CN1207091A - 1-arylsulphonyl, aryl(thio) carbonyl pyridazino derivatives and methods of preparation - Google Patents
1-arylsulphonyl, aryl(thio) carbonyl pyridazino derivatives and methods of preparation Download PDFInfo
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- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/50—Pyridazines; Hydrogenated pyridazines
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- 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
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- 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
- A61P15/06—Antiabortive agents; Labour repressants
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
- C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
- C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
- C07D237/36—Benzo-cinnolines
Abstract
The present invention describes 1-Arylsulphonyl, arylcarbonyl and aryl(thio)carbonyl pyridazino derivatives and processes for making said derivatives. The novel derivatives are non-steroidal heterocyclic compounds which act as selective progestins and/or antiprogestins having a high in vitro affinity for either the uterine, breast or bone progestin receptor. As such, the non-steroidal heterocyclic derivatives are useful for treatment in contraception, menopause, osteoporosis or endometriosis.
Description
Background of invention
In the claimed compound of synthetic the present invention, some intermediate is known.For example, Holava and Partyka disclose 3,4-diaza-1,2,3,9,10,10a-six hydrogen phenanthrene-2-ketone (A) and 3,4,4a, 5,6,7-six hydrogen-2H-benzo [6,7] suberane also [1,2c] pyridazine-2-ketone (B), people such as Toma and Cignarella disclose 2,4,4a, 5-tetrahydrochysene-3H-indeno [1,2-c] pyridazin-3-one (C).
The R.Danheiser professor has reported (oral) method by the synthetic used relevant midbody compound 7-bromo-4-methyl isophthalic acid-Tetralone an intermediate of Sertraline of the present invention (E) of 4-methyl isophthalic acid-Tetralone an intermediate of Sertraline (D) in MIT.Although Danheiser discloses the synthetic method of the compound of putting down in writing in the described document, the present invention adopts its similarity method to prepare to be used for the former not known compound of synthetic The compounds of this invention.
Trihalogenated benzene and cycloalkanones compound were not disclosed in the document.
As dihalo benzo cycloalkanones compound, has only Owton, W.M. and Brunavs, M. at Synthetic Communications 21,981, disclose 6 in (1991), 7-two fluoro-and 6,7-dichloro Tetralone an intermediate of Sertraline compound, but they prepare by different approaches.
Dibromo-benzene and cycloalkanones compound are unknown.
Except 8-bromo-1-Tetralone an intermediate of Sertraline, all bromo Tetralone an intermediate of Sertraline compounds all are known.
Claimed compounds of the present invention did not all disclose.
Detailed Description Of The Invention
The present invention relates to the compound that following formula I represents:
Wherein:
L is CO, CS or SO
2
R
1And R
2Be independently selected from following any one group: H, halogen, alkyl (C
1-C
6), haloalkyl (C
1-C
6), nitro, cyano group, carboxyl and carbalkoxy (C
1-C
6); Condition is, when L is SO
2The time, R
1And R
2Not hydrogen simultaneously;
R
3Be independently in following any replacement form one, two or three: H, halogen, alkyl (C
1-C
6), haloalkyl (C
1-C
6), nitro, carboxyl or carbalkoxy (C
1-C
6);
X is formula (CH
2)
nOr Y-(CH
2)
N-1Double-basis, wherein n is the integer of 1-3; With Y be O or S.
Except as otherwise noted, when using from the object of the invention and when independent use or with other groups, alkyl is meant 1-6 carbon atom, and it can be a straight chained alkyl, or when at least 3 carbon atoms, can be branched-chain alkyl.Halogen is meant chlorine, bromine, fluorine or iodine.Alkoxyl group is meant by the alkanol deutero-group with 1-6 carbon atom, and haloalkyl is meant the group of the alkyl that contains 1-3 carbon atom, for example trifluoromethyl.
Compound of the present invention is non-steroid heterocyclic compounds, and it can do external uterus, breast or bone progesterone receptor to be had selectivity progestogen and/or antiprogestin than high-affinity, and through intravenously, subcutaneous and Orally administered biologically active.Thereby they can be used for relevant contraception, menopause, endometriosis, mammary cancer, cyclesynchrony, termination of pregnancy, childbirth is induced or the treatment of osteoporosis.
Preferred embodiment
More particularly, the present invention relates to a series of non-steroid class Hete rocyclic derivatives, its active parody is outer to have activity than the progestogen and/or the antiprogestin of high-affinity to uterus, breast or bone progesterone receptor.
Preferred compound of the present invention is that wherein L is SO
2, R
1And R
2In at least one be halogen, R
3Be halogen and/or CF
3With X be (CH
2)
n, the compound of n=1-3 wherein.Another is organized preferred The compounds of this invention and comprises that wherein L is CO or CS, R
1And R
2Be hydrogen, R
3Be 3,4-dichloro and X are (CH
2)
n, the compound of n=1-3 wherein.
Compound of the present invention can prepare by following reaction scheme 1:
Reaction scheme 1
By reaction scheme 1 as can be seen, with method well known in the art for example Holava and the described method of Partyka (J.Med.Chem.14,262, (1971)), the benzo naphthenone (II) that suits to replace can be transformed into described ring-type hydrazone compound (III).Usually, this process comprises with Glyoxylic acid hydrate and alkali Compound I I is transformed into the acid of α beta unsaturated ketone, handles described reductive ketone acid by heating with zinc with described unsaturated compound reduction and with hydrazine subsequently in acetate, generates compound III.
Then, according to ordinary method J-L.Aubagnac for example, J.Elguero, R.Jacquier and R.Robert are at Bull.Chem.Soc.France 2859, (1972) method described in, in suitable solvent for example in the tetrahydrofuran (THF) (THF), by with for example lithium aluminium hydride or diborane reaction of reductive agent, the ring-type acylhydrazone (III) of described replacement can be transformed into described ring-type hydrazone compound (IV).
For example in the pyridine or containing alkali for example in the organic solvent such as THF or toluene of triethylamine, the benzoyl halogen of available suitable replacement or sulfonic acid halide form described non-steroid class Hete rocyclic derivatives (I) with gained ring-type hydrazone (IV) acidylate in suitable solvent.
Separate and the described product of purifying with well known to a person skilled in the art method, for example with described reaction mixture impouring diluted acid for example in the hydrochloric acid and with organic solvent for example methylene dichloride or the described mixture of ethyl acetate extraction, organic layer is concentrated, make residue crystallized or through the silica gel chromatography purifying, to contain the level part evaporation of described product and, obtain required compound described resistates recrystallization.
By in toluene with Lawesons reagent or P
2S
5Reaction can be transformed into thioamide analog compound (L=CS) with the acid amides that this method obtains.
Some described halo raw material is never known in the document.These compounds can prepare according to method described in the reaction scheme 2.
Reaction scheme 2
As implied above, in the presence of aluminum chloride, add 1.2 equivalent halogenating agents, can obtain two kinds of isomerized phenyl-monohalides and cycloalkanones compound, wherein said halogen be introduced in described ketone group between the position.In the presence of aluminum chloride, add greater than 2 normal halogenating agents, obtain described dihalo benzo cycloalkanones compound and two kinds of isomerized trihalogenated benzene and cycloalkanones compound.In addition, phenyl-monohalide and cycloalkanones compound can be with different halogen halogenations, the compound that obtains mixing replacement for example: 6-bromo-5-chloro-1-Tetralone an intermediate of Sertraline or 5-chloro-7-iodo-1-Tetralone an intermediate of Sertraline.
The activity of compound of the present invention is illustrated in conjunction with test and the test of stripped progestogenic by progesterone receptor.
Progesterone receptor is in conjunction with test
Method therefor is J.L.McGuire basically, and C.D.Bariso and A.P.Shroff are in the method described in the Biochemistry 13,319 (1974).
The uterus of new zealand rabbit (1.5-2.5kg) is placed among the cold buffer liquid A (0.01 M Tris-HCl, pH8.0,0.001M EDTA, 0.25M sucrose),, clean and homogenize in cold buffer liquid A the uterus chopping.With described homogenate (2g wet tissue/ml damping fluid) in 4 ℃, 200, under the 000G centrifugal 1 hour.Ultracentrifugal supernatant liquor level part is used as the acceptor goods.
By inciting somebody to action
3H-R5020 mixes and adds the known quantity non-labelled compound with described acceptor goods, is at war with in conjunction with test.This mixture was hatched under 4 ℃ 18 hours, with the activated carbon of dextran dressing will with the described compound of described receptors bind be free on compound separation in the solution, measure isotopic amount with described receptors bind.Compare with the isotopic keying action of contrast, resistance inhibitor action reaches 20% or when higher, it is significant that resistance inhibitor action is considered to.
Similar methods also can be used for measuring the binding affinity to the progesterone receptor that comes from breast or osseous tissue.
The antiprogestin that exsomatizes is tested
Utilize
3H-thymidine and T47-D cell combine to described compound to the T47-D proliferation of cells effect test.The compounds of this invention can be used for treating the physiological maladies that progestogen is regulated in the body, wherein demonstrates the enough influences to the growth of T47-D cell.
With of the effect of similar methods determination test compound to TE85 people's osteocyte.
T47-D (human breast clone) with conventional sterilising technology processing.Cell is kept in RPMI 1640 substratum that are supplemented with foetal calf serum (10%) and Regular Insulin (0.2I.U./ml).Make the cell trypsinize and go down to posterity with ordinary method.
Cell is placed 96 hole microtitre culture dish, in 37 ℃ of 95% air/5%CO
2Under the atmosphere, by in RPMI substratum (foetal calf serum of no phenol red, no Regular Insulin, 5% activated carbon treatment), hatching.After about 48 hours, substitute the substratum that is consumed, described cell was hatched about 22 hours, add with the fresh culture thing that contains the test compound (ultimate density is 0.1%) that is dissolved among the DMSO
3The H-thymidine also makes the described process of hatching carry out about 4 hours again, then, by adding excessive unlabelled thymidine described test is stopped.Clean cell, make it not contain the solubility thymidine, carry out trypsin acting and collection with ordinary method.Be attached among the DNA with liquid scintillation number scale mensuration
3The amount of H-thymidine.Main benchmark is a Promegestone, a kind of effective synthetic progestin and RU486, a kind of antiprogestin.Usually in the 0.1-1000nM concentration range, test compound is screened.If compound can activate or suppress the thymidine keying action, think that then this compound has activity.The result improves hyperplasia the concentration (SC of the required test compound of twice with compared with the control
200) or suppress the concentration (EC of Promegestone inductive hyperplasia 50% required compound
50) expression.When numerical value was lower than 1000nM, thinking had activity.The application facet of method therefor can be referring to following document: C.Christensen, D.Gunter, and D.Saunders and V.Malviya,
Gynecol.Oncol., 28, 25 (1987); J.Puzas, R.Drivdahl, G.Howard and D.Baylink,
Proc.Soc.Exp.Biol.Med., 166, 113 (1981); And I.Keydar, L.Chen, S.Karby, F.Weiss, J.Delarea, M.Raduy, S.Chaitcik and H.Brenner,
Eur.J.Cancer, 15, 659 (1979).
Table
Table 1 has provided molecular formula, fusing point, the described affinity in conjunction with test of the embodiment of the invention, and this affinity is to replace 50% by described rabbit uterus cytosol progesterone receptor (PR) is middle
3The concentration of the R5020 required compound of H mark is represented (IC
50), concentration unit is mmole/liters (* 10
-9And the ability that promotes or suppress R 5020 inductive T47D human breast cancer cell (T47D) proliferative effects M).In the T47D hurdle, if there is not records of values, then expression is not tested this specific compound.
Table 2 and 3 has provided molecular formula, fusing point and the activity of the several embodiment of the present invention, and this activity is with the average increment (CP) of 5 concentration sending down the fishbone hyperplasia effects expression or with by displacement 50%I in people's bone progesterone receptor (BPR)
125The vinyl of mark goes the concentration of testosterone required compound to represent (IC
50), concentration unit is mmole/liters (* 10
-9M).In the CP row, if there is not records of values, then expression is not tested this specific compound.
Table 1 sulfonamides
# R1 R2 X R3 PR T47D Molecular formula MP1 H Br (CH
2)
34-1 76 C
19H
18BrIN
2O
2S 180-12 H Br (CH
2)
24-1 10 C
18H
16BrIN
2O
2S 197-83 Br Br (CH
2)
24-1 2.4+337 C
18H
15Br
2IN
2O
2S 202-34 Cl H (CH
2)
24-1 8.3-654 C
18H
10ClIN
2O
2S 194-65 Br H (CH
2)
22,5-diCl 34-495 C
18H
15Cl
3N
2O
2S 186-7+ represents agonist SC
200NM (2 times to the irritating concentration of contrast)-expression is to the antagonist EC of R5020 inductive proliferative effect
50NM
Table 2 amides
# X R3 CP BPR Molecular formula MP6 (CH
2)
23,4-diCl 115 C
19H
16Cl
2N
2O 154-57 (CH
2)
33,5-diCl 120 8.4 C
20H
18Cl
2N
2O 115-68 (CH
2)
33,4-diF 4.8 C
20H
18F
2N
2O 117-89 (CH
2)
33,4-diCl 123 107 C
20H
18Cl
2N
2O 136-710 (CH
2)
23,4-diF 112 C
19H
16F
2N
2O 146-711 (CH
2)
23,5-diCl 113 11.6 C
19H
16Cl
2N
2O 141-212 OCH
23,4-diCl 107 3.6 C
18H
14Cl
2N
2O
2166-713 SCH
23,4-diCl 50 C
18H
14Cl
2N
2OS 145-614 CH
23,4-diCl 9.0 C
18H
14Cl
2N
2O 122-4
Table 3 thioamide analog
# X R3 CP BPR Molecular formula MP15 (CH
2)
33,5-diCl 109 23.3 C
20H
18Cl
2N
2S 149-5016 (CH
2)
33,4-diF 111 C
20H
18F
2N
2S 134-617 (CH
2)
33,4-diCl 115 32 C
20H
18Cl
2N
2S 140-118 (CH
2)
23,4-diF C
19H
16F
2N
2S 170-119 (CH
2)
23,4-diCl 87 44.3 C
19H
16Cl
2N
2S 110-120 (CH
2)
23,5-diCl 103 10.2 C
19H
16Cl
2N
2S 162-321 OCH
23,4-diCl 2.0 C
18H
14Cl
2N
2OS 187-822 CH
23,4-diCl 0.5 C
18H
14Cl
2N
2S 138-40
Contain well-mixed with pharmaceutical carrier, as the pharmaceutical composition process for preparing medicine preparation routinely of the The compounds of this invention of activeconstituents.According to the required dosage form of using, for example intravenously is used, oral or non-enteron aisle is used, and described carrier can be selected for use various multi-form.When the composition of preparation oral dosage form, can use any conventional medicine medium, can use for example water, ethylene glycol, oil, alcohol, seasonings, sanitas, toning agent etc. for oral liquid (as suspension, elixir and solution); Perhaps can use for example carriers such as starch, sucrose, thinner, granule, lubricant, tackiness agent, disintegrating agent for oral solid formulation (as pulvis, capsule or tablet).For the ease of using, tablet and capsule preferably exist with the oral unit dosage form form, obviously wherein will use solid pharmaceutical carriers.If desired, tablet can carry out sweet tablet or enteric coating with ordinary method.For non-enteron aisle preparation, in order to strengthen solvability or for anticorrosion purpose, although can use other compositions, common described carrier is to be made of sterilized water; Simultaneously the injection suspension agent can also be prepared, wherein appropriate liquid carrier, suspension agent etc. can be used.Usually, contain and had an appointment 1-500mg/kg/ days and preferably about 10-100mg/kg/ days described activeconstituents unitary doses pharmaceutical composition of the present invention of tablet, capsule, pulvis etc. for example, may be used for relevant contraception, menopause, endometriosis, mammary cancer, cyclesynchrony, termination of pregnancy, childbirth is induced or the treatment of osteoporosis, most possibly is used for the treatment of endometriosis, contraception and osteoporosis.Definite drug dose can be decided according to the situation of patient's age and the state of an illness and the specified disease for the treatment of.Example I. prepare the preparation of raw materials used and midbody compound in the final product of the present invention
Following A, B and C have partly described the preparation method of the raw material and the midbody compound that are used to prepare compound of the present invention.
A. the preparation of halo benzo cycloalkanones compound
In the following example, N-bromosuccinimide substitutes bromine and available N-chlorosuccinimide or chlorine and prepares described chlorinated compound.Can obtain described iodo analogue by N-iodosuccinimide.
2,3-bihydrogen-1-indenone (VI) VIIa, X=Br; VIIb, Y=Br; VIIc, X=Y=Br6-bromo-2,3-dihydro 1-Indanone (VIIb) and 4-bromo-2,3-dihydro 1-Indanone (VIIa)
Three mouthfuls of round-bottomed flasks of 250ml are installed water-cooled Liebig condenser, mechanical stirrer and with all pressures addition funnel of drying tube protection.In described flask, add Aluminum chloride anhydrous (16.6g, 0.125mol) and under agitation, in 3 minutes, divide two parts of addings to grind to form 2 of fine powder with mortar and pestle, and 3-bihydrogen-1-indenone (VI) (6.60g, 0.05mol), be accompanied by gentle heat release, discharge a large amount of HCl gas, described mixture became Vandyke brown homogeneous phase soup compound rapidly, with its restir 10 minutes.
In 10 minutes, and dripping bromine in the mixture under abundant stirring (3.1ml, 0.06mol).After adding bromine, molten mixture was heated 5 minutes in 80 ℃ of water-baths.Under awfully hot situation, in described mixture impouring 100g trash ice and 20ml concentrated hydrochloric acid, then described ice mixture was stirred 10 minutes, (2 * 100ml) extract with the dilution of 100ml water and with ether.(2 * 100ml) washings are also used anhydrous sodium sulfate drying to the ether extraction liquid water that merges, and concentrate, and obtain the 10.6g red oil, and it is left standstill crystallization under room temperature.
Product is through the GC-MS analysis revealed, and product is 1: 1 one a bromo mixture of isomers.(45 * 10cm) upward carry out chromatographic separation with normal hexane/THF (8: 1), thereby separate described isomer in silicagel column with described product.Isolating isomer obtains 3.8g 6-bromo-2 respectively at recrystallization in the hexane, 3-dihydro 1-Indanone (VIIa) and 4.0g 4-bromo-2,3-dihydro 1-Indanone (VIIb).
VIIa: productive rate 37.7%; Mp 108-109 ℃, light yellow prism; IR (KBr) 1712cm
-1 1H NMR (CDCl
3) δ 2.70-2.74 (m, 2H), 3.08-3.12 (m, 2H), 7.35-7.38 (d, 1H), 7.66-7.70 (dd, 1H), 7.87-7.88 (d, 1H); Ms m/z 211; Ultimate analysis C
9H
7BrO: calculated value: C, 51.22; H, 3.34.Measured value: C, 51.10; H, 3.25.
VIIb: productive rate 35.8%; Mp 90-92 ℃, light yellow prism; IR (KBr) 1709cm
-1 1H NMR (CDCl
3) δ 2.71-2.75 (m, 2H), 3.06-3.09 (m, 2H), 7.25-7.30 (dd, 1H), 7.69-7.71 (d, 1H), 7.74-7.76 (dd, 1H); Ms m/z 211; Ultimate analysis C
9H
7BrO: calculated value: C, 51.22; H, 3.34.Measured value: C, 50.38; H, 3.24.7-bromo-1-Tetralone an intermediate of Sertraline (IXa) and 5-bromo-1-Tetralone an intermediate of Sertraline (IXb)
The 1-Tetralone an intermediate of Sertraline, (Vm) IXa, X=Br; IXb, Y=Br
In following 3 minutes of vigorous stirring, with 1-Tetralone an intermediate of Sertraline (VIII) (7.3g, 0.05mol) be added drop-wise to Aluminum chloride anhydrous (16.6g, 0.125mol) in, in 10 minutes, in the gained soup compound, add bromine (3.71ml, 0.06mol).After adding bromine,, the mixture that still is molten is poured in the 150g trash ice that contains 20ml 12N HCl mixture heating up to 80 ℃ 5 minutes.After handling as described in the embodiment 1, obtain the 10.85g brown oil.(45 * 10cm) upward use hexane: THF (8: 1) to carry out chromatographic separation to described graft in silicagel column.Isolating isomer obtains 4.2g 7-bromo-1-Tetralone an intermediate of Sertraline (IXa) and 4.5g 5-bromo-1-Tetralone an intermediate of Sertraline (IXb) respectively at recrystallization in the hexane.
IXa: productive rate 37.2%; Mp 74-75 ℃, light yellow prism; IR (KBr) 1676cm
-1 1H NMR (CDCl
3) δ 2.09-2.18 (m, 2H), 2.63-2.67 (t, 2H), 2.89-2.93 (t, 2H), 7.13-7.16 (d, 1H), 7.55-7.58 (dd, 1H), 8.14-8.15 (d, 1H); Ms m/z 225; Ultimate analysis C
10H
9BrO: calculated value: C, 53.36; H, 4.03.Measured value: C, 53.14; H, 3.96.
IXb: productive rate 39.8%; Mp 45-46 ℃, light yellow prism; IR (KBr) 1679cm
-1 1H NMR (CDCL
3) δ 2.11-2.20 (m, 2H), 2.62-2.67 (t, 2H), 2.94-3.03 (t, 2H), 7.15-7.21 (dd, 1H), 7.71-7.74 (dd, 2H), 7.99-8.02 (dd, 1H); Ms m/z 225; Ultimate analysis C
10H
9BrO: calculated value: C, 53.36; H, 4.03.Measured value: C, 52.97; H, 3.94.5,7-two bromo-1-Tetralone an intermediate of Sertraline (IXc), 5,6,7-three bromo-1-Tetralone an intermediate of Sertraline (IXd) and 5,7,8-three bromo-1-Tetralone an intermediate of Sertraline (Ixe)
IXc，X＝Y＝Br，W＝Z＝H
IXd，X＝Y＝W＝Br，Z＝H；IXe，X＝Y＝Z＝Br，W＝H
As described in embodiment 1, (7.42g 0.12mol) is added drop-wise to that (16.6g 0.125mol) and 1-Tetralone an intermediate of Sertraline (VIII) (0.05mol) in the soup compound of gained, obtains the 15.0g brown oil, it is left standstill crystallization handle by Aluminum chloride anhydrous with bromine.GC-MS shows that mixture contains 1: 1 mixture of 87% 2 bromo product and 13% 3 bromo product.Through chromatographic separation and in hexane recrystallization, obtain 7.7g.
IXc: productive rate 51%; Mp 60-61 ℃, light yellow prism; IR (KBr) 1690cm
-1 1H NMR (CDCl
3) δ 2.11-2.20 (m, 2H), 2.62-2.66 (dd, 2H), 2.93-2.97 (t, 2H, J=6.2Hz), 7.88 (d, 1H, J=2Hz), 8.13 (d, 1H, J=2Hz), ms m/z 304; Ultimate analysis C
10H
8Br
2O: calculated value: C, 39.51; H, 2.65.Measured value: C, 39.41; H, 2.49.8-bromo-1-benzosuberone (XIa) and 6-bromo-1-benzosuberone (XIb)
X XIa, X=Br; XIb, Y=Br; XIc, X=Y=Br
General method according to the described bromo Tetralone an intermediate of Sertraline of preparation as detailed above compounds, after routine is handled, by benzosuberone (X) (8.01g, 0.05mol), aluminum chloride (16.6g, 0.125mol) and bromine (3.07ml, mixture 0.06mol) makes the 11.87g brown oil.GC-MS shows that it is 1: 1 mixture that contains a bromo isomer of 2% described two bromo isomer.
XIa: productive rate 30%; Mp 38-38.5 ℃, pale powder; Ms m/z 239; Ultimate analysis C
11H
11BrO: calculated value: C, 55.25; H, 4.64.Measured value: C, 54.83; H, 4.62.
XIb: productive rate 32%; Transparent oily matter bp 101-105@0.12mmHg; Ms m/z=239; Ultimate analysis C
11H
11BrO: calculated value: C, 55.25; H, 4.64.Measured value: C, 55.32; H, 4.59.5,6-two bromo-1-Tetralone an intermediate of Sertraline XIIa and 6,7-two bromo-1-Tetralone an intermediate of Sertraline XIIb
XII XIIa, Y=Br, X=H
XIIb，X＝Br，Y＝H
According to the same procedure of as detailed above bromination Tetralone an intermediate of Sertraline, after routine is handled, by 6-bromo-1-Tetralone an intermediate of Sertraline XII (2g, mmol), aluminum chloride (16.6g, 0.125mol) and bromine (3.07ml, mixture 0.06mol) makes the 1.87g brown oil.
B. the preparation 3 of ring-type acylhydrazone compounds, 4-diaza-1,2,3,9,9a-tetrahydrochysene fluorenes-2-ketone (XIII)
As Toma, L., Cignarella, G., Bariocco, D. and Ronchetti, F. are at J.Med.Chem.33, and 1591-4 prepares described title compound described in 1990.3,4-diaza-1,2,3,9,10,10a-six hydrogen phenanthrene-2-ketone (XIV)
As Holava, H.M. and Partyka, R.A. be at J.Med.Chem.14, and 262, the described title compound of preparation described in (1971).3,4,4a, 5,6,7-six hydrogen-2H-benzo [6,7] suberane is [1,2-c] pyridazine-2-ketone (XV) also
As Holava, H.M. and Partyka, R.A. be at J.Med.Chem.14, and 262, the described title compound of preparation described in (1971).8-bromo-3,4-diaza-1,2,3,9,10,10a-six hydrogen phenanthrene-2-ketone (XVI)
Described title compound prepares by following method, promptly use Glyoxylic acid hydrate (20mmol) to handle 5-bromo-1-Tetralone an intermediate of Sertraline (IXb) (20mmol), according to Holava, H M. and Partyka, R.A. at J.Med.Chem.14,262, ordinary method described in (1971), in acetate, described product is handled with the excess zinc reduction and with excessive hydrazine, obtained described title compound.7,8-two bromo-3,4-diaza-1,2,3,9,10,10a-six hydrogen phenanthrene-2-ketone (XVII)
Described title compound prepares by following method, promptly use Glyoxylic acid hydrate (10mmol) to handle 5,6-two bromo-1-Tetralone an intermediate of Sertraline (XIIa) (10mmol), as Holava, H.M. and Partyka, R.A. is at J.Med.Chem.14,262, (1971) described in, in acetate, described product is also handled with excessive hydrazine subsequently with the excess zinc reduction, obtained described title compound.7-chloro-3,4-diaza-1,2,3,9,10,10a-six hydrogen phenanthrene-2-ketone (XVIII)
Described title compound prepares by following method, promptly uses Glyoxylic acid hydrate 50mmol and alkaline purification 6-chloro-1-Tetralone an intermediate of Sertraline (Rosowsky, A., Chaykovsky, M., Yeager, S.A., wait people J.Her.Chem.8,809, (1971)) 50mmol, then as Holava, H.M. and Partyka, R.A. at J.Med.Chem.14,262, described in (1971), in acetate,, obtain described title compound with the excess zinc reduction and subsequently with excessive hydrazine processing.8-bromo-3,4,4a, 5,6,7-six hydrogen-2H-benzo [6,7] suberane is [1,2-c] pyridazine-2-ketone (XIX) also
Described title compound prepares by following method, promptly handle 6-bromo-1-benzosuberone XIb with Glyoxylic acid hydrate, then as Holava, H.M. and Partyka, R.A. at J.Med.Chem.14,262, described in (1971), in acetate,, obtain described title compound with the excess zinc reduction and subsequently with excessive hydrazine processing.
C. the preparation 3 of ring-type hydrazone compounds, 4-diaza-1,2,3,9,10,10a-six hydrogen phenanthrene (XX)
With 3,4-diaza-1,2,3,9,10, (2.5g 12.5mmol) is dissolved in THF and drip 1 equivalent lithium aluminium hydride (21ml, 1M THF solution) to 10a-six hydrogen phenanthrene-2-ketone (XIV).In 22 ℃ after 30 minutes, drip 15%NaOH solution and with sedimentation and filtration as a form of gel.Filtrate is with dried over mgso and filter, be evaporated to dried, an oily matter, need not purifying, used as described raw material.7-chloro-3,4-diaza-1,2,3,9,10,10a-six hydrogen phenanthrene (XXI)
With 7-chloro-3,4-diaza-1,2,3,9,10,10a-six hydrogen phenanthrene-2-ketone (XVIII) are dissolved in THF and drip 1 equivalent lithium aluminium hydride (1M THF solution).In 22 ℃ after 30 minutes, drip 15%NaOH solution and with sedimentation and filtration.Filtrate is used dried over mgso, filter and be evaporated to dried, an oily matter, need not purifying, used as described raw material.8-bromo-3,4,4a, 5,, 6,7-six hydrogen-2H-benzo [6,7] suberane is [1,2-c] pyridazine (XXII) also
With 8-bromo-3,4,4a, 5,6,7-six hydrogen-2H-benzo [6,7] suberane also [1,2-c] pyridazine-2-ketone (XIX) (1g 3.4mmol) is dissolved in THF and drip 2 equivalent diboranes (1M THF solution).In 22 ℃ after 2 hours, reaction is with 1ml 6M HCl quenching and with the neutralization of 50%NaOH solution, then with dried over mgso and filter.Filtrate is evaporated to dried, an oily matter, need not purifying, directly the use.8-bromo-3,4-diaza-1,2,3,9,10,10a-six hydrogen phenanthrene (XXIII)
With 8-bromo-3,4-diaza-1,2,3,9,10, (1.0g 3.6mmol) is dissolved in THF (100ml) and drip 2 equivalent diboranes (1M THF solution) to 10a-six hydrogen phenanthrene-2-ketone (XVI).In 22 ℃ after 1 hour, reacted in the vapor bath heating 5 minutes, then with 1ml 6M HCl quenching and with the neutralization of 15%NaOH solution, then with dried over mgso and filter.Filtrate is evaporated to dried, an oily matter, need not purifying, directly the use.7,8-two bromo-3,4-diaza-1,2,3,9,10,10a-six hydrogen phenanthrene (XXIV)
With 7,8-two bromo-3,4-diaza-1,2,3,9,10, (0.71g 1.98mmol) is suspended among the THF and dropping 2 equivalent diboranes (3.96ml 1M THF solution) under 22 ℃ 10a-six hydrogen phenanthrene-2-ketone (XVII).Mixture is heated to 45 ℃ slightly, so that all solids dissolving was stirred 60 hours then under room temperature.Reaction is used 1ml 6M HCl quenching and is neutralized with 50%NaOH solution, then with dried over mgso and filtration.Filtrate is evaporated to dried, an oily matter, need not purifying, used as described raw material.3,4-diaza-1,2,3,9,9a-tetrahydrochysene fluorenes (XXV)
With 3,4-diaza-1,2,3,9, (3.5g 17.5mmol) is dissolved in THF and drip 1 equivalent lithium aluminum hydride (1M THF solution) to 9a-tetrahydrochysene fluorenes-2-ketone (XIII).In 22 ℃ after 30 minutes, drip 15%NaOH solution and also filter precipitation as a form of gel.Filtrate is used dried over mgso, filter and be evaporated to dried, an oily matter, need not purifying, used as described raw material.3,4-diaza-9-oxa--1,2,3,9,10,10a-six hydrogen phenanthrene (XXVI)
As mentioned above, will be with 2 equivalent diboranes as Cignarella, G.; Barlocco, D.; Curzu, M.M.; Pinna, G.A.; Cazzulani, P.; Cassin, M.; Lumachi, B.Eur.J.Med.Chem.25 (9), 749-56, described in (1990) 3 of preparation, 4-diaza-9-oxa--1,2,3,9,10, the reduction of 10a-six hydrogen phenanthrene-2-ketone (15mmol).3,4-diaza-9-thia-1,2,3,9,10,10a-six hydrogen phenanthrene (XXVII)
As mentioned above, will be with 2 equivalent diboranes as Nakao, Tohru; Tanaka, Hiroshi; Morimoto, Yasuto; Takehara, Shuzo; Demizu, Kenichi; Tahara, TetsuyaYakugaku Zasshi, 110 (12), 922-31, described in (1990) 3 of preparation, 4-diaza-9-thia-1,2,3,9,10, the reduction of 10a-six hydrogen phenanthrene-2-ketone (10mmol).
The following example only is used to illustrate the present invention, and the scope of the invention is not played the qualification effect.
EXAMPLE Example 1:8-bromo-3,4,4a, 5,6,7-six hydrogen-2-(4-iodobenzene alkylsulfonyl)-2H-benzo [6,7] suberane is [1,2-c] pyridazine also
In 50ml methylene dichloride and 50ml pyridine, with 8-bromo-3,4,4a, 5,6,7-six hydrogen-2H-benzo [6,7] suberane is [1,2-c] pyridazine (XIX) (1.0g also, 3.6mmol) and Pipsyl Chloride (1.1g 3.6mmol) mixes, and mixture stirred 64 hours down in 22 ℃, became scarlet.With the mixture concentrating under reduced pressure and with in pyridine solution impouring 6M HCl and the ice, use dichloromethane extraction.With the organic layer concentrating under reduced pressure and through filtered through silica gel, use the methylene dichloride wash-out, obtain the 1.3g pale solid, with its recrystallization in isopropanol/chloroform, obtain white solid, mp180-181 ℃.Ultimate analysis C
19H
18BrIN
2O
2S: calculated value: C, 41.85; H, 3.33; N, 5.14.Measured value: C, 41.68; H, 3.27; N, 5.03.Embodiment 2:8-bromo-3,4-diaza-1,2,3,9,10,10a-six hydrogen-3-(4-iodobenzene alkylsulfonyl) phenanthrene
In the 100ml pyridine with 8-bromo-3,4-diaza-1,2,3,9,10,10a-six hydrogen phenanthrene (XXI) (1.0g, 3.77mmol) and Pipsyl Chloride (1.14g 3.77mmol) mixes, and mixture stirred 16 hours down in 22 ℃, became scarlet.With in mixture impouring 6M HCl and the ice, use dichloromethane extraction then.With the organic layer concentrating under reduced pressure and through filtered through silica gel, use the methylene dichloride wash-out, obtain the 0.3g crude product, with its recrystallization in hexane, obtain the 0.28g pale solid, mp197-198 ℃.Ultimate analysis C
18H
16BrIN
2O
2S: calculated value: C, 40.76; H, 3.04; N, 5.27.Measured value: C, 40.59; H, 2.89; N, 5.06.Embodiment 3:7,8-two bromo-3,4-diaza-1,2,3,9,10,10a-six hydrogen-3-(4-iodobenzene alkylsulfonyl) phenanthrene
In the 100ml pyridine with 7,8-two bromo-3,4-diaza-1,2,3,9,10,10a-six hydrogen phenanthrene (XVII) (0.7g, 1.9mmol) and Pipsyl Chloride (0.65g 2.1mmol) mixes, and mixture stirred 16 hours down in 22 ℃, became scarlet.In mixture impouring 6M HCl and ice, use dichloromethane extraction.With the organic layer concentrating under reduced pressure and through filtered through silica gel, use the methylene dichloride wash-out, obtain crude product, with its recrystallization in hexane, obtain the 0.1g white solid, mp 202-203 ℃.Ultimate analysis C
18H
15Br
2IN
2O
2S: calculated value: C, 35.44; H, 2.48; N, 4.59.Measured value: C, 35.54; H, 2.47; N, 4.61.Embodiment 4:7-chloro-3,4-diaza-1,2,3,9,10,10a-six hydrogen-3-(4-iodobenzene alkylsulfonyl) phenanthrene
In 50ml methylene dichloride and 50ml pyridine, with 7-chloro-3,4-diaza-1,2,3,9,10,10a-six hydrogen phenanthrene (XXI) (1.1g, 5.0mmol) and Pipsyl Chloride (1.2g 3.9mmol) mixes, and mixture stirred 20 hours down in 22 ℃, became scarlet.With the mixture concentrating under reduced pressure and with in pyridine solution impouring 6M HCl and the ice, use dichloromethane extraction.With the organic layer concentrating under reduced pressure and through filtered through silica gel, use the methylene dichloride wash-out, obtain pale solid, with its recrystallization in hexane, obtain the 0.5g white solid, mp194-196 ℃.Ultimate analysis C
18H
10ClIN
2O
2S: calculated value: C, 44.42; H, 3.31; N, 5.76.Measured value: C, 44.73; H, 3.24; N, 5.31.Embodiment 5:7-chloro-3,4-diaza-1,2,3,9,10,10a-six hydrogen-3-(2,5-dichlorobenzene alkylsulfonyl) phenanthrene
In the 100ml pyridine with 7-chloro-3,4-diaza-1,2,3,9,10, (1.0g, 4.7mmol) and 2, (1.2g 4.9mmol) mixes the 5-two chloro phenylsulfonyl chloride 10a-six hydrogen phenanthrene (XXI), and mixture stirred 16 hours down in 22 ℃, became scarlet.In mixture impouring 6M HCl and ice, use dichloromethane extraction.With the organic layer concentrating under reduced pressure and through filtered through silica gel, use the methylene dichloride wash-out, obtain the 0.5g crude product, with its recrystallization in hexane/chloroform, obtain the 0.25g pale solid, mp186-187 ℃.Ultimate analysis C
18H
15Cl
3N
2O
2S: calculated value: C, 50.31; H, 3.52; N, 6.52.Measured value: C, 50.23; H, 3.45; N, 6.44.Embodiment 6:3-(3,4-dichloro-benzoyl base)-3,4-diaza-1,2,3,9,10,10a-six hydrogen phenanthrene
In the 100ml pyridine with 3,4-diaza-1,2,3,9,10, (2.67g, 14.3mmol) and 3,4-dichlorobenzoyl chloride (3.0g) mixes and is incorporated in 22 ℃ and stirred 16 hours down 10a-six hydrogen phenanthrene (XXI).With in the mixture impouring methylene dichloride and with 2M HCl washed twice, then with dried over mgso and filtration.Filtrate is concentrated and, use the methylene dichloride wash-out, obtain the 3.7g pale solid, mp154-5 ℃ through filtered through silica gel.Ultimate analysis C
19H
16Cl
2N
2O: calculated value: C, 63.52; H, 4.49; N, 7.80.Measured value: C, 63.18; H, 4.39; N, 7.52.Embodiment 7:2-(3,5-dichloro-benzoyl base)-3,4,4a, 5,6,7-six hydrogen-2H-benzo [6,7] suberane is [1,2c] pyridazine also
In the 75ml methylene dichloride, with 3,4,4a, 5,6,7-six hydrogen-2H-benzo [6,7] suberane also [1,2c] pyridazine (XV) (2.0g, 10mmol) and 3, (2.1g 10mmol) mixes and adds the 5ml triethylamine to the 5-dichlorobenzoyl chloride.Mixture stirred 16 hours down in 22 ℃, and reduction vaporization is to doing.Described resistates is dissolved in methylene dichloride and with rare HCl washing, and dried over mgso is filtered and composed purifying in the enterprising circumstances in which people get things ready for a trip of silica gel, uses the methylene dichloride wash-out, obtains the 2.5g white solid, mp115-116 ℃.Ultimate analysis C
20H
18Cl
2N
2O: calculated value: C, 64.35; H, 4.86; N, 7.50.Measured value: C, 64.38; H, 4.56; N, 7.56.Embodiment 8:2-(3,4-difluoro thiobenzoyl)-3,4,4a, 5,6,7-six hydrogen-2H-benzo [6,7] suberane is [1,2c] pyridazine also
In the 75ml methylene dichloride, with 3,4,4a, 5,6,7-six hydrogen-2H-benzo [6,7] suberane also [1,2c] pyridazine (XV) (2.0g, 10mmol) and 3, (2.1g 10mmol) mixes and adds the 5ml triethylamine to the 4-difluoro benzoyl chloride.Mixture stirred 16 hours down in 22 ℃, and reduction vaporization is to doing.Described resistates is dissolved in methylene dichloride and with rare HCl washing, and dried over mgso is filtered and composed purifying in the enterprising circumstances in which people get things ready for a trip of silica gel, uses the methylene dichloride wash-out, obtains the 2.8g light yellow solid, mp117-118 ℃.Ultimate analysis C
20H
18F
2N
2O: calculated value: C, 70.58; H, 5.33; N, 8.23.Measured value: C, 70.59; H, 5.26; N, 8.35.Embodiment 9:2-(3,4-dichloro-benzoyl base)-3,4,4a, 5,6,7-six hydrogen-2H-benzo [6,7] suberane is [1,2c] pyridazine also
In the 100ml methylene dichloride, with 3,4,4a, 5,6,7-six hydrogen-2H-benzo [6,7] suberane also [1,2c] pyridazine (XV) (2.24g, 11.2mmol) and 3, (2.34g 11.2mmol) mixes and adds the 10ml triethylamine to the 4-dichlorobenzoyl chloride.Mixture stirred 16 hours down in 22 ℃, and reduction vaporization is to doing.Described resistates is dissolved in methylene dichloride and with rare HCl washing, and dried over mgso is filtered and composed purifying in the enterprising circumstances in which people get things ready for a trip of silica gel, uses the methylene dichloride wash-out, obtains the 2.0g light yellow solid, mp136-137 ℃.Ultimate analysis C
20H
18Cl
2N
2O: calculated value: C, 64.35; H, 4.86; N, 7.50.Measured value: C, 64.29; H, 4.80; N, 7.39.Embodiment 10:3-(3, the 4-difluoro benzoyl)-3,4-diaza-1,2,3,9,10,10a-six hydrogen phenanthrene
In the 75ml methylene dichloride, with 3,4-diaza-1,2,3,9,10, (1.83g, 9.82mmol) with 3, (1.73g 9.82mmol) mixes and adds the 5ml triethylamine to the 4-difluoro benzoyl chloride to 10a-six hydrogen phenanthrene (XIV).Mixture stirred 16 hours down in 22 ℃, and reduction vaporization is to doing.Described resistates is dissolved in methylene dichloride and with rare HCl washing, and dried over mgso is filtered and composed purifying in the enterprising circumstances in which people get things ready for a trip of silica gel, uses the methylene dichloride wash-out, obtains the 1.4g white solid, mp146-147 ℃.Ultimate analysis C
19H
16F
2N
2O: calculated value: C, 69.93; H, 4.94; N, 8.58.Measured value: C, 69.78; H, 4.72; N, 8.79.Embodiment 11:3-(3,5-dichloro-benzoyl base)-3,4-diaza-1,2,3,9,10,10a-six hydrogen phenanthrene
In the 250ml methylene dichloride, with 3,4-diaza-1,2,3,9,10, (2.67g, 14.3mmol) with 3,5-dichlorobenzoyl chloride (3.0g) mixes and also adds the 10ml triethylamine 10a-six hydrogen phenanthrene (XIV).Mixture stirred 1 hour down in 22 ℃, and reduction vaporization is to doing.Described yellow residue is dissolved in methylene dichloride and with rare HCl washing, and dried over mgso is filtered and in the enterprising circumstances in which people get things ready for a trip spectrum of silica gel purifying, used ether/methylene dichloride (2: 1) wash-out, obtains the 3.0g white solid, mp141-142 ℃.Ultimate analysis C
19H
16Cl
2N
2O: calculated value: C, 63.52; H, 4.49; N, 7.84.Measured value: C, 63.45; H, 4.14; N, 7.70.Embodiment 12:3-(3,4-dichloro-benzoyl base)-3,4-diaza-9-oxa--1,2,3,9,10,10a-six hydrogen phenanthrene
In the 200ml methylene dichloride, with 3,4-diaza-9-oxa--1,2,3,9,10, (1.73g, 9.2mmol) with 3,4-dichlorobenzoyl chloride (1.93g) mixes and also adds the 150ml triethylamine the luxuriant and rich with fragrance XXVI of 10a-six hydrogen.Mixture stirred 14 hours down in 22 ℃, and reduction vaporization is to doing.Described yellow residue is dissolved in methylene dichloride and with rare HCl washing, and dried over mgso is filtered and composed purifying in the enterprising circumstances in which people get things ready for a trip of silica gel, uses the methylene dichloride wash-out, obtains the 1.2g pale solid, mp166-167 ℃.Ultimate analysis C
18H
14Cl
2N
2O
2: calculated value: C, 59.85; H, 3.91; N, 7.75.Measured value: C, 59.83; H, 3.86; N, 7.73.Embodiment 13:3-(3,4-dichloro-benzoyl base)-3,4-diaza-9-thia-1,2,3,9,10,10a-six hydrogen phenanthrene
In the 100ml methylene dichloride, with 3,4-diaza-9-thia-1,2,3,9,10, (1.33g, 6.6mmol) with 3, (1.38g 6.6mmol) mixes and adds the 100ml triethylamine to 4-two-chloro-benzoyl chloride to the luxuriant and rich with fragrance XXVII of 10a-six hydrogen.Mixture stirred 48 hours down in 22 ℃, and reduction vaporization is to doing.Described yellow residue is dissolved in methylene dichloride and with rare HCl washing, and dried over mgso is filtered and composed purifying in the enterprising circumstances in which people get things ready for a trip of silica gel, with ether/methylene dichloride (2: 1) wash-out, obtain the 1.0g pale solid, with its recrystallization in benzene-hexane, obtain the 0.84g white solid, mp145-146 ℃.Ultimate analysis C
18H
14Cl
2N
2OS: calculated value: C, 59.85; H, 3.91; N, 7.75.Measured value: C, 59.83; H, 3.86; N, 7.73.Embodiment 14:3-(3,4-dichloro-benzoyl base)-3,4-diaza-1,2,3,9,9a-tetrahydrochysene fluorenes
In the 100ml methylene dichloride, with 3,4-diaza-1,2,3,9, (1.6g, 9.3mmol) with 3, (1.95g 9.3mmol) mixes and adds the 10ml triethylamine to the 4-dichlorobenzoyl chloride to 9a-tetrahydrochysene fluorenes (XXV).Mixture stirred 16 hours down in 22 ℃, and reduction vaporization is to doing.Described resistates is dissolved in methylene dichloride and with rare HCl washing, and dried over mgso is filtered and composed purifying in the enterprising circumstances in which people get things ready for a trip of silica gel, uses the methylene dichloride wash-out, obtains the 1.1g pale solid, mp122-124 ℃.Ultimate analysis C
18H
14Cl
2N
2O: calculated value: C, 62.60; H, 4.09; N, 8.12.Measured value: C, 62.50; H, 4.11; N, 7.90.Embodiment 15:2-(3,5-dichloro thiobenzoyl)-3,4,4a, 5,6,7-six hydrogen-2H-benzo [6,7] suberane is [1,2c] pyridazine also
In 200ml toluene, with 2-described in the embodiment 7 (3,5-dichloro-benzoyl base)-3,4; 4a, 5,6,7-six hydrogen-2H-benzo [6; 7] suberane also [1,2c] pyridazine (1.22g, 3.27mmol) and thiophosphoric anhydride (2.14g, 3.9mmol) mix and be heated to 100 ℃ 1 hour.Filter with the mixture cooling and through layer of silica gel, use washed with dichloromethane.Filtrate is evaporated to dry doubling through the column chromatography purifying, uses the methylene dichloride wash-out, obtain the 1.2g yellow solid,, obtain required compound (1.0g), mp149-150 ℃ its recrystallization in ether.Ultimate analysis C
20H
18Cl
2N
2S: calculated value: C, 61.40; H, 4.66; N, 7.19.Measured value: C, 61.67; H, 4.65; N, 7.06.Embodiment 16:2-(3,4-difluoro thiobenzoyl)-3,4,4a, 5,6,7-six hydrogen-2H-benzo [6,7] suberane is [1,2c] pyridazine also
In 200ml toluene, with 2-described in the embodiment 8 (3,4-difluoro thiobenzoyl)-3,4; 4a, 5,6,7-six hydrogen-2H-benzo [6; 7] suberane also [1,2c] pyridazine (1.5g, 4.4mmol) and thiophosphoric anhydride (1.74g 5.3mmol) mixes and reflux 1 hour.Filter with the mixture cooling and through layer of silica gel, use washed with dichloromethane.Filtrate is evaporated to dry doubling through the column chromatography purifying, uses the methylene dichloride wash-out, obtain the 1.3g yellow solid,, obtain required compound (0.83g), mp134-136 ℃ its recrystallization in ether.Ultimate analysis C
20H
18F
2N
2S: calculated value: C, 67.40; H, 5.09; N, 7.86.Measured value: C, 67.28; H, 5.03; N, 7.94.Embodiment 17:2-(3,4-dichloro thiobenzoyl)-3,4,4a, 5,6,7-six hydrogen-2H-benzo [6,7] suberane is [1,2c] pyridazine also
In 150ml toluene, with 2-described in the embodiment 9 (3,4-dichloro-benzoyl base)-3,4; 4a, 5,6,7-six hydrogen-2H-benzo [6; 7] suberane also [1,2c] pyridazine (1.5g, 4.0mmol) and thiophosphoric anhydride (2.7g, 6mmol) mix and be heated to 100 ℃ 30 minutes.Filter with the mixture cooling and through layer of silica gel, use washed with dichloromethane.Filtrate is evaporated to dry doubling through the column chromatography purifying, uses the methylene dichloride wash-out, obtain the 1.3g yellow solid,, obtain required compound (1.0g), mpl40-141 ℃ its recrystallization in ether.Ultimate analysis C
20H
18Cl
2N
2S: calculated value: C, 61.40; H, 4.66; N, 7.19.Measured value: C, 61.78; H, 4.69; N, 7.09.Embodiment 18:3-(3,4-difluoro thiobenzoyl)-3,4-diaza-1,2,3,9, l0,10a-six hydrogen phenanthrene
In 150ml toluene, with 3-described in the embodiment 10 (3, the 4-difluoro benzoyl)-3,4-diaza-l, 2,3,9,10,10a-six hydrogen phenanthrene (1.0g, 3.06mmol) and thiophosphoric anhydride (2.05g 4.6mmol) mixes and reflux 1.5 hours.Filter with the mixture cooling and through layer of silica gel, use washed with dichloromethane.Filtrate is evaporated to dry doubling through the column chromatography purifying, uses the methylene dichloride wash-out, obtain the 0.8g yellow solid, mp170-171 ℃.Ultimate analysis C
19H
16F
2N
2S: calculated value: C, 66.65; H, 4.71; N, 8.18.Measured value: C, 66.32; H, 4.76; N, 8.19.Embodiment 19:3-(3,4-dichloro thiobenzoyl)-3,4-diaza-1,2,3,9,10,10a-six hydrogen phenanthrene
In 150ml toluene, with 3-described in the embodiment 10 (3,4-dichloro-benzoyl base)-3,4-diaza-1,2,3,9,10,10a-six hydrogen phenanthrene (1.06g, 2.95mmol) and thiophosphoric anhydride (1.17g 3.83mmol) mixes and reflux 1.5 hours.Filter with the mixture cooling and through layer of silica gel, use washed with dichloromethane.Filtrate is evaporated to dry doubling through the column chromatography purifying, uses the methylene dichloride wash-out, obtain the 0.8g yellow solid, mp110-111 ℃.Ultimate analysis C
19H
16Cl
2N
2S: calculated value: C, 60.80; H, 4.30; N, 7.46.Measured value: C, 60.74; H, 4.11; N, 7.47.Embodiment 20:3-(3,5-dichloro thiobenzoyl)-3,4-diaza-1,2,3,9,10,10a-six hydrogen phenanthrene
In 150ml toluene, with 3-described in the embodiment 11 (3,5-dichloro-benzoyl base)-3,4-diaza-1,2,3,9,10,10a-six hydrogen phenanthrene (1.5g, 4.2mmol) and thiophosphoric anhydride (1.69g, 4.2mmol) mix and be heated to 80 ℃ 1 hour.Filter with the mixture cooling and through layer of silica gel, use washed with dichloromethane.Filtrate is evaporated to dry doubling through the column chromatography purifying, uses the methylene dichloride wash-out, recrystallization in ether/hexane obtains the 1.1g yellow solid, mp162-163 ℃.Ultimate analysis C
19H
16Cl
2N
2S: calculated value: C, 60 80; H, 4.30; N, 7.46.Measured value: C, 60.78; H, 4.26; N, 7.22.Embodiment 21:3-(3,4-dichloro thiobenzoyl)-3,4-diaza-9-oxa--1,2,3,9,10,10a-six hydrogen phenanthrene
In 100ml toluene, with 3-described in the embodiment 12 (3,4-dichloro-benzoyl base)-3,4-diaza-9-oxa-1,2,3,9,10,10a-six hydrogen phenanthrene (0.6g, 1.66mmol) and thiophosphoric anhydride (0.96g 2.1mmol) mixes and reflux 1.5 hours.Filter with the mixture cooling and through layer of silica gel, use washed with dichloromethane.Filtrate is evaporated to dry doubling through the column chromatography purifying, uses the methylene dichloride wash-out, obtain the 0.5g yellow solid, mp187-188 ℃.Ultimate analysis C
18H
14Cl
2N
2OS: calculated value: C, 57.30; H, 3.74; N, 7.43.Measured value: C, 57.09; H, 3.75; N, 7.29.Embodiment 22:3-(3,4-dichloro thiobenzoyl)-3,4-diaza-1,2,3,9,9a-tetrahydrochysene fluorenes
In 100ml toluene, with 3-described in the embodiment 14 (3,4-dichloro-benzoyl base)-3,4-diaza-1,2,3,9,9a-tetrahydrochysene fluorenes (0.63g, 1.8mmol) and thiophosphoric anhydride (1.05g 2.3mmol) mixes and reflux 1.5 hours.Filter with the mixture cooling and through layer of silica gel, use washed with dichloromethane.Filtrate is evaporated to dry doubling through the column chromatography purifying, uses the methylene dichloride wash-out, obtain the 0.5g yellow solid, mp138-140 ℃.Ultimate analysis C
18H
14Cl
2N
2S: calculated value: C, 59.84; H, 3.91; N, 7.76.Measured value: C, 59.77; H, 3.97; N, 7.76.
Claims (16)
1. the compound represented of following formula:
Wherein L is selected from CO, CS and SO
2
R wherein
1And R
2Be independently selected from following groups: hydrogen, halogen, alkyl (C
1-C
6), haloalkyl (C
1-C
6), nitro, cyano group, carboxyl and carbalkoxy (C
1-C
6); Condition is, when L is SO
2The time, R
1And R
2Not hydrogen simultaneously;
R wherein
3Be independently selected from 1-3 following groups: hydrogen, halogen, alkyl (C
1-C
6), haloalkyl (C
1-C
6), nitro, carboxyl and carbalkoxy (C
1-C
6); With
Wherein X is selected from formula (CH
2)
nOr Y-(CH
2)
N-1, wherein Y is O or S, n is the integer of 1-3.
2. the compound of claim 1, wherein L is SO
2, R
1And R
2In at least one be halogen, R
3Be independently selected from halogen or CF
3In any one and X be (CH
2)
n, wherein n is 1-3.
3. the compound of claim 1, wherein L is CO or CS, R
1And R
2Each is hydrogen naturally, R
3Be 3,4-dichloro and X are (CH
2)
n, wherein n is 1-3.
4. the compound of claim 1, it is selected from following one group of compound: 8-bromo-3,4,4a, 5,6,7-six hydrogen-2-(4-iodobenzene alkylsulfonyl)-2H-benzo [6,7] suberane is [1,2c] pyridazine also; 8-bromo-3,4-diaza-1,2,3,9,10,10a-six hydrogen-3-(4-iodobenzene alkylsulfonyl) phenanthrene; 7,8-two bromo-3,4-diaza-1,2,3,10,10a-six hydrogen-3-(4-iodobenzene alkylsulfonyl) phenanthrene; 3-(3,4-dichloro-benzoyl base)-3,4-diaza-1,2,3,9,10, the luxuriant and rich with fragrance and 2-(3,5-dichloro-benzoyl base)-3,4 of 10a-six hydrogen, 4a, 5,6,7-six hydrogen-2H-benzo [6,7] suberane is [1,2c] pyridazine also.
5. the compound of claim 1, it is selected from following one group of compound: 2-(3,4-difluoro thiobenzoyl)-3,4,4a, 5,6,7-six hydrogen-2H-benzo [6,7] suberane is [1,2c] pyridazine also; 2-(3,4-dichloro-benzoyl base)-3,4,4a, 5,6,7-six hydrogen-2H-benzo [6,7] suberane is [1,2c] pyridazine also; 3-(3, the 4-difluoro benzoyl)-3,4-diaza-1,2,3,9,10,10a-six hydrogen phenanthrene; 3-(3,5-dichloro-benzoyl base)-3,4-diaza-1,2,3,9,10, the luxuriant and rich with fragrance and 3-(3,4-dichloro-benzoyl base)-3 of 10a-six hydrogen, 4-diaza-9-oxa--1,2,3,9,10,10a-six hydrogen phenanthrene.
6. the compound of claim 1, it is selected from following one group of compound: 3-(3,4-dichloro-benzoyl base)-3,4-diaza-9-thia-1,2,3,9,10,10a-six hydrogen phenanthrene; 3-(3,4-dichloro-benzoyl base)-3,4-diaza-1,2,3,9,9a-tetrahydrochysene fluorenes; 2-(3,5-dichloro thiobenzoyl)-3,4,4a, 5,6,7-six hydrogen-2H-benzo [6,7] suberane is [1,2c] pyridazine also; 2-(3,4-difluoro thiobenzoyl)-3,4,4a, 5,6,7-six hydrogen-2H-benzo [6,7] suberane is [1,2c] pyridazine and 2-(3,4-dichloro thiobenzoyl)-3,4 also, 4a, 5,6,7-six hydrogen-2H-benzo [6,7] suberane is [1,2c] pyridazine also.
7. the compound of claim 1, it is selected from following one group of compound: 3-(3,4-difluoro thiobenzoyl)-3,4-diaza-1,2,3,9,10,10a-six hydrogen phenanthrene; 3-(3,4-dichloro thiobenzoyl)-3,4-diaza-1,2,3,9,10,10a-six hydrogen phenanthrene; 3-(3,5-dichloro thiobenzoyl)-3,4-diaza-1,2,3,9,10,10a-six hydrogen phenanthrene; 3-(3,4-dichloro thiobenzoyl)-3,4-diaza-9-oxa--1,2,3,9,10,10a-six hydrogen phenanthrene; 7-chloro-3,4-diaza-1,2,3,9,10,10a-six hydrogen-3-(4-iodobenzene alkylsulfonyl) phenanthrene; 7-chloro-3,4-diaza-1,2,3,9,10, the luxuriant and rich with fragrance and 3-(3,4-dichloro thiobenzoyl)-3 of 10a-six hydrogen-3-(2,5-dichlorobenzene alkylsulfonyl), 4-diaza-1,2,3,9,9a-tetrahydrochysene fluorenes.
8. the preparation method of following formula: compound:
R wherein
1, R
2, R
3, L and X as defined in claim 1, described method comprises: (a) with following formula benzo naphthenone:
With the Glyoxylic acid hydrate reaction, formed product reduces with reductive agent, and handles the reduzate that forms with hydrazine, forms following formula ring-type acylhydrazone:
With described ring-type acylhydrazone and second kind of reductive agent reaction, form following formula ring-type hydrazone:
And with described ring-type hydrazone and acylation reaction, wherein L is CS, (b) with formed acid amides be selected from Lawesons reagent or P
2S
5Reagent react.
9. the described method of claim 8, wherein first kind of reductive agent is the zinc in the acetate.
10. the described method of claim 8, wherein second kind of reductive agent is selected from lithium aluminium hydride and diborane.
11. the described method of claim 8, wherein said acylating agent is selected from benzoyl halogen and sulfonic acid halide.
12. the described method of claim 11, wherein said acylating agent is a benzene sulfonyl chloride.
13. the described method of claim 11, wherein said acylating agent is a Benzoyl chloride.
14. a pharmaceutical composition, said composition contain the described compound of the claim 1 for the treatment of significant quantity and with the pharmaceutically acceptable carrier of its blended.
15. one kind treat contraception, menopause, endometriosis, mammary cancer, cyclesynchrony, termination of pregnancy, childbirth is induced or osteoporosis in the method for any disease, this method comprise to the contraception of patient's administering therapeutic, menopause, endometriosis, mammary cancer, cyclesynchrony, termination of pregnancy, childbirth is induced or osteoporosis in the described compound of claim 1 of any disease treatment significant quantity.
16. the described method of claim 15, wherein dosage is 1-500mg/kg/ days.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US790095P | 1995-11-06 | 1995-11-06 | |
| US60/007,900 | 1995-11-06 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1207091A true CN1207091A (en) | 1999-02-03 |
| CN1110485C CN1110485C (en) | 2003-06-04 |
Family
ID=21728709
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN96199481A Expired - Fee Related CN1110485C (en) | 1995-11-06 | 1996-10-10 | 1-arylsulphonyl, aryl(thio) carbonyl pyridazino derivatives and methods of preparation |
Country Status (17)
| Country | Link |
|---|---|
| JP (1) | JP2000501073A (en) |
| KR (1) | KR100360614B1 (en) |
| CN (1) | CN1110485C (en) |
| AU (1) | AU704507B2 (en) |
| BR (1) | BR9611407A (en) |
| CZ (1) | CZ286789B6 (en) |
| HU (1) | HU225162B1 (en) |
| IL (1) | IL124320A (en) |
| MX (1) | MX9803605A (en) |
| NO (1) | NO310460B1 (en) |
| NZ (1) | NZ319979A (en) |
| PL (1) | PL185618B1 (en) |
| RU (1) | RU2175969C2 (en) |
| TW (1) | TW460467B (en) |
| UA (1) | UA48989C2 (en) |
| WO (1) | WO1997017332A1 (en) |
| ZA (1) | ZA969298B (en) |
-
1996
- 1996-10-10 UA UA98052267A patent/UA48989C2/en unknown
- 1996-10-10 KR KR10-1998-0703345A patent/KR100360614B1/en not_active IP Right Cessation
- 1996-10-10 RU RU98110813/04A patent/RU2175969C2/en not_active IP Right Cessation
- 1996-10-10 PL PL96326669A patent/PL185618B1/en not_active IP Right Cessation
- 1996-10-10 CZ CZ19981380A patent/CZ286789B6/en not_active IP Right Cessation
- 1996-10-10 WO PCT/US1996/016227 patent/WO1997017332A1/en active IP Right Grant
- 1996-10-10 CN CN96199481A patent/CN1110485C/en not_active Expired - Fee Related
- 1996-10-10 HU HU0201305A patent/HU225162B1/en not_active IP Right Cessation
- 1996-10-10 AU AU72637/96A patent/AU704507B2/en not_active Ceased
- 1996-10-10 NZ NZ319979A patent/NZ319979A/en unknown
- 1996-10-10 BR BR9611407-0A patent/BR9611407A/en not_active Application Discontinuation
- 1996-10-10 IL IL12432096A patent/IL124320A/en not_active IP Right Cessation
- 1996-10-10 JP JP9518177A patent/JP2000501073A/en not_active Ceased
- 1996-11-05 ZA ZA9609298A patent/ZA969298B/en unknown
- 1996-11-25 TW TW085114479A patent/TW460467B/en not_active IP Right Cessation
-
1998
- 1998-05-05 NO NO19982030A patent/NO310460B1/en unknown
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Also Published As
| Publication number | Publication date |
|---|---|
| CN1110485C (en) | 2003-06-04 |
| HU225162B1 (en) | 2006-07-28 |
| PL185618B1 (en) | 2003-06-30 |
| KR19990067340A (en) | 1999-08-16 |
| JP2000501073A (en) | 2000-02-02 |
| AU704507B2 (en) | 1999-04-22 |
| NO310460B1 (en) | 2001-07-09 |
| IL124320A (en) | 2001-10-31 |
| RU2175969C2 (en) | 2001-11-20 |
| PL326669A1 (en) | 1998-10-12 |
| TW460467B (en) | 2001-10-21 |
| CZ286789B6 (en) | 2000-07-12 |
| CZ138098A3 (en) | 1998-09-16 |
| IL124320A0 (en) | 1998-12-06 |
| MX9803605A (en) | 1998-09-30 |
| HUP0201305A2 (en) | 2002-12-28 |
| WO1997017332A1 (en) | 1997-05-15 |
| NO982030L (en) | 1998-06-23 |
| HUP0201305A3 (en) | 2003-02-28 |
| BR9611407A (en) | 1999-12-28 |
| NZ319979A (en) | 1999-11-29 |
| KR100360614B1 (en) | 2003-06-02 |
| NO982030D0 (en) | 1998-05-05 |
| AU7263796A (en) | 1997-05-29 |
| UA48989C2 (en) | 2002-09-16 |
| ZA969298B (en) | 1998-05-05 |
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