US20070054882A1 - Male anti-fertility agents - Google Patents
Male anti-fertility agents Download PDFInfo
- Publication number
- US20070054882A1 US20070054882A1 US11/503,635 US50363506A US2007054882A1 US 20070054882 A1 US20070054882 A1 US 20070054882A1 US 50363506 A US50363506 A US 50363506A US 2007054882 A1 US2007054882 A1 US 2007054882A1
- Authority
- US
- United States
- Prior art keywords
- carbons
- body weight
- group
- compound
- alkyl
- 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
- 239000003433 contraceptive agent Substances 0.000 title description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 68
- 230000021595 spermatogenesis Effects 0.000 claims abstract description 40
- 238000000034 method Methods 0.000 claims abstract description 38
- 241000124008 Mammalia Species 0.000 claims abstract description 27
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 81
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 37
- 230000037396 body weight Effects 0.000 claims description 33
- 229910052739 hydrogen Inorganic materials 0.000 claims description 28
- 150000003839 salts Chemical class 0.000 claims description 18
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
- 210000000582 semen Anatomy 0.000 claims description 3
- 239000000203 mixture Substances 0.000 abstract description 15
- 238000009472 formulation Methods 0.000 abstract description 7
- LHUPKWKWYWOMSK-UHFFFAOYSA-N 4-[2-[4-(4-ethylphenyl)-2,2-dimethylthiochromen-6-yl]ethynyl]benzoic acid Chemical compound C1=CC(CC)=CC=C1C1=CC(C)(C)SC2=CC=C(C#CC=3C=CC(=CC=3)C(O)=O)C=C12 LHUPKWKWYWOMSK-UHFFFAOYSA-N 0.000 description 61
- 241001465754 Metazoa Species 0.000 description 58
- 241000700159 Rattus Species 0.000 description 43
- 102000003702 retinoic acid receptors Human genes 0.000 description 41
- 108090000064 retinoic acid receptors Proteins 0.000 description 41
- 239000000243 solution Substances 0.000 description 38
- 229940079593 drug Drugs 0.000 description 33
- 239000003814 drug Substances 0.000 description 33
- 238000011084 recovery Methods 0.000 description 31
- 239000005557 antagonist Substances 0.000 description 29
- 230000000694 effects Effects 0.000 description 25
- 238000012360 testing method Methods 0.000 description 25
- 210000001550 testis Anatomy 0.000 description 21
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 20
- 229940125425 inverse agonist Drugs 0.000 description 20
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 18
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 description 18
- 230000000920 spermatogeneic effect Effects 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- 125000000753 cycloalkyl group Chemical group 0.000 description 17
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 125000001072 heteroaryl group Chemical group 0.000 description 15
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 14
- 125000003342 alkenyl group Chemical group 0.000 description 14
- 210000004369 blood Anatomy 0.000 description 14
- 239000008280 blood Substances 0.000 description 14
- 125000005037 alkyl phenyl group Chemical group 0.000 description 13
- 210000004027 cell Anatomy 0.000 description 13
- 229910052801 chlorine Inorganic materials 0.000 description 13
- 239000000460 chlorine Substances 0.000 description 13
- 102000005962 receptors Human genes 0.000 description 12
- 108020003175 receptors Proteins 0.000 description 12
- 229920006395 saturated elastomer Polymers 0.000 description 12
- 210000002863 seminiferous tubule Anatomy 0.000 description 12
- 238000005160 1H NMR spectroscopy Methods 0.000 description 11
- 0 CC.CC.[14*]/C1=C/CCC2=CC=C(CC*B)C=C21 Chemical compound CC.CC.[14*]/C1=C/CCC2=CC=C(CC*B)C=C21 0.000 description 11
- 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 11
- 230000002829 reductive effect Effects 0.000 description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 10
- FPIPGXGPPPQFEQ-OVSJKPMPSA-N all-trans-retinol Chemical compound OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-OVSJKPMPSA-N 0.000 description 10
- 238000002474 experimental method Methods 0.000 description 10
- 239000001257 hydrogen Substances 0.000 description 10
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 10
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 10
- 125000004076 pyridyl group Chemical group 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- 125000001544 thienyl group Chemical group 0.000 description 10
- 210000001519 tissue Anatomy 0.000 description 10
- 102000012673 Follicle Stimulating Hormone Human genes 0.000 description 9
- 108010079345 Follicle Stimulating Hormone Proteins 0.000 description 9
- 125000003545 alkoxy group Chemical group 0.000 description 9
- 239000006071 cream Substances 0.000 description 9
- 235000019439 ethyl acetate Nutrition 0.000 description 9
- 229940028334 follicle stimulating hormone Drugs 0.000 description 9
- 125000001624 naphthyl group Chemical group 0.000 description 9
- 229910052760 oxygen Inorganic materials 0.000 description 9
- 239000006187 pill Substances 0.000 description 9
- 239000011780 sodium chloride Substances 0.000 description 9
- -1 steroids Chemical class 0.000 description 9
- 229960003604 testosterone Drugs 0.000 description 9
- FPIPGXGPPPQFEQ-UHFFFAOYSA-N 13-cis retinol Natural products OCC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-UHFFFAOYSA-N 0.000 description 8
- 108090000623 proteins and genes Proteins 0.000 description 8
- 210000000717 sertoli cell Anatomy 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 7
- 239000007943 implant Substances 0.000 description 7
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 7
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 7
- 239000012044 organic layer Substances 0.000 description 7
- 229910052717 sulfur Inorganic materials 0.000 description 7
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- 102000007399 Nuclear hormone receptor Human genes 0.000 description 6
- 108020005497 Nuclear hormone receptor Proteins 0.000 description 6
- FPIPGXGPPPQFEQ-BOOMUCAASA-N Vitamin A Natural products OC/C=C(/C)\C=C\C=C(\C)/C=C/C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-BOOMUCAASA-N 0.000 description 6
- 125000000304 alkynyl group Chemical group 0.000 description 6
- 230000033228 biological regulation Effects 0.000 description 6
- 230000035558 fertility Effects 0.000 description 6
- 125000002541 furyl group Chemical group 0.000 description 6
- 125000002883 imidazolyl group Chemical group 0.000 description 6
- 239000003921 oil Substances 0.000 description 6
- 235000019198 oils Nutrition 0.000 description 6
- 210000000056 organ Anatomy 0.000 description 6
- 125000003373 pyrazinyl group Chemical group 0.000 description 6
- 125000002098 pyridazinyl group Chemical group 0.000 description 6
- 125000000714 pyrimidinyl group Chemical group 0.000 description 6
- 230000002441 reversible effect Effects 0.000 description 6
- 230000000699 topical effect Effects 0.000 description 6
- 210000002700 urine Anatomy 0.000 description 6
- 235000019155 vitamin A Nutrition 0.000 description 6
- 239000011719 vitamin A Substances 0.000 description 6
- 229940045997 vitamin a Drugs 0.000 description 6
- 241000282693 Cercopithecidae Species 0.000 description 5
- 108010038912 Retinoid X Receptors Proteins 0.000 description 5
- 102000034527 Retinoid X Receptors Human genes 0.000 description 5
- 125000004414 alkyl thio group Chemical group 0.000 description 5
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 description 5
- 210000002469 basement membrane Anatomy 0.000 description 5
- 238000004440 column chromatography Methods 0.000 description 5
- 230000002254 contraceptive effect Effects 0.000 description 5
- 201000010063 epididymitis Diseases 0.000 description 5
- 239000000499 gel Substances 0.000 description 5
- 210000004602 germ cell Anatomy 0.000 description 5
- 229940088597 hormone Drugs 0.000 description 5
- 239000005556 hormone Substances 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 239000010410 layer Substances 0.000 description 5
- 239000002583 male contraceptive agent Substances 0.000 description 5
- 125000002971 oxazolyl group Chemical group 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 239000000583 progesterone congener Substances 0.000 description 5
- 230000009467 reduction Effects 0.000 description 5
- 229930002330 retinoic acid Natural products 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 125000000335 thiazolyl group Chemical group 0.000 description 5
- 229960001727 tretinoin Drugs 0.000 description 5
- 210000005239 tubule Anatomy 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 102000001554 Hemoglobins Human genes 0.000 description 4
- 108010054147 Hemoglobins Proteins 0.000 description 4
- 241000282412 Homo Species 0.000 description 4
- 102000009151 Luteinizing Hormone Human genes 0.000 description 4
- 108010073521 Luteinizing Hormone Proteins 0.000 description 4
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 4
- 239000000556 agonist Substances 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 230000006870 function Effects 0.000 description 4
- 239000000893 inhibin Substances 0.000 description 4
- ZPNFWUPYTFPOJU-LPYSRVMUSA-N iniprol Chemical compound C([C@H]1C(=O)NCC(=O)NCC(=O)N[C@H]2CSSC[C@H]3C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@H](C(N[C@H](C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC=4C=CC=CC=4)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC=4C=CC=CC=4)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC2=O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H]2N(CCC2)C(=O)[C@@H](N)CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N2[C@@H](CCC2)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N2[C@@H](CCC2)C(=O)N3)C(=O)NCC(=O)NCC(=O)N[C@@H](C)C(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H](C(=O)N1)C(C)C)[C@@H](C)O)[C@@H](C)CC)=O)[C@@H](C)CC)C1=CC=C(O)C=C1 ZPNFWUPYTFPOJU-LPYSRVMUSA-N 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 210000000265 leukocyte Anatomy 0.000 description 4
- 229940040129 luteinizing hormone Drugs 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 230000035935 pregnancy Effects 0.000 description 4
- 230000002265 prevention Effects 0.000 description 4
- 230000001105 regulatory effect Effects 0.000 description 4
- 150000004492 retinoid derivatives Chemical class 0.000 description 4
- 210000001625 seminal vesicle Anatomy 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 230000001954 sterilising effect Effects 0.000 description 4
- 238000004659 sterilization and disinfection Methods 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- 231100000607 toxicokinetics Toxicity 0.000 description 4
- 201000010653 vesiculitis Diseases 0.000 description 4
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000007832 Na2SO4 Substances 0.000 description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 3
- 108091027981 Response element Proteins 0.000 description 3
- 102100023606 Retinoic acid receptor alpha Human genes 0.000 description 3
- 102100033909 Retinoic acid receptor beta Human genes 0.000 description 3
- 102100033912 Retinoic acid receptor gamma Human genes 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 102000010640 androgen binding protein Human genes 0.000 description 3
- 108010077825 androgen binding protein Proteins 0.000 description 3
- 229910052786 argon Inorganic materials 0.000 description 3
- 230000000903 blocking effect Effects 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 210000000188 diaphragm Anatomy 0.000 description 3
- 210000000918 epididymis Anatomy 0.000 description 3
- 210000003743 erythrocyte Anatomy 0.000 description 3
- 229940011871 estrogen Drugs 0.000 description 3
- 239000000262 estrogen Substances 0.000 description 3
- 125000001153 fluoro group Chemical group F* 0.000 description 3
- 235000012631 food intake Nutrition 0.000 description 3
- 230000036541 health Effects 0.000 description 3
- 125000005842 heteroatom Chemical group 0.000 description 3
- 239000003446 ligand Substances 0.000 description 3
- 239000006210 lotion Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 210000001672 ovary Anatomy 0.000 description 3
- 239000000186 progesterone Substances 0.000 description 3
- 229960003387 progesterone Drugs 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 108091008726 retinoic acid receptors α Proteins 0.000 description 3
- 108091008761 retinoic acid receptors β Proteins 0.000 description 3
- 108091008760 retinoic acid receptors γ Proteins 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 150000003431 steroids Chemical class 0.000 description 3
- 125000000547 substituted alkyl group Chemical group 0.000 description 3
- 239000000829 suppository Substances 0.000 description 3
- 239000006188 syrup Substances 0.000 description 3
- 235000020357 syrup Nutrition 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 125000005389 trialkylsiloxy group Chemical group 0.000 description 3
- 125000004665 trialkylsilyl group Chemical group 0.000 description 3
- VLPFTAMPNXLGLX-UHFFFAOYSA-N trioctanoin Chemical compound CCCCCCCC(=O)OCC(OC(=O)CCCCCCC)COC(=O)CCCCCCC VLPFTAMPNXLGLX-UHFFFAOYSA-N 0.000 description 3
- WWYNJERNGUHSAO-XUDSTZEESA-N (+)-Norgestrel Chemical compound O=C1CC[C@@H]2[C@H]3CC[C@](CC)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 WWYNJERNGUHSAO-XUDSTZEESA-N 0.000 description 2
- WRDYRGXFEHQRKW-UHFFFAOYSA-N (2,2-dimethyl-4-oxo-3h-thiochromen-6-yl) trifluoromethanesulfonate Chemical compound FC(F)(F)S(=O)(=O)OC1=CC=C2SC(C)(C)CC(=O)C2=C1 WRDYRGXFEHQRKW-UHFFFAOYSA-N 0.000 description 2
- URFPRAHGGBYNPW-UHFFFAOYSA-N 1-bromo-4-ethylbenzene Chemical compound CCC1=CC=C(Br)C=C1 URFPRAHGGBYNPW-UHFFFAOYSA-N 0.000 description 2
- ANHULLCTXBJTJW-UHFFFAOYSA-N 2,2-dimethyl-6-(2-trimethylsilylethynyl)-3h-thiochromen-4-one Chemical compound C[Si](C)(C)C#CC1=CC=C2SC(C)(C)CC(=O)C2=C1 ANHULLCTXBJTJW-UHFFFAOYSA-N 0.000 description 2
- QRPOZDMXOXTFSH-UHFFFAOYSA-N 3-(4-methoxyphenyl)sulfanyl-3-methylbutanoic acid Chemical compound COC1=CC=C(SC(C)(C)CC(O)=O)C=C1 QRPOZDMXOXTFSH-UHFFFAOYSA-N 0.000 description 2
- YYPNJNDODFVZLE-UHFFFAOYSA-N 3-methylbut-2-enoic acid Chemical compound CC(C)=CC(O)=O YYPNJNDODFVZLE-UHFFFAOYSA-N 0.000 description 2
- NCEQLLNVRRTCKJ-UHFFFAOYSA-N 4-[2-[5,5-dimethyl-8-(4-methylphenyl)-6h-naphthalen-2-yl]ethynyl]benzoic acid Chemical compound C1=CC(C)=CC=C1C1=CCC(C)(C)C2=CC=C(C#CC=3C=CC(=CC=3)C(O)=O)C=C12 NCEQLLNVRRTCKJ-UHFFFAOYSA-N 0.000 description 2
- KRHBJNQZNOFVRB-UHFFFAOYSA-N 6-ethynyl-2,2-dimethyl-3h-thiochromen-4-one Chemical compound C#CC1=CC=C2SC(C)(C)CC(=O)C2=C1 KRHBJNQZNOFVRB-UHFFFAOYSA-N 0.000 description 2
- HERROWJXACVBFN-UHFFFAOYSA-N 6-hydroxy-2,2-dimethyl-3h-thiochromen-4-one Chemical compound OC1=CC=C2SC(C)(C)CC(=O)C2=C1 HERROWJXACVBFN-UHFFFAOYSA-N 0.000 description 2
- BLDKYBCSARSGBR-UHFFFAOYSA-N 6-methoxy-2,2-dimethyl-3h-thiochromen-4-one Chemical compound S1C(C)(C)CC(=O)C2=CC(OC)=CC=C21 BLDKYBCSARSGBR-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- 240000005343 Azadirachta indica Species 0.000 description 2
- BPYKTIZUTYGOLE-IFADSCNNSA-N Bilirubin Chemical compound N1C(=O)C(C)=C(C=C)\C1=C\C1=C(C)C(CCC(O)=O)=C(CC2=C(C(C)=C(\C=C/3C(=C(C=C)C(=O)N\3)C)N2)CCC(O)=O)N1 BPYKTIZUTYGOLE-IFADSCNNSA-N 0.000 description 2
- 201000004569 Blindness Diseases 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- NMJREATYWWNIKX-UHFFFAOYSA-N GnRH Chemical compound C1CCC(C(=O)NCC(N)=O)N1C(=O)C(CC(C)C)NC(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)CNC(=O)C(NC(=O)C(CO)NC(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C(CC=1NC=NC=1)NC(=O)C1NC(=O)CC1)CC1=CC=C(O)C=C1 NMJREATYWWNIKX-UHFFFAOYSA-N 0.000 description 2
- WZUVPPKBWHMQCE-UHFFFAOYSA-N Haematoxylin Chemical compound C12=CC(O)=C(O)C=C2CC2(O)C1C1=CC=C(O)C(O)=C1OC2 WZUVPPKBWHMQCE-UHFFFAOYSA-N 0.000 description 2
- 206010062767 Hypophysitis Diseases 0.000 description 2
- 235000013500 Melia azadirachta Nutrition 0.000 description 2
- 235000019502 Orange oil Nutrition 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 101000857870 Squalus acanthias Gonadoliberin Proteins 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 230000005856 abnormality Effects 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 210000004100 adrenal gland Anatomy 0.000 description 2
- 125000005103 alkyl silyl group Chemical group 0.000 description 2
- 230000004888 barrier function Effects 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- YNHIGQDRGKUECZ-UHFFFAOYSA-L bis(triphenylphosphine)palladium(ii) dichloride Chemical compound [Cl-].[Cl-].[Pd+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 description 2
- 238000004820 blood count Methods 0.000 description 2
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 238000012754 cardiac puncture Methods 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 230000007812 deficiency Effects 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 235000013601 eggs Nutrition 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- ZFZSCWASFPMMOX-UHFFFAOYSA-N ethyl 4-[2-(2,2-dimethyl-4-oxo-3h-thiochromen-6-yl)ethynyl]benzoate Chemical compound C1=CC(C(=O)OCC)=CC=C1C#CC1=CC=C(SC(C)(C)CC2=O)C2=C1 ZFZSCWASFPMMOX-UHFFFAOYSA-N 0.000 description 2
- XSLHKWWBNMHWGA-UHFFFAOYSA-N ethyl 4-[2-[2,2-dimethyl-4-(trifluoromethylsulfonyloxy)thiochromen-6-yl]ethynyl]benzoate Chemical compound C1=CC(C(=O)OCC)=CC=C1C#CC1=CC=C(SC(C)(C)C=C2OS(=O)(=O)C(F)(F)F)C2=C1 XSLHKWWBNMHWGA-UHFFFAOYSA-N 0.000 description 2
- YCGIBQQQANUABI-UHFFFAOYSA-N ethyl 4-[2-[4-(4-ethylphenyl)-2,2-dimethylthiochromen-6-yl]ethynyl]benzoate Chemical compound C1=CC(C(=O)OCC)=CC=C1C#CC1=CC=C(SC(C)(C)C=C2C=3C=CC(CC)=CC=3)C2=C1 YCGIBQQQANUABI-UHFFFAOYSA-N 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 230000014509 gene expression Effects 0.000 description 2
- 210000002216 heart Anatomy 0.000 description 2
- 239000000960 hypophysis hormone Substances 0.000 description 2
- 208000000509 infertility Diseases 0.000 description 2
- 230000036512 infertility Effects 0.000 description 2
- 230000000977 initiatory effect Effects 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 210000002332 leydig cell Anatomy 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 230000035800 maturation Effects 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- 230000011278 mitosis Effects 0.000 description 2
- 239000007922 nasal spray Substances 0.000 description 2
- 108020004017 nuclear receptors Proteins 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 239000010502 orange oil Substances 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 2
- 230000001575 pathological effect Effects 0.000 description 2
- 239000000813 peptide hormone Substances 0.000 description 2
- 210000003635 pituitary gland Anatomy 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 210000002307 prostate Anatomy 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 230000022532 regulation of transcription, DNA-dependent Effects 0.000 description 2
- 230000001850 reproductive effect Effects 0.000 description 2
- 229960003471 retinol Drugs 0.000 description 2
- 235000020944 retinol Nutrition 0.000 description 2
- 239000011607 retinol Substances 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 230000001568 sexual effect Effects 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 210000004336 spermatogonium Anatomy 0.000 description 2
- 210000000952 spleen Anatomy 0.000 description 2
- 238000013223 sprague-dawley female rat Methods 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- 239000012049 topical pharmaceutical composition Substances 0.000 description 2
- 238000013518 transcription Methods 0.000 description 2
- 230000035897 transcription Effects 0.000 description 2
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- 210000000689 upper leg Anatomy 0.000 description 2
- 238000002562 urinalysis Methods 0.000 description 2
- OBHRVMZSZIDDEK-UHFFFAOYSA-N urobilinogen Chemical compound CCC1=C(C)C(=O)NC1CC1=C(C)C(CCC(O)=O)=C(CC2=C(C(C)=C(CC3C(=C(CC)C(=O)N3)C)N2)CCC(O)=O)N1 OBHRVMZSZIDDEK-UHFFFAOYSA-N 0.000 description 2
- 229960005486 vaccine Drugs 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 description 1
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 description 1
- NIFAOMSJMGEFTQ-UHFFFAOYSA-N 4-methoxybenzenethiol Chemical compound COC1=CC=C(S)C=C1 NIFAOMSJMGEFTQ-UHFFFAOYSA-N 0.000 description 1
- SHGAZHPCJJPHSC-ZVCIMWCZSA-N 9-cis-retinoic acid Chemical compound OC(=O)/C=C(\C)/C=C/C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-ZVCIMWCZSA-N 0.000 description 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 206010002961 Aplasia Diseases 0.000 description 1
- 206010003694 Atrophy Diseases 0.000 description 1
- 229910015845 BBr3 Inorganic materials 0.000 description 1
- 208000008035 Back Pain Diseases 0.000 description 1
- KYNSBQPICQTCGU-UHFFFAOYSA-N Benzopyrane Chemical group C1=CC=C2C=CCOC2=C1 KYNSBQPICQTCGU-UHFFFAOYSA-N 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- LCEQZOWOZIFJQL-UHFFFAOYSA-N C1=CC=C(/C2=C/CCC3=CC=CC=C32)C=C1.CC.CC.CC.CC.CC(=O)NC1=CC=C(C)C=C1 Chemical compound C1=CC=C(/C2=C/CCC3=CC=CC=C32)C=C1.CC.CC.CC.CC.CC(=O)NC1=CC=C(C)C=C1 LCEQZOWOZIFJQL-UHFFFAOYSA-N 0.000 description 1
- ZRHHGEFRGCBWHM-JDYIGCTCSA-N C=CCCCOC1=C(C(C)(C)C)C=C(/C(C)=C/C=C/C(C)=C/C(=O)O)C=C1C(C)(C)C Chemical compound C=CCCCOC1=C(C(C)(C)C)C=C(/C(C)=C/C=C/C(C)=C/C(=O)O)C=C1C(C)(C)C ZRHHGEFRGCBWHM-JDYIGCTCSA-N 0.000 description 1
- QOVYFDUMLAQZHG-OWERKXPCSA-N CC(/C=C/C=C(\C)C1=CC(C(C)(C)C)=CC(C(=O)O)=C1)=C\C(=O)O Chemical compound CC(/C=C/C=C(\C)C1=CC(C(C)(C)C)=CC(C(=O)O)=C1)=C\C(=O)O QOVYFDUMLAQZHG-OWERKXPCSA-N 0.000 description 1
- WICPLWKVWDISHC-ZIAGMJOISA-N CC(/C=C/C=C(\C)C1=CC(C(C)(C)C)=CC(OCC2=CC=C(C(C)(C)C)C=C2)=C1)=C\C(=O)O Chemical compound CC(/C=C/C=C(\C)C1=CC(C(C)(C)C)=CC(OCC2=CC=C(C(C)(C)C)C=C2)=C1)=C\C(=O)O WICPLWKVWDISHC-ZIAGMJOISA-N 0.000 description 1
- AFOZSYSBPFJVOB-UHFFFAOYSA-N CC1=CC=C(C#CC2=CC3=C(C=C2)C(C)(C)CC=C3C2=CC=C(C)C=C2)C=C1 Chemical compound CC1=CC=C(C#CC2=CC3=C(C=C2)C(C)(C)CC=C3C2=CC=C(C)C=C2)C=C1 AFOZSYSBPFJVOB-UHFFFAOYSA-N 0.000 description 1
- GQCMGMSXJKNFGI-UHFFFAOYSA-N CCC1=CC(C)(C)SC2=C1C=C(C#CC1=CC=C(C)C=C1)C=C2 Chemical compound CCC1=CC(C)(C)SC2=C1C=C(C#CC1=CC=C(C)C=C1)C=C2 GQCMGMSXJKNFGI-UHFFFAOYSA-N 0.000 description 1
- QMXUKIBCYDXUIB-XUXWEHMISA-N CCOC1=C(C(C)(C)C)C=C(/C(C)=C/C=C/C(C)=C/C(=O)O)C=C1C(C)(C)C Chemical compound CCOC1=C(C(C)(C)C)C=C(/C(C)=C/C=C/C(C)=C/C(=O)O)C=C1C(C)(C)C QMXUKIBCYDXUIB-XUXWEHMISA-N 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- 108091026890 Coding region Proteins 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 208000032170 Congenital Abnormalities Diseases 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 1
- 241000557626 Corvus corax Species 0.000 description 1
- 102000008175 FSH Receptors Human genes 0.000 description 1
- 108010060374 FSH Receptors Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 241000238631 Hexapoda Species 0.000 description 1
- 101001093899 Homo sapiens Retinoic acid receptor RXR-alpha Proteins 0.000 description 1
- 101000640876 Homo sapiens Retinoic acid receptor RXR-beta Proteins 0.000 description 1
- 101000640882 Homo sapiens Retinoic acid receptor RXR-gamma Proteins 0.000 description 1
- 102000003864 Human Follicle Stimulating Hormone Human genes 0.000 description 1
- 108010082302 Human Follicle Stimulating Hormone Proteins 0.000 description 1
- 206010021135 Hypovitaminosis Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 208000007101 Muscle Cramp Diseases 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- 238000011887 Necropsy Methods 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- 102000001708 Protein Isoforms Human genes 0.000 description 1
- 108010029485 Protein Isoforms Proteins 0.000 description 1
- 102100035178 Retinoic acid receptor RXR-alpha Human genes 0.000 description 1
- 102100034253 Retinoic acid receptor RXR-beta Human genes 0.000 description 1
- 102100034262 Retinoic acid receptor RXR-gamma Human genes 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 206010040030 Sensory loss Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 206010040880 Skin irritation Diseases 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 206010067802 Sperm granuloma Diseases 0.000 description 1
- 206010043298 Testicular atrophy Diseases 0.000 description 1
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 208000010011 Vitamin A Deficiency Diseases 0.000 description 1
- XEEPVWTTWGFDAU-UHFFFAOYSA-N [H]N(C(=O)C1=CC(C(C)(C)C)=C(OCC)C(C(C)(C)C)=C1)C1=CC=C(C(=O)O)C=C1 Chemical compound [H]N(C(=O)C1=CC(C(C)(C)C)=C(OCC)C(C(C)(C)C)=C1)C1=CC=C(C(=O)O)C=C1 XEEPVWTTWGFDAU-UHFFFAOYSA-N 0.000 description 1
- CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 229960001445 alitretinoin Drugs 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 239000003098 androgen Substances 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000003466 anti-cipated effect Effects 0.000 description 1
- 230000000469 anti-sperm effect Effects 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 210000000709 aorta Anatomy 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000037444 atrophy Effects 0.000 description 1
- 201000010788 atrophy of testis Diseases 0.000 description 1
- 208000019804 backache Diseases 0.000 description 1
- 210000003651 basophil Anatomy 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000002146 bilateral effect Effects 0.000 description 1
- 210000000601 blood cell Anatomy 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 229960001631 carbomer Drugs 0.000 description 1
- 229940075509 carbomer 1342 Drugs 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 210000004534 cecum Anatomy 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 210000003679 cervix uteri Anatomy 0.000 description 1
- 238000010367 cloning Methods 0.000 description 1
- 230000015271 coagulation Effects 0.000 description 1
- 238000005345 coagulation Methods 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 210000002777 columnar cell Anatomy 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 229940124558 contraceptive agent Drugs 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 231100000517 death Toxicity 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 238000002716 delivery method Methods 0.000 description 1
- 239000007933 dermal patch Substances 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- IPZJQDSFZGZEOY-UHFFFAOYSA-N dimethylmethylene Chemical group C[C]C IPZJQDSFZGZEOY-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 210000001198 duodenum Anatomy 0.000 description 1
- 108010057988 ecdysone receptor Proteins 0.000 description 1
- 201000003511 ectopic pregnancy Diseases 0.000 description 1
- YQGOJNYOYNNSMM-UHFFFAOYSA-N eosin Chemical compound [Na+].OC(=O)C1=CC=CC=C1C1=C2C=C(Br)C(=O)C(Br)=C2OC2=C(Br)C(O)=C(Br)C=C21 YQGOJNYOYNNSMM-UHFFFAOYSA-N 0.000 description 1
- 210000003979 eosinophil Anatomy 0.000 description 1
- 210000002745 epiphysis Anatomy 0.000 description 1
- 210000003238 esophagus Anatomy 0.000 description 1
- YCBJOQUNPLTBGG-UHFFFAOYSA-N ethyl 4-iodobenzoate Chemical compound CCOC(=O)C1=CC=C(I)C=C1 YCBJOQUNPLTBGG-UHFFFAOYSA-N 0.000 description 1
- 238000013401 experimental design Methods 0.000 description 1
- 238000013265 extended release Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 229940124566 female contraceptive agent Drugs 0.000 description 1
- 230000004720 fertilization Effects 0.000 description 1
- 210000000630 fibrocyte Anatomy 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000003862 glucocorticoid Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 230000001456 gonadotroph Effects 0.000 description 1
- 230000036449 good health Effects 0.000 description 1
- 230000005484 gravity Effects 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 125000004970 halomethyl group Chemical group 0.000 description 1
- 210000003128 head Anatomy 0.000 description 1
- 238000005534 hematocrit Methods 0.000 description 1
- 230000002489 hematologic effect Effects 0.000 description 1
- 239000000833 heterodimer Substances 0.000 description 1
- 238000005734 heterodimerization reaction Methods 0.000 description 1
- 238000010562 histological examination Methods 0.000 description 1
- 238000007489 histopathology method Methods 0.000 description 1
- 230000003054 hormonal effect Effects 0.000 description 1
- 239000003688 hormone derivative Substances 0.000 description 1
- 108091008039 hormone receptors Proteins 0.000 description 1
- 230000002267 hypothalamic effect Effects 0.000 description 1
- 210000003405 ileum Anatomy 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 231100000535 infertility Toxicity 0.000 description 1
- 208000021267 infertility disease Diseases 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 210000001630 jejunum Anatomy 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 210000000629 knee joint Anatomy 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 229960004400 levonorgestrel Drugs 0.000 description 1
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 230000032646 lung growth Effects 0.000 description 1
- 210000001165 lymph node Anatomy 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 210000005075 mammary gland Anatomy 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 229940057917 medium chain triglycerides Drugs 0.000 description 1
- 230000021121 meiosis Effects 0.000 description 1
- 208000007106 menorrhagia Diseases 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 230000029052 metamorphosis Effects 0.000 description 1
- 238000007431 microscopic evaluation Methods 0.000 description 1
- 239000002395 mineralocorticoid Substances 0.000 description 1
- 210000001616 monocyte Anatomy 0.000 description 1
- 229940097496 nasal spray Drugs 0.000 description 1
- 210000000440 neutrophil Anatomy 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 239000003539 oral contraceptive agent Substances 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- 208000025661 ovarian cyst Diseases 0.000 description 1
- 238000012261 overproduction Methods 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 230000000849 parathyroid Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- 239000003614 peroxisome proliferator Substances 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 230000001817 pituitary effect Effects 0.000 description 1
- 239000002861 polymer material Substances 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 230000029279 positive regulation of transcription, DNA-dependent Effects 0.000 description 1
- 238000011886 postmortem examination Methods 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000025078 regulation of biosynthetic process Effects 0.000 description 1
- 230000014493 regulation of gene expression Effects 0.000 description 1
- 102000027483 retinoid hormone receptors Human genes 0.000 description 1
- 108091008679 retinoid hormone receptors Proteins 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 210000003079 salivary gland Anatomy 0.000 description 1
- 231100000241 scar Toxicity 0.000 description 1
- 210000003497 sciatic nerve Anatomy 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000009291 secondary effect Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- 210000001741 seminiferous epithelium Anatomy 0.000 description 1
- 230000009919 sequestration Effects 0.000 description 1
- 125000004469 siloxy group Chemical group [SiH3]O* 0.000 description 1
- 210000002027 skeletal muscle Anatomy 0.000 description 1
- 230000036556 skin irritation Effects 0.000 description 1
- 231100000475 skin irritation Toxicity 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 1
- 210000001082 somatic cell Anatomy 0.000 description 1
- 229940035049 sorbitan monooleate Drugs 0.000 description 1
- 235000011069 sorbitan monooleate Nutrition 0.000 description 1
- 239000001593 sorbitan monooleate Substances 0.000 description 1
- 230000019100 sperm motility Effects 0.000 description 1
- 239000000934 spermatocidal agent Substances 0.000 description 1
- 230000002199 spermatogenetic effect Effects 0.000 description 1
- 230000001150 spermicidal effect Effects 0.000 description 1
- 238000013222 sprague-dawley male rat Methods 0.000 description 1
- 238000012453 sprague-dawley rat model Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 210000001562 sternum Anatomy 0.000 description 1
- 239000003270 steroid hormone Substances 0.000 description 1
- 230000000365 steroidogenetic effect Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000000153 supplemental effect Effects 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 210000000538 tail Anatomy 0.000 description 1
- 230000002381 testicular Effects 0.000 description 1
- 231100001044 testicular atrophy Toxicity 0.000 description 1
- 210000000115 thoracic cavity Anatomy 0.000 description 1
- 210000001541 thymus gland Anatomy 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
- 239000005495 thyroid hormone Substances 0.000 description 1
- 229940036555 thyroid hormone Drugs 0.000 description 1
- 102000004217 thyroid hormone receptors Human genes 0.000 description 1
- 108090000721 thyroid hormone receptors Proteins 0.000 description 1
- 210000002303 tibia Anatomy 0.000 description 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
- 210000002105 tongue Anatomy 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 229940100611 topical cream Drugs 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 210000003437 trachea Anatomy 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- LADGBHLMCUINGV-UHFFFAOYSA-N tricaprin Chemical compound CCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCC)COC(=O)CCCCCCCCC LADGBHLMCUINGV-UHFFFAOYSA-N 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- CWMFRHBXRUITQE-UHFFFAOYSA-N trimethylsilylacetylene Chemical group C[Si](C)(C)C#C CWMFRHBXRUITQE-UHFFFAOYSA-N 0.000 description 1
- 238000009810 tubal ligation Methods 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- 210000000626 ureter Anatomy 0.000 description 1
- 210000003708 urethra Anatomy 0.000 description 1
- 210000003932 urinary bladder Anatomy 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- 210000001177 vas deferen Anatomy 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 238000007879 vasectomy Methods 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 102000009310 vitamin D receptors Human genes 0.000 description 1
- 108050000156 vitamin D receptors Proteins 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 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
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
- A61K31/382—Heterocyclic compounds having sulfur as a ring hetero atom having six-membered rings, e.g. thioxanthenes
-
- 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
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
- A61K31/203—Retinoic acids ; Salts thereof
-
- 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
- A61K31/352—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 condensed with carbocyclic rings, e.g. methantheline
- A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
-
- 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
- A61K31/695—Silicon compounds
-
- 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
- A61P15/16—Masculine contraceptives
Definitions
- the present invention concerns methods and compositions for inhibiting or blocking fertility in a male mammal by the administration of a retinoid or retinoid derivative that is able to act as an antagonist or inverse agonist of a retinoic acid receptor (RAR).
- RAR retinoic acid receptor
- the most common non-surgical birth control method in the United States is the birth control pill (“the Pill”), which contains synthetic progestin and estrogen; synthetic hormones similar to those produced naturally in a woman's body.
- the Pill works primarily by suppressing the release of eggs from a woman's ovaries.
- Condoms made of either synthetic polymer materials or animal skin, are less effective than birth control pills and their effectiveness is further subject to subversion through the possibility that small breaks may be present, permitting leakage of semen. Additionally, the use of a condom requires the affirmative action of the male, usually immediately prior to the initiation of sexual intercourse and some men report a loss of sensation through the use of condoms. Hence, subject non-compliance is also an issue in the use of condoms.
- Subdermal implants such as the NORPLANT® implant device, are quite effective contraceptive means.
- the implant comprises a set of silicone rods that are inserted under the skin of the upper arm.
- the implant contains hormones, such as progestin, levonorgestrel and progesterone, that are slowly released over a period of time of up to five years. Side effects may be similar to those involved in the use of birth control pills, and include a risk of developing ovarian cysts. Additionally, while the implant can be removed, the procedure is difficult even for skilled surgeons due to the formation of scar tissue around the implant.
- Intrauterine devices are small devices that are typically either made of copper or impregnated with progesterone. These must be inserted (and removed) by a doctor. Depending on the design, the devices appear to interfere with sperm motility or the implantation of the fertilized egg in the uterine wall. Side effects can include cramps, backache, spotting, or heavy periods, and women may have an increased risk of ectopic pregnancy or infertility. IUDs are usually not recommended for women who have not had children or who think they will have children in the future due to these latter risks. Normally, the contraceptive effects are reversible upon removal of the device.
- Barriers such as diaphragms and sponges are usually used in conjunction with a spermicidal cream, foam, or gel.
- the effectiveness of such devices is between about 90% and about 95%. The user can insert them as long as a number of hours before sexual intercourse, and the effects are temporary; if pregnancy is subsequently desired, the woman can discontinue their use with a concomitant return of fertility.
- GnRH hypothalamic peptide hormone
- LH luteinizing hormone
- FSH follicle-stimulating hormone
- LGFV Lung Growth Factor Variant
- U.S. Pat. No. 5,753,231 to Herr, et al., describes a female contraceptive vaccine prepared from antibodies raised to a recombinant primate acrosomal sperm antigen. The vaccine elicits an anti-sperm immune response, resulting in inhibition of fertilization. Also described are contraceptive compositions containing such an antibody in a carrier for vaginal application.
- the present invention concerns the discovery that certain agents that are able to block the binding of retinoic acid (RA) or other RAR ligands to RAR receptors, and thereby prevent activation of RARs, are also able to inhibit spermatogenesis in a male mammal.
- RA retinoic acid
- vitamin A-deficient rats in which there was a complete spermatogenic arrest
- vitamin A replacement results in restoration of normal spermatogenesis; reinitiation of spermatogenesis occurs in rats within 24-48 hours following vitamin A replacement.
- nuclear hormone receptors are able to bind to cis-acting regulatory elements present in the promoters of the target genes.
- the glucocorticoid, estrogen, androgen, progestin, and mineralcorticoid receptors have been found to bind as homodimers to specific response elements organized as inverted repeats.
- RAR retinoid acid receptor
- RXR retinoid X receptor
- RAR and RXR like many nuclear receptors, exist as a number of subtypes (RAR ⁇ , RAR ⁇ , RAR ⁇ , and RXR ⁇ , RXR ⁇ , and RXR ⁇ ). Additionally, each subtype may exist in different isoforms.
- an RAR antagonist or RAR inverse agonist results in the arrest of spermatogenesis in male mammals.
- antagonist is meant that an agent is able to bind to the retinoic acid binding site of an RAR, thereby blocking the binding of retinoic acid to, and activation of the RAR.
- inverse agonist is meant an agent able to suppress the basal level of RAR activity (homo- or heterodimerization and trans-acting transcriptional control of various genes whose regulation is normally responsive to RAR modulation).
- a compound will normally be an RAR antagonist if it is an inverse agonist, but the converse is not necessarily true.
- the spermatogenetic arrest resulting from treatment of a male mammal with an effective amount of an RAR antagonist or inverse agonist is not accompanied by most other symptoms of hypovitaminosis A, such as blindness, abnormal growth or susceptibility to infectious disease. Testosterone levels appear to remain normal; thus the preferred agents do not significantly affect male libido and sexuality.
- compositions have applicability as agents for veterinary or therapeutic application as a male contraceptive.
- a class of preferred compounds has the structure: wherein X is S, O, NR′ where R′ is H or alkyl of 1 to 6 carbons, or
- X is [C(R 1 ) 2 ] n where R 1 is independently H or alkyl of 1 to 6 carbons, and n is an integer between, and including, 0 and 2, and;
- R 2 is hydrogen, lower alkyl of 1 to 6 carbons, F, Cl, Br, I, CF 3 , fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons, and;
- R 3 is hydrogen, lower alkyl of 1 to 6 carbons or F, and
- n is an integer having the value of 0-3, and;
- o is an integer having the value of 0-3, and;
- Y is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R 2 groups, or
- Y represents a direct valence bond between said (CR 2 ⁇ CR 2 ) n′ group and B;
- A is (CH 2 ) q where q is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds;
- B is hydrogen, COOH or a pharmaceutically acceptable salt thereof, COOR 8 , CONR 9 R 10 , —CH 2 OH, CH 2 OR 11 , CH 2 OCOR 11 , CHO, CH(OR 12 ) 2 , CHOR 13 O, —COR 7 , CR 7 (OR 12 ) 2 , CR 7 OR 13 O, or tri-lower alkylsilyl, where R 7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R 8 is an alkyl group of 1 to 10 carbons or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R 8 is phenyl or lower alkylphenyl, R 9 and R 10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R 11
- R 14 is (R 15 ) r -phenyl, (R 15 ) r -naphthyl, or (R 15 ) r -heteroaryl where the heteroaryl group has 1 to 3 heteroatoms selected from the group consisting of O, S and N, r is an integer having the values of 0-5, and
- R 15 is independently H, F, Cl, Br, I, NO 2 , N(R 8 ) 2 , N(R 8 )COR 8 , NR 8 CON(R 8 ) 2 , OH, OCOR 8 , OR 8 , CN, an alkyl group having 1 to 10 carbons, fluoro substituted alkyl group having 1 to 10 carbons, an alkenyl group having 1 to 10 carbons and 1 to 3 double bonds, alkynyl group having 1 to 10 carbons and 1 to 3 triple bonds, or a trialkylsilyl or trialkylsilyloxy group where the alkyl groups independently have 1 to 6 carbons.
- Another preferred class of compounds has the structure:
- X is S, O, NR′ where R′ is H or alkyl of 1 to 6 carbons, or
- X is [C(R 1 ) 2 ] n where R 1 is independently H or alkyl of 1 to 6 carbons, and n is an integer between, and including, 0 and 2, and;
- R 2 is hydrogen, lower alkyl of 1 to 6 carbons, F, Cl, Br, I, CF 3 , fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons, and;
- R 3 is hydrogen, lower alkyl of 1 to 6 carbons or F, and
- n is an integer having the value of 0, 1, 2, or 3, and;
- o is an integer having the value of 0, 1, 2, or 3, and;
- Y is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R 2 groups, and;
- A is (CH 2 ) q where q is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds, and;
- B is hydrogen, COOH or a pharmaceutically acceptable salt thereof, COOR 8 , CONR 9 R 10 , —CH 2 OH, CH 2 OR 11 , CH 2 OCOR 11 , CHO, CH(OR 12 ) 2 , CHOR 13 O, —COR 7 , CR 7 (OR 12 ) 2 , CR 7 OR 13 O, or tri-lower alkylsilyl, where R 7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R 8 is an alkyl group of 1 to 10 carbons or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R 8 is phenyl or lower alkylphenyl, R 9 and R 10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R 11
- R 14 is (R 15 ) r -phenyl, (R 15 ) r -naphthyl, or (R 15 ) r -heteroaryl where the heteroaryl group has 1 to 3 heteroatoms selected from the group consisting of O, S and N, r is an integer having the values of 0, 1, 2, 3, 4 or 5, and;
- R 15 is independently H, F, Cl, Br, I, NO 2 , N(R 8 ) 2 , N(R 8 )COR 8 , NR 8 CON(R 8 ) 2 , OH, OCOR 8 , OR 8 , CN, an alkyl group having 1 to 10 carbons, fluoro substituted alkyl group having 1 to 10 carbons, an alkenyl group having 1 to 10 carbons and 1 to 3 double bonds, alkyl group having 1 to 10 carbons and 1 to 3 triple bonds, or a trialkylsilyl or trialkylsilyloxy group where the alkyl groups independently have 1 to 6 carbons, and;
- R 16 is H, lower alkyl of 1 to 6 carbons, and
- R 17 is H, lower alkyl of 1 to 6 carbons, OH or OCOR 11 , and;
- p is 0 or 1, with the proviso that when p is 1 then there is no R17 substituent group, and m is an integer between, and including, 0 and 2.
- a further preferred class of compounds is the class of the structure: where X is C(R 1 ) 2 or O, and; R 1 is H or alkyl of 1 to 6 carbons, and; R 2 is lower alkyl of 1 to 6 carbons, F, Cl, Br, I, CF 3 , fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons, and; m is an integer having the value of 0-3, and; R 3 is lower alkyl of 1 to 6 carbons of F, and; o is an integer having the value of 0-3, and; s is an integer having the value of 1-3, and; R 8 is an alkyl group of 1 to 10 carbons or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R 8 is phenyl or lower alkylphenyl, and; R 15 is independently
- Another preferred class of compounds is that of the structure: where X is C(CH 3 ) 2 or O, and; R 2 is H or Br, and; R 2′ and R 2′′ independently are H or F, and; R 3 is H or CH 3 , and; R 8 is H, lower alkyl of 1 to 6 carbons, or a pharmaceutically acceptable salt of said compound.
- a further preferred class of such compounds has the structure:
- X 1 is S or O
- X 2 is CH or N
- R 2 is H, F, CF 3 or alkoxy of 1 to 6 carbons
- R 2 H, F, or CF 3 ;
- R 8 is H, or lower alkyl of 1 to 6 carbons
- R 14 is unsubstituted phenyl, thienyl or pyridyl, or phenyl, thienyl or pyridyl substituted with one to three R 15 groups, where R 15 is lower alkyl of 1 to 6 carbons, chlorine, CF 3 , or alkoxy of 1 to 6 carbons, or a pharmaceutically acceptable salt of said compound.
- the compound has the structure:
- X 2 is CH or N, and
- R 2 is H, F, or OCH 3 , and
- R 8 is H, or lower alkyl of 1 to 6 carbons, and
- R 14 is selected from the group consisting of phenyl, 4-(lower-alkyl)phenyl, 5-(lower alkyl)-2-thienyl, and 6-(lower alkyl)-3-pyridyl where lower alkyl has 1 to 6 carbons, or a pharmaceutically acceptable salt of said compound.
- a further preferred class of such compounds has the structure: where
- X 1 is S or O
- X 2 is CH or N
- R 2 is H, F, CF 3 or alkoxy of 1 to 6 carbons
- R 2 H, F, or CF 3 ;
- R 8 is H, or lower alkyl of 1 to 6 carbons
- R 14 is unsubstituted phenyl, thienyl or pyridyl, or phenyl, thienyl or pyridyl substituted with one to three R 15 groups, where R 15 is lower alkyl of 1 to 6 carbons, chlorine, CF 3 , or alkoxy of 1 to 6 carbons, or a pharmaceutically acceptable salt of said compound.
- the compound has the structure:
- X 2 is CH or N, and
- R 2 is H, F, or OCH 3 , and
- R 8 is H, or lower alkyl of 1 to 6 carbons, and
- R 14 is selected from the group consisting of phenyl, 4-(lower-alkyl)phenyl, 5-(lower alkyl)-2-thienyl, and 6-(lower alkyl)-3-pyridyl where lower alkyl has 1 to 6 carbons, or a pharmaceutically acceptable salt of said compound.
- R 8 is H, or lower alkyl of 1 to 6 carbons
- R 14 is selected from the group consisting of phenyl, and 4-(lower-alkyl)phenyl, where lower alkyl has 1 to 6 carbons, or a pharmaceutically acceptable salt of said compound.
- Another preferred compound class has the following structure: where R 8 is H, lower alkyl of 1 to 6 carbons, or a pharmaceutically acceptable salt of said compound.
- Yet another preferred compound is one having the following structure: where R 8 is H, lower alkyl of 1 to 6 carbons, or a pharmaceutically acceptable salt of said compound.
- R 8 is H
- this compound is termed AGN 193109.
- Yet another class of compounds contemplated for use in the present invention is that having the structure: wherein X 1 is: —C(R 1 ) 2 —, —C(R 1 ) 2 —C(R 1 ) 2 —, —S—, —O—, —NR 1 —, —C(R 1 ) 2 —O—, —C(R 1 ) 2 —S—, or C(R 1 ) 2 —NR 1 —; and R 1 is independently H or alkyl of 1 to 6 carbons; and R 2 is optional and is defined as lower alkyl of 1 to 6 carbons, F, Cl, Br, I, CF 3 , fluoro substituted alkyl of 1 to 6 carbons, OH SH, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons; and m is an integer between, and including, 0 and 4; and n is an integer between, and including, 0 and 2; and o is an integer between, and including
- Y 1 is phenyl, naphthyl, or heteroaryl selected from the group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazonyl, ozazolyl, imidazolyl, and pyrrazolyl, said phenyl, naphthyl, and heteroaryl groups being substituted with an R 1 group, and further substituted or unsubstituted with one or two R 2 groups;
- R 1 is C 1-10 alkyl, 1-ademantyl, 2-tetrahydropyranoxy, trialkylsilanyloxy where alkyl has up to 6 carbons, OH, alkoxy where the alkyl group has up to 10 carbons, alkylthio where the alkyl group has up to 10 carbons, or OCH 2 OC 1-6 alkyl;
- R 2 is lower alkyl of 1 to 6 carbons, F, Cl, Br, I, CF 3 , CF 2 CF 3 , OH, OR 3 , NO 2 , N(R 3 ) 2 , CN, N 3 , COR 3 , NHCOR 3 , COOH, or COOR 3 ;
- X is (C(R 3 ) 2 , S, SO, SO 2 , O or NR 3 ;
- R 3 is independently H or lower alkyl of 1 to 6 carbons
- Y 2 is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl, naphthyl and heteroaryl groups being unsubstituted or substituted with one or two R 2 groups, or
- Y 2 represents a direct valence bond between said —(CR 3 ⁇ CR 3 ) n group and B;
- Y 3 is phenyl, naphthyl, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl, naphthyl and heteroaryl groups being unsubstituted or substituted with one to three R 4 groups, where R 4 is alkyl of 1 to 10 carbons, fluoro-substituted alkyl of 1 to 10 carbons, alkenyl of 2 to 10 carbons and having 1 to 3 triple bonds, F, Cl, Br, I, NO 2 , CN, NR 3 , N 3 , COOH, COOC 1-6 alkyl, OH, SH, OC 1-6 alkyl, and SC 1-6 alkyl;
- A is (CH 2 ) q where q is from 0-5, lower branched alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl, having 2-6 carbons and 1-2 double bonds, alkynyl having 2-6 carbons and 1 to 2 triple bonds, and
- B is hydrogen, COOH or a pharmaceutically acceptable salt thereof, COOR 8 , CONR 9 R 10 , —CH 2 OH, CH 2 OR 11 , CH 2 OCOR 11 , CHO, CH(OR 12 ) 2 , CHOR 13 O, —COR 7 , CR 7 (OR 12 ) 2 , CR 7 OR 13 O, or Si(C 1-6 alkyl) 3 , where R 7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R 8 is an alkyl group of 1 to 10 carbons or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R 8 is phenyl or lower alkylphenyl, R 9 and R 10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R
- n is an integer from 1 to 10.
- n is an integer from 1 to 10.
- a particularly preferred subgroup of RAR antagonists or inverse agonists is the set of those RAR antagonists or inverse agonists that lack antagonist or inverse agonist activity at one or more subclass of RARs, such as the RAR ⁇ , RAR ⁇ , or RAR ⁇ receptors; such “subclass-specific” activity may result in the minimization of toxicity of the drug.
- Such compounds may have activity only at the RAR ⁇ , RAR ⁇ , or RAR ⁇ receptors, or at any combination of these (other than at all of them). Determination of whether a compound has subclass-specific specific inverse agonist activity is done through translational screening as disclosed in U.S. patent application Ser. No. 09/042,943, to Klein et al., and Ser. No. 09/108,298, to Nagpal et al., both of which are incorporated by reference herein in their entirety.
- the effective agents of the present invention may be provided orally, as in a liquid, syrup, suspension, tablet, capsule, gelatin-coated formulation or the like. Additionally, the contraceptive agents of the present invention have been demonstrated to be effective when applied topically.
- Topical delivery means include creams, gels, lotions, emulsions, suspensions, skin patches and the like. Additional delivery means may include inhalants, suppositories, and nasal sprays. Time-release formulations may be made for either oral or topical delivery.
- the antagonist compounds are incorporated into pharmaceutical compositions, such as tablets, pills, capsules, solutions, suspensions, creams, ointments, gels, salves, lotions and the like, using such pharmaceutically acceptable excipients and vehicles which per se are well known in the art.
- preparation of topical formulations are well described in Remington's Pharmaceutical Science, Edition 17, Mack Publishing Company, Easton, Pa.; incorporated by reference herein.
- the RAR antagonist or inverse agonist compounds could also be administered as a powder or spray, particularly in aerosol form. If the drug is to be administered systemically, it may be prepared as a powder, pill, tablet or the like or as a syrup or elixir suitable for oral administration.
- the drug compound will be prepared as a solution or suspension capable of being administered by injection. In certain cases, it may be useful to formulate the antagonist compounds by injection. In certain cases, it may be useful to formulate the antagonist compounds in suppository form or as extended release formulation for deposit under the skin or intramuscular injection.
- the antagonist or inverse agonist compounds will be administered in a therapeutically effective dose in accordance with the invention.
- a therapeutic concentration will be that concentration which is effective to cause diminution or cessation of spermatogenesis in the testes of the male mammal. It is currently thought that a formulation containing between about 0.5 and about 0.001 mg/kg of body weight, more preferably between about 0.3 mg/kg and 0.005 mg/kg, even more preferably about 0.075 mg/kg of body weight and about 0.01 mg/kg of body weight will constitute a therapeutically effective concentration for oral application, with routine experimentation providing adjustments to these concentrations for other routes of administration if necessary.
- the present invention comprises a method of inhibiting spermatogenesis in a mammal comprising the administration of an effective amount of an RAR antagonist or RAR inverse agonist at time intervals sufficient to inhibit or arrest spermatogenesis.
- the mammal is a human.
- the RAR antagonist or RAR inverse agonist is administered orally through the use of a liquid, syrup, suspension, tablet, capsule, or gelatin-coated formulation.
- the RAR antagonist or RAR inverse agonist is topically administered, through the use of means including a patch, cream, lotion, emulsion, or gel.
- the RAR antagonist or RAR inverse agonist is formulated in an inhalant, suppository or nasal spray.
- the present invention concerns compositions and methods for the prophylactic prevention of pregnancy by the inhibition or arrest of spermatogenesis in male mammals.
- Spermatogenesis occurs in the seminiferous tubules of the testes of sexually mature male mammals. These tubules consist of a basement membrane surrounding an intra-tubule lumen. Specialized columnar cells termed Sertoli cells lie against the basement membrane and protrude into the lumen; the germ cells remain closely associated with the Sertoli cells throughout spermatogenesis.
- Spermatogonia male gamete stem cells
- Mitosis of a spermatogonium gives rise to two daughter cells; one may remain near the basement membrane as a spermatogonium and the other may develop, through subsequent rounds of mitosis, into a primary spermatocyte. As it develops the cells that become diploid primary spermatocytes are crowded closer to the tubule lumen.
- the primary spermatocyte then enters meiosis and gives rise to haploid spermatids. These spermatids remain closely associated with the Sertoli cell, now at a location close to the lumen, and undergo a metamorphosis mediated partly by the Sertoli cell, maturing into spermatozoa. These cells are then released into the lumen of the seminiferous tubule.
- the seminiferous tubules are closely packed together in the testes, being separated by connective tissue containing fibrocytes and vessels.
- An inhabitant of the spaces between the tubules is a steroidogenic somatic cell termed the Leydig cell.
- These cells synthesize the steroid hormone testosterone, which is an important stimulus for the differentiation of germ cells; the hormone diffuses into the seminiferous tubules where it stimulates spermatogenesis.
- the time course of complete spermatogenesis is long; approximately 64 days in humans and 54 days in rats. This time course can be divided into 4 stages. In the first stage, spermatocytogenesis, the spermatogonia divide and give rise to primary spermatocytes. In the second stage, the primary spermatocytes undergo meosis and give rise to spermatids. In the third stage, spermoigenesis, the spermatids metamorphize into spermatozoa. In the final stage, maturation, the spermatozoa mature and are released into the seminiferous tubule. The spermatozoa undergo final maturation in the epiphysis.
- Cells in each of these four stages can be seen as “layers” in normal seminiferous tubules, with the least mature cells nearer the basement membrane, and the most mature cells near the lumen.
- the absence of cells of one or more stage is indicative of an event blocking or arresting a stage in spermatogenesis.
- testosterone production is regulated by the pituitary hormone, luteinizing hormone (LH).
- LH luteinizing hormone
- FSH follicle-stimulating hormone
- ABP androgen-binding protein
- inhibin Another peptide, termed inhibin, is thought to be secreted by Sertoli cells in response to the binding of FSH. Inhibin, in turn, appears to act on target cells within the pituitary to inhibit FSH secretion. Thus, inhibin may operate to act as a negative feedback regulator for the release of FSH and thus the production of ABP, with one consequence being the prevention of overstimulation by testosterone. Overproduction of inhibin could serve to lower the concentration of testosterone within the seminiferous tubules.
- spermatogenesis appears to include the regulation of gene expression and synthesis of a number of factors that either act as peptide hormones themselves or are involved in the sequestration or regulation of hormones important in spermatogenesis.
- Retinoid nuclear receptors retinoic acid receptors (RAR) and retinoid X receptors (RXR)
- RAR retinoic acid receptors
- RXR retinoid X receptors
- AGN 194310 has the following chemical structure: This compound, 4-[[4-(4-ethylphenyl)-2,2-dimethyl-(2H)-thiochromen-6-yl]-ethynyl]-benzoic acid, may be synthesized using conventional organic synthetic means. The following reaction scheme is Applicants' currently preferred method of making this compound.
- Step 1 A heavy-walled screw cap tube was charged with 3-methyl-2-butenoic acid (13.86 g, 138.4 mmol), 4-methoxy thiophenol (20.0 g, 138.4 mmol), and piperidine (3.45 g, 41.6 mmol). This mixture was heated to 105° C. for 32 hours, cooled to room temperature and dissolved in EtOAc (700 mL). The resulting solution was washed with 1M aqueous HCl, H 2 O, and saturated aqueous NaCl before being dried over Na 2 SO 4 . Concentration of the dry solution under reduced-pressure afforded an oil which upon standing in the freezer provided a crystalline solid.
- Step 2 To a solution of 3-(4-methoxy-phenylsulfanyl)-3-methyl-butyric acid (20.0 g, 83.2 mmol) in 250 mL of benzene at room temperature was added a solution of oxalyl chloride (15.84 g, 124.8 mmol) in 10 mL of benzene over 30 minutes. After 4 hours the solution was washed with ice cold 5% aqueous NaOH (CAUTION: a large volume of gas is released during this procedure), followed by ice cold H 2 O, and finally saturated aqueous NaCl. The solution was dried (Na 2 SO 4 ) and concentrated under reduced pressure to give a clear yellow oil.
- CAUTION a large volume of gas is released during this procedure
- Step 3 To a solution of the acyl chloride product of Step 2 (21.5 g, 83.2 mmol) in 250 mL of CH 2 Cl 2 at 0° C. was added dropwise a solution of SnCl 4 (21.7 g, 83.2 mmol) in 30 mL of CH 2 Cl 2 . After 2 hours the reaction was quenched by slow addition of 150 mL H 2 O.
- Step 4 To a solution of 6-methoxy-2,2-dimethyl-thiochroman-4-one (6.0 g, 27 mmol) in 50 mL CH 2 Cl 2 cooled to ⁇ 23° C. was added BBr 3 (20.0 g, 80.0 mmol; 80.0 mL of a 1M solution in CH 2 Cl 2 ) over a 20 minute period. After stirring for 5 hours at ⁇ 23° C. the solution was cooled to ⁇ 78° C. and quenched by the slow addition of 50 mL of H 2 O.
- Step 5 To a solution of 6-hydroxy-2,2-dimethylthiochroman-4-one (165.0 mg, 0.79 mmol) in 5.0 mL of anhydrous pyridine at 0° C. was added trifluoromethanesulfonic anhydride (245.0 mg, 0.87 mmol). After 4 hours at 0° C. the solution was concentrated and the residual oil dissolved in Et 2 O, washed with H 2 O followed by saturated aqueous NaCl, and dried over MgSO 4 .
- Step 6 A solution of 2,2-dimethyl-4-oxo-thiochroman-6-yl trifluoromethanesulfonate (2.88 g, 8.50 mmol) in 10 mL Et 3 N and 20.0 mL DMF was sparged with argon for 10 minutes. To this solution was added trimethylsilylacetylene (4.15 g, 42.0 mmol) and bis(triphenylphosphine)-palladium(II) chloride (298.0 mg, 0.425 mmol). The solution was heated to 95° C. for 5 hours, cooled to room temperature, and diluted with H 2 O.
- Step 7 A solution of 2,2-dimethyl-6-trimethylsilanylethynyl-thiochroman-4-one (110.0 mg, 0.38 mmol) and K 2 CO 3 (40.0 mg, 0.29 mmol) in 10.0 mL MeOH was stirred overnight at room temperature. The solution was diluted with H 2 O and extracted with Et 2 O. The combined organic layers were washed with H 2 O and saturated aqueous NaCl and dried over MgSO 4 . Removal of the solvent under reduced pressure afforded 81 mg (99%) of the 6-ethynyl-2,2-dimethylthiochroman-4-one as an orange oil.
- Step 8 A solution of 6-ethynyl-2,2-dimethylthiochroman-4-one (82.0 mg, 0.38 mmol) and ethyl 4-iodobenzoate (104.9 mg, 0.38 mmol) in 5.0 mL Et 3 N was purged with argon for 10 minutes. To this solution were added bis(triphenylphosphine)-palladium(II) chloride (88.0 mg, 0.12 mmol) and copper(I) iodide (22.9 mg, 0.12 mmol). After sparging for an additional 5 minutes with argon, the solution was stirred overnight at room temperature. The reaction mixture was filtered through a pad of Celite using an Et 2 O wash.
- Step 9 A solution of sodium bis(trimethylsilyl)amide (1.12 g, 6.13 mmol) in 16.2 mL of THF was cooled to ⁇ 78° C. and a solution of ethyl 4-(2,2-dimethyl-4-oxo-thiochroman-6-ylethynyl)-benzoate (1.86 g, 5.10 mmol) in 15.0 mL was added slowly. After 30 minutes a solution of 2-[N,N-bis(trifluoromethanesulfonyl)amino]-5-pyridine (2.40 g, 6.13 mmol) in 10 mL of THF was added. After 5 minutes the solution was warmed to room temperature and stirred overnight.
- Step 10 A solution of 4-ethylbromobenzene (670.9 mg, 3.63 mmol) in 4.0 mL of THF was cooled to ⁇ 78° C. and tert-butyllithium (464.5 mg, 7.25 mmol, 4.26 mL of a 1.7M solution in pentane) was added to give a yellow solution. After 30 minutes a solution of ZnCl 2 (658.7 mg, 4.83 mmol) in 8.0 mL THF was slowly added via cannula.
- Step 11 To a solution of ethyl 4-[[4-(4-ethylphenyl)-2,2-dimethyl-(2H)-thiochromen-6-yl]-ethynyl]-benzoate (940.0 mg, 2.08 mmol) in 10.0 mL THF and 5.0 mL EtOH was added NaOH (416.0 mg, 10.4 mmol, 5.2 mL of a 2M aqueous solution). The resulting solution was stirred overnight at room temperature. The reaction mixture was acidified with 10% aqueous HCl and extracted with EtOAc.
- the AGN 194310 compound was provided as follows: the compound was dissolved in capric/caprylic triglyceride (CCT) at a variety of doses, either 0.001% (v/v) AGN 194310, 0.003% (v/v) AGN 194310, or 0.01% (v/v) AGN 194310. Control animals received the CCT vehicle without the AGN 194310 active ingredient (AGN 194310 Vehicle). Although many retinoids and retinoid analogs are light labile, this compound is relatively stable to normal light.
- CCT capric/caprylic triglyceride
- Groups 1 through 5 were Main Study groups.
- Groups 6-9 were used for Toxicokinetic studies.
- Groups 10-13 were Main Study Recovery groups. The characteristics of each group are shown in Table 1 below. TABLE 1 Total Daily Amount of Total Daily AGN Amount of Group Number Test 194310 Test Prep. No.
- the drug was administered using a graduated syringe and a 20 ⁇ 3 inch animal feeding needle. Drug was given to each animal in a single dose per day. Animals were observed at lease once daily during the course of the study for mortality, general health, behavior and any apparent physical or pharmacological abnormalities.
- Urine was collected from animals in the Main Study and Recovery groups during week 4 of the treatment period, and from Recovery group animals during week 4 of the recovery period. Urine was analyzed for: blood (hemoglobin and erythrocytes), bilirubin, color, glucose, ketones, leukocytes, microscopic evaluations of any urine sediment, nitrate, pH, protein, specific gravity, transparency, and urobilinogen.
- blood hemoglobin and erythrocytes
- bilirubin color
- glucose ketones
- leukocytes microscopic evaluations of any urine sediment, nitrate, pH, protein, specific gravity, transparency, and urobilinogen.
- hematocrit total blood cell volume
- total hemoglobin mean cell volume
- mean corpuscular hemoglobin MCH
- mean corpuscular hemoglobin concentration MHC
- platelet count RBC
- total white blood cell count WBC
- a differential WBC count for basophils, eosinophils, lymphocytes, monocytes, neutrophils.
- the concentration of drug in the blood was determined from blood drawn from the retro-orbital sinus of the right eye on Day 7 of the study as follows: for rats in groups 7 through 9 (4/sex/group/timepoint, with each animal being bled no more than 3 times), blood (approximately 1 ml) was drawn prior to being given the drug, and at approximately 2, 6, 8, 12 and 24 hours post-dosing. The vehicle-treated rats (group 6) were bled at approximately 8 and 24 hours post-dosing. The rats in groups 6 through 9 were similarly bled on Day 22 of the study, then euthanized. All blood was drawn into tubes containing EDTA to prevent coagulation, and placed on ice prior to analysis. The blood was assayed for the presence of AGN 194310 by gas chromatography/mass spectrometry.
- organs were weighed for necroscopized animals: adrenal glands, ovaries, kidneys, pituitary gland, liver, spleen, heart, testes, and brain. In the case of organ pairs, both organs were weighed together.
- adrenal glands mammary gland (with skin), aorta, ovaries, bone/bone marrow, pancreas, femur, pituitary gland, tibia, prostate gland, knee joint, salivary glands, parotid, brain, sub-maxillary, cervix sciatic nerve, diaphragm, seminal vesicle, epididymides, skeletal muscle (thigh), eyes, spinal chord (thoracic), spleen, esophagus, sternum, stomach, testes, duodenum, thymus, jejunum, thyroid gland with parathyroids, ileum, any tissues with lesion(s), cecum, tongue, colon, trachea, heart, bladder, kidneys, uterus, liver, ureter, lungs, urethra, lymph nodes (vaginal, cervical,
- Target tissues and organs from the Vehicle (control) and high-dose groups were imbedded in paraffin, and tissue sections made.
- the sections were mounted and stained with hematoxylin and eosin using standard histological techniques; such histopathological evaluation was performed using techniques well known in the art.
- AGN 194310 was systemically absorbed following oral administration to rats and approached the peak concentration in plasma (Cmax) at 2 or 6 hours post dosing (Tmax). A dose dependent increase in systemic exposure to AGN 194310 was observed across the concentrations of AGN 194310. Similar Cmax and AUC 0-24hr values (Area Under the Curve from 0 to 24 hours after dosage; this measures the concentration of drug in the blood during this time period monitored) were observed when rat blood was tested between the two collection periods.
- Leydig cells appeared unaffected, nor was any evidence of an atrophic change seen in the secondary sex glands, such as the seminal vesicles and prostate, of the high dose males. In other words, the drug appears to target the seminiferous epithelium. Changes in the testes were not readily evident, either through visual or microscopic inspection at the end of the treatment period.
- the rats in the Recovery group were permitted approximately a one-month period without exposure to the drug.
- testicular atrophy was evident and accompanied morphologically by continuing cessation of spermatogenesis, monitored according to the criteria and methods mentioned above.
- reversibility of such inhibition was also evident, as could be seen by a focal increase in germ cell layers in individual tubules.
- the extent of this recovery varied from animal to animal and within a single testicular section.
- this experiment shows that daily oral delivery of the RAR antagonist AGN 194310 is sufficient to cause spermatogenic arrest in mammals, and that the effects of spermatogenic arrest in treated animals are reversed following cessation of AGN 194310 treatment.
- the exact mechanism of inhibition is not known, and, while not wishing to be bound by theory, the Applicants believe that the drug appears especially to affect, either directly or indirectly, primary spermatocytes.
- germ cells that have differentiated beyond the primary spermatocyte stage when treatment with an RAR antagonist or inverse agonist is initiated will continue to mature and differentiate into spermatozoa, while spermatogonia do not appear to differentiate beyond the primary spermatocytes stage.
- Example 2 An experiment was conducted in a manner substantially similar to that described in Example 1, with the following differences. Twenty-nine male and twenty-nine female Sprague-Dawley rats, approximately 7 weeks old were used for the study. Five rats/sex/group were designated as Main Study animals: (vehicle control, 0.025 mg/kg/day AGN 194310, and 0.25 mg/kg/day AGN 194310), and 7/sex/group designated as toxicokinetic satellite animals (0.025 mg/kg/day AGN 194310 and 0.25 mg/kg/day AGN 194310). No “vehicle alone” control group was made for the toxicokinetic satellite animals. In this study there was no Recovery group.
- the animals' backs were maintained shaven during the course of the study for application of the topical cream.
- the animals were treated daily with a topical formulation containing either AGN 194310 vehicle cream alone, 0.01% (w/w) AGN 194310 in the same vehicle cream, or 0.1% (w/w) AGN 194310 in the same vehicle cream.
- the vehicle cream consisted of a mixture of the following ingredients: Benzyl Alcohol 1% (w/w) Medium Chain Triglycerides 25% (w/w) Carbomer 1342 0.2% (w/w) Sorbitan Monooleate 0.2% (w/w) Carbomer 934P 1% (w/w) EDTA 0.05% (w/w) 5 N Sodium Hydroxide 2.72 (w/w) Water q.s. to 100% (w/w)
- Daily dosages were calculated using the most recently obtained body weights, as shown below.
- the test or control creams were applied for 28 consecutive days to the shaved back of each animal in an area approximately equal to 35.5 cm 2 .
- Application was made using a repeat pipettor, and the drug gently massaged into the skin.
- An Elizabethan collar was affixed around each animal's neck for a period of about 6 hours following treatment to prevent removal or systemic ingestion of the drug.
- Topical skin application of AGN 194310 did not result in any evidence of treatment-related skin irritation. No treatment-related clinical observations, differences in body weight, differences in food consumption, or in gross pathology were observed.
- Example 1 This experiment was conducted in a manner substantially similar to that of Example 1.
- Groups of male Sprague Dawley rats were treated orally for 4 weeks with either 0, 0.075, or 0.150 mg/kg/day of AGN 194310.
- Three to six animals from each group were sacrificed after 2 weeks of treatment, 6 animals from each group were sacrificed following 4 weeks of treatment and 6 animals from each group were sacrificed after 18-23 weeks of subsequent recovery after cessation of treatment. Histological and pathological examinations were done of the sacrificed animals, as in Example 1. Additionally, the animals in the 23 week recovery group were mated to normal, untreated female Sprague Dawley rats before being sacrificed to assess the reproductive function.
- control group of rats displayed no abnormal histological or biochemical differences during the time course of the experiment, except for a single individual, which was found to have bilateral severe sperm granulomas due to segmental aplasia of the epididymides (a congenital defect).
- results indicate that the effects of the drug are fully reversible when administration of AGN 194310 is halted. Additionally, the results are expected to be substantially similar whether the drug is applied orally or topically.
- Example 3 This experiment is conducted as indicated in Example 2, except that the drug is 193109 rather than AGN 194310, and a Recovery group is monitored for a period of time post-treatment as in Example 3. Dosages of the '109 drug is the same as for the topical treatment with the '310 drug.
- spermatogenic arrest can be seen within thirty days after initiation of treatment by examination of the testes of the treated animals.
- a histological analysis of the testes reveals the absence of primary spermatocytes, spermatids and spermatozoa in the majority of animals' seminiferous tubules. These effects are reversible; a similar analysis conducted on the testes of males rats 12 weeks after administration demonstrates the repopulation of the tubules with males gametes in various stages of development.
Abstract
Methods and compositions for inhibiting or preventing spermatogenesis in a male mammal. Also disclosed are compounds and formulations for use in such methods.
Description
- This application is a continuation of U.S. application Ser. No. 10/304,665, filed Nov. 25, 2002, which is a continuation of U.S. application Ser. No. 09/591,253, filed on Jun. 9, 2000, now U.S. Pat. No. 6,521,641, which is a continuation-in-part of U.S. application Ser. No. 09/405,748, filed Sep. 27, 1999, now abandoned, which claims the benefit of Provisional Application No. 60/103,507, filed Apr. 14, 1998.
- The entire teachings of the above application(s) are incorporated herein by reference.
- The present invention concerns methods and compositions for inhibiting or blocking fertility in a male mammal by the administration of a retinoid or retinoid derivative that is able to act as an antagonist or inverse agonist of a retinoic acid receptor (RAR). The effect is reversible upon cessation of treatment with the RAR antagonist or inverse agonist.
- The prevention of unplanned pregnancy in humans and other mammals is of continuing concern for both the developing and the developed world. A variety of methods and products have been proposed or developed for the prevention of pregnancy; these products include: surgical sterilization, condoms, birth control pills containing progestin or a combination of progestin and estrogen, subdermal implants containing delayed release forms of progesterone, intrauterine devices, spermicidal creams or gels, and intravaginal barriers such as sponges or diaphragms.
- These various methods each have certain advantages and certain drawbacks. The most common non-surgical birth control method in the United States is the birth control pill (“the Pill”), which contains synthetic progestin and estrogen; synthetic hormones similar to those produced naturally in a woman's body. The Pill works primarily by suppressing the release of eggs from a woman's ovaries.
- Within two years after its introduction in 1960, approximately 1.2 million women were using oral birth control, and by 1973, about 10 million women were using the Pill. However, in recent years questions have arisen about the health risks involved in continued long term use of contraceptive hormones. There have been reports of increased risk of certain forms of cancer, such as breast and cervical cancer, though the use of the Pill.
- Surgical sterilization, whether through tubal ligation or vasectomy, is nearly 100% effective, but is only sometimes reversible. Reversal of surgical sterilization usually requires further surgery.
- Condoms, made of either synthetic polymer materials or animal skin, are less effective than birth control pills and their effectiveness is further subject to subversion through the possibility that small breaks may be present, permitting leakage of semen. Additionally, the use of a condom requires the affirmative action of the male, usually immediately prior to the initiation of sexual intercourse and some men report a loss of sensation through the use of condoms. Hence, subject non-compliance is also an issue in the use of condoms.
- Subdermal implants, such as the NORPLANT® implant device, are quite effective contraceptive means. The implant comprises a set of silicone rods that are inserted under the skin of the upper arm. The implant contains hormones, such as progestin, levonorgestrel and progesterone, that are slowly released over a period of time of up to five years. Side effects may be similar to those involved in the use of birth control pills, and include a risk of developing ovarian cysts. Additionally, while the implant can be removed, the procedure is difficult even for skilled surgeons due to the formation of scar tissue around the implant.
- Intrauterine devices (IUDs) are small devices that are typically either made of copper or impregnated with progesterone. These must be inserted (and removed) by a doctor. Depending on the design, the devices appear to interfere with sperm motility or the implantation of the fertilized egg in the uterine wall. Side effects can include cramps, backache, spotting, or heavy periods, and women may have an increased risk of ectopic pregnancy or infertility. IUDs are usually not recommended for women who have not had children or who think they will have children in the future due to these latter risks. Normally, the contraceptive effects are reversible upon removal of the device.
- Barriers such as diaphragms and sponges are usually used in conjunction with a spermicidal cream, foam, or gel. The effectiveness of such devices is between about 90% and about 95%. The user can insert them as long as a number of hours before sexual intercourse, and the effects are temporary; if pregnancy is subsequently desired, the woman can discontinue their use with a concomitant return of fertility.
- With the exception of surgical sterilization and the use of condoms, all of the methods in common use affect female fertility with no effect on male fertility. As mentioned above, the former of these methods is irreversible and the latter is neither inherently as effective as other methods, nor is compliance as high. A male contraceptive that is not required to be applied immediately prior to intercourse would provide a contraceptive alternative to the traditional methods of contraception.
- A number of compositions have been proposed for use as a male contraceptive. Thus, U.S. Pat. No. 5,501,855, to Talwar et al., describes application of neem (Azadirachta indica) oil by injection to the vas deferens in an amount effective to block the fertility of the male by spermatogenic arrest. A single injection was reported to be effective to block fertility over the 9 month period of observation reported in the '855 patent.
- U.S. Pat. No. 4,677,193 and International Patent Publication No. WO 94/19370, both to Rivier et al., describe a hypothalamic peptide hormone (termed GnRH) that functions to trigger the release of gonadotropic hormones such a luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in the female. These references also mention that antagonists of GnRH are effective to arrest spermatogenesis in male mammals. This treatment apparently requires supplemental testosterone to be provided with the treatment in order to maintain libido.
- U.S. Pat. No. 5,744,448, to Kelton et al., describes the cloning, expression, and purification of human FSH receptor, or mutants or fragments thereof that retain the ability to bind FSH. One possible use of the FSH receptor is described as a method for preventing spermatogenesis in a male patient.
- U.S. Pat. No. 4,182,891, to Metcalf et al., and U.S. Pat. No. 4,134,918, to Bey et al. describe compounds said to be useful in inhibiting spermatogenesis. The '891 patent describes acetylenic derivatives of amino acids, and the '918 patent describes halomethyl derivatives of amines.
- International Patent Publication No. WO 97/24901, to Bandman et al., describes the amino acid sequence of a polypeptide termed Lung Growth Factor Variant (LGFV), which is said to play a role in various physiological processes, including spermatogenesis.
- U.S. Pat. No. 5,753,231, to Herr, et al., describes a female contraceptive vaccine prepared from antibodies raised to a recombinant primate acrosomal sperm antigen. The vaccine elicits an anti-sperm immune response, resulting in inhibition of fertilization. Also described are contraceptive compositions containing such an antibody in a carrier for vaginal application.
- None of the references cited herein are admitted in any manner to be prior art against the present application.
- The present invention concerns the discovery that certain agents that are able to block the binding of retinoic acid (RA) or other RAR ligands to RAR receptors, and thereby prevent activation of RARs, are also able to inhibit spermatogenesis in a male mammal.
- It has been known for some time that among the various results of a severe vitamin A (retinol) deficiency in mammals is sterility and blindness. See Eskild W. & Hansson. V., Vitamin A Functions in the Reproductive Organs in Vitamin A in Health and Disease 531 (Blomhoff, R. ed., 1994) (hereinafter Eskild). A complete deficiency in retinoids is fatal. Administration of retinoic acid in the absence of retinol can alleviate many of the symptoms of vitamin A deficiency, giving rise to blind and sterile animals that remain otherwise healthy.
- Researchers have also noted that treatment of vitamin A-deficient rats (in which there was a complete spermatogenic arrest) with vitamin A replacement results in restoration of normal spermatogenesis; reinitiation of spermatogenesis occurs in rats within 24-48 hours following vitamin A replacement. Huang, et al., 112 Endocrinology 1163-71 (1983), incorporated by reference herein.
- A vast array of specific metabolic, developmental, and catabolic processes appear to be directly or indirectly regulated in vivo by comparatively small molecules such as steroids, retinoids and thyroid hormones. The mechanism whereby a single such compound can contribute to the regulation of numerous different cellular events was the subject of much speculation until relatively recently, when it was discovered that these compounds each share the ability to bind to transcriptionally active proteinaceous receptors. These protein receptors, in turn, are able to bind specific cis-acting nucleic acid regulatory sequence regions, termed response elements or RE's, located upstream of the coding sequence of certain genes and to activate the transcription of these genes. Thus, these proteinaceous receptors can serve as specific, ligand-dependent regulators of gene transcription and expression.
- The amino acid sequences of these various receptors were quickly found to share regions of homology, thus making each such receptor a member of a family of ligand-modulated receptor molecules. This family has been termed the steroid superfamily of nuclear hormone receptors; nuclear, because the receptors are usually found in high concentration in the nucleus of the cell, although it is not clear that these are always the only relevant locations in which these receptors are found, or that transcriptional activation is the only activity that the receptors possess.
- Further study of the structural and functional relationship between the nuclear hormone receptors has shown certain characteristics in common between them in addition to sequence homology. See e.g., Evans et al. Science 240:889-895 (1988). As stated above, the nuclear hormone receptors are able to bind to cis-acting regulatory elements present in the promoters of the target genes. The glucocorticoid, estrogen, androgen, progestin, and mineralcorticoid receptors have been found to bind as homodimers to specific response elements organized as inverted repeats.
- Another class of nuclear hormone receptors, which includes the retinoid receptor RAR (retinoic acid receptor), the thyroid receptor, the vitamin D receptor, the peroxisome proliferator receptor, and the insect ecdysone receptor bind their response element as a heterodimer in conjunction with the retinoid X receptor (RXR), which in turn is positively activated by 9-cis retinoic acid. See Mangelsdorf, et al., The Retinoid Receptors in The Retinoids: Biology, Chemistry and Medicine Ch. 8 (Sporn et al., eds. 2d ed., Raven Press Ltd. 1994); Nagpal and Chandraratna, Current Pharm. Design 2:295-316 (1996), which are both incorporated by reference herein. The retinoid receptors RAR and RXR, like many nuclear receptors, exist as a number of subtypes (RARα, RARβ, RARγ, and RXRα, RXRβ, and RXRγ). Additionally, each subtype may exist in different isoforms.
- The present Applicants have surprisingly discovered that administration of an RAR antagonist or RAR inverse agonist results in the arrest of spermatogenesis in male mammals. By “antagonist” is meant that an agent is able to bind to the retinoic acid binding site of an RAR, thereby blocking the binding of retinoic acid to, and activation of the RAR. By “inverse agonist” is meant an agent able to suppress the basal level of RAR activity (homo- or heterodimerization and trans-acting transcriptional control of various genes whose regulation is normally responsive to RAR modulation). A compound will normally be an RAR antagonist if it is an inverse agonist, but the converse is not necessarily true.
- The spermatogenetic arrest resulting from treatment of a male mammal with an effective amount of an RAR antagonist or inverse agonist is not accompanied by most other symptoms of hypovitaminosis A, such as blindness, abnormal growth or susceptibility to infectious disease. Testosterone levels appear to remain normal; thus the preferred agents do not significantly affect male libido and sexuality.
- This, these compositions have applicability as agents for veterinary or therapeutic application as a male contraceptive.
- Some examples of structures and methods of making and using preferred RAR antagonists and inverse agonists are provided in U.S. Pat. No. 5,776,699 and U.S. patent application Ser. Nos. 08/998,319, 08/880,823, and 08/840,040 which are all incorporated by reference herein in their entirety. Many of the following compounds are included in one or more of these applications.
-
- X is [C(R1)2]n where R1 is independently H or alkyl of 1 to 6 carbons, and n is an integer between, and including, 0 and 2, and;
- R2 is hydrogen, lower alkyl of 1 to 6 carbons, F, Cl, Br, I, CF3, fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons, and;
- R3 is hydrogen, lower alkyl of 1 to 6 carbons or F, and;
- m is an integer having the value of 0-3, and;
- o is an integer having the value of 0-3, and;
-
- Z is —C≡C—,
- —N═N—,
- —N═CR1—,
- —CR1═N,
- —(CR1═CR1)n′— where n′ is an integer having the value 0-5,
- —CO—NR1—,
- —CS—NR1—,
- —NR1—CO,
- —NR1—CS,
- —COO—,
- —OCO—;
- —CSO—;
- —OCS—;
- Y is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R2 groups, or
- when Z is —(CR1═CR1)n′— and n′ is 3, 4 or 5 then Y represents a direct valence bond between said (CR2═CR2)n′ group and B;
- A is (CH2)q where q is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds;
- B is hydrogen, COOH or a pharmaceutically acceptable salt thereof, COOR8, CONR9R10, —CH2OH, CH2OR11, CH2OCOR11, CHO, CH(OR12)2, CHOR13O, —COR7, CR7(OR12)2, CR7OR13O, or tri-lower alkylsilyl, where R7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R8 is an alkyl group of 1 to 10 carbons or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R8 is phenyl or lower alkylphenyl, R9 and R10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R11 is lower alkyl, phenyl or lower alkylphenyl, R12 is lower alkyl, and R13 is divalent alkyl radical of 2-5 carbons, and
- R14 is (R15)r-phenyl, (R15)r-naphthyl, or (R15)r-heteroaryl where the heteroaryl group has 1 to 3 heteroatoms selected from the group consisting of O, S and N, r is an integer having the values of 0-5, and
- R15 is independently H, F, Cl, Br, I, NO2, N(R8)2, N(R8)COR8, NR8CON(R8)2, OH, OCOR8, OR8, CN, an alkyl group having 1 to 10 carbons, fluoro substituted alkyl group having 1 to 10 carbons, an alkenyl group having 1 to 10 carbons and 1 to 3 double bonds, alkynyl group having 1 to 10 carbons and 1 to 3 triple bonds, or a trialkylsilyl or trialkylsilyloxy group where the alkyl groups independently have 1 to 6 carbons.
-
- wherein X is S, O, NR′ where R′ is H or alkyl of 1 to 6 carbons, or
- X is [C(R1)2]n where R1 is independently H or alkyl of 1 to 6 carbons, and n is an integer between, and including, 0 and 2, and;
- R2 is hydrogen, lower alkyl of 1 to 6 carbons, F, Cl, Br, I, CF3, fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons, and;
- R3 is hydrogen, lower alkyl of 1 to 6 carbons or F, and;
- m is an integer having the value of 0, 1, 2, or 3, and;
- o is an integer having the value of 0, 1, 2, or 3, and;
- Y is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R2 groups, and;
- A is (CH2)q where q is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds, and;
- B is hydrogen, COOH or a pharmaceutically acceptable salt thereof, COOR8, CONR9R10, —CH2OH, CH2OR11, CH2OCOR11, CHO, CH(OR12)2, CHOR13O, —COR7, CR7(OR12)2, CR7OR13O, or tri-lower alkylsilyl, where R7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R8 is an alkyl group of 1 to 10 carbons or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R8 is phenyl or lower alkylphenyl, R9 and R10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R11 is lower alkyl, phenyl or lower alkylphenyl, R12 is lower alkyl, and R13 is divalent alkyl radical of 2-5 carbons, and;
- R14 is (R15)r-phenyl, (R15)r-naphthyl, or (R15)r-heteroaryl where the heteroaryl group has 1 to 3 heteroatoms selected from the group consisting of O, S and N, r is an integer having the values of 0, 1, 2, 3, 4 or 5, and;
- R15 is independently H, F, Cl, Br, I, NO2, N(R8)2, N(R8)COR8, NR8CON(R8)2, OH, OCOR8, OR8, CN, an alkyl group having 1 to 10 carbons, fluoro substituted alkyl group having 1 to 10 carbons, an alkenyl group having 1 to 10 carbons and 1 to 3 double bonds, alkyl group having 1 to 10 carbons and 1 to 3 triple bonds, or a trialkylsilyl or trialkylsilyloxy group where the alkyl groups independently have 1 to 6 carbons, and;
- R16 is H, lower alkyl of 1 to 6 carbons, and;
- R17 is H, lower alkyl of 1 to 6 carbons, OH or OCOR11, and;
- p is 0 or 1, with the proviso that when p is 1 then there is no R17 substituent group, and m is an integer between, and including, 0 and 2.
- A further preferred class of compounds is the class of the structure:
where X is C(R1)2 or O, and;
R1 is H or alkyl of 1 to 6 carbons, and;
R2 is lower alkyl of 1 to 6 carbons, F, Cl, Br, I, CF3, fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons, and;
m is an integer having the value of 0-3, and;
R3 is lower alkyl of 1 to 6 carbons of F, and;
o is an integer having the value of 0-3, and;
s is an integer having the value of 1-3, and;
R8 is an alkyl group of 1 to 10 carbons or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R8 is phenyl or lower alkylphenyl, and;
R15 is independently H, F, Cl, Br, I, NO2, N(R8)2, COR8, NR8CON(R8)2, OCOR8, OR8, CN, an alkyl group having 1 to 10 carbons, fluoro substituted alkyl group having 1 to 10 carbons, an alkenyl group having 1 to 10 carbons and 1 to 3 double bonds, an alkynyl group having 1 to 10 carbons and 1 to 3 triple bonds, or a trialkylsilyl or trialkylsilyloxy group where the alkyl groups independently have 1 to 6 carbons, and;
t is an integer having the values of 0, 1, 2, 3, 4, or 5, and;
the CONH group is in the 6 or 7 position of the benzopyran, and in the 2 or 3 position of the dihydronaphthaline ring, or a pharmaceutically acceptable salt of said compound. -
-
- where X1 is S or O;
- X2 is CH or N;
- R2 is H, F, CF3 or alkoxy of 1 to 6 carbons;
- R2* H, F, or CF3;
- R8 is H, or lower alkyl of 1 to 6 carbons;
- R14 is unsubstituted phenyl, thienyl or pyridyl, or phenyl, thienyl or pyridyl substituted with one to three R15 groups, where R15 is lower alkyl of 1 to 6 carbons, chlorine, CF3, or alkoxy of 1 to 6 carbons, or a pharmaceutically acceptable salt of said compound.
-
- wherein X2 is CH or N, and;
- R2 is H, F, or OCH3, and;
- R2* H or F, and;
- R8 is H, or lower alkyl of 1 to 6 carbons, and;
- R14 is selected from the group consisting of phenyl, 4-(lower-alkyl)phenyl, 5-(lower alkyl)-2-thienyl, and 6-(lower alkyl)-3-pyridyl where lower alkyl has 1 to 6 carbons, or a pharmaceutically acceptable salt of said compound.
-
- X1 is S or O;
- X2 is CH or N;
- R2 is H, F, CF3 or alkoxy of 1 to 6 carbons;
- R2* H, F, or CF3;
- R8 is H, or lower alkyl of 1 to 6 carbons;
- R14 is unsubstituted phenyl, thienyl or pyridyl, or phenyl, thienyl or pyridyl substituted with one to three R15 groups, where R15 is lower alkyl of 1 to 6 carbons, chlorine, CF3, or alkoxy of 1 to 6 carbons, or a pharmaceutically acceptable salt of said compound.
-
- wherein X2 is CH or N, and;
- R2 is H, F, or OCH3, and;
- R2* H or F, and;
- R8 is H, or lower alkyl of 1 to 6 carbons, and;
- R14 is selected from the group consisting of phenyl, 4-(lower-alkyl)phenyl, 5-(lower alkyl)-2-thienyl, and 6-(lower alkyl)-3-pyridyl where lower alkyl has 1 to 6 carbons, or a pharmaceutically acceptable salt of said compound.
-
-
- where R2* is H or F;
- R8 is H, or lower alkyl of 1 to 6 carbons, and
- R14 is selected from the group consisting of phenyl, and 4-(lower-alkyl)phenyl, where lower alkyl has 1 to 6 carbons, or a pharmaceutically acceptable salt of said compound.
-
-
- Yet another class of compounds contemplated for use in the present invention is that having the structure:
wherein X1 is: —C(R1)2—, —C(R1)2—C(R1)2—, —S—, —O—, —NR1—, —C(R1)2—O—, —C(R1)2—S—, or C(R1)2—NR1—; and
R1 is independently H or alkyl of 1 to 6 carbons; and
R2 is optional and is defined as lower alkyl of 1 to 6 carbons, F, Cl, Br, I, CF3, fluoro substituted alkyl of 1 to 6 carbons, OH SH, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons; and
m is an integer between, and including, 0 and 4; and
n is an integer between, and including, 0 and 2; and
o is an integer between, and including, 0 and 3; and
R3 is H, lower alkyl of 1 to 6 carbons, F, Cl, Br or I; and
R4 is (R5)p-phenyl, (R5)p-naphthyl, (R5)p-heteroaryl where the heteroaryl group is five-membered or 6-membered and has 1 to 3 heteroatoms selected from the group consisting of O, S, and N; and
p is an integer between, and including, 0 and 5; and
R5 is optional and is defined as independently F, Cl, Br, I, NO2, N(R8)2, N(R8)COR8, N(R8)CON(R8)2, OH, OCOR8, OR8, CN, COOH, COOR8, an alkyl group having from 1 to 10 carbons, an alkenyl group having from 1 to 10 carbons and 1 to three double bonds, alkynyl group having from 1 to 10 carbons and 1 to 3 triple bonds, or a (trialkyl)silyl or (trialkyl)silyloxy group where the alkyl groups independently have from 1 to 6 carbons; and
Y is a phenyl or naphthyl group, or a heteroaryl selected from the group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R2 groups, or Y is —(CR3═CR3)r—; and
r is an integer between, and including, 1 and 3; and
A is (CH2)q where q is an integer from 0-5, lower branched chain alkyl having from 3 to 6 carbons, cycloalkyl having from 3 to 6 carbons, alkenyl having from 2 to 6 carbons and 1 or 2 double bonds, alkenyl having from 2 to 6 carbons and 1 or 2 triple bonds, with the proviso that when Y is —(CR3═CR3)r— then A is (CH2)q and q is 0; and
B is H, COOH or a pharmaceutically acceptable salt thereof, COOR8, CONR9R10, —CH2OH, CH2OR11, CH2OCOR11, CHO, CH(OR12)2, CHOR13O, —COR7, CR7(OR12)2, CR7OR13O, or Si(C1-6alkyl)3, wherein R7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R8 is an alkyl group of 1 to 10 carbons or (trimethylsilyl)alkyl, where the alkyl groups has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R8 is phenyl or lower alkylphenyl, R9 and R10 independently are H, a lower alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R11 is lower alkyl, phenyl or lower alkylphenyl, R12 is lower alkyl, and R13 is a divalent alkyl radical of 2-5 carbons. A non-exclusive list of compounds falling within this description, and methods for making this class of compounds are disclosed in U.S. Pat. No. 5,728,846 to Vuligonda et al., the disclosure of which is hereby incorporated by reference as part of this application. - Also useful in the present invention are compounds of the formula:
Y3(R4)—X—Y1(R1R2)-Z-Y2(R2)-A-B
Where Y1 is phenyl, naphthyl, or heteroaryl selected from the group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazonyl, ozazolyl, imidazolyl, and pyrrazolyl, said phenyl, naphthyl, and heteroaryl groups being substituted with an R1 group, and further substituted or unsubstituted with one or two R2 groups; - R1 is C1-10 alkyl, 1-ademantyl, 2-tetrahydropyranoxy, trialkylsilanyloxy where alkyl has up to 6 carbons, OH, alkoxy where the alkyl group has up to 10 carbons, alkylthio where the alkyl group has up to 10 carbons, or OCH2OC1-6 alkyl;
- R2 is lower alkyl of 1 to 6 carbons, F, Cl, Br, I, CF3, CF2CF3, OH, OR3, NO2, N(R3)2, CN, N3, COR3, NHCOR3, COOH, or COOR3;
- X is (C(R3)2, S, SO, SO2, O or NR3;
- Z is
-
- —C≡C—,
- —N═N—,
- —N(O)═N—,
- —N═N(O)—,
- —N═CR3—,
- —CR3═N,
- —(CR3═CR3)n— where n is an integer having the value 0-5,
- —CO—NR3—,
- —CS—NR3—,
- —NR3—CO,
- —NR3—CS,
- —COO—,
- —OCO—;
- —CSO—;
- —OCS—; or
- —CO—CR3═R3—O,
- R3 is independently H or lower alkyl of 1 to 6 carbons;
- Y2 is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl, naphthyl and heteroaryl groups being unsubstituted or substituted with one or two R2 groups, or
- when Z is —(CR3═CR3)n— and n is 3, 4 or 5 then Y2 represents a direct valence bond between said —(CR3═CR3)n group and B;
- Y3 is phenyl, naphthyl, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl, naphthyl and heteroaryl groups being unsubstituted or substituted with one to three R4 groups, where R4 is alkyl of 1 to 10 carbons, fluoro-substituted alkyl of 1 to 10 carbons, alkenyl of 2 to 10 carbons and having 1 to 3 triple bonds, F, Cl, Br, I, NO2, CN, NR3, N3, COOH, COOC1-6 alkyl, OH, SH, OC1-6 alkyl, and SC1-6 alkyl;
- A is (CH2)q where q is from 0-5, lower branched alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl, having 2-6 carbons and 1-2 double bonds, alkynyl having 2-6 carbons and 1 to 2 triple bonds, and
- B is hydrogen, COOH or a pharmaceutically acceptable salt thereof, COOR8, CONR9R10, —CH2OH, CH2OR11, CH2OCOR11, CHO, CH(OR12)2, CHOR13O, —COR7, CR7(OR12)2, CR7OR13O, or Si(C1-6 alkyl)3, where R7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R8 is an alkyl group of 1 to 10 carbons or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R8 is phenyl or lower alkylphenyl, R9 and R10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R11 is lower alkyl, phenyl or lower alkylphenyl, R12 is lower alkyl, and R13 is divalent alkyl radical of 2-5 carbons, or a pharmaceutically acceptable salt of said compound. These compounds are disclosed in U.S. patent application Ser. No. 08/840,040, to Song et al., which application shares common ownership with the present application and is incorporated by reference herein in its entirety.
- Additional RAR antagonists or inverse agonists are described in U.S. patent application Ser. No. 08/845,019, to Song and Chandraratna, which is incorporated by reference herein in its entirety; this application shares common ownership with the present application. Also, compounds useful in the methods of the present invention are disclosed in International Application Publication No. WO 94/14777, to Yoshimura et al., which is also incorporated by reference herein in its entirety. This latter application discloses RAR antagonists. A non-exclusive list of the structures of some preferred compounds disclosed therein can be found in FIG. 1hereof.
-
-
-
- A particularly preferred subgroup of RAR antagonists or inverse agonists is the set of those RAR antagonists or inverse agonists that lack antagonist or inverse agonist activity at one or more subclass of RARs, such as the RARα, RARβ, or RARγ receptors; such “subclass-specific” activity may result in the minimization of toxicity of the drug. Such compounds may have activity only at the RARα, RARβ, or RARγ receptors, or at any combination of these (other than at all of them). Determination of whether a compound has subclass-specific specific inverse agonist activity is done through translational screening as disclosed in U.S. patent application Ser. No. 09/042,943, to Klein et al., and Ser. No. 09/108,298, to Nagpal et al., both of which are incorporated by reference herein in their entirety.
- The compounds disclosed herein clearly suggest the synthesis and use of other compounds structurally similar to these, for use in the methods of the present invention. In addition to the compounds referred to herein, other agents that have RAR antagonist and/or inverse agonist activity are also anticipated to arrest spermatogenesis in mammals and thus be useful as male contraceptive agents in the invention of the present application.
- The effective agents of the present invention may be provided orally, as in a liquid, syrup, suspension, tablet, capsule, gelatin-coated formulation or the like. Additionally, the contraceptive agents of the present invention have been demonstrated to be effective when applied topically. Topical delivery means include creams, gels, lotions, emulsions, suspensions, skin patches and the like. Additional delivery means may include inhalants, suppositories, and nasal sprays. Time-release formulations may be made for either oral or topical delivery.
- For therapeutic applications in accordance with the present invention the antagonist compounds are incorporated into pharmaceutical compositions, such as tablets, pills, capsules, solutions, suspensions, creams, ointments, gels, salves, lotions and the like, using such pharmaceutically acceptable excipients and vehicles which per se are well known in the art. For example, preparation of topical formulations are well described in Remington's Pharmaceutical Science, Edition 17, Mack Publishing Company, Easton, Pa.; incorporated by reference herein. For topical application, the RAR antagonist or inverse agonist compounds could also be administered as a powder or spray, particularly in aerosol form. If the drug is to be administered systemically, it may be prepared as a powder, pill, tablet or the like or as a syrup or elixir suitable for oral administration. For intravenous or intraperitoneal administration, the drug compound will be prepared as a solution or suspension capable of being administered by injection. In certain cases, it may be useful to formulate the antagonist compounds by injection. In certain cases, it may be useful to formulate the antagonist compounds in suppository form or as extended release formulation for deposit under the skin or intramuscular injection.
- The antagonist or inverse agonist compounds will be administered in a therapeutically effective dose in accordance with the invention. A therapeutic concentration will be that concentration which is effective to cause diminution or cessation of spermatogenesis in the testes of the male mammal. It is currently thought that a formulation containing between about 0.5 and about 0.001 mg/kg of body weight, more preferably between about 0.3 mg/kg and 0.005 mg/kg, even more preferably about 0.075 mg/kg of body weight and about 0.01 mg/kg of body weight will constitute a therapeutically effective concentration for oral application, with routine experimentation providing adjustments to these concentrations for other routes of administration if necessary.
- Accordingly, in one embodiment the present invention comprises a method of inhibiting spermatogenesis in a mammal comprising the administration of an effective amount of an RAR antagonist or RAR inverse agonist at time intervals sufficient to inhibit or arrest spermatogenesis. In a further embodiment, the mammal is a human.
- In a further preferred embodiment, the RAR antagonist or RAR inverse agonist is administered orally through the use of a liquid, syrup, suspension, tablet, capsule, or gelatin-coated formulation. In another preferred embodiment, the RAR antagonist or RAR inverse agonist is topically administered, through the use of means including a patch, cream, lotion, emulsion, or gel. In yet another embodiment, the RAR antagonist or RAR inverse agonist is formulated in an inhalant, suppository or nasal spray.
- The present invention concerns compositions and methods for the prophylactic prevention of pregnancy by the inhibition or arrest of spermatogenesis in male mammals. Spermatogenesis occurs in the seminiferous tubules of the testes of sexually mature male mammals. These tubules consist of a basement membrane surrounding an intra-tubule lumen. Specialized columnar cells termed Sertoli cells lie against the basement membrane and protrude into the lumen; the germ cells remain closely associated with the Sertoli cells throughout spermatogenesis.
- Spermatogonia, male gamete stem cells, lie between the Sertoli cells and the basement membrane. Mitosis of a spermatogonium gives rise to two daughter cells; one may remain near the basement membrane as a spermatogonium and the other may develop, through subsequent rounds of mitosis, into a primary spermatocyte. As it develops the cells that become diploid primary spermatocytes are crowded closer to the tubule lumen.
- The primary spermatocyte then enters meiosis and gives rise to haploid spermatids. These spermatids remain closely associated with the Sertoli cell, now at a location close to the lumen, and undergo a metamorphosis mediated partly by the Sertoli cell, maturing into spermatozoa. These cells are then released into the lumen of the seminiferous tubule.
- The seminiferous tubules are closely packed together in the testes, being separated by connective tissue containing fibrocytes and vessels. An inhabitant of the spaces between the tubules is a steroidogenic somatic cell termed the Leydig cell. These cells synthesize the steroid hormone testosterone, which is an important stimulus for the differentiation of germ cells; the hormone diffuses into the seminiferous tubules where it stimulates spermatogenesis.
- The time course of complete spermatogenesis is long; approximately 64 days in humans and 54 days in rats. This time course can be divided into 4 stages. In the first stage, spermatocytogenesis, the spermatogonia divide and give rise to primary spermatocytes. In the second stage, the primary spermatocytes undergo meosis and give rise to spermatids. In the third stage, spermoigenesis, the spermatids metamorphize into spermatozoa. In the final stage, maturation, the spermatozoa mature and are released into the seminiferous tubule. The spermatozoa undergo final maturation in the epiphysis. Cells in each of these four stages can be seen as “layers” in normal seminiferous tubules, with the least mature cells nearer the basement membrane, and the most mature cells near the lumen. The absence of cells of one or more stage is indicative of an event blocking or arresting a stage in spermatogenesis.
- Although the exact mechanism underlying hormonal and gene regulation occurring in spermatogenesis is not precisely known, and the scope of the present invention is not to be limited by theory, it is believed that testosterone production is regulated by the pituitary hormone, luteinizing hormone (LH). Another pituitary hormone, follicle-stimulating hormone (FSH), is also involved in the regulation of spermatogenesis, with primary hormone receptors being present on the Sertoli cells. One effect of FSH on Sertoli cells is to stimulate the production of androgen-binding protein (ABP), which has a high binding affinity for testosterone and helps retain the steroid within the seminiferous tubules and sustain its effect on spermatogenesis.
- Another peptide, termed inhibin, is thought to be secreted by Sertoli cells in response to the binding of FSH. Inhibin, in turn, appears to act on target cells within the pituitary to inhibit FSH secretion. Thus, inhibin may operate to act as a negative feedback regulator for the release of FSH and thus the production of ABP, with one consequence being the prevention of overstimulation by testosterone. Overproduction of inhibin could serve to lower the concentration of testosterone within the seminiferous tubules.
- Thus, the regulation of spermatogenesis appears to include the regulation of gene expression and synthesis of a number of factors that either act as peptide hormones themselves or are involved in the sequestration or regulation of hormones important in spermatogenesis. Retinoid nuclear receptors (retinoic acid receptors (RAR) and retinoid X receptors (RXR)) are known to be involved in the ligand-mediated transcriptional regulation of various genes, which may include some of these factors.
- The following examples are intended to illustrate further embodiments of the present invention and do not limit the scope of the invention, which is defined solely by the claims concluding this specification.
- Ninety-eight male and ninety-eight female Sprague-Dawley (Crl:CD®(SD) IGS BR) Charles River, Hollister, Calif. 95023) rats, approximately 8 to 10 weeks old, were used for the study. The rats were divided into the following groups: non-treated control, vehicle control, 0.005 mg/kg/day, 0.015 mg/kg/day and 0.15 mg/kg/day AGN 194310. AGN 194310 has the following chemical structure:
This compound, 4-[[4-(4-ethylphenyl)-2,2-dimethyl-(2H)-thiochromen-6-yl]-ethynyl]-benzoic acid, may be synthesized using conventional organic synthetic means. The following reaction scheme is Applicants' currently preferred method of making this compound. - Step 1: A heavy-walled screw cap tube was charged with 3-methyl-2-butenoic acid (13.86 g, 138.4 mmol), 4-methoxy thiophenol (20.0 g, 138.4 mmol), and piperidine (3.45 g, 41.6 mmol). This mixture was heated to 105° C. for 32 hours, cooled to room temperature and dissolved in EtOAc (700 mL). The resulting solution was washed with 1M aqueous HCl, H2O, and saturated aqueous NaCl before being dried over Na2SO4. Concentration of the dry solution under reduced-pressure afforded an oil which upon standing in the freezer provided a crystalline solid. 3-(4-methoxy-phenylsulfanyl)-3-methyl-butyric acid was isolated as pale-yellow crystals by washing the crystalline solid with pentane. (27.33 g, 82%). 1H NMR (300 MHz, CDCl3) δ: 7.48 (2H, d, J=9.0 Hz), 6.89 (2H, d, J=8.9 Hz), 3.83 (3H, s), 2.54 (2H, s), 1.40 (6H, s).
- Step 2: To a solution of 3-(4-methoxy-phenylsulfanyl)-3-methyl-butyric acid (20.0 g, 83.2 mmol) in 250 mL of benzene at room temperature was added a solution of oxalyl chloride (15.84 g, 124.8 mmol) in 10 mL of benzene over 30 minutes. After 4 hours the solution was washed with ice cold 5% aqueous NaOH (CAUTION: a large volume of gas is released during this procedure), followed by ice cold H2O, and finally saturated aqueous NaCl. The solution was dried (Na2SO4) and concentrated under reduced pressure to give a clear yellow oil. This material was used without further purification in the next step. 1H NMR (300 MHz, CDCl3) δ: 7.45 (2H, d, J=8.8 Hz), 6.90 (2H, d, J=8.8 Hz), 3.84 (3H, s), 3.12 (2H, s), 1.41 (6H, s). Step 3: To a solution of the acyl chloride product of Step 2 (21.5 g, 83.2 mmol) in 250 mL of CH2Cl2 at 0° C. was added dropwise a solution of SnCl4 (21.7 g, 83.2 mmol) in 30 mL of CH2Cl2. After 2 hours the reaction was quenched by slow addition of 150 mL H2O. The organic layer was washed with 1M aqueous HCl, 5% aqueous NaOH, H2O, and finally saturated aqueous NaCl before being dried over MgSO4. Concentration under reduced pressure and vacuum distillation of the residual oil (Bulb-to-bulb, 125-135° C., 5 mm/Hg) afforded 14.48 g (78%) of 6-methoxy-2,2-dimethyl-thiochroman-4-one as a pale-yellow oil. 1H NMR (300 MHz, CDCl3) δ: 7.62 (1H, d, J=2.9 Hz), 7.14 (1H, d, J=8.6 Hz), 7.03 (1H, dd, J=2.8, 8.3 Hz), 3.83 (3H, s), 2.87 (2H, s), 1.46 (6H, s).
- Step 4: To a solution of 6-methoxy-2,2-dimethyl-thiochroman-4-one (6.0 g, 27 mmol) in 50 mL CH2Cl2 cooled to −23° C. was added BBr3 (20.0 g, 80.0 mmol; 80.0 mL of a 1M solution in CH2Cl2) over a 20 minute period. After stirring for 5 hours at −23° C. the solution was cooled to −78° C. and quenched by the slow addition of 50 mL of H2O. Upon warming to room temperature the aqueous layer was extracted with CH2Cl2 and the combined organic layers were washed with saturated aqueous NaHCO3, H2O, and saturated aqueous NaCl before being dried over MgSO4. Removal of the solvents under reduced pressure gave a green-brown solid which upon recrystalization (Et2O/hexanes) afforded 2.25 g (40%) of 6-hydroxy-2,2-dimethylthiochroman-4-one as a light brown solid. 1H NMR (300 MHz, CDCl3) δ: 7.63 (1H, d, J=2.8 Hz), 7.15 (1H, d, J=8.5 Hz), 7.01 (1H, dd, J=2.8, 8.5 Hz), 2.87 (2H, s), 1.46 (6H, s).
- Step 5: To a solution of 6-hydroxy-2,2-dimethylthiochroman-4-one (165.0 mg, 0.79 mmol) in 5.0 mL of anhydrous pyridine at 0° C. was added trifluoromethanesulfonic anhydride (245.0 mg, 0.87 mmol). After 4 hours at 0° C. the solution was concentrated and the residual oil dissolved in Et2O, washed with H2O followed by saturated aqueous NaCl, and dried over MgSO4. Removal of the solvents under reduced pressure and column chromatography (5% EtOAc/hexanes) afforded 126.0 mg (47%) of 2,2-Dimethyl-4-oxo-thiochroman-6-yl trifluoromethanesulfonate as a colorless solid. 1H NMR (300 MHz, CDCl3) δ: 7.97 (1H, s), 7.32 (2H, s), 2.90 (2H, s), 1.49 (6H, s).
- Step 6: A solution of 2,2-dimethyl-4-oxo-thiochroman-6-yl trifluoromethanesulfonate (2.88 g, 8.50 mmol) in 10 mL Et3N and 20.0 mL DMF was sparged with argon for 10 minutes. To this solution was added trimethylsilylacetylene (4.15 g, 42.0 mmol) and bis(triphenylphosphine)-palladium(II) chloride (298.0 mg, 0.425 mmol). The solution was heated to 95° C. for 5 hours, cooled to room temperature, and diluted with H2O. Extraction with EtOAc was followed by washing the combined organic layers with H2O and saturated aqueous NaCl and drying over MgSO4. Concentration of the dry solution under reduced pressure and isolation of the product by column chromatography (3% EtOAc/hexanes) afforded 2.23 g (91%) of the 2,2-dimethyl-6-trimethylsilanylethynyl-thiochroman-4-one as an orange oil. 1H NMR (300 MHz, CDCl3) δ: 8.18 (1H, d, J=1.9 Hz), 7.34 (1H, dd, J=1.9, 8.1 Hz), 7.15 (1H, d, J=8.1 Hz), 2.85 (2H, s), 1.45 (6H, s), 0.23 (9H, s).
- Step 7: A solution of 2,2-dimethyl-6-trimethylsilanylethynyl-thiochroman-4-one (110.0 mg, 0.38 mmol) and K2CO3 (40.0 mg, 0.29 mmol) in 10.0 mL MeOH was stirred overnight at room temperature. The solution was diluted with H2O and extracted with Et2O. The combined organic layers were washed with H2O and saturated aqueous NaCl and dried over MgSO4. Removal of the solvent under reduced pressure afforded 81 mg (99%) of the 6-ethynyl-2,2-dimethylthiochroman-4-one as an orange oil. 1H NMR (300 MHz, CDCl3) δ: 8.20 (1H, d, J=1.9 Hz), 7.46 (1H, dd, J=1.9, 8.1 Hz), 7.18 (1H, d, J=8.1 Hz), 3.08 (1H, s), 2.86 (2H, s), 1.46 (6H, s).
- Step 8: A solution of 6-ethynyl-2,2-dimethylthiochroman-4-one (82.0 mg, 0.38 mmol) and ethyl 4-iodobenzoate (104.9 mg, 0.38 mmol) in 5.0 mL Et3N was purged with argon for 10 minutes. To this solution were added bis(triphenylphosphine)-palladium(II) chloride (88.0 mg, 0.12 mmol) and copper(I) iodide (22.9 mg, 0.12 mmol). After sparging for an additional 5 minutes with argon, the solution was stirred overnight at room temperature. The reaction mixture was filtered through a pad of Celite using an Et2O wash. Concentration of the filtrate under reduced pressure, followed by column chromatography of the residual solid, afforded 100 mg (72%) of ethyl 4-[(2,2-dimethyl-4-oxo-thiochroman-6-yl)ethynyl]-benzoate as a yellow solid. 1H NMR (300 MHz, CDCl3) δ: 8.25 (1H, d, J=1.8 Hz), 8.00 (2H, d, J=8.4 Hz), 7.55 (2H, d, J=8.4 Hz), 7.53 (1H, dd, J=1.8, 8.2 Hz), 7.21 (1H, d, J=8.2 Hz), 4.37 (2H, q, J=7.1 Hz), 2.88 (2H, s), 1.47 (6H, s), 1.39 (3H, t, J=7.1 Hz).
- Step 9: A solution of sodium bis(trimethylsilyl)amide (1.12 g, 6.13 mmol) in 16.2 mL of THF was cooled to −78° C. and a solution of ethyl 4-(2,2-dimethyl-4-oxo-thiochroman-6-ylethynyl)-benzoate (1.86 g, 5.10 mmol) in 15.0 mL was added slowly. After 30 minutes a solution of 2-[N,N-bis(trifluoromethanesulfonyl)amino]-5-pyridine (2.40 g, 6.13 mmol) in 10 mL of THF was added. After 5 minutes the solution was warmed to room temperature and stirred overnight. The reaction was quenched by the addition of saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were washed with 5% aqueous NaOH and H2O before being dried (MgSO4) and concentrated under reduced pressure. Ethyl 4-((2,2-dimethyl-4-trifluoromethanesulfonyloxy-(2H)-thiochromen-6-yl)ethynyl)-benzoate, 1.53 g (61%), was isolated by column chromatography (2% EtOAc/hexanes) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ: 8.03 (2H, d, J=8.4 Hz), 7.61 (1H, d, J=1.8 Hz), 7.59 (2H, d, J=8.4 Hz), 7.41 (1H, dd, J=1.8, 8.1 Hz), 7.29 (1H, d, J=8.1 Hz), 5.91 (1H, s), 4.39 (2H, q, J=7.1 Hz), 1.53 (6H, s), 1.41 (3H, t, J=7.1 Hz).
- Step 10: A solution of 4-ethylbromobenzene (670.9 mg, 3.63 mmol) in 4.0 mL of THF was cooled to −78° C. and tert-butyllithium (464.5 mg, 7.25 mmol, 4.26 mL of a 1.7M solution in pentane) was added to give a yellow solution. After 30 minutes a solution of ZnCl2 (658.7 mg, 4.83 mmol) in 8.0 mL THF was slowly added via cannula. The resulting solution was warmed to room temperature and transferred via cannula to a solution of ethyl 4-(2,2-dimethyl-4-trifluoromethanesulfonyloxy-(2H)-thiochromen-6-ylethynyl)-benzoate (1.20 g, 2.42 mmol) and tetrakis(triphenylphosphine)palladium(0) (111.7 mg, 0.097 mmol) in 8.0 mL THF. This solution was heated to 50° C. for 1 hour, cooled to room temperature, and the reaction quenched by the addition of saturated aqueous NH4Cl. The solution was extracted with EtOAc and the combined organic layers were washed with H2O and saturated aqueous NaCl before being dried (MgSO4) and concentrated under reduced pressure. Ethyl 4-[[4-(4-ethylphenyl)-2,2-dimethyl-(2H)-thiochromen-6-yl]-ethynyl]-benzoate was isolated by column chromatography (5% EtOAc/hexanes) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ: 7.99 (2H, d, J=8.2 Hz), 7.52 (2H, d, J=8.4 Hz), 7.40 (5H, m), 7.35 (2H, m), 5.85 (1H, s), 4.38 (2H, q, J=7.1 Hz), 2.72 (2H, q, J=7.6 Hz), 1.48 (6H, s), 1.40 (3H, t, J=7.1 Hz), 1.30 (3H, t, J=7.6 Hz).
- Step 11: To a solution of ethyl 4-[[4-(4-ethylphenyl)-2,2-dimethyl-(2H)-thiochromen-6-yl]-ethynyl]-benzoate (940.0 mg, 2.08 mmol) in 10.0 mL THF and 5.0 mL EtOH was added NaOH (416.0 mg, 10.4 mmol, 5.2 mL of a 2M aqueous solution). The resulting solution was stirred overnight at room temperature. The reaction mixture was acidified with 10% aqueous HCl and extracted with EtOAc. The combined organic layers were washed with H2O, saturated aqueous NaCl, and dried (Na2SO4) before removing the solvent under reduced pressure. The residual solid was recrystallized from CH3CN to give 786.0 mg (89%) of 4-[[4-(4-ethylphenyl)-2,2-dimethyl-(2H)-thiochromen-6-yl]-ethynyl]-benzoic acid as a colorless solid. 1H NMR (300 MHz, d6-acetone) δ: 8.01 (2H, d, J=8.3 Hz), 7.60 (2H, d, J=8.5 Hz), 7.42 (2H, m), 7.29 (2H, m), 7.22 (3H, m), 5.94 (1H, s), 2.69 (2H, q, J=7.7 Hz), 1.47 (6H, s), 1.25 (3H, t, J=7.7 Hz). This compound, the final desired product, was termed AGN 194310.
- The AGN 194310 compound was provided as follows: the compound was dissolved in capric/caprylic triglyceride (CCT) at a variety of doses, either 0.001% (v/v) AGN 194310, 0.003% (v/v) AGN 194310, or 0.01% (v/v) AGN 194310. Control animals received the CCT vehicle without the AGN 194310 active ingredient (AGN 194310 Vehicle). Although many retinoids and retinoid analogs are light labile, this compound is relatively stable to normal light.
- Newly arrived animals were quarantined for at least 7 days prior to their use in the study. All animals used in the study appeared to be in good health, with no evidence of disease or physical abnormality.
- One hundred ninety-six animals were distributed into thirteen groups as follows: Groups 1 through 5 were Main Study groups. Groups 6-9 were used for Toxicokinetic studies. Groups 10-13 were Main Study Recovery groups. The characteristics of each group are shown in Table 1 below.
TABLE 1 Total Daily Amount of Total Daily AGN Amount of Group Number Test 194310 Test Prep. No. & Sex Material (mg/kg/day) (ml/kg/day) 1 10M/10F Non-Treated Control N/A N/A 2 10M/10F AGN 194310 Vehicle N/A 1.5 3 10M/10F 0.001% AGN 194310 0.005 0.5 4 10M/10F 0.003% AGN 194310 0.015 0.5 5 10M/10F 0.01% AGN 194310 0.15 1.5 6 4M/4F AGN 194310 Vehicle N/A 1.5 7 8M/8F 0.001% AGN 194310 0.005 0.5 8 8M/8F 0.003% AGN 194310 0.015 0.5 9 8M/8F 0.01% AGN 194310 0.15 1.5 10 5M/5F AGN 194310 Vehicle N/A 1.5 11 5M/5F 0.001% AGN 194310 0.005 0.5 12 5M/5F 0.003% AGN 194310 0.015 0.5 13 5M/5F 0.01% AGN 194310 0.15 1.5 - The drug was administered using a graduated syringe and a 20×3 inch animal feeding needle. Drug was given to each animal in a single dose per day. Animals were observed at lease once daily during the course of the study for mortality, general health, behavior and any apparent physical or pharmacological abnormalities.
- Animals were weighed on the first day of the study and once per week thereafter, and the body weights recorded. The body weights were used for the dosage calculations. For all the Main Study and Recovery animals, food (Purina Certified Rodent Chow, meal form) was placed into tared glass jars and left in the animal cages. Jars were removed and weighed once weekly. Food was added to the jars when necessary. Food consumption was not recorded for the animals used in the toxicokinetic satellite studies.
- Urine was collected from animals in the Main Study and Recovery groups during week 4 of the treatment period, and from Recovery group animals during week 4 of the recovery period. Urine was analyzed for: blood (hemoglobin and erythrocytes), bilirubin, color, glucose, ketones, leukocytes, microscopic evaluations of any urine sediment, nitrate, pH, protein, specific gravity, transparency, and urobilinogen.
- Blood was collected from animals constituting the Main Study and Recovery groups at the end of the treatment and recovery periods, respectively. Before blood collection, the animals were allowed to fast for 16 hours, then blood was collected from each animal via cardiac puncture under anesthesia. The animals were sacrificed thereafter.
- The following tests were performed using the blood samples collected: hematocrit (total blood cell volume), total hemoglobin, mean cell volume, mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), platelet count, red blood cell count (RBC), total white blood cell count (WBC), and a differential WBC count for basophils, eosinophils, lymphocytes, monocytes, neutrophils.
- The concentration of drug in the blood was determined from blood drawn from the retro-orbital sinus of the right eye on Day 7 of the study as follows: for rats in groups 7 through 9 (4/sex/group/timepoint, with each animal being bled no more than 3 times), blood (approximately 1 ml) was drawn prior to being given the drug, and at approximately 2, 6, 8, 12 and 24 hours post-dosing. The vehicle-treated rats (group 6) were bled at approximately 8 and 24 hours post-dosing. The rats in groups 6 through 9 were similarly bled on Day 22 of the study, then euthanized. All blood was drawn into tubes containing EDTA to prevent coagulation, and placed on ice prior to analysis. The blood was assayed for the presence of AGN 194310 by gas chromatography/mass spectrometry.
- Animals were euthanized by inhalation of carbon dioxide. A complete necropsy was performed on all Main Study and Recovery group animals that died, or were euthanized due to moribund conditions, or were euthanized on scheduled sacrifice.
- The following organs were weighed for necroscopized animals: adrenal glands, ovaries, kidneys, pituitary gland, liver, spleen, heart, testes, and brain. In the case of organ pairs, both organs were weighed together.
- The following tissues and organs were isolated, trimmed if necessary, and preserved in 10% buffered formalin for histopathological evaluation: adrenal glands, mammary gland (with skin), aorta, ovaries, bone/bone marrow, pancreas, femur, pituitary gland, tibia, prostate gland, knee joint, salivary glands, parotid, brain, sub-maxillary, cervix sciatic nerve, diaphragm, seminal vesicle, epididymides, skeletal muscle (thigh), eyes, spinal chord (thoracic), spleen, esophagus, sternum, stomach, testes, duodenum, thymus, jejunum, thyroid gland with parathyroids, ileum, any tissues with lesion(s), cecum, tongue, colon, trachea, heart, bladder, kidneys, uterus, liver, ureter, lungs, urethra, lymph nodes (vaginal, cervical, mediastinal, mesenteric).
- Target tissues and organs from the Vehicle (control) and high-dose groups were imbedded in paraffin, and tissue sections made. The sections were mounted and stained with hematoxylin and eosin using standard histological techniques; such histopathological evaluation was performed using techniques well known in the art.
- After review and comparison of the histological findings obtained at the end of treatment period in the vehicle alone control group (group 2) and Main Study high dose (0.15 mg/kg/day) group (group 5), only those tissues determined to be affected by the drug at the high dose were evaluated in the Main Study intermediate (0.015 mg/kg/day) and low dose (0.005 mg/kg/day) groups (groups 3 and 4, respectively). Similarly, only when treatment-related histological effects were observed in a given tissue or dosage group of animals were the affected tissues and dosage groups evaluated in the Recovery group. In the Recovery dosage groups that were so evaluated, the selected tissues were prepared and evaluated as set forth above.
- No treatment-related deaths of study animals occurred during the course of the study. There were no statistically significant treatment-related effects on body weight during the treatment or recovery periods. The mean body weights of all study group animals were comparable throughout the study period. Nor were there treatment-related effects on food consumption between animals of different groups.
- There were no apparent treatment-related effects among animals of different groups in any urinalysis parameters at the end of the treatment period. By contrast, urinalysis of Recovery group animals at the end of the recovery period revealed no spermatozoa counts in the 0.15 mg/kg/day male rat urine samples. There were no other treatment-related effects in any other groups at the end of the recovery period.
- AGN 194310 was systemically absorbed following oral administration to rats and approached the peak concentration in plasma (Cmax) at 2 or 6 hours post dosing (Tmax). A dose dependent increase in systemic exposure to AGN 194310 was observed across the concentrations of AGN 194310. Similar Cmax and AUC0-24hr values (Area Under the Curve from 0 to 24 hours after dosage; this measures the concentration of drug in the blood during this time period monitored) were observed when rat blood was tested between the two collection periods. Pharmacokinetic parameters are presented in the following table:
TABLE II Formulation (dosage) 0.001% AGN 194310 0.003% AGN 194310 0.01% AGN 194310 (0.005 mg/kg/day) (0.015 mg/kg/day) (0.15 mg/kg/day) Cmaxa Day 7c 1.83 ± 0.55 4.73 ± 1.2 43.1 ± 7.2 (ng/ml) Day 22c 1.97 ± 0.75 5.32 ± 1.56 42.4 ± 9.3 Tmax Day 7c 2 2 6 (hr) Day 22c 2 2 6 AUC24 hr Day 7c 19.6 ± 1.1 57.6 ± 2.6 668 ± 24 (ng · hr/ml)b Day 22c 20.8 ± 1.1 63.6 ± 2.7 675 ± 25
aMean ± SD (N = 8/dose/time point).
bMean ± SEM (N = 8/dose/time point).
cThe day 7 data were not statistically different from the day 22 data.
- There were no noticeable differences between study animals observed during the postmortem pathological examination at the end of the treatment period. At the end of the recovery period, postmortem examinations revealed an apparent reduction of testes size in all five male rats that had been treated with AGN 194310 at a dosage level of 0.15 mg/kg/day. This finding was supported by a reduction in testes weight in male rats give the high drug dose (0.15 mg/kg/day) at the end of the treatment and recovery periods. Male rats in the other dosage groups showed no statistically significant reduction of testes weight.
- Histological examination of thin sections of the testes revealed that all (10/10) of the male rats given the high dose of AGN 194310 underwent spermatogenic arrest at the end of treatment. No such effect appeared in males given the intermediate (0.015 mg/kg/day or low (0.005 mg/kg/day) dosages of the drug. The seminiferous tubules of the high dose males were lined with one to two layers of germinal cells, rather than the usual four or more layers seen in normal seminiferous tubules. This change reflects a complete block of spermatogenesis.
- Leydig cells appeared unaffected, nor was any evidence of an atrophic change seen in the secondary sex glands, such as the seminal vesicles and prostate, of the high dose males. In other words, the drug appears to target the seminiferous epithelium. Changes in the testes were not readily evident, either through visual or microscopic inspection at the end of the treatment period.
- The rats in the Recovery group were permitted approximately a one-month period without exposure to the drug. In the male rats of the Recovery group, testicular atrophy was evident and accompanied morphologically by continuing cessation of spermatogenesis, monitored according to the criteria and methods mentioned above. However, reversibility of such inhibition was also evident, as could be seen by a focal increase in germ cell layers in individual tubules. The extent of this recovery varied from animal to animal and within a single testicular section.
- None of the high dose male rats, either in the Main Study Group or the Recovery group, displayed inflammation or damage to stromal or vascular elements of the testis. Physiological effects of drug treatment other than those associated with spermatogenic arrest were not observed. The epididymis of the high dose rats showed an increase in exfoliated cells at the end of treatment and the absence of stored epididymal sperm at the end of recovery; these changes are expected secondary effects of spermatogenic arrest.
- As the total time course of spermatogenesis is approximately 54 days in rats, the time period required to observe reversibility of complete spermatogenic arrest would be at least this long. Also, this time period would be expected to be additionally lengthened, depending upon the time required for the drug to be clear from the subject's system. In a separate experiment 88% of the drug was shown to be excreted within 2 weeks following treatment. Thus, this experiment provides evidence of reinitiation of spermatogenesis in animals of the Recovery group.
- Thus, this experiment shows that daily oral delivery of the RAR antagonist AGN 194310 is sufficient to cause spermatogenic arrest in mammals, and that the effects of spermatogenic arrest in treated animals are reversed following cessation of AGN 194310 treatment. Although the exact mechanism of inhibition is not known, and, while not wishing to be bound by theory, the Applicants believe that the drug appears especially to affect, either directly or indirectly, primary spermatocytes. Thus, germ cells that have differentiated beyond the primary spermatocyte stage when treatment with an RAR antagonist or inverse agonist is initiated will continue to mature and differentiate into spermatozoa, while spermatogonia do not appear to differentiate beyond the primary spermatocytes stage. Since the 2nd, 3rd, and 4th stages of spermatogenesis occur over an extended period before the release of the spermatozoa into the epididymis, this is why spermatozoa were still seen in the urine of the Main Study male rats at the end of treatment (despite clear spermatogenic arrest being visible in the testes tissue sections), while the male rats of the Recovery group have no detected spermatozoa in their urine (despite clear indications of renewed spermatogenesis in the testes of these rats).
- Thus, in this experiment daily oral dosage of an RAR antagonist (inverse agonist), AGN 194310, at 0.15 mg/kg/day was sufficient to cause reversible spermatogenic arrest. By presenting these data the Applicants are not indicating that the experiment demonstrates an optimal dose, delivery method, or frequency of treatment. However, this experiment clearly shows the unanticipated result that an RAR antagonist or inverse agonist may be used as an effective male contraceptive, as claimed.
- An experiment was conducted in a manner substantially similar to that described in Example 1, with the following differences. Twenty-nine male and twenty-nine female Sprague-Dawley rats, approximately 7 weeks old were used for the study. Five rats/sex/group were designated as Main Study animals: (vehicle control, 0.025 mg/kg/day AGN 194310, and 0.25 mg/kg/day AGN 194310), and 7/sex/group designated as toxicokinetic satellite animals (0.025 mg/kg/day AGN 194310 and 0.25 mg/kg/day AGN 194310). No “vehicle alone” control group was made for the toxicokinetic satellite animals. In this study there was no Recovery group.
- The animals' backs were maintained shaven during the course of the study for application of the topical cream. The animals were treated daily with a topical formulation containing either AGN 194310 vehicle cream alone, 0.01% (w/w) AGN 194310 in the same vehicle cream, or 0.1% (w/w) AGN 194310 in the same vehicle cream. The vehicle cream consisted of a mixture of the following ingredients:
Benzyl Alcohol 1% (w/w) Medium Chain Triglycerides 25% (w/w) Carbomer 1342 0.2% (w/w) Sorbitan Monooleate 0.2% (w/w) Carbomer 934P 1% (w/w) EDTA 0.05% (w/w) 5 N Sodium Hydroxide 2.72 (w/w) Water q.s. to 100% (w/w) - The following Table shows the experimental design:
TABLE 3 Total Daily Total Daily Amount of Amount of Group Number AGN 194310 Test Prep. No. & Sex Test Material (mg/kg/day) (gm/kg/day) 1 5M/5F Vehicle Cream N/A 0.25 2 5M/5F 0.01% AGN 194310 0.025 0.25 3 5M/5F 0.1% AGN 194310 0.25 0.25 4 7M/7F 0.01% AGN 194310 0.025 0.25 5 7M/7F 0.1% AGN 194310 0.25 0.25 - Daily dosages were calculated using the most recently obtained body weights, as shown below. The test or control creams were applied for 28 consecutive days to the shaved back of each animal in an area approximately equal to 35.5 cm2. Application was made using a repeat pipettor, and the drug gently massaged into the skin. An Elizabethan collar was affixed around each animal's neck for a period of about 6 hours following treatment to prevent removal or systemic ingestion of the drug.
- Blood was drawn at day 29 via cardiac puncture, as described in Example 1. The animals were first permitted to fast for approximately 16 hours prior to blood collection. Satellite animals were sacrificed on day 28.
- Topical skin application of AGN 194310 did not result in any evidence of treatment-related skin irritation. No treatment-related clinical observations, differences in body weight, differences in food consumption, or in gross pathology were observed.
- Male rats in all groups displayed no statistically significant hematological differences versus the control rats. However, there is a dose-dependent reduction in triglycerides in the male rats given the drug. Histopathological analysis reveals atrophy of the seminiferous tubules, with concomitant spermatogenic arrest in 0 out of 5 male rats in the 0.025 mg/kg/day group and 5 out of 5 male rats in the 0.25 mg/kg/day; spermatogenic arrest was detected as described in Example 1. Additionally, there was a notable reduction of germ cells in the head of the epididymis in the majority of males displaying spermatogenic arrest.
- This experiment was conducted in a manner substantially similar to that of Example 1. Groups of male Sprague Dawley rats were treated orally for 4 weeks with either 0, 0.075, or 0.150 mg/kg/day of AGN 194310. Three to six animals from each group were sacrificed after 2 weeks of treatment, 6 animals from each group were sacrificed following 4 weeks of treatment and 6 animals from each group were sacrificed after 18-23 weeks of subsequent recovery after cessation of treatment. Histological and pathological examinations were done of the sacrificed animals, as in Example 1. Additionally, the animals in the 23 week recovery group were mated to normal, untreated female Sprague Dawley rats before being sacrificed to assess the reproductive function.
- As in the previous examples, the control group of rats (no drug) displayed no abnormal histological or biochemical differences during the time course of the experiment, except for a single individual, which was found to have bilateral severe sperm granulomas due to segmental aplasia of the epididymides (a congenital defect).
- All rats treated with 0.075 mg/kg of AGN 194310 displayed evidence of spernatogenic arrest after 2 and 4 weeks of treatment. No increase of round spermatidis were seen in the epididymal caput and cauda of these animals. The weight of the testes and epididymides of the treated animals was significantly reduced after 4 weeks of treatment, and this weight decrease persisted to some degree in rats sacrificed after 18 weeks of recovery. Histological analysis revealed that active spermatogenesis had resumed in the treated animals, but no mature sperm were seen in the epididymides.
- After 23 weeks of recovery, 2 of the 3 rats had completely recovered with normal testes weights, a complete spermatogenesis cycle, and mature sperm in the epididymides. The remaining animals had complete spermatogenesis in the left testis, incomplete spermatogenesis in the right testis, and mature sperm in both epididymides. Interestingly, the seminal vesicles, of all the treated animals were normal; seminal vesicle weight is dependent on serum testosterone. These data suggest that serum testosterone function remains normal during treatment with AGN 194310. All tested animals were fertile after 23 weeks of recovery and able to reproduce healthy pups.
- Among the animals treated with 0.150 mg/kg AGN 194310 similar results were seen. Spermatogenic arrest was observed in all rats treated after 2 and 4 weeks of treatment. After 23 weeks of recovery, 4 out of 6 rats appeared to have completely recovered, with active and complete spermatogenesis seen, and normal testes weight. These 4 rats were able to reproduce normally. The remaining two animals had incomplete spermatogenesis no mature sperm seen in the epididymides histologically.
- These results indicate that the effects of the drug are fully reversible when administration of AGN 194310 is halted. Additionally, the results are expected to be substantially similar whether the drug is applied orally or topically.
- This experiment is conducted as indicated in Example 2, except that the drug is 193109 rather than AGN 194310, and a Recovery group is monitored for a period of time post-treatment as in Example 3. Dosages of the '109 drug is the same as for the topical treatment with the '310 drug.
- The results are substantially similar to those reported in Example 3 for AGN 194310. At the effective dose, spermatogenic arrest can be seen within thirty days after initiation of treatment by examination of the testes of the treated animals. A histological analysis of the testes reveals the absence of primary spermatocytes, spermatids and spermatozoa in the majority of animals' seminiferous tubules. These effects are reversible; a similar analysis conducted on the testes of males rats 12 weeks after administration demonstrates the repopulation of the tubules with males gametes in various stages of development.
- In a preliminary test using a small population (5) male cynomologus monkeys, treatment with AGN 194310 at a daily dosage of 1.25 mg/kg did not result in inhibition or arrest of spermatogenesis. Those of skill in the art will recognize that these are initial results. Assuming arguendo these results are reproducible the results could be due to many factors, including, without limitation, suboptimal dosage, delivery vehicles or modes of treatment that are differentially effective in cynomologus monkeys and rats, or the possibility that AGN 194310 has different effects in monkeys as compared to rats. Those of skill in the art will also recognize that both rats and monkeys are commonly used and accepted animal models for drug efficacy in humans.
- In light of the disclosure of this patent specification, the person of ordinary skill in the art would expect that treatment of a male human with an effective dosage of a RAR antagonist or inverse agonist able to inhibit spermatogenesis in male non-human mammals such as rats and/or monkeys, would have similar effects in humans, both in terms of spermatogenic arrest as well as reversibility. Depending upon the Kd of the antagonist or inverse agonist, such drugs may have to be given at dosage levels, or frequencies, other than those described above. By “Kd” is meant the binding constant; defined as that concentration of the drug at which 50% of the drug is bound to an RAR receptor. Additionally, the Applicants intend to make no statement herein that should be construed as a representation that the dosage levels and dosage frequencies mentioned herein are necessarily optimal.
- It will be recognized by the person of ordinary skill in the art that the ability or failure of a given drug to stimulate a specific response, such as spermatogenic arrest, in one species or genus of male mammal is not necessarily indicative of the ability or failure of the same drug to stimulate the same response in another species or genus of mammals.
- The invention is not to be seen as limited by the foregoing examples, which merely set forth certain preferred embodiments of the invention. Other embodiments can be found in the claims that conclude this specification.
Claims (17)
1-42. (canceled)
43. A method for inhibiting the ability of a male mammal to conceive progeny, comprising administering to said male mammal, for a period time effective to sufficiently reduce or eliminate spermatozoa in the semen of said male mammal, an effective amount of a compound represented by the following structure:
44. The method of claim 43 , wherein the effective amount of the compound is in a range of between about 0.5 mg/kg of body weight and about 0.001 mg/kg of body weight.
45. The method of claim 44 , wherein the effective amount of the compound is in a range of between about 0.3 mg/kg of body weight and about 0.005 mg/kg of body weight.
46. The method of claim 45 , wherein the effective amount of the compound is in a range of between about 0.075 mg/kg of body weight and about 0.01 mg/kg of body weight.
47. A method for inhibiting the ability of a male mammal to conceive progeny, comprising administering to said male mammal, for a period time effective to sufficiently reduce or eliminate spermatozoa in the semen of said male mammal, an effective amount of a compound represented by the following structure:
48. The method of claim 47 , wherein the effective amount of the compound is in a range of between about 0.5 mg/kg of body weight and about 0.001 mg/kg of body weight.
49. The method of claim 48 , wherein the effective amount of the compound is in a range of between about 0.3 mg/kg of body weight and about 0.005 mg/kg of body weight.
50. The method of claim 49 , wherein the effective amount of the compound is in a range of between about 0.075 mg/kg of body weight and about 0.01 mg/kg of body weight.
51. A method for inhibiting spermatogenesis in a male mammal, comprising administering to said male mammal, over a period of time effective to prevent conception, an effective amount of a compound represented by the following structure:
52. The method of claim 51 , wherein the effective amount of the compound is in a range of between about 0.5 mg/kg of body weight and about 0.001 mg/kg of body weight.
53. The method of claim 52 , wherein the effective amount of the compound is in a range of between about 0.3 mg/kg of body weight and about 0.005 mg/kg of body weight.
54. The method of claim 53 , wherein the effective amount of the compound is in a range of between about 0.075 mg/kg of body weight and about 0.01 mg/kg of body weight.
56. The method of claim 55 , wherein the effective amount of the compound is in a range of between about 0.5 mg/kg of body weight and about 0.001 mg/kg of body weight.
57. The method of claim 56 , wherein the effective amount of the compound is in a range of between about 0.3 mg/kg of body weight and about 0.005 mg/kg of body weight.
58. The method of claim 57 , wherein the effective amount of the compound is in a range of between about 0.075 mg/kg of body weight and about 0.01 mg/kg of body weight.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US11/503,635 US20070054882A1 (en) | 1998-10-08 | 2006-08-14 | Male anti-fertility agents |
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US10350798P | 1998-10-08 | 1998-10-08 | |
US40574899A | 1999-09-27 | 1999-09-27 | |
US09/591,253 US6521641B1 (en) | 1998-10-08 | 2000-06-09 | Male anti-fertility agents |
US10/304,665 US20030144256A1 (en) | 1998-10-08 | 2002-11-25 | Male anti-fertility agents |
US11/503,635 US20070054882A1 (en) | 1998-10-08 | 2006-08-14 | Male anti-fertility agents |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/304,665 Continuation US20030144256A1 (en) | 1998-10-08 | 2002-11-25 | Male anti-fertility agents |
Publications (1)
Publication Number | Publication Date |
---|---|
US20070054882A1 true US20070054882A1 (en) | 2007-03-08 |
Family
ID=26800542
Family Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09/591,253 Expired - Fee Related US6521641B1 (en) | 1998-10-08 | 2000-06-09 | Male anti-fertility agents |
US10/304,665 Abandoned US20030144256A1 (en) | 1998-10-08 | 2002-11-25 | Male anti-fertility agents |
US11/503,635 Abandoned US20070054882A1 (en) | 1998-10-08 | 2006-08-14 | Male anti-fertility agents |
Family Applications Before (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09/591,253 Expired - Fee Related US6521641B1 (en) | 1998-10-08 | 2000-06-09 | Male anti-fertility agents |
US10/304,665 Abandoned US20030144256A1 (en) | 1998-10-08 | 2002-11-25 | Male anti-fertility agents |
Country Status (1)
Country | Link |
---|---|
US (3) | US6521641B1 (en) |
Cited By (27)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20090105289A1 (en) * | 2004-10-12 | 2009-04-23 | Novo Nordisk A/S | 11beta-hydroxysteroid dehydrogenase type 1 active spiro compounds |
US20090118259A1 (en) * | 2005-11-01 | 2009-05-07 | John Paul Kilburn | Pharmaceutical use of substituted amides |
US20090124598A1 (en) * | 2005-11-01 | 2009-05-14 | Henrik Sune Andersen | Pharmaceutical use of substituted amides |
WO2009077158A1 (en) * | 2007-12-14 | 2009-06-25 | University Of Ulster | Use of fkbpl gene to identify a cause of infertitlity |
US20090176862A1 (en) * | 2006-05-16 | 2009-07-09 | Vitae Pharmaceuticals, Inc. | Methods for treating chemotherapy and radiation therapy side effects |
US20090306048A1 (en) * | 2006-06-16 | 2009-12-10 | John Paul Kilburn | Pharmaceutical use of substituted piperidine carboxamides |
US20090325932A1 (en) * | 2006-07-13 | 2009-12-31 | Soren Ebdrup | 4-piperidylbenzamides as 11-beta-hydroxysteroid dehydrogenase type 1 inhibitors |
US20100009968A1 (en) * | 2006-07-13 | 2010-01-14 | High Point Pharmaceuticals, Llc | 11beta-hydroxysteroid dehydrogenase type 1 active compounds |
US20100056600A1 (en) * | 2007-03-28 | 2010-03-04 | Soren Ebdrup | 11beta-hsd1 active compounds |
US20100076041A1 (en) * | 2007-03-09 | 2010-03-25 | John Paul Kilburn | Indole- and benzimidazole amides as hydroxysteroid dehydrogenase inhibitors |
US20100087543A1 (en) * | 2007-04-24 | 2010-04-08 | Soren Ebdrup | Pharmaceutical use of substituted amides |
US20100137377A1 (en) * | 2007-04-11 | 2010-06-03 | Soren Ebdrup Et Al | Novel compounds |
US20100168083A1 (en) * | 2006-03-21 | 2010-07-01 | Soren Ebdrup | Adamantane derivatives for the treatment of the metabolic syndrome |
US20100331366A1 (en) * | 2007-02-23 | 2010-12-30 | High Point Pharmaceuticals ,Llc | N-adamantyl benzamides as inhibitors of 11-beta-hydroxysteroid dehydrogenase |
US20110003856A1 (en) * | 2007-02-23 | 2011-01-06 | Soren Ebdrup | N-adamantyl benzamides as inhibitors of 11-beta-hydroxysteroid dehydrogenase |
US20110003852A1 (en) * | 2007-02-23 | 2011-01-06 | Soren Ebdrup | N-adamantyl benzamides as inhibitors of 11-beta-hydroxysteroid dehydrogenase |
US20110039853A1 (en) * | 2007-02-23 | 2011-02-17 | High Point Pharmaceuticals, Llc | N-adamantyl benzamides as inhibitors of 11-beta-hydroxysteroid dehydrogenase |
US8053447B2 (en) | 2006-04-07 | 2011-11-08 | High Point Pharmaceuticals, Llc | 11β-hydroxysteroid dehydrogenase type 1 active compounds |
US9308186B2 (en) | 2005-09-30 | 2016-04-12 | Io Therapeutics, Inc. | Treatment of cancer with specific RXR agonists |
US10588881B2 (en) | 2015-10-31 | 2020-03-17 | Io Therapeutics, Inc. | Treatment of nervous system disorders using combinations of RXR agonists and thyroid hormones |
US10835507B2 (en) | 2016-03-10 | 2020-11-17 | Io Therapeutics, Inc. | Treatment of muscular disorders with combinations of RXR agonists and thyroid hormones |
US10946001B2 (en) | 2016-03-10 | 2021-03-16 | Io Therapeutics, Inc. | Treatment of autoimmune diseases with combinations of RXR agonists and thyroid hormones |
US10945976B2 (en) | 2011-12-13 | 2021-03-16 | Io Therapeutics, Inc. | Autoimmune disorder treatment using RXR agonists |
US10966950B2 (en) | 2019-06-11 | 2021-04-06 | Io Therapeutics, Inc. | Use of an RXR agonist in treating HER2+ cancers |
CN115335367A (en) * | 2019-12-19 | 2022-11-11 | 奥弗恩制药公司 | RAR-alpha compounds for use in inflammatory diseases and male contraception |
US11517549B2 (en) | 2017-09-20 | 2022-12-06 | Io Therapeutics, Inc. | Treatment of disease with esters of selective RXR agonists |
US11896558B2 (en) | 2021-12-07 | 2024-02-13 | Io Therapeutics, Inc. | Use of an RXR agonist and taxanes in treating Her2+ cancers |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7105566B2 (en) * | 2002-10-22 | 2006-09-12 | Allergan, Inc. | Methods of treatment during vascular procedures |
EP3150589A1 (en) * | 2007-06-08 | 2017-04-05 | MannKind Corporation | Ire-1a inhibitors |
WO2012015715A1 (en) | 2010-07-27 | 2012-02-02 | High Point Pharmaceuticals, Llc | Substituted thiazol-2-ylamine derivatives, pharmaceutical compositions, and methods of use as 11-beta hsd1 modulators |
PT3013813T (en) | 2013-06-27 | 2019-06-14 | Pfizer | Heteroaromatic compounds and their use as dopamine d1 ligands |
Citations (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4134918A (en) * | 1977-09-06 | 1979-01-16 | Merrell Toraude Et Compagnie | Alpha-halomethyl derivatives of amines |
US4182891A (en) * | 1977-07-01 | 1980-01-08 | Merrell Toraude Et Compagnie | α-Acetylenic derivatives of α-amino acids |
US4677193A (en) * | 1985-02-22 | 1987-06-30 | The Salk Institute For Biological Studies | Peptides containing an aliphatic-aromatic ketone side chain |
US5472706A (en) * | 1992-02-18 | 1995-12-05 | Pharmos Corp. | Dry compositions for preparing submicron emulsions |
US5501855A (en) * | 1993-09-02 | 1996-03-26 | Talwar; Gursaran P. | Neem oil as a male contraceptive |
US5648385A (en) * | 1994-01-03 | 1997-07-15 | Bristol-Myers Squibb Co. | Retinoid-like compounds |
US5728846A (en) * | 1996-12-12 | 1998-03-17 | Allergan | Benzo 1,2-g!-chrom-3-ene and benzo 1,2-g!-thiochrom-3-ene derivatives |
US5744448A (en) * | 1991-03-15 | 1998-04-28 | Applied Research Systems Ars Holding N.V. | Human follicle stimulating hormone receptor |
US5753231A (en) * | 1989-03-03 | 1998-05-19 | University Of Virginia | Primate intra-acrosomal sperm antigen for use in a contraceptive vaccine |
US5776699A (en) * | 1995-09-01 | 1998-07-07 | Allergan, Inc. | Method of identifying negative hormone and/or antagonist activities |
US5877207A (en) * | 1996-03-11 | 1999-03-02 | Allergan Sales, Inc. | Synthesis and use of retinoid compounds having negative hormone and/or antagonist activities |
US5919970A (en) * | 1997-04-24 | 1999-07-06 | Allergan Sales, Inc. | Substituted diaryl or diheteroaryl methanes, ethers and amines having retinoid agonist, antagonist or inverse agonist type biological activity |
US5958954A (en) * | 1995-09-01 | 1999-09-28 | Allergan Sales, Inc. | Synthesis and use of retinoid compounds having negative hormone and/or antagonist activities |
US6008204A (en) * | 1995-09-01 | 1999-12-28 | Allergan Sales, Inc. | Synthesis and use of retinoid compounds having negative hormone and/or antagonist activities |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1994014777A1 (en) | 1992-12-28 | 1994-07-07 | Eisai Co., Ltd. | Heterocyclic carbonic acid derivatives which bind to retinoid receptors (rar) |
IL108509A0 (en) | 1993-02-22 | 1994-05-30 | Salk Inst For Biological Studi | GnRH antagonist peptides |
US5972658A (en) | 1996-12-05 | 1999-10-26 | Incyte Pharmaceuticals, Inc. | DNA encoding lung growth factor variant |
-
2000
- 2000-06-09 US US09/591,253 patent/US6521641B1/en not_active Expired - Fee Related
-
2002
- 2002-11-25 US US10/304,665 patent/US20030144256A1/en not_active Abandoned
-
2006
- 2006-08-14 US US11/503,635 patent/US20070054882A1/en not_active Abandoned
Patent Citations (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4182891A (en) * | 1977-07-01 | 1980-01-08 | Merrell Toraude Et Compagnie | α-Acetylenic derivatives of α-amino acids |
US4134918A (en) * | 1977-09-06 | 1979-01-16 | Merrell Toraude Et Compagnie | Alpha-halomethyl derivatives of amines |
US4677193A (en) * | 1985-02-22 | 1987-06-30 | The Salk Institute For Biological Studies | Peptides containing an aliphatic-aromatic ketone side chain |
US5753231A (en) * | 1989-03-03 | 1998-05-19 | University Of Virginia | Primate intra-acrosomal sperm antigen for use in a contraceptive vaccine |
US5744448A (en) * | 1991-03-15 | 1998-04-28 | Applied Research Systems Ars Holding N.V. | Human follicle stimulating hormone receptor |
US5472706A (en) * | 1992-02-18 | 1995-12-05 | Pharmos Corp. | Dry compositions for preparing submicron emulsions |
US5501855A (en) * | 1993-09-02 | 1996-03-26 | Talwar; Gursaran P. | Neem oil as a male contraceptive |
US5648385A (en) * | 1994-01-03 | 1997-07-15 | Bristol-Myers Squibb Co. | Retinoid-like compounds |
US5776699A (en) * | 1995-09-01 | 1998-07-07 | Allergan, Inc. | Method of identifying negative hormone and/or antagonist activities |
US5958954A (en) * | 1995-09-01 | 1999-09-28 | Allergan Sales, Inc. | Synthesis and use of retinoid compounds having negative hormone and/or antagonist activities |
US6008204A (en) * | 1995-09-01 | 1999-12-28 | Allergan Sales, Inc. | Synthesis and use of retinoid compounds having negative hormone and/or antagonist activities |
US5877207A (en) * | 1996-03-11 | 1999-03-02 | Allergan Sales, Inc. | Synthesis and use of retinoid compounds having negative hormone and/or antagonist activities |
US5728846A (en) * | 1996-12-12 | 1998-03-17 | Allergan | Benzo 1,2-g!-chrom-3-ene and benzo 1,2-g!-thiochrom-3-ene derivatives |
US5919970A (en) * | 1997-04-24 | 1999-07-06 | Allergan Sales, Inc. | Substituted diaryl or diheteroaryl methanes, ethers and amines having retinoid agonist, antagonist or inverse agonist type biological activity |
Cited By (61)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20090105289A1 (en) * | 2004-10-12 | 2009-04-23 | Novo Nordisk A/S | 11beta-hydroxysteroid dehydrogenase type 1 active spiro compounds |
US8138342B2 (en) | 2004-10-12 | 2012-03-20 | High Point Pharmacueticals, LLC | 11β-hydroxysteroid dehydrogenase type 1 active spiro compounds |
US10039731B2 (en) | 2005-09-30 | 2018-08-07 | Io Therapeutics, Inc. | Treatment of cancer with specific RXR agonists |
US10188618B2 (en) | 2005-09-30 | 2019-01-29 | Io Therapeutics, Inc. | Treatment of cancer with specific RXR agonists |
US10973788B2 (en) | 2005-09-30 | 2021-04-13 | Io Therapeutics, Inc. | Treatment of cancer with specific RXR agonists |
US9308186B2 (en) | 2005-09-30 | 2016-04-12 | Io Therapeutics, Inc. | Treatment of cancer with specific RXR agonists |
US9655872B2 (en) | 2005-09-30 | 2017-05-23 | Io Therapeutics, Inc. | Treatment of cancer with specific RXR agonists |
US9717702B2 (en) | 2005-09-30 | 2017-08-01 | Io Therapeutics, Inc. | Treatment of cancer with specific RXR agonists |
US10596133B2 (en) | 2005-09-30 | 2020-03-24 | Io Therapeutics, Inc. | Treatment of cancer with specific RXR agonists |
US20090124598A1 (en) * | 2005-11-01 | 2009-05-14 | Henrik Sune Andersen | Pharmaceutical use of substituted amides |
US20090118259A1 (en) * | 2005-11-01 | 2009-05-07 | John Paul Kilburn | Pharmaceutical use of substituted amides |
US8053431B2 (en) | 2005-11-01 | 2011-11-08 | High Point Pharmaceuticals, Llc | Pharmaceutical use of substituted amides |
US20100168083A1 (en) * | 2006-03-21 | 2010-07-01 | Soren Ebdrup | Adamantane derivatives for the treatment of the metabolic syndrome |
US8053447B2 (en) | 2006-04-07 | 2011-11-08 | High Point Pharmaceuticals, Llc | 11β-hydroxysteroid dehydrogenase type 1 active compounds |
US20090176862A1 (en) * | 2006-05-16 | 2009-07-09 | Vitae Pharmaceuticals, Inc. | Methods for treating chemotherapy and radiation therapy side effects |
US9271946B2 (en) | 2006-05-16 | 2016-03-01 | Io Therapeutics, Inc. | Use of a RAR antagonist or inverse agonist for the treatment of chemotherapy and/or radiation therapy side effects |
US20090306048A1 (en) * | 2006-06-16 | 2009-12-10 | John Paul Kilburn | Pharmaceutical use of substituted piperidine carboxamides |
US20100009968A1 (en) * | 2006-07-13 | 2010-01-14 | High Point Pharmaceuticals, Llc | 11beta-hydroxysteroid dehydrogenase type 1 active compounds |
US20090325932A1 (en) * | 2006-07-13 | 2009-12-31 | Soren Ebdrup | 4-piperidylbenzamides as 11-beta-hydroxysteroid dehydrogenase type 1 inhibitors |
US8048908B2 (en) | 2006-07-13 | 2011-11-01 | High Point Pharmaceuticals, Llc | 11β-hydroxysteroid dehydrogenase type 1 active compounds |
US20110003856A1 (en) * | 2007-02-23 | 2011-01-06 | Soren Ebdrup | N-adamantyl benzamides as inhibitors of 11-beta-hydroxysteroid dehydrogenase |
US20110039853A1 (en) * | 2007-02-23 | 2011-02-17 | High Point Pharmaceuticals, Llc | N-adamantyl benzamides as inhibitors of 11-beta-hydroxysteroid dehydrogenase |
US8334305B2 (en) | 2007-02-23 | 2012-12-18 | High Point Pharmaceuticals, Llc | N-adamantyl benzamides as inhibitors of 11-β-hydroxysteroid dehydrogenase |
US8383820B2 (en) | 2007-02-23 | 2013-02-26 | High Point Pharmaceuticals, Llc | N-adamantyl benzamides as inhibitors of 11-β-hydroxysteroid dehydrogenase |
US8809540B2 (en) | 2007-02-23 | 2014-08-19 | High Point Pharmaceuticals, Llc | N-adamantyl benzamides as inhibitors of 11-beta-hydroxysteroid dehydrogenase |
US20110003852A1 (en) * | 2007-02-23 | 2011-01-06 | Soren Ebdrup | N-adamantyl benzamides as inhibitors of 11-beta-hydroxysteroid dehydrogenase |
US20100331366A1 (en) * | 2007-02-23 | 2010-12-30 | High Point Pharmaceuticals ,Llc | N-adamantyl benzamides as inhibitors of 11-beta-hydroxysteroid dehydrogenase |
US8153798B2 (en) | 2007-03-09 | 2012-04-10 | High Point Pharmaceuticals, Llc | Indole- and benzimidazole amides as hydroxysteroid dehydrogenase inhibitors |
US20100076041A1 (en) * | 2007-03-09 | 2010-03-25 | John Paul Kilburn | Indole- and benzimidazole amides as hydroxysteroid dehydrogenase inhibitors |
US20100056600A1 (en) * | 2007-03-28 | 2010-03-04 | Soren Ebdrup | 11beta-hsd1 active compounds |
US20100137377A1 (en) * | 2007-04-11 | 2010-06-03 | Soren Ebdrup Et Al | Novel compounds |
US20100087543A1 (en) * | 2007-04-24 | 2010-04-08 | Soren Ebdrup | Pharmaceutical use of substituted amides |
US8383683B2 (en) | 2007-04-24 | 2013-02-26 | High Point Pharmaceuticals, Llc | Pharmaceutical use of substituted amides |
US20100305082A1 (en) * | 2007-12-14 | 2010-12-02 | Stephen Downes | Use of FKBPL gene to identify a cause of infertility |
WO2009077158A1 (en) * | 2007-12-14 | 2009-06-25 | University Of Ulster | Use of fkbpl gene to identify a cause of infertitlity |
US10945976B2 (en) | 2011-12-13 | 2021-03-16 | Io Therapeutics, Inc. | Autoimmune disorder treatment using RXR agonists |
US11246845B2 (en) | 2011-12-13 | 2022-02-15 | Io Therapeutics, Inc. | Autoimmune disorder treatment using RXR agonists |
US11547684B2 (en) | 2011-12-13 | 2023-01-10 | Io Therapeutics, Inc. | Autoimmune disorder treatment using RXR agonists |
US11793781B2 (en) | 2011-12-13 | 2023-10-24 | Io Therapeutics, Inc. | Autoimmune disorder treatment using RXR agonists |
US11166927B2 (en) | 2011-12-13 | 2021-11-09 | Io Therapeutics, Inc. | Autoimmune disorder treatment using RXR agonists |
US11576881B2 (en) | 2011-12-13 | 2023-02-14 | Io Therapeutics, Inc. | Autoimmune disorder treatment using RXR agonists |
US10973791B2 (en) | 2015-10-31 | 2021-04-13 | Io Therapeutics, Inc. | Treatment of nervous system disorders using combinations of RXR agonists and thyroid hormones |
US10695312B2 (en) | 2015-10-31 | 2020-06-30 | Io Therapeutics, Inc. | Treatment of nervous system disorders using combinations of RXR agonists and thyroid hormones |
US10857117B2 (en) | 2015-10-31 | 2020-12-08 | Io Therapeutics, Inc. | Treatment of nervous system disorders using combinations of RXR agonists and thyroid hormones |
US10702489B2 (en) | 2015-10-31 | 2020-07-07 | Io Therapeutics, Inc. | Treatment of nervous system disorders using combinations of RXR agonists and thyroid hormones |
US10588881B2 (en) | 2015-10-31 | 2020-03-17 | Io Therapeutics, Inc. | Treatment of nervous system disorders using combinations of RXR agonists and thyroid hormones |
US10980760B2 (en) | 2015-10-31 | 2021-04-20 | Io Therapeutics, Inc. | Treatment of nervous system disorders using combinations of RXR agonists and thyroid hormones |
US10980759B2 (en) | 2015-10-31 | 2021-04-20 | Io Therapeutics, Inc. | Treatment of nervous system disorders using combinations of RXR agonists and thyroid hormones |
US10980761B2 (en) | 2015-10-31 | 2021-04-20 | Io Therapeutics, Inc. | Treatment of nervous system disorders using combinations of RXR agonists and thyroid hormones |
US11065219B2 (en) | 2015-10-31 | 2021-07-20 | Io Therapeutics, Inc. | Treatment of nervous system disorders using combinations of RXR agonists and thyroid hormones |
US10842764B2 (en) | 2015-10-31 | 2020-11-24 | Io Therapeutics, Inc. | Treatment of nervous system disorders using combinations of RXR agonists and thyroid hormones |
US10806713B2 (en) | 2015-10-31 | 2020-10-20 | Io Therapeutics, Inc. | Treatment of nervous system disorders using combinations of RXR agonists and thyroid hormones |
US10946001B2 (en) | 2016-03-10 | 2021-03-16 | Io Therapeutics, Inc. | Treatment of autoimmune diseases with combinations of RXR agonists and thyroid hormones |
US11690831B2 (en) | 2016-03-10 | 2023-07-04 | Io Therapeutics, Inc. | Treatment of autoimmune diseases with combinations of RXR agonists and thyroid hormones |
US11690832B2 (en) | 2016-03-10 | 2023-07-04 | Io Therapeutics | Treatment of autoimmune diseases with combinations of RXR agonists and thyroid hormones |
US10835507B2 (en) | 2016-03-10 | 2020-11-17 | Io Therapeutics, Inc. | Treatment of muscular disorders with combinations of RXR agonists and thyroid hormones |
US11517549B2 (en) | 2017-09-20 | 2022-12-06 | Io Therapeutics, Inc. | Treatment of disease with esters of selective RXR agonists |
US11224583B2 (en) | 2019-06-11 | 2022-01-18 | Io Therapeutics, Inc. | Use of an RXR agonist in treating HER2+ cancers |
US10966950B2 (en) | 2019-06-11 | 2021-04-06 | Io Therapeutics, Inc. | Use of an RXR agonist in treating HER2+ cancers |
CN115335367A (en) * | 2019-12-19 | 2022-11-11 | 奥弗恩制药公司 | RAR-alpha compounds for use in inflammatory diseases and male contraception |
US11896558B2 (en) | 2021-12-07 | 2024-02-13 | Io Therapeutics, Inc. | Use of an RXR agonist and taxanes in treating Her2+ cancers |
Also Published As
Publication number | Publication date |
---|---|
US6521641B1 (en) | 2003-02-18 |
US20030144256A1 (en) | 2003-07-31 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US6521641B1 (en) | Male anti-fertility agents | |
US20210008079A1 (en) | Treatment for dry eye | |
AU764452B2 (en) | Method of promoting cervical and vaginal secretions | |
US6096733A (en) | Drugs for topical application of sex steroids in the treatment of dry eye syndrome, and methods of preparation and application | |
CN103191129A (en) | Oxylipin compositions for the treatment of ophthalmic conditions | |
EP1991218A1 (en) | Use of cyclolignans for the treatment of type 2 diabetes and as contraceptives | |
US20100016264A1 (en) | Treatment for dry eye using testosterone and progestagen | |
JPH08502294A (en) | Methods for treating pneumocystis-carinii pneumonia and compounds useful therefor | |
EP1119350B1 (en) | Rar antagonists as male anti-fertility agents | |
WO2009052140A1 (en) | Use of tnf receptor antagonists for treating dry eye | |
EP1986653A1 (en) | The treatment of ocular conditions and the systemic side-effects of glucocorticoids | |
JP2020502272A (en) | Use of chymase inhibitors for the treatment of endometriosis, postoperative fibrosis, and diseases characterized by fibrosis | |
JP2563158B2 (en) | Nonatetraenoic acid derivative | |
US20220071924A1 (en) | Treatment of ocular diseases with ophthalmic tapinarof compositions | |
US20080287408A1 (en) | Endometriosis treatment | |
JP2003292442A (en) | Remedy for glaucoma comprising bunazosin and prostaglandins | |
US20060173062A1 (en) | Use of selective cyclooxygenase-2 inhibitors for the treatment of endometriosis | |
Combs | Male contraception | |
KR20080110760A (en) | Prophylactic or therapeutic agent for allergic ophthalmic disease or allergic nasal disease, comprising tricyclic triazolobenzazepine derivative | |
US20180008569A1 (en) | Prostaglandin transporter inhibitors for inhibiting ovulation | |
CN115568282A (en) | Use of anti-aging glycopeptides to treat dry eye, retinal degenerative diseases, or ocular inflammation | |
IT9068059A1 (en) | ANTI-INFLAMMATORY PREPARATION FOR OPHTHALMIC USE. | |
SK122897A3 (en) | Application of 8,9-dehydroestrone as an estrogen with neutral effect on the prolactin level | |
WO2013179253A1 (en) | Dose combination comprising nsaid and steroidal anti-inflammatory agent for treating post operative ocular inflammation | |
MXPA97006964A (en) | Use of 8,9-dehydroestrone as a estrogen with neutral effects on the levels of prolact |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |