CN1110485C - 1-arylsulphonyl, aryl(thio) carbonyl pyridazino derivatives and methods of preparation - Google Patents

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

1-arylsulfonyl, aryl(thio)carbonyl-pyridazino derivatives and their preparation methods

Background of the invention

In the synthesis of the compounds claimed in this invention, certain intermediates are well known. For example, Holava and Partyka disclose 3,4-diaza-1,2,3,9,10,10a-hexahydrophenanthrene-2-one (A) and 3,4,4a,5,6,7- Hexahydro-2H-benzo[6,7]cyclohepta[1,2c]pyridazin-2-one (B), Toma and Cignarella et al. disclose 2,4,4a,5-tetrahydro-3H -Indeno[1,2-c]pyridazin-3-one (C).

Professor R.Danheiser reported (orally) in MIT the synthesis of the relevant intermediate compound 7-bromo-4-methyl-1-tetralone used in the present invention from 4-methyl-1-tetralone (D) (E) method. Although Danheiser discloses the synthesis method of the compounds described in said literature, the present invention employs its analogous method to prepare previously unknown compounds for the synthesis of the compounds of the present invention.

Trihalogenated benzocycloalkanones have not been disclosed in the literature.

As dihalogenated benzocycloalkanones, only Owton, W.M. and Brunavs, M. disclosed 6,7-difluoro- and 6,7-dichlorotetrahydro in Synthetic Communications 21, 981, (1991) Naphthalenone compounds, but they are prepared by different routes.

Dibromobenzocycloalkanones are unknown.

With the exception of 8-bromo-1-tetralone, all monobromotetralones are known.

None of the compounds claimed in the present invention have been disclosed.

Detailed description of the invention

其中：The present invention relates to the compound represented by following formula I:

in:

L is CO, CS or _SO2 ;

R ₁ and R ₂ are independently selected from any one of the following groups: H, halogen, alkyl (C ₁ -C ₆ ), haloalkyl (C ₁ -C ₆ ), nitro, cyano, carboxyl and alkyl ester groups (C ₁ -C ₆ ); with the proviso that, when L is SO ₂ , R ₁ and R ₂ are not simultaneously hydrogen;

_R3 is independently one, two or three of any of the following substitution forms: H, halogen, alkyl (C ₁ -C ₆ ), haloalkyl (C ₁ -C ₆ ), nitro, carboxyl or alkyl ester group (C ₁ -C ₆ );

X is a diradical of formula ( _CH2 ) _n or Y-( _CH2 ) _n-1 , wherein n is an integer from 1 to 3; and Y is O or S.

Unless otherwise stated, for the purposes of the present invention and when used alone or in combination with other groups, alkyl means 1 to 6 carbon atoms, which may be straight chain alkyl, or when at least 3 carbon atoms , it may be a branched chain alkyl group. Halogen means chlorine, bromine, fluorine or iodine. Alkoxy refers to a group derived from an alkanol having 1 to 6 carbon atoms, and haloalkyl refers to a group containing an alkyl group of 1 to 3 carbon atoms, such as trifluoromethyl.

The compound of the present invention is a non-steroidal heterocyclic compound, which can be used as a selective progestin and/or anti-progestin with higher affinity to uterine, breast or bone progesterone receptors in vitro, and can be used as And oral administration is biologically active. Thus, they can be used in the treatment of contraception, menopause, endometriosis, breast cancer, cyclesynchrony, pregnancy termination, labor induction or osteoporosis.

preferred embodiment

More particularly, the present invention relates to a series of non-steroidal heterocyclic derivatives whose activity mimics in vitro the activity of progestogens and/or antiprogestogens with higher affinity for uterine, breast or bone progesterone receptors.

Preferred compounds of the present invention are wherein L is SO ₂ , at least one of R ₁ and R ₂ is halogen, R ₃ is halogen and/or CF ₃ and X is (CH ₂ ) _n , where n=1-3 compound. Another preferred group of compounds of the invention includes those wherein L is CO or CS, _R1 and _R2 are hydrogen, _R3 is 3,4-dichloro and X is ( _CH2 ) _n , where n=1-3 .

The compound of the present invention can be prepared by the following reaction scheme 1:

Reaction scheme 1

As can be seen from Scheme 1, a suitably substituted benzocycloalkanone (II) can be synthesized using methods well known in the art, such as those described by Holava and Partyka (J. Med. Chem. 14, 262, (1971)). into the cyclic acylhydrazone compound (III). Typically, this procedure involves conversion of compound II to an αβ unsaturated ketoacid with glyoxylic acid and a base, subsequent reduction of the unsaturated compound in acetic acid by heating with zinc and treatment of the reduced ketoacid with hydrazine to yield compound III.

Then, in a suitable solvent such as tetrahydrofuran (THF), by The substituted cyclic acylhydrazone (III) can be converted into the cyclic hydrazone compound (IV) by reaction with a reducing agent such as lithium aluminum hydride or diborane.

The resulting cyclic hydrazone (IV) can be acylated with an appropriately substituted benzoyl or sulfonyl halide in a suitable solvent such as pyridine or in an organic solvent such as THF or toluene containing a base such as triethylamine to form the non- Steroid Heterocyclic Derivatives (I).

The product is isolated and purified by methods known to those skilled in the art, such as pouring the reaction mixture into dilute acid such as hydrochloric acid and extracting the mixture with an organic solvent such as dichloromethane or ethyl acetate, concentrating the organic layer to make The residue is crystallized or purified by silica gel chromatography, fractions containing the product are evaporated and the residue is recrystallized to give the desired compound.

Amides obtained in this way can be converted to thioamides (L=CS) by reaction with Lawesons _reagent or _P2S5 in toluene.

Some of said halogenated starting materials are not known in the literature. These compounds can be prepared as described in Scheme 2.

如上所示，在氯化铝存在下，加入1.2当量卤化剂，可得到两种异构化的一卤代苯并环烷酮类化合物，其中所述卤素被引入到所述酮基的间位。在氯化铝存在下，加入大于2当量的卤化剂，得到所述二卤代苯并环烷酮类化合物以及两种异构化的三卤代苯并环烷酮类化合物。另外，一卤代苯并环烷酮类化合物可以用不同的卤素卤化，得到混合取代的化合物例如：6-溴-5-氯-1-四氢萘酮或5-氯-7-碘-1-四氢萘酮。Reaction Scheme 2

As shown above, in the presence of aluminum chloride, adding 1.2 equivalents of a halogenating agent, two isomerized monohalogenated benzocycloalkanone compounds can be obtained, wherein the halogen is introduced into the meta-position of the ketone group . In the presence of aluminum chloride, more than 2 equivalents of a halogenating agent are added to obtain the dihalogenated benzocycloalkanone compound and two isomerized trihalogenated benzocycloalkanone compounds. Alternatively, monohalobenzocycloalkanones can be halogenated with different halogens to give mixed substituted compounds such as: 6-bromo-5-chloro-1-tetralone or 5-chloro-7-iodo-1 - Tetralone.

The activity of the compounds of the present invention is demonstrated by progesterone receptor binding assays and in vitro progestational assays.

progesterone receptor binding assay

The method used is essentially that described by J.L McGuire, C.D. Bariso and A.P. Shroff in Biochemistry 13, 319 (1974).

The uteri of New Zealand rabbits (1.5-2.5kg) were placed in cold buffer A (0.01M Tris-HCl, pH8.0, 0.001M EDTA, 0.25M sucrose), the uteri were minced, washed and placed in cold buffer A Homogenize. The homogenate (2 g wet tissue/ml buffer) was centrifuged at 200,000G for 1 hour at 4°C. The supernatant fraction from high speed centrifugation was used as receptor preparation.

Competition binding assays were performed by mixing ³ H-R5020 with the receptor preparation and adding known amounts of unlabeled compound. This mixture was incubated at 4°C for 18 hours, and the compound bound to the receptor was released from solution using dextran-coated activated carbon. During isolation of compounds, the amount of isotope bound to the receptor is determined. Repression was considered significant when it reached 20% or greater compared to the incorporation of the control isotope.

Similar methods can also be used to determine binding affinity for progesterone receptors derived from breast or bone tissue.

in vitro antiprogestin test

The proliferative effect of the compounds on T47-D cells was tested by binding ³ H-thymidine to T47-D cells. The compounds of the present invention are useful in the treatment of progesterone-regulated physiological diseases in vivo, where sufficient effects on the growth of T47-D cells are shown.

The effect of the test compound on TE85 human bone cells was determined in a similar manner.

T47-D (human breast cell line) processed by conventional sterilization techniques. Cells were maintained in RPMI 1640 medium supplemented with fetal bovine serum (10%) and insulin (0.2 I.U./ml). Cells were trypsinized and passaged by conventional methods.

Cells were placed in a 96-well microtiter culture dish, and cultured in RPMI medium (no phenol red, no insulin, 5% charcoal-treated fetal bovine serum) at 37°C under 95% air/5% _CO2 atmosphere. Incubation. After about 48 hours, the spent medium was replaced with fresh culture containing the test compound in DMSO (final concentration 0.1%), the cells were incubated for about 22 hours, ³ H-thymidine was added and allowed to The incubation was continued for approximately 4 hours, after which the assay was terminated by the addition of excess unlabeled thymidine. Cells were washed free of soluble thymidine, trypsinized and collected by conventional methods. The amount of ³ H-thymidine incorporated into the DNA was determined by liquid scintillation counting. The primary benchmarks were promelystrenone, a potent synthetic progestin, and RU486, an antiprogestin. Screening of test compounds is typically performed at a concentration range of 0.1-1000 nM. A compound is considered active if it either activates or inhibits thymidine incorporation. Results are expressed as the concentration of the test compound required to increase cell proliferation two-fold (SC ₂₀₀ ) or to inhibit promethylestrenone-induced cell proliferation by 50% (EC ₅₀ ) compared to control. Activity was considered to be active when the value was below 1000 nM.

Applications of the methods used can be found in the following literature: C.Christensen, D.Gunter, 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).

surface

Table 1 presents the molecular formula, melting point, and affinity of the binding assay of the examples of the present invention, which are represented by 50% ³ H-labeled in the rabbit uterine cytoplasmic progesterone receptor (PR). The concentration of the compound required for R5020 is indicated (IC ₅₀ ), the concentration unit is millimole/liter (×10 ^-9 M), and the ability to promote or inhibit the proliferation of T47D human breast cancer cells (T47D) induced by R5020. In column T47D, if no value is recorded, it means that the particular compound was not tested.

Table 2 and 3 have provided molecular formula, fusing point and activity of several embodiments of the present invention, and this activity is expressed with the mean increase (CP) of osteocyte hyperplasia under 5 concentrations or by human bone progesterone receptor (BPR) The concentration of the compound required to displace 50% of the I ¹²⁵ -labeled vinyl nortestosterone is indicated (IC ₅₀ ), and the unit of concentration is millimolar (×10 ^-9 M). In the CP column, if no value is recorded, it means that that particular compound was not tested.

Table 1 Sulfonamides

# R1 R2 X R3 PR T47D Formula MP

1 H Br (CH ₂ ) ₃ 4-1 76 C ₁₉ H ₁₈ BrIN ₂ O ₂ S 180-1

2 H Br (CH ₂ ) ₂ 4-1 10 C ₁₈ H ₁₆ BrIN ₂ O ₂ S 197-8

3 Br Br (CH ₂ ) ₂ 4-1 2.4 +337 C ₁₈ H ₁₅ Br ₂ IN ₂ O ₂ S 202-3

4 Cl H (CH ₂ ) ₂ 4-1 8.3 -654 C ₁₈ H ₁₀ ClIN ₂ O ₂ S 194-6

5 Br H (CH ₂ ) ₂ 2.5-diCl 34 -495 C ₁₈ H ₁₅ Cl ₃ N ₂ O ₂ S 186-7

+ means agonist SC ₂₀₀ nM (2 times the stimulating concentration of the control)

- Indicates antagonist EC ₅₀ nM for R5020-induced proliferation

Table 2

Amides

# X R3 CP BPR formula MP

6 (CH ₂ ) ₂ 3,4-diCl 115 C ₁₉ H ₁₆ Cl ₂ N ₂ O 154-5

7 (CH ₂ ) ₃ 3,5-diCl 120 8.4 C ₂₀ H ₁₈ Cl ₂ N ₂ O 115-6

8 (CH ₂ ) ₃ 3,4-diF 4.8 C ₂₀ H ₁₈ F ₂ N ₂ O 117-8

9 (CH ₂ ) ₃ 3,4-diCl 123 107 C ₂₀ H ₁₈ Cl ₂ N ₂ O 136-7

10 (CH ₂ ) ₂ 3,4-diF 112 C ₁₉ H ₁₆ F ₂ N ₂ O 146-7

11 (CH ₂ ) ₂ 3,5-diCl 113 11.6 C ₁₉ H ₁₆ Cl ₂ N ₂ O 141-2

12 OCH ₂ 3,4-diCl 107 3.6 C ₁₈ H ₁₄ Cl ₂ N ₂ O ₂ 166-7

13 SCH ₂ 3,4-diCl 50 C ₁₈ H ₁₄ Cl ₂ N ₂ OS 145-6

14 CH ₂ 3,4-diCl 9.0 C ₁₈ H ₁₄ Cl ₂ N ₂ O 122-4

table 3

Thioamides

# X R3 CP BPR formula MP

15 (CH ₂ ) ₃ 3,5-diCl 109 23.3 C ₂₀ H ₁₈ Cl ₂ N ₂ S 149-50

16 (CH ₂ ) ₃ 3,4-diF 111 C ₂₀ H ₁₈ F ₂ N ₂ S 134-6

17 (CH ₂ ) ₃ 3,4-diCl 115 32 C ₂₀ H ₁₈ Cl ₂ N ₂ S 140-1

18 (CH ₂ ) ₂ 3,4-diF C ₁₉ H ₁₆ F ₂ N ₂ S 170-1

19 (CH ₂ ) ₂ 3,4-diCl 87 44.3 C ₁₉ H ₁₆ Cl ₂ N ₂ S 110-1

20 (CH ₂ ) ₂ 3,5-diCl 103 10.2 C ₁₉ H ₁₆ Cl ₂ N ₂ S 162-3

21 OCH ₂ 3,4-diCl 2.0 C ₁₈ H ₁₄ Cl ₂ N ₂ OS 187-8

22 CH ₂ 3,4-diCl 0.5 C ₁₈ H ₁₄ Cl ₂ N ₂ S 138-40

A pharmaceutical composition containing the compound of the present invention as an active ingredient in admixture with a pharmaceutical carrier can be prepared according to conventional pharmaceutical preparation methods. Depending on the desired form of preparation for administration, such as intravenous administration, oral administration or parenteral administration, the carrier can be selected from various forms. In preparing compositions for oral dosage form, any conventional pharmaceutical medium may be used, for oral liquid preparations such as suspensions, elixirs and solutions such as water, glycols, oils, alcohols, flavorings, preservatives, Coloring agents, etc.; or for oral solid preparations (such as powders, capsules or tablets), carriers such as starch, sucrose, diluents, granules, lubricants, binders, and disintegrants can be used. For ease of administration, tablets and capsules are preferably presented in oral unit dosage form, obviously using a solid pharmaceutical carrier. Tablets may be sugar-coated or enteric-coated by conventional methods, if desired. For parenteral formulations, the carrier generally consists of sterile water, although other ingredients may be used to enhance solubility or for preservation purposes; injectable suspensions may also be prepared in which a suitable liquid carrier may be used. , suspending agent, etc. Usually, the pharmaceutical composition of the present invention containing about 1-500 mg/kg/day and preferably about 10-100 mg/kg/day of the active ingredient in unit doses such as tablets, capsules, powders, etc., may be used in relation to Treatment of contraception, menopause, endometriosis, breast cancer, cyclesynchrony, pregnancy termination, labor induction, or osteoporosis, most likely for endometriosis, contraception, and osteoporosis. The exact drug dosage will vary depending on the age and condition of the patient and the particular condition being treated.

Embodiment I. Preparation of raw materials and intermediate compounds used in the preparation of the final product of the present invention

The following Sections A, B and C describe the preparation of starting materials and intermediate compounds useful in the preparation of the compounds described in this invention.

A. Preparation of Halogenated Benzocycloalkanones

2，3-二氢-1-茚酮(VI)VIIa，X＝Br；VIIb，Y＝Br；VIIc，X＝Y＝Br6-溴-2，3-二氢茚-1-酮(VIIb)和4-溴-2，3-二氢茚-1-酮(VIIa)In the following examples, N-bromosuccinimide is substituted for bromine and the chlorinated compounds can be prepared with N-chlorosuccinimide or chlorine. The iodolou analogs can be obtained from N-iodosuccinimide.

2,3-Dihydro-1-indanone (VI) VIIa, X=Br; VIIb, Y=Br; VIIc, X=Y=Br6-bromo-2,3-dihydroindan-1-one (VIIb) and 4-bromo-2,3-indan-1-one (VIIa)

A 250ml three-neck round bottom flask was installed with a water-cooled Liebig condenser, a mechanical stirrer and a pressure equalizing addition funnel protected by a drying tube. Anhydrous aluminum chloride (16.6 g, 0.125 mol) was added to the flask and 2,3-dihydro- 1-Indanone (VI) (6.60 g, 0.05 mol), accompanied by a mild exotherm, with the evolution of a large amount of HCl gas, the mixture quickly turned into a dark brown homogeneous slurry, which was stirred for another 10 minutes.

To the well stirred mixture was added bromine (3.1 ml, 0.06 mol) dropwise over 10 minutes. After the bromine addition was complete, the molten mixture was heated in an 80°C water bath for 5 minutes. While very hot, the mixture was poured into 100 g crushed ice and 20 ml conc. hydrochloric acid, then the ice mixture was stirred for 10 minutes, diluted with 100 ml water and extracted with diethyl ether (2 x 100 ml). The combined ether extracts were washed with water (2×100 ml), dried over anhydrous sodium sulfate, and concentrated to give 10.6 g of a red oil, which was crystallized at room temperature.

Analysis of the product by GC-MS indicated that the product was a 1:1 mixture of monobromo isomers. The product was chromatographed on a silica gel column (45×10 cm) with n-hexane/THF (8:1) to separate the isomers. The separated isomers were recrystallized in hexane respectively to obtain 3.8g 6-bromo-2,3-dihydroinden-1-one (VIIa) and 4.0g 4-bromo-2,3-dihydroindane-1 - a ketone (VIIb).

VIIa: Yield 37.7%; mp108-109℃, light yellow prisms; IR(KBr)1712cm ^-1 ; ¹ H NMR(CDCl ₃ )δ2.70-2.74(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; Elemental analysis for _C9H7BrO : Calcd: C, 51.22; H, 3.34. Found: C, 51.10; H, 3.25.

VIIb: Yield 3 5.8%; mp90-92°C, pale yellow prisms; IR (KBr) 1709 cm ^-1 ; ¹ H NMR (CDCl ₃ ) δ2.71-2.75 (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; Elemental analysis for _C9H7BrO : Calculated: C, 51 22; H, 3.34. Found: C, 50.38; H, 3.24. 7-Bromo-1-tetralone (IXa) and 5-bromo-1-tetralone (IXb)

1-tetralone, (VIII) IXa, X=Br; IXb, Y=Br

Under vigorous stirring within 3 minutes, 1-tetralone (VIII) (7.3g, 0.05mol) was added dropwise to anhydrous aluminum chloride (16.6g, 0.125mol), and the resulting slurry was added to the Bromine (3.71ml, 0.06mol) was added. After the bromine addition was complete, the mixture was heated to 80°C for 5 minutes and the still molten mixture was poured into 150 g of crushed ice containing 20 ml of 12N HCl. After working up as described in Example 1, 10.85 g of a brown oil were obtained. The grafts were chromatographed on a silica gel column (45 x 10 cm) with hexane:THF (8:1). The separated isomers were recrystallized in hexane, respectively, to obtain 4.2 g of 7-bromo-1-tetralone (IXa) and 4.5 g of 5-bromo-1-tetralone (IXb).

IXa: Yield 37.2%; mp74-75°C, pale yellow prisms; IR (KBr) 1676cm ^-1 ; ¹ H NMR (CDCl ₃ ) δ2.09-2.18(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; elemental analysis C ₁₀ H ₉ BrO: Calculated: C, 53.36; H, 4.03. Found: C, 53.14; H, 3.96.

IXb: Yield 39.8%; mp45-46°C, pale yellow prisms; IR (KBr) 1679cm ^-1 ; ¹ H NMR (CDCl ₃ ) δ2.11-2.20(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; elemental analysis C ₁₀ H ₉ BrO: Calculated: C, 53.36; H, 4.03. Found: C, 52.97; H, 3.94. 5,7-Dibromo-1-tetralone (IXc), 5,6,7-Tribromo-1-tetralone (IXd) and 5,7 , 8-tribromo-1-tetralone (Ixe)

IXc, X=Y=Br, W=Z=H

IXd, X=Y=W=Br, Z=H; IXe, X=Y=Z=Br, W=H

Bromine (7.42 g, 0.12 mol) was added dropwise to a slurry obtained from anhydrous aluminum chloride (16.6 g, 0.125 mol) and 1-tetralone (VIII) (0.05 mol) as described in Example 1. In the mixture, 15.0 g of a brown oil was obtained, which was left to stand for crystallization. GC-MS showed that the mixture contained a 1:1 mixture of 87% dibrominated product and 13% tribrominated product. Chromatography and recrystallization from hexane gave 7.7g.

IXc: Yield 51%; mp60-61°C, pale yellow prisms; IR (KBr) 1690cm ^-1 ; ¹ H NMR (CDCl ₃ ) δ2.11-2.20 (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; elemental analysis C ₁₀ H _{8 Br2O} : Calculated: C, 39.51; H, 2.65. Found: C, 39.41; H, 2.49. 8-Bromo-1-benzocycloheptanone (XIa) and 6-bromo-1-benzocycloheptanone (XIb)

XIa, X=Br; XIb, Y=Br; XIc, X=Y=Br

According to the general method for the preparation of the brominated tetralone compounds as described in detail above, after conventional treatment, from benzocycloheptanone (X) (8.01g, 0.05mol), aluminum chloride (16.6g, 0.125 mol) and bromine (3.07ml, 0.06mol) yielded 11.87g of a brown oil. GC-MS showed it to be a 1:1 mixture of the monobromo isomer containing 2% of the dibromo isomer.

XIa: Yield 30%; mp 38-38.5°C, off-white powder; ms m/z 239; Elemental analysis for C ₁₁ H ₁₁ BrO: Calculated: C, 55.25; H, 4.64. Found: C, 54.83; H, 4.62.

XIb: 32% yield; clear oil bp101-105 @ 0.12 mmHg; ms m/z = 239; elemental analysis for _C11H11BrO : calculated: C, _55.25 ; H, 4.64. Found: C, 55.32; H, 4.59. 5,6-Dibromo-1-tetralone XIIa and 6,7-dibromo-1-tetralone XIIb

XII XIIa, Y=Br, X=H

XIIb, X=Br, Y=H

Following the same procedure as detailed above for brominated tetralones, after conventional workup, 6-bromo-1-tetralone XII (2 g, mmol), aluminum chloride (16.6 g, 0.125 mol) and bromine (3.07ml, 0.06mol) of the mixture yielded 1.87g of a brown oil.

B. Preparation of cyclic acylhydrazone compounds 3,4-diaza-1,2,3,9,9a-tetrahydrofluoren-2-one (XIII)

The title compound was prepared as described by Toma, L., Cignarella, G., Bariocco, D. and Ronchetti, F. in J. Med. Chem. 33, 1591-4, 1990 . 3,4-diazepin-1,2,3,9,10,10a-hexahydrophenanthrene-2-one (XIV)

The title compound was prepared as described by Holava, H.M. and Partyka, R.A. in J. Med. Chem. 14, 262, (1971). 3,4,4a,5,6,7-Hexahydro-2H-benzo[6,7]cyclohepta[1,2-c]pyridazin-2-one (XV)

The title compound was prepared as described by Holava, H.M. and Partyka, R.A. in J. Med. Chem. 14, 262, (1971). 8-Bromo-3,4-diazapine-1,2,3,9,10,10a-hexahydrophenanthrene-2-one (XVI)

The title compound was prepared by treating 5-bromo-1-tetralone (IXb) (20 mmol) with glyoxylic acid (20 mmol) according to Holava, H.M. and Partyka, R.A. in J. Med. Chem. 14, 262, (1971), reduction of the product with excess zinc in acetic acid and treatment with excess hydrazine affords the title compound. 7,8-Dibromo-3,4-diaza-1,2,3,9,10,10a-hexahydrophenanthrene-2-one (XVII)

The title compound was prepared by treating 5,6-dibromo-1-tetralone (XIIa) (10 mmol) with glyoxylic acid (10 mmol) as described by Holava, H.M. and Partyka, R.A. in J.Med Reduction of the product with excess zinc in acetic acid followed by treatment with excess hydrazine gave the title compound as described in Chem. 14, 262, (1971). 7-Chloro-3,4-diazepine-1,2,3,9,10,10a-hexahydrophenanthrene-2-one (XVIII)

The title compound was prepared by treating 6-chloro-1-tetralone with glyoxylic acid 50 mmol and base (Rosowsky, A., Chaykovsky, M., Yeager, S.A., et al. J. Het. Chem 8,809, (1971)) 50 mmol, then reduced with excess zinc in acetic acid and subsequently with excess hydrazine as described by Holava, H.M. and Partyka, R.A. in J.Med.Chem.14, 262, (1971) Work up to give the title compound. 8-Bromo-3,4,4a,5,6,7-hexahydro-2H-benzo[6,7]cyclohepta[1,2-c]pyridazin-2-one (XIX)

The title compound was prepared by treating 6-bromo-1-benzocycloheptanone XIb with glyoxylic acid and then as described in Holava, H.M. and Partyka, R.A. in J.Med.Chem.14, 262, (1971 ), reduction with excess zinc in acetic acid and subsequent treatment with excess hydrazine afforded the title compound.

C. Preparation of cyclic hydrazone compounds 3,4-diaza-1,2,3,9,10,10a-hexahydrophenanthrene (XX)

3,4-Diaza-1,2,3,9,10,10a-hexahydrophenanthrene-2-one (XIV) (2.5 g, 12.5 mmol) was dissolved in THF and 1 equivalent of lithium aluminum hydride ( 21ml, 1M THF solution). After 30 minutes at 22°C, 15% NaOH solution was added dropwise and the gelled precipitate was filtered. The filtrate was dried over magnesium sulfate and filtered, and evaporated to dryness to give an oil which was used as the starting material without purification. 7-Chloro-3,4-diaza-1,2,3,9,10,10a-hexahydrophenanthrene (XXI)

Dissolve 7-chloro-3,4-diaza-1,2,3,9,10,10a-hexahydrophenanthrene-2-one (XVIII) in THF and add 1 equivalent lithium aluminum hydride (1M THF solution) dropwise ). After 30 minutes at 22°C, 15% NaOH solution was added dropwise and the precipitate was filtered. The filtrate was dried over magnesium sulfate, filtered and evaporated to dryness to give an oil which was used as the starting material without purification. 8-bromo-3,4,4a,5,,6,7-hexahydro-2H-benzo[6,7]cyclohepta[1,2-c]pyridazine (XXII)

8-Bromo-3,4,4a,3,6,7-hexahydro-2H-benzo[6,7]cyclohepta[1,2-c]pyridazin-2-one (XIX) ( 1 g, 3.4 mmol) was dissolved in THF and 2 equivalents of diborane (1M THF solution) were added dropwise. After 2 hours at 22°C, the reaction was quenched with 1 ml 6M HCl and neutralized with 50% NaOH solution, then dried over magnesium sulfate and filtered. The filtrate was evaporated to dryness to give an oil which was used directly without further purification. 8-bromo-3,4-diaza-1,2,3,9,10,10a-hexahydrophenanthrene (XXIII)

Dissolve 8-bromo-3,4-diaza-1,2,3,9,10,10a-hexahydrophenanthren-2-one (XVI) (1.0g, 3.6mmol) in THF (100ml) and drop Add 2 equivalents of diborane (1M in THF). After 1 hour at 22°C, the reaction was heated on a steam bath for 5 minutes, then quenched with 1 ml of 6M HCl and neutralized with 15% NaOH solution, then dried over magnesium sulfate and filtered. The filtrate was evaporated to dryness to give an oil which was used directly without further purification. 7,8-Dibromo-3,4-diaza-1,2,3,9,10,10a-hexahydrophenanthrene (XXIV)

7,8-Dibromo-3,4-diaza-1,2,3,9,10,10a-hexahydrophenanthrene-2-one (XVII) (0.71 g, 1.98 mmol) was suspended in THF and 2 equivalents of diborane (3.96 ml of 1M THF solution) were added dropwise at 22°C. The mixture was warmed briefly to 45°C to dissolve all solids, then stirred at room temperature for 60 hours. The reaction was quenched with 1 ml 6M HCl and neutralized with 50% NaOH solution, then dried over magnesium sulfate and filtered. The filtrate was evaporated to dryness to give an oil which was used as the starting material without purification. 3,4-diaza-1,2,3,9,9a-tetrahydrofluorene (XXV)

3,4-diaza-1,2,3,9,9a-tetrahydrofluoren-2-one (XIII) (3.5 g, 17.5 mmol) was dissolved in THF and 1 equivalent of lithium aluminum hydride (1M THF solution). After 30 minutes at 22°C, 15% NaOH solution was added dropwise and the gelled precipitate was filtered. The filtrate was dried over magnesium sulfate, filtered and evaporated to dryness to give an oil which was used as the starting material without purification. 3,4-diaza-9-oxa-1,2,3,9,10,10a-hexahydrophenanthrene (XXVI)

As mentioned above, with 2 equivalents of diborane such as Cignarella, G.; Barlocco, D.; Curzu, M.M.; Pinna, G.A.; Cazzulani, P.; Cassin, M.; 3,4-diaza-9-oxa-1,2,3,9,10,10a-hexahydrophenanthrene-2- The ketone (15 mmol) was reduced. 3,4-diaza-9-thia-1,2,3,9,10,10a-hexahydrophenanthrene (XXVII)

As mentioned above, with 2 equivalents of diborane, such as Nakao, Tohru; Tanaka, Hiroshi; Morimoto, Yasuto; Takehara, Shuzo; Demizu, Kenichi; The prepared 3,4-diaza-9-thia-1,2,3,9,10,10a-hexahydrophenanthrene-2-one (10 mmol) was reduced.

The following examples are only used to illustrate the present invention, and are not intended to limit the scope of the present invention.

Examples Example 1: 8-bromo-3,4,4a,5,6,7-hexahydro-2-(4-iodobenzenesulfonyl)-2H-benzo[6,7]cyclohepta[ 1,2-c]pyridazine

In 50ml of dichloromethane and 50ml of pyridine, 8-bromo-3,4,4a,5,6,7-hexahydro-2H-benzo[6,7]cyclohepta[1,2-c] Pyridazine (XIX) (1.0 g, 3.6 mmol) and 4-iodobenzenesulfonyl chloride (1.1 g, 3.6 mmol) were mixed, and the mixture was stirred at 22° C. for 64 hours, turning dark red. The mixture was concentrated under reduced pressure and the pyridine solution was poured into 6M HCl and ice, extracted with dichloromethane. The organic layer was concentrated under reduced pressure and filtered through silica gel eluting with dichloromethane to give 1.3 g off-white solid which was recrystallized from isopropanol/chloroform to give a white solid, mp 180-181°C. Elemental Analysis _{for C19H18BrIN2O2S} : Calculated: C, 41.85; H, 3.33; _N , _5.14 . Found: C, 41.68; H, 3.27; N, 5.03. Example 2: 8-bromo-3,4-diaza-1,2,3,9,10,10a-hexahydro-3-(4-iodobenzenesulfonyl)phenanthrene

In 100ml of pyridine, 8-bromo-3,4-diaza-1,2,3,9,10,10a-hexahydrophenanthrene (XXI) (1.0g, 3.77mmol) and 4-iodobenzenesulfonyl chloride ( 1-14g, 3.77mmol) were mixed, and the mixture was stirred at 22°C for 16 hours and turned dark red. The mixture was then poured into 6M HCl and ice and extracted with dichloromethane. The organic layer was concentrated under reduced pressure and filtered through silica gel eluting with dichloromethane to give 0.3 g of crude product which was recrystallized from hexane to give 0.28 g of an off-white solid, mp 197-198°C. _Elemental Analysis for _{C18H16BrIN2O2S} : Calculated: C, 40.76; H, 3.04; _N , _5.27 . Found: C, 40.59; H, 2.89; N, 5.06. Example 3: 7,8-dibromo-3,4-diaza-1,2,3,9,10,10a-hexahydro-3-(4-iodobenzenesulfonyl)phenanthrene

In 100ml of pyridine, 7,8-dibromo-3,4-diaza-1,2,9,10,10a-hexahydrophenanthrene (XVII) (0.7g, 1.9mmol) and 4-iodobenzenesulfonyl chloride (0.65 g, 2.1 mmol) were mixed, and the mixture was stirred at 22°C for 16 hours and turned dark red. The mixture was poured into 6M HCl and ice and extracted with dichloromethane. The organic layer was concentrated under reduced pressure and filtered through silica gel eluting with dichloromethane to give crude product which was recrystallized from hexane to give 0.1 g of white solid, mp 202-203°C. _{Elemental Analysis for C18H15Br2IN2O2S} : Calculated: C, 35.44; H, _2.48 ; N, 4.59. Found: C, 35.54; H, 2.47; N, 4.61. Example 4: 7-chloro-3,4-diaza-1,2,3,9,10,10a-hexahydro-3-(4-iodobenzenesulfonyl)phenanthrene

In 50ml of dichloromethane and 50ml of pyridine, 7-chloro-3,4-diaza-1,2,3,9,10,10a-hexahydrophenanthrene (XXI) (1-1g, 5.0mmol) and 4-Iodobenzenesulfonyl chloride (1.2 g, 39 mmol) was mixed, and the mixture was stirred at 22°C for 20 hours, turning dark red. The mixture was concentrated under reduced pressure and the pyridine solution was poured into 6M HCl and ice, extracted with dichloromethane. The organic layer was concentrated under reduced pressure and filtered through silica gel eluting with dichloromethane to give an off-white solid which was recrystallized from hexane to give 0.5 g of a white solid, mp 194-196°C. _Elemental Analysis for _{C18H10ClIN2O2S :} Calculated: C, 44.42; H, 3.31; _N , 5.76. Found: C, 44.73; H, 3.24; N, 5.31. Example 5: 7-chloro-3,4-diaza-1,2,3,9,10,10a-hexahydro-3-(2,5-dichlorobenzenesulfonyl)phenanthrene

In 100ml pyridine, 7-chloro-3,4-diaza-1,2,3,9,10,10a-hexahydrophenanthrene (XXI) (1.0g, 4.7mmol) and 2,5-dichlorobenzene Sulfonyl chloride (1.2 g, 4.9 mmol) was mixed and the mixture was stirred at 22°C for 16 hours, turning dark red. The mixture was poured into 6M HCl and ice and extracted with dichloromethane. The organic layer was concentrated under reduced pressure and filtered through silica gel eluting with dichloromethane to give 0.5 g of crude product which was recrystallized from hexane/chloroform to give 0.25 g of off-white solid, mp 186-187°C. Elemental Analysis _{for C18H15Cl3N2O2S} : Calculated: C, 50.31; H, _3.52 ; _N , _6.52 . Found: C, 50.23; H, 3.45; N, 6.44. Example 6: 3-(3,4-dichlorobenzoyl)-3,4-diaza-1,2,3,9,10,10a-hexahydrophenanthrene

In 100ml pyridine, 3,4-diaza-1,2,3,9,10,10a-hexahydrophenanthrene (XXI) (2.67g, 14.3mmol) and 3,4-dichlorobenzoyl chloride (3.0 g) Mix and stir at 22°C for 16 hours. The mixture was poured into dichloromethane and washed twice with 2M HCl, then dried over magnesium sulfate and filtered. The filtrate was concentrated and filtered through silica gel eluting with dichloromethane to afford 3.7 g of an off-white solid, mp 154-5°C. Elemental Analysis _{for C19H16Cl2N2O} : Calculated: C, 63.52; H, _4.49 ; N, _7.80 . Found: C, 63.18; H, 4.39; N, 7.52. Example 7: 2-(3,5-dichlorobenzoyl)-3,4,4a,5,6,7-hexahydro-2H-benzo[6,7]cyclohepta[1,2c ] Pyridazine

In 75ml of dichloromethane, 3,4,4a,5,6,7-hexahydro-2H-benzo[6,7]cyclohepta[1,2c]pyridazine (XV) (2.0g, 10mmol) and 3,5-dichlorobenzoyl chloride (2.1g, 10mmol) were mixed and 5ml triethylamine was added. The mixture was stirred at 22°C for 16 hours and evaporated to dryness under reduced pressure. The residue was dissolved in dichloromethane and washed with dilute HCl, dried over magnesium sulfate, filtered and chromatographed on silica gel eluting with dichloromethane to give 2.5 g of a white solid, mp 115-116°C. Elemental Analysis for _C20H18C12N2O : Calculated: _C , 64.35; H, 4.86; _N , _7.50 . Found: C, 64.38; H, 4.56; N, 7.56. Example 8: 2-(3,4-difluorothiobenzoyl)-3,4,4a,5,6,7-hexahydro-2H-benzo[6,7]cyclohepta[1 , 2c] pyridazine

In 75ml of dichloromethane, 3,4,4a,5,6,7-hexahydro-2H-benzo[6,7]cyclohepta[1,2c]pyridazine (XV) (2.0g, 10mmol) and 3,4-difluorobenzoyl chloride (2.1g, 10mmol) were mixed and 5ml triethylamine was added. The mixture was stirred at 22°C for 16 hours and evaporated to dryness under reduced pressure. The residue was dissolved in dichloromethane and washed with dilute HCl, dried over magnesium sulfate, filtered and chromatographed on silica gel eluting with dichloromethane to give 2.8 g of a pale yellow solid, mp 117-118°C. _Elemental Analysis for _C20H18F2N2O : Calculated: _C , 70.58; H, 5.33; _N , 8.23. Found: C, 70.59; H, 5.26; N, 8.35. Example 9: 2-(3,4-dichlorobenzoyl)-3,4,4a,5,6,7-hexahydro-2H-benzo[6,7]cyclohepta[1,2c ] Pyridazine

In 100ml of dichloromethane, 3,4,4a,5,6,7-hexahydro-2H-benzo[6,7]cyclohepta[1,2c]pyridazine (XV) (2.24g, 11.2mmol) and 3,4-dichlorobenzoyl chloride (2.34g, 11.2mmol) were mixed and 10ml triethylamine was added. The mixture was stirred at 22°C for 16 hours and evaporated to dryness under reduced pressure. The residue was dissolved in dichloromethane and washed with dilute HCl, dried over magnesium sulfate, filtered and chromatographed on silica gel eluting with dichloromethane to give 2.0 g of a pale yellow solid, mp 136-137°C. Elemental Analysis for _C20H18Cl2N2O : Calculated: _C , 64.35; H, 4.86; _N , 7.50 _. Found: C, 64.29; H, 4.80; N, 7.39. Example 10: 3-(3,4-difluorobenzoyl)-3,4-diaza-1,2,3,9,10,10a-hexahydrophenanthrene

In 75ml of dichloromethane, 3,4-diaza-1,2,3,9,10,10a-hexahydrophenanthrene (XIV) (1.83g, 9.82mmol) and 3,4-difluorobenzyl The acid chloride (1.73g, 9.82mmol) was mixed and 5ml of triethylamine was added. The mixture was stirred at 22°C for 16 hours and evaporated to dryness under reduced pressure. The residue was dissolved in dichloromethane and washed with dilute HCl, dried over magnesium sulfate, filtered and chromatographed on silica gel eluting with dichloromethane to give 1.4 g of a white solid, mp 146-147°C. _Elemental Analysis for _C19H16F2N2O : Calculated: _C , 69.93; H, _4.94 ; N, 8.58. Found: C, 69.78; H, 4.72; N, 8.79. Example 11: 3-(3,5-dichlorobenzoyl)-3,4-diaza-1,2,3,9,10,10a-hexahydrophenanthrene

In 250ml of dichloromethane, 3,4-diaza-1,2,3,9,10,10a-hexahydrophenanthrene (XIV) (2.67g, 14.3mmol) and 3,5-dichlorobenzyl The acid chloride (3.0 g) was mixed and 10 mL of triethylamine was added. The mixture was stirred at 22°C for 1 hour and evaporated to dryness under reduced pressure. The yellow residue was dissolved in dichloromethane and washed with dilute HCl, dried over magnesium sulfate, filtered and chromatographed on silica gel eluting with ether/dichloromethane (2:1) to give 3.0 g of a white solid, mp 141- 142°C. Elemental Analysis for _C19H16Cl2N2O : Calculated: C, 63.52; H, _4.49 ; _N , _7.84 . Found: C, 63.45; H, 4.14; N, 7.70, Example 12: 3-(3,4-dichlorobenzoyl)-3,4-diaza-9-oxa-1,2, 3, 9, 10, 10a-hexahydrophenanthrene

In 200ml of dichloromethane, 3,4-diaza-9-oxa-1,2,3,9,10,10a-hexahydrophenanthrene XXVI (1.73g, 9.2mmol) and 3,4-bis Chlorobenzoyl chloride (1.93g) was mixed and 150ml of triethylamine was added. The mixture was stirred at 22°C for 14 hours and evaporated to dryness under reduced pressure. The yellow residue was dissolved in dichloromethane and washed with dilute HCl, dried over magnesium sulfate, filtered and chromatographed on silica gel eluting with dichloromethane to give 1.2 g of an off-white solid, mp 166-167°C. Elemental analysis C ₁₈ H ₁₄ Cl ₂ N ₂ O ₂ : Calculated: C, 59.85; H, 3.91; N, 7.75, Found: C, 59.83; H, 3.86; N, 7.73, Example 13: 3-( 3,4-dichlorobenzoyl)-3,4-diaza-9-thia-1,2,3,9,10,10a-hexahydrophenanthrene

In 100ml of dichloromethane, 3,4-diaza-9-thia-1,2,3,9,10,10a-hexahydrophenanthrene XXVII (1.33g, 6.6mmol) and 3,4-bis Chlorobenzoyl chloride (1.38 g, 6.6 mmol) was mixed and 100 mL of triethylamine was added. The mixture was stirred at 22°C for 48 hours and evaporated to dryness under reduced pressure. The yellow residue was dissolved in dichloromethane and washed with dilute HCl, dried over magnesium sulfate, filtered and chromatographed on silica gel eluting with diethyl ether/dichloromethane (2:1) to give 1.0 g of an off-white solid which was It was recrystallized from benzene-hexane to give 0.84 g of a white solid, mp 145-146°C. Elemental Analysis _{for C18H14Cl2N2OS} : Calculated: C, 59.85; H, _3.91 ; _N , 7.75. Found: C, 59.83; H, 3.86; N, 7.73. Example 14: 3-(3,4-Dichlorobenzoyl)-3,4-diaza-1,2,3,9,9a-tetrahydrofluorene

In 100ml of dichloromethane, 3,4-diaza-1,2,3,9,9a-tetrahydrofluorene (XXV) (1.6g, 9.3mmol) and 3,4-dichlorobenzoyl chloride ( 1.95g, 9.3mmol) were mixed and 10ml triethylamine was added. The mixture was stirred at 22°C for 16 hours and evaporated to dryness under reduced pressure. The residue was dissolved in dichloromethane and washed with dilute HCl, dried over magnesium sulfate, filtered and chromatographed on silica gel eluting with dichloromethane to give 1.1 g of an off-white solid, mp 122-124°C. _Elemental Analysis for _C18H14Cl2N2O : Calculated: C, 62.60; H, 4.09; _N , _8.12 . Found: C, 62.50; H, 4.11; N, 7.90. Example 15: 2-(3,5-dichlorothiobenzoyl)-3,4,4a,5,6,7-hexahydro-2H-benzo[6,7]cyclohepta[1 , 2c] pyridazine

In 200ml of toluene, 2-(3,5-dichlorobenzoyl)-3,4,4a,5,6,7-hexahydro-2H-benzo[6,7] described in Example 7 Cycloheptano[1,2c]pyridazine (1.22g, 3.27mmol) and phosphorus pentasulfide (2.14g, 3.9mmol) were mixed and heated to 100°C for 1 hour. The mixture was cooled and filtered through a layer of silica gel, washing with dichloromethane. The filtrate was evaporated to dryness and purified by column chromatography eluting with dichloromethane to give 1.2 g of a yellow solid which was recrystallized from ether to give the desired compound (1.0 g), mp 149-150°C. Elemental Analysis for _C20H18Cl2N2S : Calculated: _C , 61.40; _H , 4.66; _N , 7.19. Found: C, 61.67; H, 4.65; N, 7.06. Example 16: 2-(3,4-Difluorothiobenzoyl)-3,4,4a,5,6,7-hexahydro-2H-benzo[6,7]cyclohepta[1 , 2c] pyridazine

In 200ml of toluene, the 2-(3,4-difluorothiobenzoyl)-3,4,4a,5,6,7-hexahydro-2H-benzo[6, 7] Cycloheptano[1,2c]pyridazine (1.5 g, 4.4 mmol) and phosphorus pentasulfide (1.74 g, 5.3 mmol) were mixed and heated to reflux for 1 hour. The mixture was cooled and filtered through a layer of silica gel, washing with dichloromethane. The filtrate was evaporated to dryness and purified by column chromatography eluting with dichloromethane to give 1.3g of a yellow solid which was recrystallized from ether to give the desired compound (0.83g), mp 134-136°C. Elemental _Analysis for _{C20H18F2N2S :} Calculated: _C , 67.40; H, 5.09; N, 7.86. Found: C, 67.28; H, 5.03; N, 7.94. Example 17: 2-(3,4-Dichlorothiobenzoyl)-3,4,4a,5,6,7-hexahydro-2H-benzo[6,7]cyclohepta[1 , 2c] pyridazine

In 150ml of toluene, 2-(3,4-dichlorobenzoyl)-3,4,4a,5,6,7-hexahydro-2H-benzo[6,7] described in Example 9 Cycloheptano[1,2c]pyridazine (1.5 g, 4.0 mmol) and phosphorus pentasulfide (2.7 g, 6 mmol) were mixed and heated to 100° C. for 30 minutes. The mixture was cooled and filtered through a layer of silica gel, washing with dichloromethane. The filtrate was evaporated to dryness and purified by column chromatography eluting with dichloromethane to give 1.3g of a yellow solid which was recrystallized from ether to give the desired compound (1.0g), mp 140-141°C. Elemental Analysis for _C20H18Cl2N2S : Calculated: _C , 61.40; _H , 4.66; _N , 7.19. Found: C, 61.78; H, 4.69; N, 7.09. Example 18: 3-(3,4-Difluorothiobenzoyl)-3,4-diaza-1,2,3,9,10,10a-hexahydrophenanthrene

In 150ml of toluene, 3-(3,4-difluorobenzoyl)-3,4-diaza-1,2,3,9,10,10a-hexahydrophenanthrene ( 1.0 g, 3.06 mmol) and phosphorus pentasulfide (2.05 g, 4.6 mmol) were mixed and heated to reflux for 1.5 hours. The mixture was cooled and filtered through a layer of silica gel, washing with dichloromethane. The filtrate was evaporated to dryness and purified by column chromatography eluting with dichloromethane to give 0.8 g of a yellow solid, mp 170-171°C. Elemental Analysis for _C19H16F2N2S : Calculated: _C , 66.65; H, _4.71 ; N, _8.18 . Found: C, 66.32; H, 4.76; N, 8.19. Example 19: 3-(3,4-dichlorothiobenzoyl)-3,4-diaza-1,2,3,9,10,10a-hexahydrophenanthrene

In 150ml of toluene, 3-(3,4-dichlorobenzoyl)-3,4-diaza-1,2,3,9,10,10a-hexahydrophenanthrene ( 1.06g, 2.95mmol) and phosphorus pentasulfide (1.17g, 3.83mmol) were mixed and heated to reflux for 1.5 hours. The mixture was cooled and filtered through a layer of silica gel, washing with dichloromethane. The filtrate was evaporated to dryness and purified by column chromatography eluting with dichloromethane to give 0.8 g of a yellow solid, mp 110-111°C. Elemental Analysis for _C19H16Cl2N2S : Calculated: _C , 60.80; H, _4.30 ; _N , 7.46. Found: C, 60.74; H, 4.11; N, 7.47. Example 20: 3-(3,5-dichlorothiobenzoyl)-3,4-diaza-1,2,3,9,10,10a-hexahydrophenanthrene

In 150ml of toluene, 3-(3,5-dichlorobenzoyl)-3,4-diaza-1,2,3,9,10,10a-hexahydrophenanthrene ( 1.5 g, 4.2 mmol) and phosphorus pentasulfide (1.69 g, 4.2 mmol) were mixed and heated to 80° C. for 1 hour. The mixture was cooled and filtered through a layer of silica gel, washing with dichloromethane. The filtrate was evaporated to dryness and purified by column chromatography eluting with dichloromethane and recrystallized from ether/hexane to give 1.1 g of a yellow solid, mp 162-163°C. Elemental Analysis for _C19H16Cl2N2S : Calculated: _C , 60.80; H, _4.30 ; _N , 7.46. Found: C, 60.78; H, 4.26; N, 7.22. Example 21: 3-(3,4-Dichlorothiobenzoyl)-3,4-diaza-9-oxa-1,2,3,9,10,10a-hexahydrophenanthrene

In 100ml of toluene, 3-(3,4-dichlorobenzoyl)-3,4-diaza-9-oxa-1,2,3,9,10,10a- Hexahydrophenanthrene (0.6g, 1.66mmol) and phosphorus pentasulfide (0.96g, 2.1mmol) were mixed and heated to reflux for 1.5 hours. The mixture was cooled and filtered through a layer of silica gel, washing with dichloromethane. The filtrate was evaporated to dryness and purified by column chromatography eluting with dichloromethane to give 0.5 g of a yellow solid, mp 187-188°C. Elemental Analysis _{for C18H14Cl2N2OS} : Calculated: C, 57.30; H, _3.74 ; _N , 7.43. Found: C, 57.09; H, 3.75; N, 7.29. Example 22: 3-(3,4-Dichlorothiobenzoyl)-3,4-diaza-1,2,3,9,9a-tetrahydrofluorene

In 100ml of toluene, 3-(3,4-dichlorobenzoyl)-3,4-diaza-1,2,3,9,9a-tetrahydrofluorene (0.63g , 1.8mmol) and phosphorus pentasulfide (1.05g, 2.3mmol) were mixed and heated to reflux for 1.5 hours. The mixture was cooled and filtered through a layer of silica gel, washing with dichloromethane. The filtrate was evaporated to dryness and purified by column chromatography eluting with dichloromethane to give 0.5 g of a yellow solid, mp 138-140°C. Elemental Analysis _{for C18H14Cl2N2S} : Calculated: C, 59.84; H, _3.91 ; _N , 7.76. Found: 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, C ₁-C ₆Alkyl, C _1-6Haloalkyl, nitro, cyano group, carboxyl and C ₁-C ₆Carbalkoxy; 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, C ₁-C ₆Alkyl, C _1-6Haloalkyl, nitro, carboxyl and C ₁-C ₆Carbalkoxy; 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-group 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 arbitrary claim among the claim 1-7 that treats significant quantity compound and with the pharmaceutically acceptable carrier of its blended.

15. among the claim 1-7 compound of arbitrary claim preparation treatment contraception, menopause, endometriosis, mammary cancer, termination of pregnancy, childbirth is induced or the medicine of osteoporosis in purposes.

16. the purposes of claim 15, the dosage of wherein said compound are 1-500mg/kg/ days.