CN1292702A - Newcontraceptive kit for monotherapy - Google Patents
Newcontraceptive kit for monotherapy Download PDFInfo
- Publication number
- CN1292702A CN1292702A CN998037710A CN99803771A CN1292702A CN 1292702 A CN1292702 A CN 1292702A CN 998037710 A CN998037710 A CN 998037710A CN 99803771 A CN99803771 A CN 99803771A CN 1292702 A CN1292702 A CN 1292702A
- Authority
- CN
- China
- Prior art keywords
- contraceptive
- sterid
- formula
- medicine box
- prodrug
- 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.)
- Pending
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- 238000009097 single-agent therapy Methods 0.000 title abstract description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 46
- 239000003433 contraceptive agent Substances 0.000 claims abstract description 32
- 230000002254 contraceptive effect Effects 0.000 claims abstract description 30
- 150000003431 steroids Chemical class 0.000 claims abstract description 24
- 230000000694 effects Effects 0.000 claims abstract description 22
- 239000000651 prodrug Substances 0.000 claims abstract description 14
- 229940002612 prodrug Drugs 0.000 claims abstract description 14
- 239000003814 drug Substances 0.000 claims description 31
- 239000000583 progesterone congener Substances 0.000 claims description 21
- 229940011871 estrogen Drugs 0.000 claims description 18
- 239000000262 estrogen Substances 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 17
- 239000003153 chemical reaction reagent Substances 0.000 claims description 13
- 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 claims description 12
- 238000002360 preparation method Methods 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 10
- 229940023488 pill Drugs 0.000 claims description 9
- 239000006187 pill Substances 0.000 claims description 9
- 230000002354 daily effect Effects 0.000 claims description 8
- 230000003203 everyday effect Effects 0.000 claims description 8
- 239000000902 placebo Substances 0.000 claims description 8
- 229940068196 placebo Drugs 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 3
- 239000007935 oral tablet Substances 0.000 claims description 2
- 229940096978 oral tablet Drugs 0.000 claims description 2
- 230000001076 estrogenic effect Effects 0.000 abstract description 6
- 230000004071 biological effect Effects 0.000 abstract description 4
- 230000000757 progestagenic effect Effects 0.000 abstract description 3
- -1 steroid compound Chemical class 0.000 abstract description 3
- 229940124558 contraceptive agent Drugs 0.000 abstract 2
- 230000003637 steroidlike Effects 0.000 abstract 1
- 239000000203 mixture Substances 0.000 description 39
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 18
- 238000012360 testing method Methods 0.000 description 18
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- 239000000243 solution Substances 0.000 description 14
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- 229920006395 saturated elastomer Polymers 0.000 description 12
- 239000011780 sodium chloride Substances 0.000 description 12
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- 208000032843 Hemorrhage Diseases 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
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- 239000012141 concentrate Substances 0.000 description 8
- 150000001241 acetals Chemical class 0.000 description 7
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- 238000005406 washing Methods 0.000 description 5
- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 4
- 229930182833 estradiol Natural products 0.000 description 4
- 229960005309 estradiol Drugs 0.000 description 4
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 4
- 238000011156 evaluation Methods 0.000 description 4
- 238000011010 flushing procedure Methods 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- BFPYWIDHMRZLRN-UHFFFAOYSA-N 17alpha-ethynyl estradiol Natural products OC1=CC=C2C3CCC(C)(C(CC4)(O)C#C)C4C3CCC2=C1 BFPYWIDHMRZLRN-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- BFPYWIDHMRZLRN-SLHNCBLASA-N Ethinyl estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 BFPYWIDHMRZLRN-SLHNCBLASA-N 0.000 description 3
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- 241000283973 Oryctolagus cuniculus Species 0.000 description 3
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- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 3
- 239000013543 active substance Substances 0.000 description 3
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- 239000008280 blood Substances 0.000 description 3
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- 239000002775 capsule Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 102000015694 estrogen receptors Human genes 0.000 description 3
- 108010038795 estrogen receptors Proteins 0.000 description 3
- 229960002568 ethinylestradiol Drugs 0.000 description 3
- 238000003810 ethyl acetate extraction Methods 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 239000007943 implant Substances 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
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- 239000000376 reactant Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 229920002554 vinyl polymer Polymers 0.000 description 3
- DNXHEGUUPJUMQT-CBZIJGRNSA-N Estrone Chemical compound OC1=CC=C2[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1 DNXHEGUUPJUMQT-CBZIJGRNSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 230000000996 additive effect Effects 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 229960003328 benzoyl peroxide Drugs 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 229960004976 desogestrel Drugs 0.000 description 2
- RPLCPCMSCLEKRS-BPIQYHPVSA-N desogestrel Chemical compound C1CC[C@@H]2[C@H]3C(=C)C[C@](CC)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 RPLCPCMSCLEKRS-BPIQYHPVSA-N 0.000 description 2
- 238000012377 drug delivery Methods 0.000 description 2
- 230000002124 endocrine Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 230000002045 lasting effect Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 230000002175 menstrual effect Effects 0.000 description 2
- 230000016087 ovulation Effects 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 2
- 235000017281 sodium acetate Nutrition 0.000 description 2
- 239000001632 sodium acetate Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 229930193551 sterin Natural products 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 238000011121 vaginal smear Methods 0.000 description 2
- 201000000736 Amenorrhea Diseases 0.000 description 1
- 206010001928 Amenorrhoea Diseases 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 229920000742 Cotton Polymers 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 206010015548 Euthanasia Diseases 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- YQEZLKZALYSWHR-UHFFFAOYSA-N Ketamine Chemical compound C=1C=CC=C(Cl)C=1C1(NC)CCCCC1=O YQEZLKZALYSWHR-UHFFFAOYSA-N 0.000 description 1
- 241000282553 Macaca Species 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 206010067171 Regurgitation Diseases 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 206010046910 Vaginal haemorrhage Diseases 0.000 description 1
- 231100000540 amenorrhea Toxicity 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
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- 230000000977 initiatory effect Effects 0.000 description 1
- 229940079322 interferon Drugs 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 239000010978 jasper Substances 0.000 description 1
- 229960003299 ketamine Drugs 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 230000035800 maturation Effects 0.000 description 1
- 230000009245 menopause Effects 0.000 description 1
- 230000005906 menstruation Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
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- 239000010413 mother solution Substances 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 1
- 229960001412 pentobarbital Drugs 0.000 description 1
- 238000011056 performance test Methods 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
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- 239000004033 plastic Substances 0.000 description 1
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- 229910003446 platinum oxide Inorganic materials 0.000 description 1
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- 239000000843 powder Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 229960003387 progesterone Drugs 0.000 description 1
- 239000000186 progesterone Substances 0.000 description 1
- 229940095055 progestogen systemic hormonal contraceptives Drugs 0.000 description 1
- 238000011160 research Methods 0.000 description 1
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- 239000011265 semifinished product Substances 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 229910001961 silver nitrate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 229920001169 thermoplastic Polymers 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 210000003462 vein Anatomy 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
-
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
- A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
- A61K31/569—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone substituted in position 17 alpha, e.g. ethisterone
-
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
-
- 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
- A61P15/18—Feminine contraceptives
Landscapes
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Reproductive Health (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Endocrinology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Gynecology & Obstetrics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Steroid Compounds (AREA)
Abstract
The invention pertains to a contraceptive kit comprising means for the daily administration of a contraceptive agent, characterised in that the single contraceptive agent is a steroid compound having an activity profile inherently combining progestagenic and estrogenic activity. Within a general class of known steroidal compounds, steroids have been found which possess an outstanding combined profile of biological properties for use in contraception, especially via monotherapy. These steroids are selected from the group consisting of steroids satisfying structural formula (I) and prodrugs thereof, wherein the dotted lines each independently indicate an optional bond.
Description
The present invention is hormonal contraceptive method field and the contraceptive medicine box that relates to the device that comprises administration contraception every day reagent.The invention still further relates to some at the sterid that aspect contraception reagent, has outstanding biological property characteristic.More particularly, the present invention relates to have and make its suitable such characterization compound that is used to practise contraception by " single current system method ", that is, be used to prevent to become pregnant required active single-activity material by giving to the women of child-bearing age itself to have.
Many traditional contraceptive medicine boxes are to give two kinds of different reagent to the women of child-bearing age, are generally progestogen and estrogen.Rely on concrete medicine box, can give these reagent by different way and according to different mechanisms.The prevailing medicine box that provides the contraception mechanism of what is called " combination contraceptive " type, wherein will contain progestogen and estrogenic daily dose unit common 21 Consecutive Days of process with single or heterogeneous administration, these be mutually by two kinds of active substances not commensurability and ratio phase region other, in the residue sky in 28 day cycle, give placebo or provide " no pill " at interval simultaneously.
The contraceptive medicine box that the single-activity material is provided is known.These are " only progestogen " type normally.Although this class " only progestogen pill " (POP) has and avoids giving estrogenic advantage, their shortcoming is that periodic Control is often unsatisfactory, from irregular bleeding and intrinsic menstruation this point as can be seen.
Therefore, wish to comprise estrogenic component, often take ethinyl estradiol for this reason.In this technology, several unwanted performance of combination contraceptive (the long-pending and cancer danger of blood stagnation) is mainly owing to this estrogenic component.The purpose of this invention is to provide contraceptive, have the living features unification compound that comprises required progestin and required estrogen activity, make good period control and do not expose above-mentioned unwanted performance by taking.And, an object of the present invention is to provide to have and do not contain ethinyl estradiol, but kept the contraceptive of ethinyl estradiol simultaneously the advantage of the advantageous effects of lipid characteristic.
In this technology, it is relevant with the aromatic A-ring that steroid such as estradiol have often to describe the estrogen receptor combination.Therefore, for example people such as Anstead is at Steroids, and 1997, vol.62, the survey article among the pages 269-303 have described the estrogen receptor combination that external a large amount of this class has the steroid structure of different substituents.The disclosure thing except not relating to the activity in vivo, is not made any prediction to the estrogen receptor combination of other non-aromatic structure yet, only relates separately to the activity of mixed estrin/progestogen simultaneously.
The present invention provides the contraceptive medicine box of the device that comprises the reagent of practising contraception every day now, is characterised in that this single contraception reagent is the sterid with active collection of illustrative plates of progestin and the intrinsic combination of estrogen activity.The present invention also is to have the purposes that the sterid of the active collection of illustrative plates of progestin and the intrinsic combination of estrogen activity is used to produce contraceptive medicament preparation, and wherein said chemical compound is this single contraception reagent.More particularly, the invention reside in use and be selected from the purposes that the acceptable salt of sterid, its prodrug and its medicine be made up of the following steroid of giving that satisfies the structure formula I is produced contraceptive medicament preparation.
The class that the present invention can find by accident particularly has the chemical compound of rare active collection of illustrative plates and realizes that wherein this compounds is progestogen (P) and estrogen (E) simultaneously, and two kinds of activity all are in high relatively level.Therefore, treat that this single contraception reagent that uses in medicine box of the present invention is the sterid of active collection of illustrative plates with intrinsic combination of progestin and estrogen activity, this activity reaches in the Allen-Doisy test that is used for estrogen activity and is used for minimum active dose (MAD) degree of μ g/kg all≤250 of the McPhail test of progestin.Those skilled in the art should know that term " single contraception reagent " do not get rid of described steroid and a small amount of do not have active other progestogen arbitrarily of contraception and/or estrogen is wished mixing of the active collection of illustrative plates degree of fine setting to reach.The reactive compound of the steroid of preferred this mixing collection of illustrative plates for only depositing.
Suitable chemical compound of the present invention comprises those that satisfy following structure formula I:
Formula I wherein dotted line shows optionally additional key separately respectively.
In one embodiment, the present invention relates to the purposes that these chemical compounds are used to produce a contraceptive medicament preparation.In another embodiment, the present invention is the contraceptive medicine box that comprises the device of the arbitrary above-mentioned steroid that gives conduct contraception reagent every day.In an embodiment again, the invention provides a kind of contraceptive device, comprise the above-mentioned sterid that gives effective dose to the women of child-bearing age.Comprise formula I chemical compound and its prodrug in the present invention, promptly substituent group easily by metabolism to the reactive compound of formula I or be easy to adhere to the related compound on this compounds given.With the most conventional prodrug, therefore the invention provides chemical compound and its pharmaceutical salts of satisfying formula II,
Formula II wherein dotted line shows optionally additional key separately respectively, Y representative (H, H), (O), (N-OH) or (H, OH); And X representative (H) or (C
2-C
7Acyl group), as-C (=O) CH
3The 3-keto compounds, promptly Y is (O), for preferably.This substituent other probability is that they have main performance of the present invention on No. 3 carbon atoms, so that they are the precursor (prodrug) of this preferred 3-keto compounds.The X substituent group is kept same insight, wherein this optionally ester group be the precursor of this preferred reactive compound, wherein this OX group is OH.In order to clearly demonstrate, describe the present invention according to the reactive compound of formula I below this paper, but intention comprises at least according to the described prodrug of formula II.
In a preferred embodiment, the used chemical compound of the present invention be (11 β, 17 α)-11-ethyl-17-hydroxy-19-nor pregnant-4-alkene-20-alkynes-3-ketone (Org 4060), it has following structure formula III:
This chemical compound of formula III, learn to be the component of a mixture from US3325520, learn as the medicine of handling the menopause disease from US5710144, learn initial compounds, unexpectedly have and be used to the performance of practising contraception very well as synthetic other steroid from GB1190240.
Another preferred implementation of the present invention is to satisfy the chemical compound of structural formula IV.
Formula IV
This chemical compound (11 β, 17 α)-11-vinyl-17-hydroxy-19-nor is pregnant-and 4-alkene-20-alkynes-3-ketone (Org 4325) is the sterid that a class is learnt from US4292251 usually.The document has been described one group of chemical compound with possibility performance.The document is not mentioned the chemical compound with specific blend E/P collection of illustrative plates (characteristic), does not mention the contraception of single current system method yet.In this preferred implementation, the present invention provides a kind of chemical compound with the dependency structure of learning from US4292251 to compare now and is demonstrating significantly different chemical compound aspect the biological property collection of illustrative plates.This remarkable difference, promptly beyond thought mixing E/P collection of illustrative plates makes Org 4325, with and prodrug and its pharmaceutical salts be suitable for very much the contraception of single current system method.
According to the present invention, preferred top steroid is used for the contraception of single current system method.But, the remarkable biological property that it will be apparent to one skilled in the art that these steroid of the present invention also can from these steroid one of any with the mixing of another active substance such as progestogen or estrogens sterin obtain.
The present invention also provides a kind of for example 18-30 that gives, and preferred 21-25 days the single-activity material with progestogen performance and estrogen performance, the residue sky in cycle are " no pill " or placebo contraceptive medicine box at interval.In principle, can be any other natural law, but because actual cause, seldom hope is like this.Also can give up no pill or placebo at interval, promptly providing continuously, (day) gives aforementioned mixed estrin/progestogenic compounds.The several advantages that can share top chemical compound like this, but so continuous mechanism will cause inherent amenorrhea, preferably include no pill or placebo at interval.
Medicine box according to the present invention provides by " single current system method " rather than by " contraception with combination of independent active component still comprises estrogenic component, so that the periodic Control that reaches contraceptive effect and can compare with the mixing contraception.No pill or placebo will make has at interval avoided hemorrhage, and this is considered to yearning usually, and wherein because imitate normal cycle so as far as possible, and because it guarantees not conceived.
Can give this steroid in every way.For example, can select to continue releasing device, but preferred doser is Consecutive Days dosage unit form, particularly oral tablet.
The term " dosage " unit " typically refer to the discrete fully unit of suitable human body dosage unit, each contains the active substance of the scheduled volume that produces required effect as calculated, for example tablet, pill, powder, suppository, capsule etc.
Producing the method for this class dosage device and forming is known for a person skilled in the art.For example, the conventional art that preparation contains the tablet of active component and pill is described in people's such as canonical reference Gennaro Reminggton ' s Pharmaceutical Sciences, (18th ed., MackPublishing Company, 1990, especially referring to the 8th part: PharmaceuticalPreparations and Their Manufacture).
With regard to the dosage device of preparation example such as tablet, attempt using conventional additive, for example filler, coloring agent, polymer binder etc.Usually any medicine acceptable additive of interferon activity chemical compound function not can be used in one or more component.
These compositionss that give with appropriate carrier comprise the lactose that uses with Sq, starch, cellulose derivative etc.Lactose is a preferred vector.Also can use carrier mixture.
The method of production medicine box of the present invention comprises that one or more of scheduled volume are had the aforementioned steroid chemical compound of progestin and estrogen activity, optionally with another estrogen or progestogens sterin, with the mixed with excipients of scheduled volume, and this mixture is transformed into dosage device.The gained medicine box can contain the daily dose unit of any amount, but the menstrual cycle of common and certain-length adapts, and has 18-30, and preferred 20-28 daily dose unit.Preferred medicine box is to adapt to the form of human body normal menstrual cycle length and contain 21-25, and most preferably 21 described day successive doses unit optionally also contains the placebo dosage device to form 28-32 daily dose unit altogether.
This mixture is transformed into dosage device and is usually directed to this mixture is molded into tablet, uses the drying composite filled capsules or uses the wet mixture filled capsules.
As mentioned above, the device that gives steroid of the present invention also can be the form except that day tablet, and for example implant or intravaginal thing are as the lasting release device of pessary or another type.
Preparation is known as the method for the lasting release device of implant and pessary in the art.In this respect, with reference to Jorge Heller Drug Delivery in the Plastics Age, in " Innovations in Drug Delivery ", Tom Sam and Jasper Fokkensed., pages 134-145.About preferred contraception implant with reference to EP303306.The many designs that discharge the pessary of two kinds of materials are well known to those skilled in the art.Can be used for preferred annular pharmaceutical delivery system of the present invention and comprise that at least one contains the compartment of thermoplastic polymer core, this core contains the sterid of this mixing collection of illustrative plates, and its amount makes biological aequum directly discharge this chemical compound.
The daily dose of steroid of the present invention can be up to 1mg, usually at 50-500 μ g, preferably at 100-300 μ g.As for the chemical compound of formula III and IV, treat that dosage was preferably 50-250 μ g/ days, more preferably 100-200 μ g/ days.Most preferred daily dose is 140-160 μ g under the situation of single current system method contraception.As for Org 37678, it is that chemical compound and two selectivity additional keys of satisfying formula I all do not have, the typically high 1.5-2 of dosage times, and preferred 200-300 μ g.
The used steroid of the present invention can be according to the routine instruction preparation of US5710144 and US4292251.
According to following examples the present invention is further explained.
Embodiment 1
By (11 β)-11-vinyl female-5-alkene-3,17-diketone ring 3-(1,2-second two acetals) according to be prepared as follows (11 β, 17 α)-11-vinyl-17-hydroxy-19-nor pregnant-4-alkene-20-alkynes-3-ketone:
ⅰ)-and will be freezing to 0 ℃ at the 57.5g potassium tert-butoxide suspension that 585ml does among the THF, then acetylene was passed through this mixture 2 hours, at this moment remove ice bath.Next, drip 15.0g (11 β)-11-vinyl female-5-alkene-3,17-diketone ring 3-(1,2-second two acetals) in 156ml do among the THF solution and at room temperature with acetylene by the gained mixture.After 2 hours, slowly add the saturated aqueous solution of 350ml ammonium chloride and with the gained mixture with twice of the ethyl acetate extraction that contains about 2% pyridine.This mixed extract also uses for twice the saturated aqueous solution (saline) of sodium chloride to wash once with the saturated aqueous solution flushing of sodium bicarbonate, through dried over sodium sulfate, and under reduced pressure concentrate, obtain 16.2g (11 β, 17 α)-and 11-vinyl-17-hydroxy-19-nor is pregnant-5-alkene-20-alkynes-3-ketone ring 3-(1,2-second two acetals).
ⅱ)-to (11 β of the 16.2g in 870ml acetone, 17 α)-and 11-vinyl-17-hydroxy-19-nor is pregnant-5-alkene-20-alkynes-3-ketone ring 3-(1,2-second two acetals) the 4N HCl of interpolation 44ml in the solution stirs the gained mixture 3.5 hours under room temperature and nitrogen environment.Then, this reactant mixture is poured in 3.51 water, it is used ethyl acetate extraction 3 times.This mixed extract uses the saturated aqueous solution of sodium bicarbonate to wash once, and twice of water flushing also uses the saturated aqueous solution (saline) of sodium chloride to wash once, through dried over sodium sulfate, and under reduced pressure concentrated, obtain the rough material of 14.0g.This semifinished product is from the mixture (K of dichloromethane and acetone
1: 1.2g, K
2: crystallization is twice 4.8g).Crystalline mother solution under reduced pressure concentrates for the second time, and residue is by flash chromatography method (toluene: ethyl acetate=8: 2) purify, obtain another 3.8g product.With this material and K
1And K
2Mix and interpolation 50ml ether.With gained suspension returning 4 hours, 5 ℃ of coolings 60 hours down, and these crystallizations, after with the flushing of 3ml cold diethyl ether, filter and collect (9.0g).Because twice this step of repetition do not improve the purity of this product, therefore use flash chromatography method (heptane: acetone=7: 3) as last purification step, thereby obtain pure (11 β, 17 the α)-11-vinyl-17-hydroxy-19-nor of 6.3g pregnant-4-alkene-20-alkynes-3-ketone.M.p.186.8 ℃ of .[α]
D 20=+29.5 ° (c=1, ethanol).
Embodiment 2
By (11 β, 17 α)-11-vinyl-17-hydroxy-19-nor pregnant-4-alkene-20-alkynes-3-ketone according to be prepared as follows (11 β, 17 α)-17-acetoxyl group-11-vinyl-19-nor-pregnant-4-alkene-20-alkynes-3-ketone:
-to the 460mg in the 4.6ml acetic anhydride (11 β, 17 α)-11-vinyl-17-hydroxy-19-nor pregnant-add the 156mg p-methyl benzenesulfonic acid in the solution of 4-alkene-20-alkynes-3-ketone, the gained mixture was stirred 4.5 hours under room temperature and nitrogen environment.Then, add the 36%HCl of 0.4ml, this mixture overnight is stirred.Then this crude mixture is poured in the 46ml water, used dichloromethane extraction 4 times.With of saturated aqueous solution (saline) washing of this mixed extract with saturated aqueous solution, water and the sodium chloride of sodium bicarbonate, concentrate down through dried over sodium sulfate and decompression, corresponding 3-acetoxy-3 is still arranged, the crude product that the 5-diene pollutes.
This crude product is dissolved in the mixture of 28ml acetone and 0.2ml36%HCl, at room temperature with gained solution stirring 24 hours (after 3 and 7.5 hours, adding 0.7ml water).Next, add 0.2ml36%HCl again, at room temperature with gained mixture stirred overnight again.At last, this crude mixture is poured in the 275ml water, it is used ethyl acetate extraction three times.This mixed extract, through dried over sodium sulfate and under reduced pressure concentrates with saturated aqueous solution (saline) washing of saturated aqueous solution, water and the sodium chloride of sodium bicarbonate, obtains the 550mg crude product.By the flash chromatography method (toluene: ethyl acetate=4: 6) purify, obtain pure (11 β, 17 the α)-17-acetoxyl group-11-vinyl-19-of 165mg nor-pregnant-4-alkene-20-alkynes-3-ketone amorphous solid.
M.p.141.1-161.1 ℃ of .[α]
D 20=-1 ° (c=0.5 ， diox).
Embodiment 3
By (11 β, 17 α)-11-vinyl-17-hydroxy-19-nor pregnant-4-alkene-20-alkynes-3-ketone according to be prepared as follows (3E/Z, 11 β, 17 α)-11-vinyl-17-hydroxy-19-nor pregnant-4-alkene-20-alkynes-3-ketoxime:
-to the 500mg in the 2.6ml pyridine (11 β, 17 α)-11-vinyl-17-hydroxy-19-nor pregnant-add 1.18g azanol .HCl in the solution of 4-alkene-20-alkynes-3-ketone, the gained mixture was stirred 1 hour under room temperature and nitrogen environment.Then, this reactant mixture is poured in the 46ml water, used dichloromethane extraction 3 times.With the washing of the saturated aqueous solution (saline) of this mixed extract water and sodium chloride, under reduced pressure concentrate, obtain 480mg (3E/Z, 11 β, 17 α)-11-vinyl-17-hydroxy-19-nor pregnant-4-alkene-20-alkynes-3-ketoxime.
Crystallization from dichloromethane, the mixture of acquisition 85: 15 3E-of 260mg and 3Z-oxime.
M.p.257 ℃ of .[α]
D 20=+58.4 ° (c=0.5 ， diox).
Embodiment 4
By (11 β, 17 α)-11-vinyl-17-hydroxy-19-nor pregnant-4-alkene-20-alkynes-3-ketone is pregnant-4 according to being prepared as follows (11 β, 17 α)-11-vinyl-17-hydroxy-19-nor, 20-diene-3-ketone:
-in 175mg Lin Dele (Lindlar) catalyst suspension in 25 minutes the 15ml ethanol of hydrogen pretreatment, make an addition to 500mg (11 β in the 5ml ethanol, 17 α)-and 11-vinyl-17-hydroxy-19-nor is pregnant-solution of 4-alkene-20-alkynes-3-ketone, and with gained mixture hydrogenation under atmospheric pressure 1 hour.Then, remove by filter catalyst in the crude mixture through Dai Kalite, filtrate under reduced pressure concentrates.The silicon dioxide that uses the silver nitrate dipping as immobile phase by the flash chromatography method with toluene/ethyl acetate (4/6) this crude product of purifying, obtain pure (11 β of 162mg, 17 α)-11-vinyl-17-hydroxy-19-nor is pregnant-4,20-diene-3-ketone amorphous solid.
M.p.62.9-70.3 ℃ of .[α]
D 20=+74.1 ° (c=0.5 ， diox).
Embodiment 5
By (11 β, 17 α)-and 11-vinyl-17-hydroxy-19-nor is pregnant-and 4-alkene-20-alkynes-3-ketone is according to being prepared as follows (3 α, 11 β, 17 α)-11-vinyl-19-nor-pregnant-4-alkene-20-alkynes-3,17-two pure and mild (3 β, 11 β, 17 α)-11-vinyl-19-nor-pregnant-4-alkene-20-alkynes-3, the 17-glycol:
-to do at 25ml 2.0g (11 β, 17 α)-11-vinyl-17-hydroxy-19-nor among the THF pregnant-add 3.14g Li (O in the solution of 4-alkene-20-alkynes-3-ketone
tBu)
3AlH stirs the gained mixture 2 hours under room temperature and nitrogen environment.Then, this reactant mixture is poured in the saturated aqueous solution of ammonium chloride, used dichloromethane extraction.The saturated aqueous solution of extracting solution water and sodium chloride (saline) washing, under reduced pressure concentrate, use dichloromethane/acetone (95/5) by flash chromatography method this crude mixture of purifying, from diisopropyl ether, after the crystallization, obtain pure (3 α of 100mg, 11 β, 17 α)-11-vinyl-19-nor-pregnant-4-alkene-20-alkynes-3,17-two pure and mild 700mg pure (3 β, 11 β, 17 α)-11-vinyl-19-nor-pregnant-4-alkene-20-alkynes-3, the 17-glycol.
3 alpha-isomers: M.p.178.5-179.1 ℃.
3 β-isomer: M.p.147.6-148.2 ℃.
Embodiment 6
By (11 β)-11-vinyl female-5-alkene-3,17-diketone ring two-(1,2-second two acetals) according to be prepared as follows (11 β, 17 α)-11-ethyl-17-hydroxy-19-nor pregnant-4-alkene-20-alkynes-3-ketone:
ⅰ)-add 5g platinum oxide (IV) to the solution of described two acetals of the 100g in 3.51 dry tetrahydrofurans, at room temperature with this mixture hydrogenation up to no longer absorbing hydrogen.This mixture is through diatomite filtration, and residue under reduced pressure should mix filtrate concentrating with oxolane flushing twice, obtain the rough crystallization of 93g (11 β)-11-ethyl female-5-alkene-3,17-diketone ring two-(1,2-second two acetals) is used it in the following step without further purifying.
ⅱ)-two ketals (10g) in the above-mentioned steps are suspended in the 50ml acetone.Careful 6.7ml water and the vitriolic solution of 3.3ml of adding in this suspension.This mixture was at room temperature stirred 1 hour, pour into then in the solution of the 20g sodium acetate in 100ml water.This mixture cools off in ice bath; The gained sedimentation and filtration is fallen, and residue washes with water up to washings to neutral; Collect residue and dry then, obtain rough (11 the β)-11-ethyl of 7.5g female-4-alkene-3, the 17-diketone is just used it for following steps without further purification.
ⅲ)-with the suspension of the 16.5g potassium tert-butoxide of acetylene gas by in the 100ml dry tetrahydrofuran 2 hours.In this suspension, drip the solution of the diketone in the 10g above-mentioned steps in the 50ml dry tetrahydrofuran.This mixture was at room temperature stirred 2 hours, pass through acetylene simultaneously continuously.Then, the vitriolic solution of the 15ml in 30ml water is added carefully and this mixture was stirred other 2 hours.Afterwards, the solution of the 40g sodium acetate in 250ml water is slowly added, with this mixture 75 ℃ of heating 15 minutes down.Distill organic solvent then and with the residue cool to room temperature.Form precipitation, it is removed by filter and be absorbed in the 600ml toluene.Add active carbon and, filter and under reduced pressure concentrate this mixture heated to 65 ℃.This crude product recrystallize from ethanol/water, obtain 6.5g (11 β, 17 α)-11-ethyl-17-hydroxy-19-nor pregnant-4-alkene-20-alkynes-3-ketone.
M.p.222 ℃ of .[α]
D 20=-16.1 ° (c=1 ， diox).
Comparative examples
(A) the embodiment II (b) with US4292251 is identical.
(B) the embodiment X III with US4292251 identical (comprising wherein embodiment VI (a) and step (b)).
The example of pharmaceutical preparation
Preparation contains the pharmaceutical composition of steroid of the present invention.As illustration, select the chemical compound (Org 4060) of embodiment 6.With standard method this chemical compound is mixed with other component, and with this mixture granulating.Compositions is as follows, and same preparation is suitable for other chemical compound that comprises Org 4325: Org 4060 (active component) 1-10wt.% corn starch (disintegrate thing) 15wt.% hydroxypropyl cellulose (binding agent) 3wt.% lactose 200M (diluent) is to 100wt.%
Experimental example A
Several steroid according to chemical compound of the present invention and not according to chemical compound of the present invention, carry out the associated biomolecule performance test, i.e. progestin and estrogen activity test.This progestin is by the McPhail test determination, and estrogen activity is by the Allen-Doisy test determination.Two tests all are known in the art, can be described below:
The McPhail test:
Use the progestogenic activity of the in vivo test of rabbit by the differentiation evaluation test chemical compound of Histological evaluation's endometrial tissue.Rabbit caused 8 days with estradiol, then, and oral progestogenic compounds 5 days.With these animal euthanasias (intravenous injection 60mg pentobarbitone/rabbit) and prepare the hematoxylin-eosin-painted cross section of two different pieces of each cornua uteri.Grow and opinion rating 0-4 (Van der Vies J., andDe Visser, J.1983.Endocrinological studies with desogestrel.Drug Res.33:231-236) with this progestogen dependent form endometrium of microscopic evaluation.
The Allen-Doisy test:
The in vivo test of using rat is by estimating the estrogen activity of cornification of vaginal epithelium evaluation test chemical compound to vaginal smear.With the oophorectomize of the female mouse of maturation, afterwards in the 3rd week, with the 1 μ g estradiol initiation (the 1st day) of single dose.Cause after 7 days, at the 8th day with test compound administration 1 time, administration in the 9th day 2 times.In the 10th day afternoon, at the 11st day 2 times with obtained vaginal smear again in the 12nd day morning.With these smears with Giemsa dyeing and measure positive smear quantity (Van der Vies J., and De Visser, J.1983.Endocrinological studies with desogestrel.Drug Res.33:231-236).
The result:
During result of the test is listed in the table below.
Experimental example B
The chemical compound of embodiment 6 is used for monkey research.
Use has the ripe female little thick tail monkey (macaque) in the age in 5-20 week that shows regular menstrual cycle.With these monkeys with about 35 female and one vasectomized male be that group lives.Test by ' Animal Use Committee ' (DEC, AEP E97A0801PV E number) checks and approves.To 3 groups of these monkeys with every day 8 μ g/kg dosage give the chemical compound of embodiment 6.First day of menstrual bleeding is considered to the 1st day of this cycle, and these tests are from pretreatment contrast cycle (test the 1st day).The 2nd day in the cycle of processing began to handle (every day) up to the 22nd day.(dosage depends on monkey, i.m.≤10mg/kg) following to the conduit oral administration of compound in the slight anesthesia of using ketamine .Then the administration animal is lived to regain consciousness and to check regurgitation separately.After 2 hours these animals are turned back in this group.After the menstrual bleeding in (wishing the time) processing cycle, begin the post processing cycle.Biweekly (Monday and Thursday) obtains the blood sample that is used to analyze estradiol and progesterone in whole test.Use Vacutainer pipe (Venoject) to obtain blood sample from the vein crureus.Also come monitoring periods by using cotton sharp applicator to obtain vaginal swab every day.Vaginal hemorrhage is divided into main hemorrhage (estimate=+) and secondary hemorrhage (evaluation=±).
All monkeys of accepting the chemical compound of embodiment 6 demonstrate and suppress ovulation; 2/3 demonstrate not hemorrhage; Neither one demonstrates hemorrhage intermittently.It is very suitable to contraceptive that these results demonstrate this mixing E/P chemical compound: very well suppressed ovulation, need not independent estrogen simultaneously, and hemorrhage collection of illustrative plates and periodic Control are good.
Claims (16)
1. the contraceptive medicine box that comprises the device of the reagent of practising contraception every day is characterised in that this single contraception reagent is the sterid with active collection of illustrative plates of progestin and the intrinsic combination of estrogen activity.
2. according to the contraceptive medicine box of claim 1, be characterised in that this sterid is selected from steroid, its prodrug and its pharmaceutical salts that satisfies the structure formula I,
Formula I wherein dotted line shows the selectivity additional key separately respectively.
3. according to the contraceptive medicine box of claim 2, be characterised in that this sterid satisfies the structure formula III,
Formula III or be its prodrug or its pharmaceutical salts.
4. according to the contraceptive medicine box of claim 2, be characterised in that this sterid satisfies the structure formula IV,
Or be its prodrug or its pharmaceutical salts.
5. the contraceptive medicine box arbitrary according to front claim, the device that is characterised in that administration every day is the form of 18-30 Consecutive Days dosage device, each contains this steroid of 100-300 μ g.
6. according to the contraceptive medicine box of claim 5, be characterised in that the unitary quantity of daily dose is 21-25.
7. according to the contraceptive medicine box of claim 6, be characterised in that by comprising the placebo dosage device to constitute total 28-32 daily dose unit.
8. the contraceptive medicine box arbitrary according to claim 5-7 is characterised in that this Consecutive Days dosage device is an oral tablet.
9. have the purposes that the sterid of the active collection of illustrative plates of progestin and the intrinsic combination of estrogen activity is used to produce contraceptive medicament preparation, wherein said chemical compound is single contraception reagent.
10. be selected from the purposes that the sterid of the steroid, its prodrug and its pharmaceutical salts that satisfy structural formula I is used to produce contraceptive medicament preparation,
Formula I wherein dotted line shows the selectivity additional key separately respectively.
11., be characterised in that this sterid is to satisfy of structure formula II, perhaps its pharmaceutical salts according to the purposes of claim 10:
Formula II wherein dotted line shows the selectivity additional key separately respectively, Y representative (H, H), (O), (N-OH) or (H, OH); And X representative (H) or (C
2-C
7Acyl group).
12., be characterised in that this sterid satisfies the structure formula III according to the purposes of claim 11:
Formula III or be its prodrug or its pharmaceutical salts.
13., be characterised in that this sterid satisfies the structure formula IV according to the purposes of claim 11:
Formula IV or be its prodrug or its pharmaceutical salts.
14., be characterised in that this pharmaceutical preparation is single current system method contraceptive according to purposes arbitrary among the claim 10-13.
15. a contraceptive device comprises that giving being selected from of effective dose to the women of child-bearing age satisfies the steroid of structure formula I or the sterid of its prodrug.
16., comprise continuous 21-25 days and give the chemical compound that 100-300 μ g satisfies formula III, then be 3-7 days no pill or placebo interval according to the contraceptive device of claim 15.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP98200744 | 1998-03-09 | ||
| EP98200744.5 | 1998-03-09 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1292702A true CN1292702A (en) | 2001-04-25 |
Family
ID=8233452
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN998037710A Pending CN1292702A (en) | 1998-03-09 | 1999-03-03 | Newcontraceptive kit for monotherapy |
Country Status (20)
| Country | Link |
|---|---|
| EP (1) | EP1061928A2 (en) |
| JP (1) | JP2002506014A (en) |
| KR (1) | KR20010041698A (en) |
| CN (1) | CN1292702A (en) |
| AR (1) | AR018313A1 (en) |
| AU (1) | AU756882B2 (en) |
| BR (1) | BR9908605A (en) |
| CA (1) | CA2319765A1 (en) |
| CO (1) | CO5070598A1 (en) |
| HU (1) | HUP0101007A3 (en) |
| ID (1) | ID25621A (en) |
| IL (1) | IL137541A0 (en) |
| NO (1) | NO20004492L (en) |
| NZ (1) | NZ506115A (en) |
| PE (1) | PE20000330A1 (en) |
| PL (1) | PL343428A1 (en) |
| RU (1) | RU2225714C2 (en) |
| TR (1) | TR200002593T2 (en) |
| WO (1) | WO1999045886A2 (en) |
| ZA (1) | ZA991851B (en) |
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|---|---|---|---|---|
| WO1999051214A2 (en) * | 1998-04-07 | 1999-10-14 | Akzo Nobel N.V. | Progestogen-only contraceptive kit |
| AU770331B2 (en) * | 1999-09-06 | 2004-02-19 | N.V. Organon | Non-aromatic estrogenic steroids with a hydrocarbon substituent in position 11 |
| PL366235A1 (en) | 2000-07-28 | 2005-01-24 | Akzo Nobel N.V. | 16alpha-methyl or ethyl substituted estrogens |
| CA2478206A1 (en) * | 2002-03-11 | 2003-09-25 | Patrick Michel Caubel | Sulfatase inhibiting continuous progestogen contraceptive regimens |
| AU2003222273A1 (en) * | 2002-03-11 | 2003-09-29 | Janssen Pharmaceutica N.V. | Sulfatase inhibiting progestogen-only contraceptive regimens |
| UA89964C2 (en) | 2004-09-08 | 2010-03-25 | Н.В. Органон | 15beta-substituted steroids having selective estrogenic activity |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NL7701384A (en) * | 1977-02-10 | 1978-08-14 | Akzo Nv | PROCESS FOR PREPARING NEW STEROIDS FROM THE OESTRAINE SERIES. |
| DE4227989A1 (en) * | 1992-08-21 | 1994-06-09 | Schering Ag | Agent for transdermal application containing 3-keto-desogestrel |
| ZA94715B (en) * | 1993-02-08 | 1994-10-24 | Akzo Nv | Steroids for treating menopausal complaints |
-
1999
- 1999-03-03 CA CA002319765A patent/CA2319765A1/en not_active Abandoned
- 1999-03-03 WO PCT/EP1999/001404 patent/WO1999045886A2/en not_active Application Discontinuation
- 1999-03-03 AU AU31437/99A patent/AU756882B2/en not_active Ceased
- 1999-03-03 ID IDW20001715A patent/ID25621A/en unknown
- 1999-03-03 RU RU2000125572/15A patent/RU2225714C2/en not_active IP Right Cessation
- 1999-03-03 NZ NZ506115A patent/NZ506115A/en unknown
- 1999-03-03 EP EP99939157A patent/EP1061928A2/en not_active Withdrawn
- 1999-03-03 JP JP2000535302A patent/JP2002506014A/en not_active Withdrawn
- 1999-03-03 BR BR9908605-0A patent/BR9908605A/en not_active IP Right Cessation
- 1999-03-03 TR TR2000/02593T patent/TR200002593T2/en unknown
- 1999-03-03 HU HU0101007A patent/HUP0101007A3/en unknown
- 1999-03-03 PL PL99343428A patent/PL343428A1/en unknown
- 1999-03-03 CN CN998037710A patent/CN1292702A/en active Pending
- 1999-03-03 KR KR1020007009917A patent/KR20010041698A/en not_active Application Discontinuation
- 1999-03-03 IL IL13754199A patent/IL137541A0/en unknown
- 1999-03-05 AR ARP990100933A patent/AR018313A1/en not_active Application Discontinuation
- 1999-03-08 ZA ZA9901851A patent/ZA991851B/en unknown
- 1999-03-08 CO CO99014138A patent/CO5070598A1/en unknown
- 1999-03-09 PE PE1999000186A patent/PE20000330A1/en not_active Application Discontinuation
-
2000
- 2000-09-08 NO NO20004492A patent/NO20004492L/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| NO20004492D0 (en) | 2000-09-08 |
| NZ506115A (en) | 2003-07-25 |
| HUP0101007A2 (en) | 2001-12-28 |
| WO1999045886A2 (en) | 1999-09-16 |
| RU2225714C2 (en) | 2004-03-20 |
| JP2002506014A (en) | 2002-02-26 |
| NO20004492L (en) | 2000-09-08 |
| WO1999045886A3 (en) | 1999-12-02 |
| KR20010041698A (en) | 2001-05-25 |
| AU756882B2 (en) | 2003-01-23 |
| ZA991851B (en) | 1999-09-22 |
| ID25621A (en) | 2000-10-19 |
| AU3143799A (en) | 1999-09-27 |
| PE20000330A1 (en) | 2000-05-16 |
| BR9908605A (en) | 2001-04-24 |
| HUP0101007A3 (en) | 2002-02-28 |
| EP1061928A2 (en) | 2000-12-27 |
| AR018313A1 (en) | 2001-11-14 |
| CA2319765A1 (en) | 1999-09-16 |
| IL137541A0 (en) | 2001-07-24 |
| CO5070598A1 (en) | 2001-08-28 |
| PL343428A1 (en) | 2001-08-13 |
| TR200002593T2 (en) | 2000-12-21 |
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| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
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