cell proliferation in humans and inhibiting uterine fibroid disease and endometriosis in women by administering compounds of formula I as shown therein. Furthermore, US patent 5,280,040 describes methods and phar-maceutical compositions for reducing bone loss using 3,4-diaryl chromans and their pharmaceutically acceptable salts. There is no disclosure in the patents of 30 using the compounds to treat or prevent menopausal symptoms.
W O 97/25035 PCT~DK97/00008 One object of the present invention is to provide compounds which can effecti-vely be used in the treatment or prophyiaxis of menopausal symptoms.
i3RlEF DESCRIPTIQN OF THIS INVENTION
It has, surprisingly, been found that compounds of ~he yentrâl fGrm.ula I as sta-ted in claim 1 can be used in the prevention and treatment of menopausal symp-toms.
DETAILED DFSCRIPTION OF THIS INVENTION
The present invention is based in part on the discovery that a representative 3,4-diarylchroman, centchroman (3,4-trans-2,2-dimethyi-3-phenyl-4-[p-(beta--pyrrolidinoethoxy)phenyl]-7-methoxychroman) is a partial estrogen antago-15 nist/agonist and elicits similar actions as estrogen in a range of animal modelsand is useful in the treatment of climacteric symptoms and complaints without having the adverse effects associated with estrogen treatment.
Within the present invention, compounds of formula I or their pharmaceutically 20 acceptable salts are used for prevention and treatment of menopausal symptoms in a patient.
~ ~R~
~1 ~2 = = .
Within formula 1, R1, R4 and R5 are individually hydrogen, hydroxy, halogen, trifluoromethyl, C1 6 alkyl, C1 6 alkoxy or ~tertiary amino)(C1 6 alkoxy); and R2 and R3 are individually hydrogen or a C1 6 alkyl. As used herein, the term "C1 6 alkyl"
includes straight and branched chain alkyl radicals containing from 1 to 6 carbon 5 atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-amyl, sec-amyl, n-hexyl, 2-ethylbutyl, 2,3-dimethylbutyl and the like. The term "C1 6 al-koxy" includes straight and branched chain alkoxy radicals containing from 1 to 6 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, n-amyloxy, sec-amyloxy, n-hexyloxy, 2-ethylbutoxy, 2,3-10 dimethylbutoxy and the like. "Halogen" includes chloro, fluoro, bromo and iodo.Herein, the term "(tertiary amino)(C1 6 alkoxy)" is a C1 6 alkoxy group which is substituted by a tertiary amino radical. The tertiary amino radical may be a N,N-dialkylamine such as a N,N-dimethylamino, N,N-diethylamino, N,N-dipropylamino and N,N-dibutylamino or a polymethyleneimine, e.g., piperidine, pyrrolidine, N-15 methylpiperazine or morpholine. Preferred compounds include those in which R1is Cl 6 alkoxy; R2 and R3 are C1 6 alkyl, especially methyl; R4 is hydrogen; and R
5 is (tertiary amino)(C1 6 alkoxy) of the polymethyleneimine type. Within particu-larly preferred embodiments, R1 j5 in the 7-position and is C1 6 alkoxy, particu-larly methoxy; each of R2 and R3 is methyl, R4 is hydrogen, and R5 is in the 4-20 position and is a (tertiary amino)(C1 6 alkoxy) radical such as 2-(pyrrolidin-1-yl)ethoxy with formula ll ~ (Il) To be included by this invention are all pharmaceutically acceptable salts of the mentioned compounds of formula 1.
_ W O 97/25035 PCT~DK97/00008 - It is preferred to use the compounds of formuia I in the transconfiguration. These compounds may be used as racemic mixtures, or the isolated d- or 1- enantiomers may be used. The trans-l-enantiomers are more preferred.
A particularly preferred compound for use within the present invention is cen-tchroman having the formula IV
~o 3 s ~,~ (lv~
Although only one enantiomer is shown, it will be understood that the formula IVis used herein to designate the transconfiguration of the 3- and 4-phenyl groupsand that both the d- and l-enantiomers, as well as the racemic mixture, are inclu-ded.
3,4-diarylchromans are prepared according to known methods, such as those di-sclosed in U.S. Patent Specification No. 3,340,276 to Carney et al., U.S. PatentSpecification No. 3,82Z,287 to Bolger, and Ray et al., ~ Med Chem 19 (1976), 276 - 279, the contents of which are incorporated herein by reference. Conver-sion of the cis isomer to the trans configuration by means of an organometallic CA 02241623 1998-06-2~
base-catalyzed rearrangement is disclosed in U.S. Patent Specification No.
3,822,287. The optically active d- and l-enantiomers may be prepared as disclo-sed by Salman et al. in U.S. Patent Specification No. 4,447,622 (incorporated herein by reference) by forming an optically active acid salt which is subjected to 5 alkaline hydroiysis to produce the desired enantiomer. If R2 is different from R3 and R4 is different from R5, the general formula I covers 8 optical isomers.
Within the present invention, 3,4-diarylchromans of formula I may be prepared inthe form of pharmaceutically acceptable salts, especially acid-addition salts, in-10 cluding salts of organic acids and mineral acids. Examples of such salts includesalts of organic acids such as formic acid, fumaric acid, acetic acid, propionic a-cid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, succinic acid, malic acid, tartaric acid, citric acid, benzoic acid, salicylic acid and the like. Suitable inorga-nic acid-addition salts include salts of hydrochloric, hydrobromic, sulphuric and 15 phosphoric acids and the like. The acid addition salts may be obtained as the di-rect products of compound synthesis. In the alternative, the free base may be dissolved in a suitable solvent containing the appropriate acid, and the salt isola-ted by evaporating the solvent or otherwise separating the salt and solvent.
20 3,4-diarylchromans of formula I and their salts are useful within human and vete-rinary medicine, for example, in the treatment of patients suffering from meno-pausal symptoms. For use within the present invention, 3,4-diarylchromans of formula I and their pharmaceutically acceptable salts are formulated with a phar-maceutically acceptable carrier to provide a medicament for parenteral, oral, na-25 sal, rectal, subdermal or intradermal or transdermal administration according toconventional methods. Formulations may further include one or more diluents, fillers, emulsifiers, preservatives, buffers, excipients, etc. and may be provided in such forms as liquids, powders, emulsions, suppositories, liposomes, transdermalpatches, controlled release, dermal implants, tablets, etc. One skilled in this art 30 may formulate the compounds of formula I in an appropriate manner, and in ac-CA 02241623 1998-06-2~
cordance with accepted practices, such as those disclosed in Remington's Phar-maceutical Sciences, Gennaro, ed., Mack Pubiishing Co., Easton, PA, 1990.
Oral administration is preferred. Thus, the active compound of formula I is prepa-5 red in a form suitable for oral administration, such as a tablet or capsule. Typi-cally, a pharmaceutically acceptable salt of the compound of formula I is com-bined with a carrier and moulded into a tablet. Suitable carriers in this regard in-clude starch, sugars, dicalcium phosphate, calcium stearate, magnesium stearate and the like. Such compositions may further include one or more auxiliary sub-10 stances, such as wetting agents, emulsifiers, preservatives, stabilizers, colouringadditives, etc.
Pharmaceutical compositions containing a compound of formula I may be admini-stered one or more times per day or week. An effective amount of such a phar-15 maceutical composition is the amount that provides a clinically significant effectagainst menopausal symptoms. Such amounts will depend, in part, on the parti-cular condition to be treated, age, weight, and general health of the patient, and other factors evident to those skilled in the art. A typical daily dose will contain a nontoxic dosage range of from about 0.001 to about 75 mg/kg patient per day 20 of a compound of the present invention.
The pharmaceutical compositions containing a compound of formula I may be administered in unit dosage form one or more times per day or week. In the al-ternative, they may be provided as controlled release formulations suitable for 25 dermal implantation. Implants are formulated to provide release of active com-pound over the desired period of time, which can be up to several years. Con-trolled-release formulations are disclosed by, for example, Sanders et al., I
Pharm Sci 73 (1964), 1294 - 1297, 1984; U.S: Patent Specification No.
4,489,056; and U.S. Patent Specification No. 4,210,644, which are incorpora-30 ted herein by reference.
=
CA 02241623 1998-06-2~
The following examples are offered by way of illustration, not limitation.
Examples of preferred compounds of formula I are centchroman as a racemic mixture and as isolated l-centchroman and d-centchroman enantiomers. Further-more, 3,4-trans-2,2-dimethyl-3-phenyl-4-[4-(2-(pyrrolidin-1-yl)ethoxy)phenyl]-7-hydroxychroman is a preferred compound. The more preferred compound is isola-ted l-centchroman (1-3 ,4-trans-2, 2-dimethyl-3-phenyl-4-[4-( 2-(pyrrolidin- 1 -yl)ethoxy)phenyl]-7-methoxychroman) .
10 Examples of pharmaceutically acceptable acid addition salts are salts with non-toxic acids, either inorganic acids such as hydrochloric acid, sulphuric acid and phosphoric acid, or organic acids such as formic acid, fumaric acid, acetic acid, propionic acid, succinic acid, gluconic acid, lactic acid, citric acid, ascorbic acid, benzoic acid, embonic acid, methanesulphonic acid and malonic acid.
The present invention is further illustrated by the following examples which, however, are not to be construed as limiting the scope of protection. The fea-tures disclosed in the foregoing description and in the following examples may, both separately and in any combination thereof, be material for realising the in-20 vention in diverse forms thereof.
EXAMPLES
Test 1 Between 3 and 20 women of the age of 45-50 years are selected as a test group. The women exhibit at least one of the sequellae of impending menopause.
A compound of the invention is given in the amount of 0,001 to 7~ mg/kg pa-tient per day and the frequency of vasomotor symptoms are closely monitored 30 together with the variables laid down in the Green Scale or Kupperman Indeks -CA 02241623 1998-06-2~
W O 97/25035 PCT~DK97/00008 monitoring systems. The dosing of the compound of the invention continues for a period of 4 weeks.
Test 2 The same test as in Test 1 is carried out, however, the administration period isfor a time of 3 months.
Test 3 This test is ran as Test 1, except the dosing period is for a period of 6 months.
Activity, defined as either total cessation of one or more sequellae of the patient, or reduced severity or occurrence thereof, or a more rapid advancement to men-opausal state, in any of the above assays indicates that the compounds of the ~5 invention are useful in the treatment of menopausal symptoms.
Use of 3,4-diphenyl chromans for the manufacture of a pharmaceutical composi-tion for the treatment or prophylaxis of menopausal symptoms FIFLD OF THIS INVENTION
The present invention relates to the use of compounds of the general formula I
for the prevention and treatment of menopausal symptoms. The present inventi-on also embraces pharmaceutical compositions comprising these compounds and methods of using the compounds and their pharmaceutical compositions.
RACKGROUND OF THIS INVENTION
The menopause is defined as the final episode of menstrual bleeding in women.
However, the term is used commonly to refer to the period of the female climac-15 teric that encompasses the transitional period between the reproductive years upto and beyond the last episode of menstrual bleeding. This period is also referred to as the peri-menopause or the climacterium. During this period there is a gra-dual but progressive loss of ovarian function and a variety of endocrine, somatic and psycological changes. The median age of the women at the time of cessati-20 on of menstrual bleeding is 50 to 51 years. Since the life expectancy of womenin developed countries is now close to 80 years, approximately one-third of a woman's life-span occurs after cessation of reproductive function.
The symptoms associated with declining estrogen levels in the perimenopause 25 include hot flashes and sweats, atrophic vaginitis, headache, dizziness, joint pain, sleeplessness, apathy, lassitude, muscular weakness, palpitations and psy-chological symptoms such as changes in mood, depression, memory and conceri-tration deficits, irritability and problems related to sexual functioning. All of these symptoms are a direct consequence of the declining estrogen production.
.
CA 02241623 1998-06-2~
Currently the treatment of these disorders involves different regimens of estro-gen administration with or without concomitant progestin administration. Estro-gen alone and in different combinations is often associated with unacceptable side effects. The effects of progestin are often poorly tolerated causing depressi-5 on and may even in some tissues negate the positive results of estrogen. Thehormone replacement theraphy often causes unpleasant effects such as water retention, frequently weight gain and prolonged therapy is associated with an in-creased risk of endometrial cancer. Thus there is a need for a new compound, which ameliorates the symptoms of the menopause, but which is safe and cau-10 ses less side effects, and preferably brings the woman into a stable post-menopausal state in a reduced period of time than known compounds.
Centchroman is a non-steroidal compound known to have antiestrogenic activity.
It is in use in India as an oral contraceptive ~see, for example, Salman et al., U.S.
Patent Specification No. 4,447,622; Singh et al., e~ Fndocrina~ (Copenh) 126 (1992), 444 - 450; Grubb, Curr Opin Obstet Gynecol 3 (1991), 491 - 495; San-karan et al., Contraception 9 (1974), 279 - 289; Indian Patent Specification No.129187). Centchroman has also been investigated as an anti-cancer agent for treatment of advanced breast cancer (Misra et al., Int J Cancer 43 (1989), 781 -20 783. Recently, centchroman as a racemate has been found as a potent choleste-rol lowering pharmaceutical expressed by a significant decrease of the serum concentrations (S.D. Bain et al., J Min ~Qn Res 9 (1994), S 394).
U.S. patent 5,453,442 describes methods of lowering serum cholesterol and in-25 hibiting smoother muscle cell proliferation in humans and inhibiting uterine fibroid disease and endometriosis in women by administering compounds of formula I as shown therein. Furthermore, US patent 5,280,040 describes methods and phar-maceutical compositions for reducing bone loss using 3,4-diaryl chromans and their pharmaceutically acceptable salts. There is no disclosure in the patents of 30 using the compounds to treat or prevent menopausal symptoms.
W O 97/25035 PCT~DK97/00008 One object of the present invention is to provide compounds which can effecti-vely be used in the treatment or prophyiaxis of menopausal symptoms.
i3RlEF DESCRIPTIQN OF THIS INVENTION
It has, surprisingly, been found that compounds of ~he yentrâl fGrm.ula I as sta-ted in claim 1 can be used in the prevention and treatment of menopausal symp-toms.
DETAILED DFSCRIPTION OF THIS INVENTION
The present invention is based in part on the discovery that a representative 3,4-diarylchroman, centchroman (3,4-trans-2,2-dimethyi-3-phenyl-4-[p-(beta--pyrrolidinoethoxy)phenyl]-7-methoxychroman) is a partial estrogen antago-15 nist/agonist and elicits similar actions as estrogen in a range of animal modelsand is useful in the treatment of climacteric symptoms and complaints without having the adverse effects associated with estrogen treatment.
Within the present invention, compounds of formula I or their pharmaceutically 20 acceptable salts are used for prevention and treatment of menopausal symptoms in a patient.
~ ~R~
~1 ~2 = = .
Within formula 1, R1, R4 and R5 are individually hydrogen, hydroxy, halogen, trifluoromethyl, C1 6 alkyl, C1 6 alkoxy or ~tertiary amino)(C1 6 alkoxy); and R2 and R3 are individually hydrogen or a C1 6 alkyl. As used herein, the term "C1 6 alkyl"
includes straight and branched chain alkyl radicals containing from 1 to 6 carbon 5 atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-amyl, sec-amyl, n-hexyl, 2-ethylbutyl, 2,3-dimethylbutyl and the like. The term "C1 6 al-koxy" includes straight and branched chain alkoxy radicals containing from 1 to 6 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, n-amyloxy, sec-amyloxy, n-hexyloxy, 2-ethylbutoxy, 2,3-10 dimethylbutoxy and the like. "Halogen" includes chloro, fluoro, bromo and iodo.Herein, the term "(tertiary amino)(C1 6 alkoxy)" is a C1 6 alkoxy group which is substituted by a tertiary amino radical. The tertiary amino radical may be a N,N-dialkylamine such as a N,N-dimethylamino, N,N-diethylamino, N,N-dipropylamino and N,N-dibutylamino or a polymethyleneimine, e.g., piperidine, pyrrolidine, N-15 methylpiperazine or morpholine. Preferred compounds include those in which R1is Cl 6 alkoxy; R2 and R3 are C1 6 alkyl, especially methyl; R4 is hydrogen; and R
5 is (tertiary amino)(C1 6 alkoxy) of the polymethyleneimine type. Within particu-larly preferred embodiments, R1 j5 in the 7-position and is C1 6 alkoxy, particu-larly methoxy; each of R2 and R3 is methyl, R4 is hydrogen, and R5 is in the 4-20 position and is a (tertiary amino)(C1 6 alkoxy) radical such as 2-(pyrrolidin-1-yl)ethoxy with formula ll ~ (Il) To be included by this invention are all pharmaceutically acceptable salts of the mentioned compounds of formula 1.
_ W O 97/25035 PCT~DK97/00008 - It is preferred to use the compounds of formuia I in the transconfiguration. These compounds may be used as racemic mixtures, or the isolated d- or 1- enantiomers may be used. The trans-l-enantiomers are more preferred.
A particularly preferred compound for use within the present invention is cen-tchroman having the formula IV
~o 3 s ~,~ (lv~
Although only one enantiomer is shown, it will be understood that the formula IVis used herein to designate the transconfiguration of the 3- and 4-phenyl groupsand that both the d- and l-enantiomers, as well as the racemic mixture, are inclu-ded.
3,4-diarylchromans are prepared according to known methods, such as those di-sclosed in U.S. Patent Specification No. 3,340,276 to Carney et al., U.S. PatentSpecification No. 3,82Z,287 to Bolger, and Ray et al., ~ Med Chem 19 (1976), 276 - 279, the contents of which are incorporated herein by reference. Conver-sion of the cis isomer to the trans configuration by means of an organometallic CA 02241623 1998-06-2~
base-catalyzed rearrangement is disclosed in U.S. Patent Specification No.
3,822,287. The optically active d- and l-enantiomers may be prepared as disclo-sed by Salman et al. in U.S. Patent Specification No. 4,447,622 (incorporated herein by reference) by forming an optically active acid salt which is subjected to 5 alkaline hydroiysis to produce the desired enantiomer. If R2 is different from R3 and R4 is different from R5, the general formula I covers 8 optical isomers.
Within the present invention, 3,4-diarylchromans of formula I may be prepared inthe form of pharmaceutically acceptable salts, especially acid-addition salts, in-10 cluding salts of organic acids and mineral acids. Examples of such salts includesalts of organic acids such as formic acid, fumaric acid, acetic acid, propionic a-cid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, succinic acid, malic acid, tartaric acid, citric acid, benzoic acid, salicylic acid and the like. Suitable inorga-nic acid-addition salts include salts of hydrochloric, hydrobromic, sulphuric and 15 phosphoric acids and the like. The acid addition salts may be obtained as the di-rect products of compound synthesis. In the alternative, the free base may be dissolved in a suitable solvent containing the appropriate acid, and the salt isola-ted by evaporating the solvent or otherwise separating the salt and solvent.
20 3,4-diarylchromans of formula I and their salts are useful within human and vete-rinary medicine, for example, in the treatment of patients suffering from meno-pausal symptoms. For use within the present invention, 3,4-diarylchromans of formula I and their pharmaceutically acceptable salts are formulated with a phar-maceutically acceptable carrier to provide a medicament for parenteral, oral, na-25 sal, rectal, subdermal or intradermal or transdermal administration according toconventional methods. Formulations may further include one or more diluents, fillers, emulsifiers, preservatives, buffers, excipients, etc. and may be provided in such forms as liquids, powders, emulsions, suppositories, liposomes, transdermalpatches, controlled release, dermal implants, tablets, etc. One skilled in this art 30 may formulate the compounds of formula I in an appropriate manner, and in ac-CA 02241623 1998-06-2~
cordance with accepted practices, such as those disclosed in Remington's Phar-maceutical Sciences, Gennaro, ed., Mack Pubiishing Co., Easton, PA, 1990.
Oral administration is preferred. Thus, the active compound of formula I is prepa-5 red in a form suitable for oral administration, such as a tablet or capsule. Typi-cally, a pharmaceutically acceptable salt of the compound of formula I is com-bined with a carrier and moulded into a tablet. Suitable carriers in this regard in-clude starch, sugars, dicalcium phosphate, calcium stearate, magnesium stearate and the like. Such compositions may further include one or more auxiliary sub-10 stances, such as wetting agents, emulsifiers, preservatives, stabilizers, colouringadditives, etc.
Pharmaceutical compositions containing a compound of formula I may be admini-stered one or more times per day or week. An effective amount of such a phar-15 maceutical composition is the amount that provides a clinically significant effectagainst menopausal symptoms. Such amounts will depend, in part, on the parti-cular condition to be treated, age, weight, and general health of the patient, and other factors evident to those skilled in the art. A typical daily dose will contain a nontoxic dosage range of from about 0.001 to about 75 mg/kg patient per day 20 of a compound of the present invention.
The pharmaceutical compositions containing a compound of formula I may be administered in unit dosage form one or more times per day or week. In the al-ternative, they may be provided as controlled release formulations suitable for 25 dermal implantation. Implants are formulated to provide release of active com-pound over the desired period of time, which can be up to several years. Con-trolled-release formulations are disclosed by, for example, Sanders et al., I
Pharm Sci 73 (1964), 1294 - 1297, 1984; U.S: Patent Specification No.
4,489,056; and U.S. Patent Specification No. 4,210,644, which are incorpora-30 ted herein by reference.
=
CA 02241623 1998-06-2~
The following examples are offered by way of illustration, not limitation.
Examples of preferred compounds of formula I are centchroman as a racemic mixture and as isolated l-centchroman and d-centchroman enantiomers. Further-more, 3,4-trans-2,2-dimethyl-3-phenyl-4-[4-(2-(pyrrolidin-1-yl)ethoxy)phenyl]-7-hydroxychroman is a preferred compound. The more preferred compound is isola-ted l-centchroman (1-3 ,4-trans-2, 2-dimethyl-3-phenyl-4-[4-( 2-(pyrrolidin- 1 -yl)ethoxy)phenyl]-7-methoxychroman) .
10 Examples of pharmaceutically acceptable acid addition salts are salts with non-toxic acids, either inorganic acids such as hydrochloric acid, sulphuric acid and phosphoric acid, or organic acids such as formic acid, fumaric acid, acetic acid, propionic acid, succinic acid, gluconic acid, lactic acid, citric acid, ascorbic acid, benzoic acid, embonic acid, methanesulphonic acid and malonic acid.
The present invention is further illustrated by the following examples which, however, are not to be construed as limiting the scope of protection. The fea-tures disclosed in the foregoing description and in the following examples may, both separately and in any combination thereof, be material for realising the in-20 vention in diverse forms thereof.
EXAMPLES
Test 1 Between 3 and 20 women of the age of 45-50 years are selected as a test group. The women exhibit at least one of the sequellae of impending menopause.
A compound of the invention is given in the amount of 0,001 to 7~ mg/kg pa-tient per day and the frequency of vasomotor symptoms are closely monitored 30 together with the variables laid down in the Green Scale or Kupperman Indeks -CA 02241623 1998-06-2~
W O 97/25035 PCT~DK97/00008 monitoring systems. The dosing of the compound of the invention continues for a period of 4 weeks.
Test 2 The same test as in Test 1 is carried out, however, the administration period isfor a time of 3 months.
Test 3 This test is ran as Test 1, except the dosing period is for a period of 6 months.
Activity, defined as either total cessation of one or more sequellae of the patient, or reduced severity or occurrence thereof, or a more rapid advancement to men-opausal state, in any of the above assays indicates that the compounds of the ~5 invention are useful in the treatment of menopausal symptoms.
Claims (20)
1. The use of compounds of the general formula I
wherein R1, R4 and R5 are individually hydrogen, hydroxy, halogen, trifluoromethyl, C1-6 alkyl, C1-6 alkoxy or (tertiary amino)(C1-6 alkoxy); and R2 and R3 are individually hydrogen or C1-6 alkyl, or as a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable carrier for the manufacture of a pharmaceutical composition for the prevention and treatment of menopausal symptoms.
wherein R1, R4 and R5 are individually hydrogen, hydroxy, halogen, trifluoromethyl, C1-6 alkyl, C1-6 alkoxy or (tertiary amino)(C1-6 alkoxy); and R2 and R3 are individually hydrogen or C1-6 alkyl, or as a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable carrier for the manufacture of a pharmaceutical composition for the prevention and treatment of menopausal symptoms.
2. The use, according to claim 1, wherein R1 in the compound used is C1-6 alkoxy, R2 and R3 are C1-6 alkyl, R4 is hydrogen and R5 is (tertiary amino) C1-6alkoxy.
3. The use according to any one of claims 1 or 2 wherein R1 is methoxy.
4. The use according to any one of claims 1-3 wherein R2 is methyl.
5. The use according to any one of claims 1-4 wherein R3 is methyl.
6. The use according to any one of claims 1-5 wherein R4 is hydrogen.
7. The use according to any one of claims 1-6 wherein R5 is a group as stated in formula II below:
8. The use according to any one of claims 1-7 wherein said compound is an isolated d- or I-enantiomer.
9. The use according to any one of the preceding claims wherein said compound has the general formula III as stated below:
wherein R1, R2, R3, R4 and R5 each are as defined in above claim 1.
wherein R1, R2, R3, R4 and R5 each are as defined in above claim 1.
10. The use according to anyone of the preceding claims wherein said compound is 3,4-trans-2,2-dimethyl-3-phenyl-4-[4-(2-(pyrrolidin-1-yl)ethoxy)phenyl]-7-hydroxychroman.
11. the use according to anyone of the preceding claims wherein said compound is an isolated I-enantiomer.
12. The use according to claim 1 wherein said compound is centchroman 3,4-trans-2,2-dimethyl-3-phenyl-4-[4-(2-(pyrrolidin-1-yl)ethoxy)phenyl]-7-methoxychroman having the formula IV as stated below:
13. The use according to claim 12 wherein said compound is an isolated I-enantiomer of 3,4-trans-2,2-dimethyl-3-phenyl-4-[4-(2-(pyrrolidin-1-yl)ethoxy)phenyl]-7-methoxychroman.
14. The use according to any one of the preceding claims wherein said composition is in a form suitable for oral administration.
15. The use according to any one of the preceding claims wherein said compound is administered as a dose in a range from about 0.001 to 75 mg/kg patient per day.
16. The use according to any one of the preceding claims wherein said composition is administered one or more times per day or week.
17. The use according to any one of the preceding claims wherein said composition is in the form of a dermal implant.
18. Method for treatment and prophylaxis of menopausal symptoms comprising administering to a patient a clinically effective amount of a compound of above formula I stated to be used in any of the preceding use claims, or a pharmaceutically acceptable salt thereof in an amount sufficient to treat or prevent menopausal symptoms.
19. A method of treating or preventing menopausal symptoms which method comprises administering a clinically effective amount of compounds and pharmaceutically acceptable compositions, according to previous claims to a patient in need of such a treatment.
20. Any novel feature or combination of features described herein.
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US983496P | 1996-01-11 | 1996-01-11 | |
US60/009,834 | 1996-01-11 | ||
US67826196A | 1996-07-11 | 1996-07-11 | |
US08/678,261 | 1996-07-11 |
Publications (1)
Publication Number | Publication Date |
---|---|
CA2241623A1 true CA2241623A1 (en) | 1997-07-17 |
Family
ID=26679921
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA002241623A Abandoned CA2241623A1 (en) | 1996-01-11 | 1997-01-09 | Use of 3,4-diphenyl chromans for the manufacture of a pharmaceutical composition for the treatment or prophylaxis of menopausal symptoms |
Country Status (12)
Country | Link |
---|---|
EP (1) | EP0873120A1 (en) |
JP (1) | JP2000506505A (en) |
KR (1) | KR19990077156A (en) |
AU (1) | AU1367297A (en) |
BR (1) | BR9706967A (en) |
CA (1) | CA2241623A1 (en) |
CZ (1) | CZ217298A3 (en) |
HU (1) | HUP9902683A3 (en) |
IL (1) | IL124882A0 (en) |
NO (1) | NO983178L (en) |
PL (1) | PL327831A1 (en) |
WO (1) | WO1997025035A1 (en) |
Families Citing this family (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7005428B1 (en) | 1998-06-11 | 2006-02-28 | Endorecherche, Inc. | Medical uses of a selective estrogen receptor modulator in combination with sex steroid precursors |
US6465445B1 (en) | 1998-06-11 | 2002-10-15 | Endorecherche, Inc. | Medical uses of a selective estrogen receptor modulator in combination with sex steroid precursors |
IL150463A0 (en) * | 1999-12-30 | 2002-12-01 | Signal Pharm Inc | Compounds and methods for modulation of estrogen receptors |
US8080675B2 (en) | 2004-09-21 | 2011-12-20 | Marshall Edwards, Inc. | Chroman derivatives, medicaments and use in therapy |
ATE532777T1 (en) | 2004-09-21 | 2011-11-15 | Marshall Edwards Inc | SUBSTITUTED CHROMEDER DERIVATIVES, MEDICATIONS AND APPLICATIONS IN THERAPY |
CA2749235C (en) | 2004-10-20 | 2014-08-12 | Endorecherche, Inc. | Sex steroid precursors alone or in combination with a selective estrogen receptor modulator and/or with estrogens and/or a type 5 cgmp phosphodiesterase inhibitor for the prevention and treatment of vaginal dryness and sexual dysfunction in postmenopausal women |
US8268806B2 (en) | 2007-08-10 | 2012-09-18 | Endorecherche, Inc. | Pharmaceutical compositions |
ME00996B (en) | 2007-10-16 | 2012-10-20 | Repros Therapeutics Inc | Trans-clomiphene for metabolic syndrome |
US20100317635A1 (en) | 2009-06-16 | 2010-12-16 | Endorecherche, Inc. | Treatment of hot flushes, vasomotor symptoms, and night sweats with sex steroid precursors in combination with selective estrogen receptor modulators |
MX2012014579A (en) | 2010-06-16 | 2013-05-22 | Endorech Inc | Methods of treating or preventing estrogen-related diseases. |
CA2816322A1 (en) | 2010-11-01 | 2012-05-10 | Marshall Edwards, Inc. | Isoflavonoid compositions and methods for the treatment of cancer |
US20150031656A1 (en) | 2012-02-29 | 2015-01-29 | Repros Therapeutics Inc. | Combination therapy for treating androgen deficiency |
EP2953938B1 (en) | 2014-02-07 | 2017-08-02 | Novogen Ltd. | Functionalised benzopyran compounds and use thereof |
US9744177B2 (en) | 2014-03-10 | 2017-08-29 | Endorecherche, Inc. | Treatment of male androgen deficiency symptoms or diseases with sex steroid precursor combined with SERM |
AU2016215515B2 (en) | 2015-02-02 | 2020-04-30 | Mei Pharma, Inc. | Combination therapies |
US11633382B2 (en) | 2015-11-10 | 2023-04-25 | Paracrine Therapeutics Ab | Treatment of ER-negative breast cancer with an PDGF-CC inhibitor and anti-estrogen |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4729999A (en) * | 1984-10-12 | 1988-03-08 | Bcm Technologies | Antiestrogen therapy for symptoms of estrogen deficiency |
-
1997
- 1997-01-09 HU HU9902683A patent/HUP9902683A3/en unknown
- 1997-01-09 CA CA002241623A patent/CA2241623A1/en not_active Abandoned
- 1997-01-09 IL IL12488297A patent/IL124882A0/en unknown
- 1997-01-09 JP JP9524768A patent/JP2000506505A/en active Pending
- 1997-01-09 PL PL97327831A patent/PL327831A1/en unknown
- 1997-01-09 AU AU13672/97A patent/AU1367297A/en not_active Abandoned
- 1997-01-09 WO PCT/DK1997/000008 patent/WO1997025035A1/en not_active Application Discontinuation
- 1997-01-09 BR BR9706967A patent/BR9706967A/en not_active Application Discontinuation
- 1997-01-09 EP EP97900200A patent/EP0873120A1/en not_active Withdrawn
- 1997-01-09 KR KR1019980705294A patent/KR19990077156A/en not_active Application Discontinuation
- 1997-01-09 CZ CZ982172A patent/CZ217298A3/en unknown
-
1998
- 1998-07-10 NO NO983178A patent/NO983178L/en unknown
Also Published As
Publication number | Publication date |
---|---|
IL124882A0 (en) | 1999-01-26 |
NO983178L (en) | 1998-07-10 |
PL327831A1 (en) | 1999-01-04 |
HUP9902683A3 (en) | 2001-08-28 |
CZ217298A3 (en) | 1999-01-13 |
AU1367297A (en) | 1997-08-01 |
HUP9902683A2 (en) | 2001-04-28 |
JP2000506505A (en) | 2000-05-30 |
EP0873120A1 (en) | 1998-10-28 |
KR19990077156A (en) | 1999-10-25 |
BR9706967A (en) | 1999-05-04 |
WO1997025035A1 (en) | 1997-07-17 |
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Legal Events
Date | Code | Title | Description |
---|---|---|---|
FZDE | Discontinued | ||
FZDE | Discontinued |
Effective date: 20010109 |