CN1353717A - Tetracyclic progesterone receptor modulator compounds and methods - Google Patents
Tetracyclic progesterone receptor modulator compounds and methods Download PDFInfo
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- CN1353717A CN1353717A CN00808438A CN00808438A CN1353717A CN 1353717 A CN1353717 A CN 1353717A CN 00808438 A CN00808438 A CN 00808438A CN 00808438 A CN00808438 A CN 00808438A CN 1353717 A CN1353717 A CN 1353717A
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- 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 1
- 229940049953 phenylacetate Drugs 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 229940075930 picrate Drugs 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-M picrate anion Chemical compound [O-]C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-M 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 150000004885 piperazines Chemical class 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000000583 progesterone congener Substances 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 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
- 238000004445 quantitative analysis Methods 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000001525 receptor binding assay Methods 0.000 description 1
- 229940075993 receptor modulator Drugs 0.000 description 1
- 238000009256 replacement therapy Methods 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 238000011935 selective methylation Methods 0.000 description 1
- 230000008313 sensitization Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000014639 sexual reproduction Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 229960001866 silicon dioxide Drugs 0.000 description 1
- 238000004088 simulation Methods 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 101150008563 spir gene Proteins 0.000 description 1
- 229940114926 stearate Drugs 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- 150000003558 thiocarbamic acid derivatives Chemical class 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000006257 total synthesis reaction Methods 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M trans-cinnamate Chemical compound [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- 238000003146 transient transfection Methods 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 150000003672 ureas Chemical class 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
- A61P5/32—Antioestrogens
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Diabetes (AREA)
- Endocrinology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Steroid Compounds (AREA)
Abstract
Nonsteroidal compounds that are high affinity, high selectivity modulators for progesterone receptors are disclosed. Also disclosed are pharmaceutical compositions incorporating such compounds, methods for employing the disclosed compounds and compositions for treating patients requiring progesterone receptor agonist, partial agonist or antagonist therapy, intermediates useful in the preparation of the compounds and processes for the preparation of the progesterone receptor modulator compounds.
Description
Invention field
The present invention relates to the non-steroid class tetracyclic compound of progesterone receptor modulator (being agonist and antagonist) and prepare method of these compounds and uses thereof.
Background of invention
Progesterone receptor modulator (PR) has been widely used in the treatment of the adjusting of woman (female) sexual reproduction system and female hormone dependence disease.But the effectiveness of known steroid class PR conditioning agent usually is subjected in the process of restriction, especially long term administration of their adverse side effects.For example, synthetic Progesterone such as norgestrel must be considered to suffer from breast cancer and cardiopathic risk with the women of this medicine when medicinal as woman's (female) property birth control.Similarly, the mifepristone of progesterohe antagonists (RU486), if when being used for chronic disease (as fibrosis of uterus, endometriosis and some hormonal dependent cancer), because its cross reactivity, will cause in patient's the body steadily unbalance as glucocorticoid receptor (GR) antagonist.Therefore, identify that PR is had good specificity, and other steroid receptoroids are not had the compound that cross reactivity or cross reactivity reduce, in improving WomanHealth, have the value of highly significant.
Disclose contain two or the tetrahydroquinoline ring as the non-steroid quasi-molecule of core pharmacophoric group as steroid receptoroid conditioning agent compound.Referring to: " as the quinoline of steroid receptoroid conditioning agent and the preparation of fused quinoline ", T.K.Jones, M.E.Goldman, C.L.F.Pooley, D.T.Winn, J.P.Edwards, S.J.West, C.M.Tegley, L.Zhi, L.G.Hamann, R.L.Davis, L.J.Farmer, PCT international application publication No.WO 96/19458; " steroid receptoroid conditioning agent compound and uses thereof ", T.K.Jones, D.T.Winn, L.Zhi, L.G.Hamann, C.M.Tegley, C.L.F.Pooley, U.S. Patent No. 5,688,808; " steroid receptoroid conditioning agent or compound and uses thereof ", T.K.Jones, M.E.Goldman, C.L.F.Pooley, D.T.Winn, J.P.Edwards, S.J.West, C.M.Tegley, L.Zhi, U.S. Patent No. 5,688,810; " steroid receptoroid conditioning agent or compound and uses thereof ", T.K.Jones, C.M.Tegley, L.Zhi, J.P.Edwards, S.J.West, U.S. Patent No. 5,693,646; " steroid receptoroid conditioning agent compound and uses thereof ", T.K.Jones, L.Zhi, C.M.Tegley, D.T.Winn, L.G.Hamann, J.P.Edwards, S.J.West, U.S. Patent No. 5,693,647; " steroid receptoroid conditioning agent compound and uses thereof ", T.K.Jones, L.Zhi, J.P.Edwards, C.M.Tegley, S.J.West, U.S. Patent No. 5,696,127; " steroid receptoroid conditioning agent compound and uses thereof ", T.K.Jones, D.T.Winn, M.E.Goldman, L.G.Hamann, L.Zhi, L.J.Farmer, R.L.Davis, U.S. Patent No. 5,696,130; " steroid receptoroid conditioning agent compound and uses thereof ", T.K.Jones, M.E.Goldman, C.L.F.Pooley, D.T.Winn, J.P.Edwards, S.J.West, C.M.Tegley, L.Zhi, L.G.Hamann, L.J.Farmer, R.L.Davis, U.S. Patent No. 5,696,133.Reported the bicyclic heterocyclic compounds that contains as cardiotonic drug.See: " cardiotonic drug of new class: 5-replace 3; 6-dihydro thiadiazine-2-ketone synthetic and with inhibition of cyclic amp phosphodiesterase esterase and sarcostyle calcium sensitization it is carried out biological evaluation ", M.-C.Forest, P.Lahouratate, M.Martin, G.Nadler, M.J.Quiniou, R.G.Zimmermann, J.Med.Chem.35 (1992) 163-172; " the heteroatoms analogue of Bemoradan: 1, the chemical property and the cardiotonic activity of 4-benzothiazine radical pyridazine ketone ", D.W.Combs, M.S.Rampulla, J.P.Demers, R.Falotico, J.B.Moore, J.Med.Chem., 35 (1992) 172-176.}
Summary of the invention
The present invention relates to compound, pharmaceutical composition and with the method for PR mediation regulate process.Specifically, the present invention relates to the non-steroidal compounds and the composition of progesterone receptor height agonist affine, high degree of specificity, part agonist (being part activator and/or tissue specificity activator) and antagonist.Also provide prepare these compounds and pharmaceutical composition and synthetic in the method for key intermediate.
In the incidental claims of this paper, will particularly point out these and other various advantages and qualitative new feature of the present invention, and constitute the part of this paper.But in order to understand the present invention, purpose that advantage and its purposes reached better, should be with reference to this paper description here and wherein said preferred embodiment.
Detailed Description Of The Invention
Hereinafter, following term is unless otherwise indicated as giving a definition.
Term alkyl, alkenyl, alkynyl and allyl group comprise optional straight chain, side chain, ring-type, saturated and/or unsaturated structure and their combination that replaces.
The alkyl structure of term haloalkyl indication comprises by one or more fluorine, chlorine, bromine or iodine or straight chain, side chain or the ring texture of their combination replacement or their combination.
The assorted alkyl of term comprises that one or more skeletal atoms are straight chain, side chain, ring-type, saturated and/or unsaturated structures of oxygen, nitrogen, sulphur or their combinations.
Term aryl refers to optional 6 yuan of aromatic rings that replace.
The term heteroaryl refers to contain one or more 5 yuan of heterocycles of aromatics that are selected from the heteroatomic optional replacement of oxygen, nitrogen and sulphur, or contains the aromatics 6-unit heterocycle of the optional replacement of one or more nitrogen.
The substituent structure of " optional replacement " comprises one or more preferred substituents that (but being not restricted to) is following: F, Cl, Br, I, CN, NO
2, NH
2, NCH
3, OH, OCH
3, OCF
3, CH
3, CF
3
Compound of the present invention is defined as those compounds with following formula or its pharmacy acceptable salt:
Wherein:
R
1To R
6Respectively be hydrogen, F, Cl, Br, I, NO
2, CN, OR
10, NR
10R
11, SR
10, COR
12, CO
2R
12, CONR
10R
11, the optional C that replaces
1-C
6Alkyl or assorted alkyl, C
1-C
6Haloalkyl, the optional C that replaces
3-C
8Cycloalkyl, the optional C that replaces
2-C
6Alkenyl or alkynyl, the optional allyl group that replaces, the optional aryl that replaces or heteroaryl or the optional arylmethyl that replaces, wherein R
10And R
11Respectively be hydrogen, C
1-C
6Alkyl or assorted alkyl or haloalkyl, aryl, heteroaryl, the optional allyl group that replaces, optional arylmethyl, the COR that replaces
13, SO
2R
13Or S (O) R
13, R wherein
12Be hydrogen, C
1-C
6Alkyl or assorted alkyl or haloalkyl, aryl, heteroaryl, the optional allyl group that replaces or the optional arylmethyl that replaces, wherein R
13Be hydrogen, C
1-C
6Alkyl or haloalkyl, aryl, heteroaryl, the optional allyl group that replaces or the optional arylmethyl that replaces;
R
7Be hydrogen, C
1-C
6Alkyl or haloalkyl or assorted alkyl, aryl, arylmethyl, heteroaryl, COR
12, CO
2R
12, SO
2R
12, S (O) R
12Or CONR
10R
11, R wherein
10-12Definition as above;
R
8And R
9Respectively be hydrogen, C
1-C
6Alkyl or haloalkyl or assorted alkyl, the optional C that replaces
2-C
6Alkenyl or alkynyl, the optional allyl group that replaces, the optional arylmethyl that replaces, the optional aryl that replaces or the optional heteroaryl that replaces;
X is OCH
2, SCH
2, NHCH
2, OC (O), SC (O), NHC (O), CH
2O, CH
2S, CH
2NH, C (O) O, C (O) S or C (O) NH;
Y is O, S or NR
10, R wherein
10Definition as above; With
And Z is O, S, NR
14, CR
14R
15, CR
14R
15CR
16R
17, OCR
14R
15, SCR
14R
15, CR
14R
15S, NR
14CR
15R
16, or CR
14R
15NR
16, R wherein
14To R
17Respectively be hydrogen, C
1-C
6Alkyl or haloalkyl or assorted alkyl, the optional C that replaces
2-C
6Alkenyl or alkynyl, the optional allyl group that replaces, the optional arylmethyl that replaces, the optional aryl that replaces or the optional heteroaryl that replaces.
On the one hand, the invention provides the composition that contains significant quantity formula I as implied above or formula II progesterone receptor modulator compounds, wherein R
1-17, X, Y and Z definition as above.
On the other hand, the invention provides method, wherein give the above-mentioned formula I of patient's significant quantity or the compound of formula II, wherein R with progesterone receptor mediation regulate process
1-17, X, Y and Z definition as above.
Any compounds of the present invention can be become the pharmacy acceptable salt that mixes in the various pharmaceutical compositions.As described herein, pharmacy acceptable salt comprises (but being not restricted to) hydrochloride, hydrobromate, hydriodate, hydrofluoride, vitriol, Citrate trianion, maleic acid salt, acetate, lactic acid salt, nicotinate, succinate, oxalate, phosphoric acid salt, malonate, salicylate, phenylacetate, stearate, pyridinium salt, ammonium salt, piperazine salt, the diethyl amine salt, the nicotinoyl amine salt, formate, urea salt, sodium salt, sylvite, calcium salt, magnesium salts, zinc salt, lithium salts, cinnamate, methylamine salt, mesylate, picrate, tartrate, triethylamine salt, the amino first salt of dimethylamine salt and three (methylol).Other pharmacy acceptable salts are well known by persons skilled in the art.
PR agonist of the present invention, part agonist and agonist compounds can be used in particular for the replacement therapy of female hormone and the conditioning agent of fertility (as contraception or anti-gestation (contragestational) medicine, no matter be single with or with the estrogenic agents coupling.PR conditioning agent compound also can be used for treating dysfunctional uterine hemorrhage, dysmenorrhoea, endometriosis, leiomyoma (fibroma uteri), hectic fever, emotionally disturbed, meningofibroblastoma and various hormonal dependent cancer (including, but are not limited to ovarian cancer, mammary cancer, uterine mucosa cancer and prostate cancer).
Those skilled in the art as can be seen, when compound of the present invention when agonist, part agonist or the antagonist, it is preferred having the compound that mixes steroid receptoroid characteristic.For example, when using PR agonist (as progestogen) in the contraception of woman's (female) property, will cause the adverse side effect of a hydropexic increase and an azoles sore usually.In this case, can mainly play the PR agonist but have and to play some AR and MR to regulate active compound be useful.Especially blended MR effect can be used for controlling intravital water balance, because the AR interaction energy helps the outbreak of any azoles sore of control.
In addition, those skilled in the art it can also be seen that: compound of the present invention (comprising the pharmaceutical composition and the preparation that contain these compounds) can be used in the combination therapy of above-mentioned disease of various treatments and illness.Therefore, compound of the present invention can be united use with other hormones and other treatment, comprises (but being not restricted to) chemotherapeutic (as cytostatics and cytotoxic drug), immunomodulator (as Interferon, rabbit, interleukin-, tethelin) and other cytokines, hormonotherapy, operation and radiotherapy.
Representative PR conditioning agent compound of the present invention (being agonist, part agonist and antagonist) comprising: 7-fluoro-4,4-dimethyl-5H-chromene (chromeno) [3,4-f]-1,3-benzo [d] oxazine-2-ketone (compound 14); 9-bromo-7-fluoro-4,4-dimethyl-5H-chromene [3,4f]-1,3-benzo [d] oxazine-2-ketone (compound 20); 7-fluoro-9-formyl radical-4,4-dimethyl-5H-chromene [3,4-f]-1,3-benzo [d] oxazine-2-ketone (compound 24); 7-fluoro-9-oxyimino methyl-4,4-dimethyl-5H-chromene-[3,4-f]-1,3-benzo [d] oxazine-2-ketone (compound 25); 9-cyano group-7-fluoro-4,4-dimethyl-5H-chromene [3,4-f]-1,3-benzo [d] oxazine-2-ketone (compound 26)
Those skilled in the art can make compound of the present invention (comprising nitrogen heterocyclic and their derivative) with the conventional chemical synthetic method, for example by the synthetic method of improvement nitrogen heterocyclic disclosed herein or total synthesis path.
The sequence step that in following generalized flowsheet, has shown synthetic The compounds of this invention.The R group (is R in each flow process
1, R
2Deng) corresponding to the specific substituting group of pointing out among the embodiment.But it will be appreciated by those skilled in the art that at formula I and II compound specifies site other functional groups disclosed herein also to comprise the potential substituting group in structural similar site in these flow processs.On the other hand, the present invention is also by preparing the potential substituting group in the similar site on these chemical structures of the present invention.On the other hand, the present invention also provides the novel method for preparing these compounds of the present invention.
Flow process I
Flow process I originates in the reference reference and prepares fluoroboric acid 2 (fluoroboronic acid),-78 ℃ to-50 ℃ in THF or ether with alkyl lithium reagents (as just-butyllithium (n-BuLi) or tert-butyl lithium be the adjacent lithiumation of fluorobenzene, add trialkyl borate (as trimethyl borate or triisopropyl borate ester) at-78 ℃ then, with aqueous acid (as HCl) acidifying, obtain boronic acid compounds 2.In room temperature under the moisture or anhydrous condition, the linked reaction by the catalytic boronic acid compounds 2 of typical palladium and bromo-benzoate 3 prepares biaryl compound 4.Then room temperature at alkaline condition (as THF/MeOH/2N Na
2CO
3) following ester hydrolysis 4, the heating that heats up in polar solvent (as DMF) obtains carboxylate and generates lactone 5.This nitro lactone 5 is changed into amino bromo-lactone 6 single jar two step in the flow process, is included in that (by the catalysis of carbon palladium) becomes amino with nitroreduction in the hydrogen, then room temperature in DMF with N-bromo-succinimide (NBS) bromination.By the catalytic linked reaction of palladium,, introduce pseudoallyl group as the Suzuki linked reaction of different propylene boric acid and bromo compound 6.Exist then under the 4-Dimethylamino pyridine and handle the aminocompound that obtains and change into carbamate 7 with methyl-chloroformate.In the presence of the acid (as TFA) of catalytic amount, with typical reductive agent (as LiAlH
4And Et
3SiH) step-by-step reduction is removed the carbonyl group on the lactone 7, obtains compound 8.In ethylene dichloride (DCE) refluxes, handle compound 8 with tosic acid (TsOH, tosic acid), generate final product 9.
Flow process II
Flow process II has described one four flow process that the step selective d-ring is modified, and wherein uses reductive agent (as LiBH
4) reduction lactone 7 obtains glycol 10, when having alkali (as triethylamine) then, with glycol 10 NBS bromination, selective methylation and NaH get involved and nucleophilic cyclisation (in DMF) then, generation compound 11.In ethylene dichloride refluxes, handle compound 11, obtain compound 12 with the acid more than 1 equivalent (as TsOH).
Flow process III comprises that carrying out selective d-ring functional group by known functional group conversion (as by the metal halogen displacement bromine being changed into aldehyde, then to the DMF nucleophilic addition(Adn)) transforms R
1-4Change into R
7-10, or handle aldehyde by azanol aldehyde changed into oxime, or handle oxime by thionyl chloride and convert it into cyano group.Flow process III
Flow process IV
Flow process IV described with Lawesson reagent (right-methoxyphenyl sulphur carbon back phosphine sulphur dipolymer) compound 12 is changed into it the ring-type thiocarbamates like thing 13.
Those skilled in the art can improve aforesaid method through understanding, but still within the scope of the present invention.
Compound of the present invention also comprises racemoid, steric isomer of described compound and composition thereof, comprises isotopic labeling and radiolabeled compound.Available standards disassemble technique (comprising component crystallization and chiral column chromatography) separates these isomer.
As mentioned above, any PR conditioning agent compound of the present invention can be mixed with pharmaceutically acceptable carrier, obtain can be used for treating Mammals as herein described (especially human patients) biological disease or disorderly medicine.The specific support that is used for these pharmaceutical compositions can be many forms, depends on required administration type (as intravenously, oral, local, suppository or parenteral).
When the composition of the oral liquid form of preparation (as suspension, elixir and solution), available typical drug media such as water, ethanol, oil, alcohol, seasonings, sanitas, pigment etc.Similarly, when preparation oral administration solid dosage form (as powder, tablet and capsule), can use carrier such as starch, sugar, thinner, granulating agent, lubricant, wedding agent, disintegrating agent etc.Because tablet and capsule are easy to administration, so they represent the most preferably oral dosage form of pharmaceutical composition of the present invention.
For administered parenterally, carrier is representative usually with the sterilized water, although also can comprise other assist in dissolving or as the component of sanitas.In addition, also can prepare injection suspension, can use this moment such as suitable liquid carrier, suspension agent etc.
For topical, available soft moistening matrix (as ointment or emulsifiable paste) prepares these compounds.Suitable ointment base example comprises that the oil-emulsion of Vaseline, Vaseline and volatility silicone, lanolin and water is (as Eucerin
TM(Beiersdorf)).The example of suitable ointment base is Nivea
TMCream (Beiersdorf), cold cream (USP), Purpose Cream
TM(Johnson ﹠amp; Johnson), hydrophilic ointment (USP) and Lubriderm
TM(Warner-Lambert).
Pharmaceutical composition of the present invention and compound can dose unit (as tablet, capsule etc.) form give usually, from about 1 μ g/kg body weight-500mg/kg body weight, are preferably about 10 μ g/kg-250mg/kg, better about 20 μ g/kg-100mg/kg.Those skilled in the art give patient's definitely the measuring certainly in many factors of pharmaceutical composition of the present invention as can be seen, comprise (but being not restricted to) required biological activity, patient's symptom and to the tolerance situation of medicine.
When radiation or isotopic labeling when measuring the part that whether exists in cell background or the extract in the PR experiment, also available compound of the present invention.Because compound of the present invention has the ability of selectivity activation progesterone receptor, when also can be used for being determined at other steroid receptoroids or relevant cell inner recipient and exist, they whether exist in the acceptor.
Because compound of the present invention is to the selectivity characteristics of steroid receptoroid, these compounds also can be used for the external steroid receptoroid of purifying sample.By sample and one or more compound of the present invention that will contain the steroid receptoroid, make these compounds be incorporated into selected acceptor, by isolate bonded ligand/receptors bind thing with separation method well known by persons skilled in the art, carry out these purifying then.These methods comprise column chromatography, filtration, centrifugal, mark and physical sepn and antibody complex etc.
Compound of the present invention and pharmaceutical composition are than identifying that steroid class conditioning agent compound has many advantages.For example, these compounds have strong especially PR activator, show maximum activation 50%PR during less than 100nM in concentration, and when being preferably concentration and being lower than 50nM, better is that concentration is lower than 20nM or lower.Equally, alternative cpd of the present invention also can not play bad cross reaction with other steroid receptoroids usually, and compound mifepristone (RU486; Roussel Uclaf) a kind of known PR antagonist just plays bad cross reaction with GR, thereby has limited the application in its long-term chronic administration.In addition, compare with known steroid, compound of the present invention is easy to synthesize as little organic molecule, advantages of higher stability is provided and is easy to the oral dosage form administration.
The following non-limiting example of reference is to further specify the present invention.
Embodiment 1
7-fluoro-4,4-dimethyl-5H-chromene [3,4f]-1,3-benzo [d] oxazine-2-ketone (compound 14; Structural formula 9 among the flow process I, wherein R
1=fluorine, R
2-6=H)
2,3-difluoro boric acid (structural formula 2 among the flow process I, wherein R
1=fluorine, R
2-4=H)
In-78 ℃, be equipped with 1,2-two fluorobenzene (15g, in the 500ml flask of tetrahydrofuran (THF) 0.13mmol) (150ml), dropwise add n-BuLi (with the 7.0M solution that hexane is joined, 19ml, 0.13mol).With reaction mixture-78 ℃ stirring 2.5 hours, add tetrahydrofuran (THF) (90ml) solution of the trimethyl borate (30ml, 0.26mol, 2.0 equivalents) that is chilled to-78 ℃ in advance then, allow mixture be warming up to ambient temperature overnight then.With HCl (3 equivalent) reaction mixture is acidified to pH～1, stirred then 15 minutes.(2 * 300ml), water (150ml) washs, Na with this mixture of ether extraction
2SO
4Dry.Solvent removed in vacuo obtains 20g (96%) solid 2 that is white in color, 3-difluoro boric acid.2, the data of 3-difluoro boric acid are: rf=0.39 (ethyl acetate: hexane, 3: 7).
2-(2, the 3-difluorophenyl)-5-nitrobenzoic acid methyl esters (compound 15; Structure 4 among the flow process I, R
1=fluorine, R
2-6=H)
Will be in toluene (200ml) and ethanol (100ml) 2,3-difluoro boric acid (20g, 0.12mol, 1.3 equivalents), 2-bromo-5-nitrobenzoic acid methyl esters (25g, 96mmol) (structure 3, wherein R
1=methyl, R
5-6=H), the mixture heating up of tetrakis triphenylphosphine palladium (0) (3.6g, 3.1mmol, 3.2% equivalent) and aqueous sodium carbonate refluxes and spend the night, show up to thin-layer chromatography TLC to react completely.(2 * 400ml) abstraction reaction mixtures are with salt solution (300ml) washing, Na with EtOAc
2SO
4Dry.Remove desolvate after, obtain brown solid, from i-PrOH: hexane recrystallization, the solid compound 15 that obtains being white in color (22.8g, 83%).15 data are rf=0.32 (CH
2Cl
2: hexane, 4: 6);
1H NMR (400MHz, CDCl
3) δ 8.87 (and d, J=1.2,1H), 8.43 (dd, J=8.3 and 1.2,1H), 7.58 (d, J=8.6,1H), 7.29-7.17 (m, 2H), 7.10-7.02 (m, 1H) and 3.82 (s, 3H).
4-fluoro-8-nitro-6H-dibenzo [b, d] pyrans-6-ketone (compound 16: the structure 5 among the flow process I, wherein R
1=fluorine, R
2-6=H)
(～2.5: 1) (20g adds the 10%NaOH aqueous solution (82ml), this reaction mixture of stirring at room 1 hour to the compound 15 in (370mL) in solution 69mmol) at THF: MeOH.Concentrate this mixture, be acidified to pH～1 with 3NHCl, (2 * 400ml) extract to use EtOAc then.With the extract that the salt water washing merges, Na
2SO
4Drying concentrates the acid that obtains being pale solid.Add NaH (4.0g, 1.5 equivalents) in the solution of the dried DMF of this crude acid (180ml), at～80 ℃ of heating this mixtures 2 hours, TLC showed and reacted completely this moment.Decompression is concentrated into small volume with reaction mixture down, adds entry (5ml) then.This mixture is cooled to-15 ℃, forms white precipitate,, obtain mixture 16 (17g, 95%) with its filtration and with cold water and hexane wash.16 data are: rf=0.36 (EtOAc: hexane, 3: 7);
1H NMR (400MHz, CDCl
3) δ 9.28 (and d, J=1.1,1H), 8.68 (dd, J=8.5 and 1.1,1H), 8.32 (d, J=8.5,1H), 7.91 (d, J=8.0,1H) and 7.46-7.36 (m, 2H).
8-amino-7-bromo-4-fluoro-6H-dibenzo [b, d] pyrans-6-ketone (compound 17: the structure 6 among the flow process I, wherein R
1=fluorine, R
2-6=H)
Room temperature is led to H
2(40-60psi) down the compound 16 of vibrations in the Parr device (8.8g, 34mmol) and DMF (150ml) solution of 10%Pd/C (0.95g, 2.5% equivalent) spend the night, react completely up to TLC demonstration hydrogenation.Carefully reaction mixture is passed through filter paper then, remove all trace Pd/C catalyzer.In filtrate, add NBS (6.0g, 34mmol), this reaction mixture of stirring at room 2-3 hour.Decompression concentrates this compound down, adds entry then and makes precipitation.Cross filter solid, use cold water washing, obtain being light brown solid compound 17 (8.6g, 83%).17 data are: rf=0.11 (EtOAc: hexane, 1: 3);
1H NMR (400MHz, DMSO-d
6) δ 8.20 (d, J=8.8,1H), 7.97 (d, J=8.0,1H), 7.38 (d, J=8.8,1H), 7.35-7.27 (m, 2H), 6.24 (s, 2H).
4-fluoro-7-sec.-propyl-8-methoxycarbonyl amino-6H-dibenzo [b, d] pyrans-6-ketone (compound 18: the structure 7 among the flow process I, wherein R
1=fluorine, R
2-6=H)
In-78 ℃, (1.2g, (1.7M that pentane is joined, 12ml 20mmol), stirred this yellow solution 10 minutes to add t-BuLi in THF 10mmol) (25ml) solution at 2-bromination propylene.(3.0ml 26mmol), spends the night slow intensification of this reaction mixture, obtains white slurries to add trimethyl borate with syringe.This reaction mixture is acidified to pH～2, heats up and stirred 1 hour, (2 * 50ml) extract, and use the salt water washing, concentrate the rough boronic acid compounds of solid that obtains being white in color then with EtOAc.
Will this rough boronic acid compounds in toluene (45ml), EtOH (45ml) and the water (20ml) (1.5g, 4.8mmol), K
2CO
3(2.8g, 20mmol) and Pd (PPh
3)
4The mixture heating up of (0.10g, 0.087mmol, 1.8% equivalent) refluxed 2 hours.This dark-coloured reaction mixture is acidified to pH～2, and (2 * 150ml) extract with EtOAc.Remove the dark-coloured solid that obtains the rough 8-of containing amino-4-fluoro-7-sec.-propyl-6H-dibenzo [b, d] pyrans-6-ketone after desolvating.Room temperature adds ClCO in the THF of this crude mixture (40ml)
2Me (1.7ml, 20mmol) and DMAP (0.53g, 4.3mmol), this muddy solution of stirring at room 5 hours.Water (50ml) cancellation reaction with EtOAc abstraction reaction mixture, is used Na
2CO
3, NH
4The Cl aqueous solution and salt water washing.Remove and desolvate, obtain being the compound 18 (0.35g, 26%) of light yellow solid after the chromatography crude mixture.18 data are: rf=0.34 (EtOAc: hexane, 1: 3);
1H NMR (400MHz, CDCl
3) δ 8.72 (and d, J=8.9,1H), 8.08 (d, J=9.0,1H), 7.79 (bd, J=6.5,1H), 7.54 (s, 1H), 7.24-7.18 (m, 2H), 5.52 (s, 1H), 4.95 (s, 1H), 3.81 (s, 3H) and 2.14 (s, 3H).
4-fluoro-7-sec.-propyl-8-methoxycarbonyl amino-6H-dibenzo [b, d] pyrans (compound 19; Structure 8 among the flow process I, wherein R
1=fluorine, R
2-6=H)
(70mg adds LiAlH in THF 0.21mmol) (8ml) solution at compound 18
4(8.0mg, 0.21mmol), this mixture of stirring at room 30 minutes.Water cancellation reaction is extracted this reaction mixture and concentrated with EtOAc.Chromatography obtains being yellow solid 4-fluoro-6-hydroxyl-7-sec.-propyl-8-methoxy carbonyl amino-6H-dibenzo [b, d] pyrans (20mg, 28%), has Et
3SiH (0.2mL) and CH
2Cl
2In the time of (4mL), room temperature was handled 2 hours with the TFA of catalytic amount.Obtain solid compounds 19 (13mg, 68%) behind the purifying.19 data are:
1H NMR (400MHz, CDCl
3) δ 8.13 (d, J=8.2,1H), 7.61 (d, J=8.6,1H), 7.46 (d, J=7.5,1H), 7.04-6.93 (m, 2H), 6.89 (s, 1H), 5.55 (s, 1H), 5.10 (d, J=13.5,1H), 5.07 (d, J=13.5,1H), 5.03 (s, 1H), 3.79 (s, 3H) and 2.01 (s, 3H).
7-fluoro-4,4-dimethyl-5H-chromene [3,4-f]-1,3-benzo [d] oxazine-2-ketone (compound 14: the structure 9 among the flow process I, wherein R
1=fluorine, R
2-6=H)
(13mg 0.041mmol) and the mixture of TsOH (16mg, 0.084) reflux 15 hours in ethylene dichloride (5m1), concentrates then with compound 19.With EtOAc (20ml) diluted mixture thing, use Na
2CO
3(2 * 5ml) aqueous solution and salt water washing.Remove and to obtain being white in color the solid product after desolvating, use EtOAc: the hexane recrystallization obtains 6mg (49%) the solid compound 14 that is white in color.14 data are: rf=0.23 (EtOAc: hexane, 1: 1);
1HNMR (400MHz, CDCl
3) δ 8.71 (and bs, 1H), 7.58 (d, J=8.4,1H), 7.40 (d, J=7.4,1H), 7.08-6.95 (m, 2H), 6.88 (d, J=8.4,1H), 5.24 (s, 2H) and 1.84 (s, 6H).
Embodiment 2
9-bromo-7-fluoro-4,4-dimethyl-5H-chromene [3,4-f]-1,3-benzo [d] oxazine-2-ketone (compound 20: the structure 12 among the flow process II, wherein R
7=fluorine, R
2-6=H)
N-methoxycarbonyl-3-methylol-4-(3-fluoro-2-hydroxyphenyl)-2-isopropyl aniline (compound 21: the structure 10 among the flow process II, wherein R
1=fluorine, R
2-6=H)
Room temperature is at compound 18 (structure 7 among the flow process II, wherein R
1=fluorine, R
2-6=H) (0.33g dropwise adds LiAlH in THF 1.0mmol) (30ml) solution
4(44mg, 2.0mmol), this reaction mixture of stirring at room 2 hours.This reaction of water cancellation is with EtOAc abstraction reaction mixture.Except that after desolvating, chromatography obtains being colourless oil body compound 21 (0.30g, 96%).21 data are: rf=0.11 (EtOAc: hexanes, 1: 3);
1H NMR (400MHz, CDCl
3), be shown as mixture of isomers.
N-methoxycarbonyl-3-methylol-4-(5-bromo-3-fluoro-2-hydroxyphenyl)-2-isopropyl aniline (structure 10 of compound 22: flow process II, wherein R
1=fluorine, R
3=bromine, R
2=R
4-6=H)
Under the room temperature with NBS (0.18g, 1.0mmol) add compound 21 (0.30g, 0.96mmol) and Et
3The CH of N (1.0ml)
2Cl
2In the mixture (12ml).After 10 minutes, with EtOAc (50ml) diluted mixture thing, water, NH
4The Cl aqueous solution and salt water washing.Except that after desolvating, the chromatography residue obtains the yellow butyrous compound 22 of 0.34g (86%).22 data are: rf=0.12 (EtOAc: hexane, 1: 3).
2-bromo-4-fluoro-7-sec.-propyl-8-methoxycarbonyl amino-6H-dibenzo [b, d] pyrans (compound 23, the structure I I among the flow process II, wherein R
7=fluorine, R
9=bromine, R
5-6=R
8=R
10=H)
(0.34g adds K in DMF 0.83mmol) (10ml) solution at compound 22
2CO
3(0.14g, 1.0mmol) and MeI (0.5ml, excessive), this mixture of stirring at room 1 hour.After the standard operation (work-up), chromatography obtains 0.28g (78%) N-methoxycarbonyl-2-pseudoallyl-3-methylol-4-(5-bromo-3-fluoro-2-methoxyphenyl) aniline.The data of this intermediate that methylates are: rf=0.52 (EtOAc: hexane, 1: 1);
1HNMR (400MHz, CDCl
3) (rotational isomer) δ 8.13/8.02 (bs, 1H), 7.30 (m, 1H), 7.17-6.95 (m, 3H), 5.61/5.53 (s, 1H), 5.21/4.97 (s, 1H), 4.50-4.12 (m, 2H), 3.79/2.95 (s, 3H), 3.62/2.88 (s, 3H) and 2.20/2.02 (s, 3H).
In 80 ℃ oil bath the heating in DMF (10ml) this methylated intermediate (0.28g, 0.65mmol) and NaH (30mg, 0.75mmol) mixture is 2 hours, up to reacting completely.After the standard operation, chromatography obtains 0.20g (80%) solid compounds 23.23 data are rf=0.65 (EtOAc: hexane, 1: 1);
1HNMR (400MHz, CDCl
3) δ 8.15 (d, J=8.7,1H), 7.58 (m, 1H), 7.56 (d, J=8.7,1H), 7.15 (dd, J=9.5 and 2.0,1H), 6.89 (s, 1H), 5.56 (s, 1H), 5.09 (d, J=12,1H), 5.07 (d, J=12,1H), 5.03 (s, 1H), 3.79 (s, 3H) and 2.00 (s, 3H).
9-bromo-7-fluoro-4,4-dimethyl-5H-chromene [3,4-f]-1,3-benzo [d] oxazine-2-ketone (compound 20: the structure 12 among the flow process II, wherein R
7=fluorine, R
9=bromine, R
5-6=R
8=R
10=H)
With compound 23 (0.12g, 0.31mmol) and TsOH (0.12g, mixture 0.62mmol) reflux 15 hours in ethylene dichloride (15ml) concentrates then.Dilute this mixture with EtOAc (50ml), use Na then
2CO
3(2 * 10ml) the aqueous solution and salt washing.Remove and to obtain being white in color the solid product after desolvating, with it from EtOAc: the hexane recrystallization obtains 60mg (49%) compound 20.20 data are: rf=0.30 (EtOAc: hexane, 1: 1);
1H NMR (400MHz, CDCl
3) δ 8.09 (and s, 1H), 7.53 (d, J=8.3,1H), 7.52 (m, 1H), 7.19 (dd, J=9.4 and 1.9,1H), 5.22 (s, 2H) and 1.82 (s, 6H).Also be recovered to some starting raw materials (55mg, 45%).
Embodiment 3
7-fluoro-9-formyl radical-4,4-dimethyl-5H-chromene [3,4-f]-1,3-benzo [d] oxazine-2-ketone (compound 24: the structure 12 among the flow process III, wherein R
7=fluorine, R
9=formyl radical, R
5-6=R
8=R
10=H)
With MeLi (1.4M in ether, 0.10ml, 0.14mmol) be added to-70 ℃ of compounds 20 (50mg in THF 0.13mmol) (12ml) solution, stirred this mixture 10 minutes, add then n-BuLi (1.6M in hexane, 0.10ml, 0.16mmol).This reaction mixture is warming up to-40 ℃, cools back-70 ℃ then.(0.40ml 5.0mmol) is added in the reaction mixture, is warming up to room temperature then, and water (10ml) cancellation is with EtOAc (2 * 20ml) extractions with DMF.Chromatography obtains 26mg (61%) the solid mixture 24 that is white in color.24 data are: rf=0.13 (EtOAc: hexane, 1: 1);
1H NMR (400MHz, CDCl
3) δ 9.97 (and d, J=1.8,1H), 9.33 (bs, 1H), 8.19 (t, J=1.3,1H), 7.90 (d, J=8.4,1H), 7.61 (dd, J=10.3 and 1.3,1H), 7.15 (d, J=8.4,1H), 5.51 (s, 2H) and 1.83 (s, 6H).
Embodiment 4
7-fluoro-9-oxyimino methyl-4,4-dimethyl-5H-chromene [3,4-f]-1,3-benzo [d] oxazine-2-ketone (compound 25: the structure 12 among the flow process III, wherein R
7=fluorine, R
9=oxyimino methyl, R
5-6=R
8=R
10=H)
With NH
2OH-HCl (10mg, 0.14mmol) and pyridine (0.1mL, 1.4mmol) be added to compound 24 (20mg, in ethanol 0.061mmol) (4ml) solution, this mixture of stirring at room 1 hour.Concentrate this reaction mixture, be dissolved in EtOAc (30ml), water and salt water washing, reconcentration obtains 18mg (86%) the solid compound 25 that is white in color.25 data are: rf=0.11 (EtOAc: hexane, 1: 1);
1H NMR (400MHz, acetone-d
6) δ 9.27 (and s, 1H), 8.15 (s, 1H), 7.80 (s, 1H), 7.78 (d, J=8.3,1H), 9.39 (d, J=11.2,1H), 7.11 (d, J=8.3,1H), 5.39 (s, 2H) and 1.81 (s, 6H).
Embodiment 5
9-cyano group-7-fluoro-4,4-dimethyl-5H-chromene [3,4-f]-1,3-benzo [d] oxazine-2-ketone (compound 26: the structure 12 among the flow process III, wherein R
7=fluorine, R
9=cyano group, R
5-6=R
8=R
10=H)
Room temperature is used thionyl chloride (0.032ml, methylene dichloride 0.043mmol) (10ml) solution-treated compound 25 (10mg, 0.029mmol) 40 minutes.Use Na
2CO
3The aqueous solution (2ml) cancellation reaction mixture, (2 * 20ml) extract, and use the salt water washing with EtOAc.Remove desolvate after, chromatography obtains 8mg (90%) the solid compound 26 that is white in color.The data of compound 26 are: rf=0.32 (EtOAc: hexane, 1: 1);
1H NMR (400MHz, acetone-d
6) δ 9.35 (and bs, 1H), 8.05 (t, J=1.5,1H), 7.90 (d, J=8.4,1H), 7.59 (dd, J=10.6 and 1.5,1H), 7.15 (d, J=8.4,1H), 5.51 (s, 2H) and 1.82 (s, 6H).
Steroid receptoroid activity
Use R.M.Evans, Science, the described cotransfection experiments of 240 (1988) 889-895 (this paper includes it as a reference in) are tested compound of the present invention, and find to have strong and specific activity especially as agonist, part agonist and antagonist.Following United States Patent (USP) (this paper all includes them as a reference in) is described this experiment in detail: " retinoic acid receptor (RAR) method ", R.M.Evans, E.Ong, P.S.Segui, C.C.Thompson, K.Umesono, V.Giguere, U.S. Patent No. 4,981,784; " the relevant experiment of hormone receptor ", R.M.Evans, C.A.Weinberger, S.M.Hollenberg, V.Giguere, J.Arriza, C.C.Thompson, E.S.Ong, U.S. Patent No. 5,071,773.
Cotransfection experiments provides the method for identifying functional agonist and part agonist (effect of simulation natural hormone) or inhibitor (suppressing the effect of natural hormone) and the quantitative method of their responsive cell inner recipient (IR) protein-actives.From this respect, system in the cotransfection experiments analogue body in the laboratory.Importantly, the activity in cotransfection experiments is very relevant with activity in vivo, thereby makes cotransfection experiments have the function of pharmacology in the qualitative and quantitative budget test compounds body.Can be referring to " interaction of glucocorticoid stand-in and people's glucocorticoid acceptor ", T.S.Berger, Z.Parandoosh, B.W.Perry and R.B.Stein, J.Steroid Biochem.Molec.Biol., 41 (1992) 733-738 (hereinafter referred to as " Berger "), this paper and including in as a reference.
In cotransfection experiments, under the control of constitutive promoter (as SV 40 promotors), the clone's of IR (as people PR, AR or GR) cDNA introducing is not had in the background cell of endogenous IR substantially by cotransfection (inducing cell absorbs the process of foreign gene).The gene of this introducing instructs recipient cell to produce significant IR albumen.Second gene introduced in (cotransfection is gone into) this cell in conjunction with the IR gene.This second gene (containing the proteic cDNA of report, as the glimmering luciferase of fire (LUC)) is controlled by the suitable hormone responsiveness promotor that contains hormone response element (HRE).This report plasmid has the function that target IR transcribed-regulated active reporter gene.Therefore this report gene can be used as usually under target acceptor and the control of its natural hormone the surrogate by the product (mRNA is protein then) of genetic expression.
This cotransfection experiments can detect small molecules agonist and the antagonist of target IR.Cells transfected is contacted with the agonist part, will increase the receptor active of transfectional cell.Easily measure this activity, as increase by luciferase output, the increase that the reporter gene of this compound of reaction dependency, IR-mediation is transcribed.In order to detect antagonist, when having the agonist (as the Progesterone of PR) of the known target IR that induces specific report signal (as the output of luciferase) of constant density, carry out this cotransfection experiments.The increase of the antagonist concentration of estimating will reduce the report signal.So cotransfection experiments can be used for detecting agonist and the antagonist of specific IR.In addition, whether it not only can measure compound and work mutually with specific I R, also can measure this interact whether simulate (agonist) or blockade (antagonist) natural adjusting molecule to expression of target gene influential and this interactional specificity and intensity.
In following examples, with cotransfection experiments and standard IR in conjunction with the selected activity of transcribing receptor modulator compounds of experimental evaluation the present invention.
Embodiment 6
Cotransfection experiments
Existing people described function and the detailed preparation flow that dyes experiment altogether.Referring to: " from the human progesterone receptor modulator of the non-steroid class of marine alga Cymopolia barbata ", C.Pathirana, R.B.Stein, T.S.Berger, W.Fenical, T.Ianiro, D.E.Mais, A.Torres, M.E.Goldman, Mol.Pharm., 47 (1995) 630-635 (hereinafter referred to as " Pathirana ").Briefly; the cotransfection test is exactly by standard coprecipitation of calcium phosphate flow process (referring to Berger); with containing reporter gene, MTV-LUC reporter gene, pBS-β-Gal and mending the plasmid of flat DNA (Rous sarcoma virus chloramphenicol acetyltransferase), in the CV-1 of transient transfection cell (African green monkey kidney fibroblast), carry out.The agonist activity is determined in expression (normalization method is replied) by check LUC, and the readout of rendeing a service is the relative value of expressing with respect to the maximum LUC that reference agonist (as the dexamethasone of the Progesterone of hPR, the dihydrotestosterone of hAR (DHT), hGR, the aldosterone of hMR and the estradiol of hER) produces.All cotransfection tests all are that 96 orifice plates (Beckman Biomomek automated workstation) with automatization carry out.
Receptor binding assays
Existing people has described and has been used for hPR-A, hGR and the AR acceptor preparation (referring to Pathirana) in conjunction with test.
Following table 1-2 has shown the agonist, antagonist of progesterone receptor modulator compounds that the present invention selectes and PR canonical reference compound and in conjunction with the result of activity test, and selected compounds is to the cross reactivity of AR, ER, MR and GR acceptor.Reply expression effectiveness with respect to above-mentioned with reference to agonist and the viewed maximum of agonist compounds with each compound.Table 1-2 has also write down the effectiveness or the IC of the antagonist of each compound
50(maximum is replied reduce by 50% concentration (nM), agonist effectiveness or EC
50(nM).
Table 1: progesterone receptor modulator compounds of the present invention and with reference to agonist compound Progesterone (Prog) with reference to the agonist of agonist compounds RU486 and ZK299, antagonist with in conjunction with active.
| Compound | PR agonist CV-1 cell | PR antagonist CV-1 cell | The PR combination | ||
| Numbering | Render a service (%) | Performance (nM) | Render a service (%) | Performance (nM) | ????K i??(nM) |
| ??Prog | ????100 | ????2.9 | ????na | ????na | ????3.5 |
| ??RU486 | ????na | ????na | ????96 | ????0.18 | ????0.58 |
| ??ZK299 | ????na | ????na | ????99 | ????1.6 | ????18 |
| ??14 | ????30 | ????2500 | ????95 | ????25 | ????172 |
| ??20 | ????30 | ????500 | ????80 | ????20 | ????17 |
| ??24 | ????na | ????na | ????84 | ????98 | ????181 |
| ??25 | ????46 | ????623 | ????87 | ????23 | ????65 |
| ??26 | ????60 | ????1000 | ????68 | ????16 | ????20 |
Na=does not have activity (i.e. effectiveness＜20 and performance＞10,000)
Nt=is test not
Table 2: the progesterone receptor modulator compounds selected of the present invention shown in the table 1 and with reference to agonist and agonist compounds total agonist and antagonist performance to PR, AR, ER, GR and MR.
| Compound | The PR performance | The AR performance | The ER performance | The GR performance | The MR performance | |||
| Numbering | Agonist (nM) | Antagonist (nM) | Agonist (nM) | Antagonist (nM) | Agonist (nM) | Antagonist (nM) | Antagonist (nM) | Antagonist (nM) |
| Compound | The PR performance | The AR performance | The ER performance | The GR performance | The MR performance | |||
| Numbering | Agonist (nM) | Antagonist (nM) | Agonist (nM) | Antagonist (nM) | Agonist (nM) | Antagonist (nM) | Antagonist (nM) | Antagonist (nM) |
| ????14 | ????2500 | ????25 | ????na | ????200 | ????na | ????na | ????na | ????na |
| ????20 | ????500 | ????20 | ????na | ????1000 | ????na | ????na | ????na | ????na |
| ????24 | ????na | ????98 | ????na | ????130 | ????na | ????na | ????na | ????na |
| ????25 | ????623 | ????23 | ????na | ????100 | ????na | ????na | ????na | ????na |
| ????26 | ????1000 | ????16 | ????na | ????300 | ????na | ????na | ????na | ????na |
| ????Prog | ????3 | ????na | ????1300 | ????na | ????na | ????na | ????na | ????nt |
| ???RU486 | ????na | ????0.1 | ????na | ????12 | ????na | ????1500 | ????0.7 | ????1100 |
| ????DHT | ????na | ????1800 | ????6 | ????na | ????1700 | ????na | ????na | ????nt |
| ????Flut | ????na | ????1900 | ????na | ????26 | ????na | ????na | ????na | ????na |
| ????Estr | ????nt | ????nt | ????na | ????na | ????7 | ????na | ????na | ????nt |
| ??ICI164 | ????na | ????na | ????na | ????na | ????na | ????160 | ????na | ????na |
| ????Spir | ????nt | ????268 | ????nt | ????nt | ????na | ????na | ????2000 | ????25 |
Na=does not have activity (i.e. effectiveness＜20 and performance＞10,000); Nt=is test not
Pharmacology and other application
As will be understood by the skilled person in the art, PR conditioning agent compound of the present invention can be used for needing in PR antagonist or the active medicinal application of agonist and needs will with the minimized medicinal application of cross reaction of other steroid receptoroids except that IR in.Use in the body of the present invention and comprise and give Mammals (especially people) compound disclosed herein.
Provide following examples so that the drug regimen composition formula to be described:
Embodiment 7
Prepare hard capsule with following composition:
Amount (mg/ capsule) compound 26 140 starch (doing) 100 Magnesium Stearates 10
Total amount (mg) 250
Said components is mixed, with every part of 250mg hard capsule of packing into.
Prepare tablet with following composition:
Amount (mg/ tablet) compound 26 140 Mierocrystalline celluloses, crystallite 200 silicon-dioxide, superfine powder 10 stearic acid 10
Total amount (mg) 360
Said components is mixed, be pressed into tablet with 360mg.
Amount (mg/ tablet) compound 26 60.0 starch 45.0 celluloses, crystallite 35.0 polyvinylpyrrolidones (PVP) (in water 10% 4.0 solution) sodium carboxymethyl starch (SCMC) 4.0 dolomols 0.5 talcum powder 1.0
Total amount (mg) 150.0
Activeconstituents, starch and Mierocrystalline cellulose are sieved with No.45 order U.S. sieve, thoroughly mix.With PVP solution and the powder mixes that so obtains, sieve with No.14 order U.S. sieve then.The particle that so produces 50 ℃ of dryings, and is sieved with No.18 order U.S. and to sieve.Sieve sieve SCMS, Magnesium Stearate and talcum powder with No.60 order U.S. in advance, be added to then in the particle, mix back compressing tablet on tabletting machine, every is 150mg.
Suppository respectively contains the 225mg activeconstituents by being prepared as follows.Compound 225mg saturated fatty acid glyceride 2,000mg
Total amount 2,225mg
Activeconstituents is sieved with No.60 order U.S. sieve, be suspended in (if desired in advance with the lowest temperature fusion) in the saturated fatty acid glyceride.Then compound is poured into (2g capacity) in the suppository mould, make its cooling.
By being prepared as follows iv formulation: compound 100mg isotonic saline solution 1,000ml glycerine 100ml
Compound dissolution in glycerine, is slowly diluted this solution with isotonic saline solution then.Give the patient with 1ml/ minute speed with the solution intravenously of mentioned component again.
In view of patent law, preferred embodiment and processing conditions are provided, but scope of the present invention has not been played any restriction.To those skilled in the art, can under situation about not departing from the scope of the present invention with spirit, carry out various improvement and variation to the present invention.
Therefore should be to the understanding of the scope of the invention with reference to appending claims.
Claims (11)
1. compound or its pharmacy acceptable salt that is following formula:
Wherein:
R
1To R
6Respectively be hydrogen, F, Cl, Br, I, NO
2, CN, OR
10, NR
10R
11, SR
10, COR
12, CO
2R
12, CONR
10R
11, the optional C that replaces
1-C
6Alkyl or assorted alkyl, C
1-C
6Haloalkyl, the optional C that replaces
3-C
8Cycloalkyl, the optional C that replaces
2-C
6Alkenyl or alkynyl, the optional allyl group that replaces, the optional aryl that replaces or heteroaryl or the optional arylmethyl that replaces, wherein R
10And R
11Respectively be hydrogen, C
1-C
6Alkyl or assorted alkyl or haloalkyl, aryl, heteroaryl, the optional allyl group that replaces, optional arylmethyl, the COR that replaces
13, SO
2R
13Or S (O) R
13, R wherein
12Be hydrogen, C
1-C
6Alkyl or assorted alkyl or haloalkyl, aryl, heteroaryl, the optional allyl group that replaces or the optional arylmethyl that replaces, wherein R
13Be hydrogen, C
1-C
6Alkyl or haloalkyl, aryl, heteroaryl, the optional allyl group that replaces or the optional arylmethyl that replaces;
R
7Be hydrogen, C
1-C
6Alkyl or haloalkyl or assorted alkyl, aryl, arylmethyl, heteroaryl, COR
12, CO
2R
12, SO
2R
12, S (O) R
12Or CONR
10R
11, R wherein
10-12Definition as above;
R
8And R
9Respectively be hydrogen, C
1-C
6Alkyl or haloalkyl or assorted alkyl, the optional C that replaces
2-C
6Alkenyl or alkynyl, the optional allyl group that replaces, the optional arylmethyl that replaces, the optional aryl that replaces or the optional heteroaryl that replaces;
X is OCH
2, SCH
2, NHCH
2, OC (O), SC (O), NHC (O), CH
2O, CH
2S, CH
2NH, C (O) O, C (O) S or C (O) NH;
Y is O, S or NR
10, R wherein
10Definition as above; With
Z is O, S, NR
14, CR
14R
15, CR
14R
15CR
16R
17, OCR
14R
15, SCR
14R
15, CR
14R
15S, NR
14CR
15R
16, or CR
14R
15NR
16, R wherein
14To R
17Respectively be hydrogen, C
1-C
6Alkyl or haloalkyl or assorted alkyl, the optional C that replaces
2-C
6Alkenyl or alkynyl, the optional allyl group that replaces, the optional arylmethyl that replaces, the optional aryl that replaces or the optional heteroaryl that replaces.
2. compound as claimed in claim 1 or its pharmacy acceptable salt is characterized in that they are selected from: 7-fluoro-4,4-dimethyl-5H-chromene [3,4-f]-1,3-benzo [d] oxazine-2-ketone (compound 14); 9-bromo-7-fluoro-4,4-dimethyl-5H-chromene [3,4f]-1,3-benzo [d] oxazine-2-ketone (compound 20); 7-fluoro-9-formyl radical-4,4-dimethyl-5H-chromene [3,4-f]-1,3-benzo [d] oxazine-2-ketone (compound 24); 7-fluoro-9-oxyimino methyl-4,4-dimethyl-5H-chromene [3,4-f]-1,3-benzo [d] oxazine-2-ketone (compound 25); 9-cyano group-7-fluoro-4,4-dimethyl-5H-chromene [3,4-f]-1,3-benzo [d] oxazine-2-ketone (compound 26).
3. a pharmaceutical composition is characterized in that, described composition contain pharmaceutically acceptablely be suitable in the intestines, the carrier and the described compound of one or more claims 1 of parenteral or topical.
4. compound as claimed in claim 1 is characterized in that, described compound is regulated the process that is mediated by one or more steroid receptoroids that are selected from progesterone receptor and androgen receptor.
5. compound as claimed in claim 1 is characterized in that, described compound can be regulated female hormone responsiveness disease.
6. compound as claimed in claim 1 is characterized in that, described compound can be regulated male hormone responsiveness disease.
7. the method with the described compounds for treating hormone response of claim 1 disease is characterized in that, in the described method with the described compound of claim 1 and progesterone receptor agonist, androgen receptor agonist or the two Combined Preparation.
8. one kind is caused the Mammals method of contraception, it is characterized in that described method comprises the described compound of the claim 1 of the Mammals of these needs medicine effective quantity or its pharmacy acceptable salt.
9. the method for a treatment or prevention Mammals uterine mucosa, ovary, mammary gland, colon or prostatic cancer or gland cancer, it is characterized in that described method comprises the described compound of the claim 1 of the Mammals of these needs medicine effective quantity or its pharmacy acceptable salt.
10. the method for treatment or the optimum or malignant neoplastic disease of prevention Mammals is characterized in that described method comprises the described compound of the Mammals of these needs claim 1 or its pharmacy acceptable salt.
11. method as claimed in claim 10, it is characterized in that, described optimum or malignant neoplastic disease is selected from: fibroma uteri, endometriosis, benign prostatic hyperplasia, the cancer of uterine mucosa, ovary, mammary gland, colon, prostate gland or hypophysis and gland cancer, meningofibroblastoma or other hormone-dependent tumors.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US30461499A | 1999-05-04 | 1999-05-04 | |
| US09/304,614 | 1999-05-04 | ||
| US09/552,353 US6358947B1 (en) | 1999-05-04 | 2000-04-19 | Tetracyclic progesterone receptor modulator compounds and methods |
| US09/552,353 | 2000-04-19 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1353717A true CN1353717A (en) | 2002-06-12 |
Family
ID=26974128
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN00808438A Pending CN1353717A (en) | 1999-05-04 | 2000-05-01 | Tetracyclic progesterone receptor modulator compounds and methods |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP1175422A2 (en) |
| CN (1) | CN1353717A (en) |
| AU (1) | AU4501800A (en) |
| CA (1) | CA2371273A1 (en) |
| HK (1) | HK1043788A1 (en) |
| WO (1) | WO2000066590A2 (en) |
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| ATE375160T1 (en) * | 1999-08-31 | 2007-10-15 | Bayer Schering Pharma Ag | MESOPROGESTINS FOR THE TREATMENT AND PREVENTION OF HORMONE-DEPENDENT BENICAENT GYNECOLOGICAL DISORDERS |
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| US8519158B2 (en) | 2004-03-12 | 2013-08-27 | Ligand Pharmaceuticals Incorporated | Androgen receptor modulator compounds and methods |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE69533180T2 (en) * | 1994-12-22 | 2005-07-14 | Ligand Pharmaceuticals, Inc., San Diego | Steroid receptor modulator compounds and methods |
| US5693646A (en) * | 1994-12-22 | 1997-12-02 | Ligand Pharmaceuticals Incorporated | Steroid receptor modulator compounds and methods |
-
2000
- 2000-05-01 CN CN00808438A patent/CN1353717A/en active Pending
- 2000-05-01 WO PCT/US2000/011750 patent/WO2000066590A2/en not_active Application Discontinuation
- 2000-05-01 EP EP00926495A patent/EP1175422A2/en not_active Ceased
- 2000-05-01 AU AU45018/00A patent/AU4501800A/en not_active Abandoned
- 2000-05-01 CA CA002371273A patent/CA2371273A1/en not_active Abandoned
-
2002
- 2002-06-28 HK HK02104861.6A patent/HK1043788A1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| WO2000066590A3 (en) | 2001-02-08 |
| CA2371273A1 (en) | 2000-11-09 |
| WO2000066590A2 (en) | 2000-11-09 |
| HK1043788A1 (en) | 2002-09-27 |
| AU4501800A (en) | 2000-11-17 |
| EP1175422A2 (en) | 2002-01-30 |
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