CN109666002A - A kind of gonadotropin-releasing hormone receptor antagonists and its purposes in endometriosis - Google Patents
A kind of gonadotropin-releasing hormone receptor antagonists and its purposes in endometriosis Download PDFInfo
- Publication number
- CN109666002A CN109666002A CN201710956302.XA CN201710956302A CN109666002A CN 109666002 A CN109666002 A CN 109666002A CN 201710956302 A CN201710956302 A CN 201710956302A CN 109666002 A CN109666002 A CN 109666002A
- Authority
- CN
- China
- Prior art keywords
- gonadotropin
- releasing hormone
- compound
- hormone receptor
- tautomer
- 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
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/52—Two oxygen atoms
- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/56—One oxygen atom and one sulfur atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention provides formula (I) compound, its stereoisomer, tautomer or pharmaceutically acceptable salt, it is as gonadotropin-releasing hormone receptor antagonists, and its application in the drug of preparation treatment masculinity femininity sex hormone related condition or pharmaceutical composition, compound disclosed by the invention has significant activity to gonadotropin-releasing hormone receptor, is with a wide range of applications.
Description
Technical field
Invention offer formula (I) compound, stereoisomer, tautomer or pharmaceutically acceptable salt, as rush
Gonadotropin releasing hormone inhibitor, remarkable inhibiting activity of the compound disclosed by the invention to gonadotropin releasing hormone.
Background technique
Endometriosis (endometriosis) refers to that active endo cell is planted in other than endometrium
Position and a kind of women Common Gynecologic Diseases formed, disease incidence is and in rising trend up to 10%, which is ached with dysmenorrhea, pelvic cavity
Pain and it is infertile be main feature, seriously affect the healthy reproduction and quality of life of women.It is estimated that the whole world have 1.76 hundred million women by
The puzzlement of endometriosis.Endo cell should be grown in uterine cavity, but since uterine cavity passes through fallopian tubal and pelvic cavity
It communicates, so that endo cell can enter pelvic cavity ectopic growth via fallopian tubal.There are many mechanism fallen ill at present to this disease
Saying, wherein what is be commonly recognized is endometrial implantation theory.This disease mostly occurs in the women of childbearing age, and preadolescence is not
Morbidity, post menopausal ectopic focus can gradually degenerate in atrophy.
The main pathological change of endometriosis is Ectopic Endometrium cyclic hemorrhage and its surrounding tissue fibrosis, shape
At dystopy tubercle, dysmenorrhea, chronic pelvic pain, menoxenia and it is infertile be its cardinal symptom.Lesion can involve all pelvic cavity
Tissue and organ, it is most common with positions such as ovary, douglas cul-de-sac, uterosacral ligaments, abdominal cavity, thoracic cavity, four limbs can also be betided
Etc..
GnRH (gonadotropin-releasing hormone (GRH)) is ten peptide hormones of hypothalamus pulsatile secretion, by hypophyseal portal vessel and is hung down
The specific high-affinity GnRH-R on body frontal lobe gonadotroph surface is combined, and promotes gonadal hormone --- follicular stimulating hormone
(FSH), lutropin (LH) --- synthesis and secretion, to maintain normal reproductive system function.
The mechanism of action of hypophysis GnRH-R are as follows: GnRH --- --- believe GnRH-R by G-protein --- phospho-esterase c --- second
Make (inositol, diacylglycerol) --- protein kinase (PKC, PKA, MAPK) and the flowing of intracellular calcium pond；GnRH is also activated
PLA2, PLD, map kinase approach conduct in core and the transcriptional regulatory of promoting sexual gland hormone plays a role cell membrane external signal.
GnRH antagonist can inhibit pituitary gonadotropin releasing hormone receptor, final to reduce gonadal hormone water in blood circulation
It is flat, become effective target for the treatment of endometriosis, the GnRH antagonist listed at present has Cetrorelix and Jia Nirui
Gram, it is polypeptide, although good effect, needs to inject.Small molecule takes orally GnRH antagonist, as Abbvie Elagolix and
The OBE-2109 of Kissei achieves preferable clinical effectiveness.But still need to the more preferable higher small molecule mouth of activity of exploitation safety
Take GnRH antagonist.
Summary of the invention
The present invention provides a kind of formula (I) compound, stereoisomer, tautomer or pharmaceutically acceptable salt,
Wherein, R1, R2It independently is oxygen atom, sulphur atom；
R3Selected from hydrogen, methyl, cyclopropyl.
Formula (I) compound of the present invention, stereoisomer, tautomer or pharmaceutically acceptable salt,
In include following compounds,
Compound of the present invention, stereoisomer, tautomer or pharmaceutically acceptable salt swash as rush property
Hormone-releasing hormone receptor antagonist, answering in the drug of preparation treatment masculinity femininity sex hormone related condition or pharmaceutical composition
With.
Specific embodiment:
The present invention is further illustrated with embodiment below, but the present invention is not intended to be limited thereto.
Embodiment 1:
The similar testing program that the present invention is provided according to document CN1819829, is prepared into compound 1, ESI-MS:m/z:
646.7[M+H]+。
Biological test result: the GnRH antagonistic activity research method provided according to document CN1819829, compound 1
The Ki value of GnRH receptor antagonist is 3nM.
Claims (3)
1. a kind of formula (I) compound, stereoisomer, tautomer or pharmaceutically acceptable salt,
Wherein, R1, R2It independently is oxygen atom, sulphur atom；
R3Selected from hydrogen, methyl, cyclopropyl.
2. formula (I) compound as described in claim 1, stereoisomer, tautomer or pharmaceutically acceptable salt,
Including following compounds,
3. the compound as described in any one of claims 1 to 2, stereoisomer, tautomer or pharmaceutically acceptable
Salt, as gonadotropin-releasing hormone receptor antagonists, preparation treatment masculinity femininity sex hormone related condition drug or
Application in pharmaceutical composition.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710956302.XA CN109666002A (en) | 2017-10-16 | 2017-10-16 | A kind of gonadotropin-releasing hormone receptor antagonists and its purposes in endometriosis |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710956302.XA CN109666002A (en) | 2017-10-16 | 2017-10-16 | A kind of gonadotropin-releasing hormone receptor antagonists and its purposes in endometriosis |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN109666002A true CN109666002A (en) | 2019-04-23 |
Family
ID=66139410
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710956302.XA Pending CN109666002A (en) | 2017-10-16 | 2017-10-16 | A kind of gonadotropin-releasing hormone receptor antagonists and its purposes in endometriosis |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109666002A (en) |
-
2017
- 2017-10-16 CN CN201710956302.XA patent/CN109666002A/en active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Millar et al. | Current and future applications of GnRH, kisspeptin and neurokinin B analogues | |
| Phillipps et al. | Patterns of prolactin secretion | |
| Maggi et al. | GnRH and GnRH receptors in the pathophysiology of the human female reproductive system | |
| ES2494842T3 (en) | Agent that prevents early ovulation | |
| Poulain et al. | Electrophysiology of hypothalamic magnocellular neurones secreting oxytocin and vasopressin | |
| Huirne et al. | Gonadotropin-releasing-hormone-receptor antagonists | |
| Dal Bosco et al. | Ovulation induction in rabbit does: current knowledge and perspectives | |
| EP0593491B1 (en) | Luteinizing hormone releasing hormone antagonist peptides | |
| Fowler et al. | Ovarian gonadotrophin surge-attenuating factor (GnSAF): where are we after 20 years of research | |
| Ortmann et al. | Pituitary and extrapituitary actions of gonadotrophin-releasing hormone and its analogues | |
| Fang et al. | The regulative effect of galanin family members on link of energy metabolism and reproduction | |
| Hu et al. | Advances in clinical applications of kisspeptin-GnRH pathway in female reproduction | |
| Murase et al. | GnRH antagonist-induced down-regulation of the mRNA expression of pituitary receptors: comparisons with GnRH agonist effects | |
| Lippert et al. | Effects of oxytocin outside pregnancy | |
| JP6800372B2 (en) | A long-acting palmitic acid-bound GnRH derivative and a pharmaceutical composition containing the same. | |
| Fuchs et al. | Induction and inhibition of labour in the rabbit | |
| Casati et al. | Physiological and pharmacological overview of the gonadotropin releasing hormone | |
| EP4114430A2 (en) | Treatment of inflammatory diseases with peptides and pharmaceutical compositions | |
| Lucio-Oliveira et al. | Effect of the interaction between food state and the action of estrogen on oxytocinergic system activity | |
| CN109666002A (en) | A kind of gonadotropin-releasing hormone receptor antagonists and its purposes in endometriosis | |
| H. Sam et al. | Kisspeptin: a critical regulator of puberty and reproductive function | |
| JP2005530818A (en) | Ovarian hyperstimulation control method and pharmaceutical kit used in the method | |
| RU2020138372A (en) | COMPOSITION FOR THE TREATMENT OF ONE OR MORE DISEASES ASSOCIATED WITH ESTROGEN | |
| Schneider et al. | Progress in research and application of gonadotropin-releasing hormone (GnRH) in animal reproduction | |
| Weiss et al. | GnRH antagonists in the treatment of infertility |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20190423 |
|
| WD01 | Invention patent application deemed withdrawn after publication |