CZ138098A3 - 1-Arylsulfonyl, aryl (thio) carbonyl derivatives of pyridazine and methods for their preparation - Google Patents

Abstract

1-Arylsulphonyl, arylcarbonyl and aryl(thio)carbonyl pyridazino derivatives and processes for making said derivatives are described. 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 in contraception, menopause, osteoporosis or endometriosis.

Description

01-987-98-Ce

1-Arylsulfonyl, aryl (Lhio) carbonyl derivatives of pyridasine and processes for their preparation

Technical field:

The present invention relates to 1-arylsulfonyl, arylcarbonyl and aryl (thio) carbonyl pyridazine derivatives and processes for their preparation.

BACKGROUND OF THE INVENTION:

Some intermediates in the syntheses of the claimed compounds are known. For example, 3,4-diazo-1,2,3,9,10,10a-hexahydrophenanthren-2-one (A) and 3,4,4a, 5,7,7-hexahydro-2H-benzo [6,7] cycloheptai 1,2c] pyridazin-2-one (B) by Holava and Partyka. 2,4,4a, 5-tetrahydro-3H-inden-1,2-clpyridin-3-one (C) reported by Torna and Cignarella et al.

A B C

Synthesis

Of 7-bromo-4-methyl-1-tetraone compounds related to intermediates used in the present invention;

4-methyl-1-tetraone (D) has been reported (verbally)

Prof.R.

Danheiser at HIT.

Although Danheiser describes the synthesis of a compound disclosed in the literature, its procedure is similar to the compounds used to synthesize compounds according to the procedure used herein to prepare predominantly unknown compounds.

invention.

D E

No tri halogenated benzocyclone-canones have been described in the literature.

Of the dihalobenzocycloalkanones, only 6,7-difluoro- and 6,7-dichlorotetralones are known, but these are prepared by another process. Owton, W.M. and Brunavs, M. Synthetic Communications, 21, 981 (1991).

No dibromobenzocycloalkanones are known.

All monobromotetralones are known except for 8-bromo-1-tetralone.

None of the claimed compounds of the present invention has been described.

SUMMARY OF THE INVENTION:

The present invention relates to compounds characterized by formula I:

I where =

L is CO, CS or SO 2;

í • · · ·

R 1 and R 2 are independently selected from H, halogen, alkyl (C 1 -C 6), haloalkyl (C 1-6), nitro, cyano, carboxyl, and carboalkoxy (C 1-6); provided that when L is SO 2, R 1 and R 2 are not simultaneously hydrogen;

R 3 is independently one, two or three of the following substituents: H, halogen, alkyl (C 1-6), haloalkyl (C 1-6), nitro, carboxyl, or carboalkoxy (C 1-6);

X is a double radical of formula (CH 2> n or Y- (CH 2) n -1, wherein n is an integer from 1 to 3, and Y is 0 or S.

For purposes of this invention, unless otherwise stated, and when used alone or with another, alkyl is defined as 1 to 6 carbon which may be branched, in which case they are at least 3 carbon atoms, or unbranched. Halogen is specified as chlorine, bromine, fluorine or iodine. Alkoxy refers to groups derived from alcohols having 1 to 6 carbon atoms, haloalkyls being defined as containing an alkyl group having 1 to 3 carbon atoms, such as trifluoromethyl.

The compounds of this invention are non-steroidal heterocycles that can act as selective progestins and / or antiprogestins that have high in vitro affinity for the uterine, breast or bone progestin receptors, as well as biological activity by intravenous subcutaneous or oral route. Accordingly, they may be useful as therapeutics in conjunction with contraceptives, menopause, endometriosis, breast cancer, pregnancy termination, induction of labor or osteoporosis.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

In particular, the present invention relates to a series of non-steroidal heterocyclic derivatives whose activity mimics the activity of progestins and / or antiprogestins having a high in vitro affinity for either uterine or breast or bone. 4 ...... 4 ...... 4 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 Progestin receptor.

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

Compounds of the present invention can be prepared according to the following Reaction Scheme 1 =

REACTION SCHEME

As can be seen from Reaction Scheme I, the appropriately substituted benzocycloalkanone (II) is converted to the cyclic acylhydrazone (III) by methods known in the art, such as the Hlava and Partyky processes (J. Med. Chem. 14, 262, (1971)). Generally, this involves converting II to an alpha-unsaturated keto acid using glyoxylic acid and a base, followed by reducing the unsaturation by heating with zinc in acetic acid and treating the reduced keto acid with hydrazine to form III and aaa · · ··· · «« · · · · · ·

The substituted cyclic acylhydrazone (III) is then converted to the cyclic hydrazone (IV) by reaction with a reducing agent such as lithium aluminum hydride or diborane in a suitable solvent such as tetrahydrofuran (THF) by conventional procedures as described by J. L.agnagnac, J. Elguero, R. Jacquier and R. Robert in Bull. Chem. Soc., France, 2859, (1972).

The obtained cyclic hydrazone (IV) is acylated with an appropriate substituted benzoyl halide or sulfonyl halide in a suitable solvent such as THF such as pyridine, or in an inorganic base such as or toluene, triethylamine to form a non-sterile heterocyclic derivative (I).

The product is isolated and purified by techniques known to those skilled in the art, such as by pouring the reaction mixture into a dilute acid, such as hydrochloric acid, by extracting the mixture with an organic solvent such as methylene chloride or ethyl acetate.

The organic layer was concentrated and the residue crystallized or purified by silica gel chromatography. The product-containing fractions are evaporated and the residue recrystallized to give the desired compounds.

The amides obtained by these thioamides (L = CS) by the reaction process can be converted to with Laweson's reagent or P2S5 in toluene.

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

• · ·

REACTION SCHEME

2.4 eqiuv Y2 / AICI3

Y Y Y

As shown, adding

1.2 equivalents of the halogenating agent in the presence of aluminum chloride yields two monohalobenzocycloalkanones where the halogen is introduced into the meta keto group.

reagents in the presence of aluminum chloride are obtained with di-benzobenzocyclic cannons as well as two isomeric tri-benzobenzocyclic cannons.

Further, monohalobenzocycloalkanones may be halogenated with various halogen to form mixed substituents 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 testing in the progestin receptor binding assay and the Ex vivo pre-gestation assay.

Progestin receptor binding

The procedure used is essentially the same as that of J. L. Mc Guire,

C.D.Bariso and A.P.Shroff in Biochemistry 13,

319 (1974).

9

New Zealand rabbits (1.5-2.5 kg) are placed in cold buffer A (0.01 M Tris-HCl, pH 8.0, 0.001)

M EDTA, 0.25 M sucrose). The uteri are ground, washed and homogenized in cold buffer A. The homogenate (2 g wet tissue / ml buffer) is centrifuged at 200,000 G for 1 h at 4 ° C. The high speed fraction of the supernatant is used as a receptor preparation.

A competitive binding assay is performed by mixing ³ H-R5020 with a receptor preparation and adding a known amount of unlabeled compound. The mixture is incubated at 4 ° C for 18 h. The receptor-bound compounds are separated from the free ones in solution using dextran coated charcoal and the amount of receptor-bound isotope is determined. A reduction of 20% or more from control isotope binding is considered significant.

A similar procedure can be used to determine the binding affinities for a breast or bone derived progestin receptor.

Ex vivo pre-gestation test

Incorporation of ³ H-thymidine into T47-D cells is used to test the effect of compounds on T47-D by cell proliferation. The compounds of the present invention have utility in the treatment of in vivo progestin-modulated biological conditions, demonstrating an acceptable effect on the growth of T47-D cells.

A similar procedure is used to measure the effect of test compounds on TE85 human bone cells.

T47-D (human breast line) was used using standard sterile procedures. Cells were stored in RPMI 1640 medium supplemented with fetal bovine serum (10%) and insulin (0.2 I.U./ml). Cells were trypsinized and passaged using standard procedures.

Cells were seeded in 96-well microtiter plates by incubation in RPMI medium (phenol red-free, insulin-be2, 5% fetal bovine ginger-treated charcoal) at 37 ° C in an atmosphere of 95% air / 5% CO 2. After approximately 48 hours, the digested medium was replaced with fresh medium containing test compounds dissolved in DMSO (0.1% final concentration) and the cells were cultured for approximately 22 hours. ³ H-thymidine was added and incubation continued for an additional 4 hours. The assay was then terminated by the addition of an excess of unlabeled thymidine. Cells were washed free of dissolved thymidine, trypsinized and recovered by standard procedures. The amount of ³ H-thymidine incorporated into the DNA was determined by liquid scintillation counting. The primary standards were promegestone, potent synthetic synthetic progestin and RU486, antiprogestin. Test compounds were generally tested at concentrations ranging from 0.1 to 1000 nM. A compound is considered to be active when it stimulates or inhibits thymidine incorporation. The results are expressed as the concentration of test compounds required to increase proliferation 2 times during control (SC200), or the concentration required to inhibit promegestone-induced proliferation by 50% (EC50). Values less than 1000 nM are considered active.

The application aspects of the procedure are described in the following: C. Christensen,

D. Gunter, D. Saunders and V.

Ma1v i ya, Gynecol, Oncol. 28, 25 (1987); J.Puzas, R.

Drivdahl, G.Howard and D.Baylink,

Proc.Soc.Exp, Biol.Med., 166,

113 (1981);

I.Keydar,

L.Chen,

S.Karby, F.Weiss, J.Delarea,

M. Raduy,

WITH.

Chaitcik and H. Brenner, Eur. J. Cancer, 15, 659 (1979).

TABLES

The table shows examples of the invention with molecular formulas, melting points, binding affinity expressed as the concentration of compound in nanomoles per liter (x 10 ^_ * Μ) required to replace 50% of H ³ labeled R5020 from the rabbit uterine cytosolic receptor progestin (PRXIC 50), and the ability to proliferate or inhibit R5020 induced proliferation of T47D human breast cancer cells (T47D). If no value is given in column T47D, then this particular compound was not tested.

Tables 2 and 3 show a number of examples of the invention with molecular formulas, melting points, activity expressed as the average increase in bone cell proliferation at nanomolar concentrations (CP) per liter or as the compound concentration required to replace 50% of 1125 labeled nortestosterone (11). VNT) from the human bone receptor progestin (BPRHIC 50). If no value is given in the column labeled CP, then the specific compound has not been tested.

Table 1

SULPHONAMIDES

£ fil HZ * 1 H Br (CH 2) 3 2 H Br (CH 2) 2 3 Br Br (CH 2) 2 4 and H , (CH 2) 2 5 Br H (CH 2) 2

fla JBH 44 76 44 10 44 2.4 +337 44 8.3 -654 2,5-diCl 34 -495

formula C19H18Br1N2O2S 180-1 C18H16Br1N2O2S 197-8 C18H18Br2N2O2S 202-3 C18H10ClIN2O2S 194-6 C18H15Cl3N2O2S 186-7

• • · ♦

9 9

9 + indicates an agonist SC200 nM (concentration stimulating

2-fold above the control) indicates the antagonist EC50 nM versus R5020 induced proliferation

Table 2

AMIDY

£ X bs £ E BBB formula 6 (CH 2) 2 3,4-diCl 115 ^c 19H16Cl2N2O 154-5 7 (CH 2) 3 3,5-diCl 120 8.4 C20H18Cl2N2O 115-6 8 (CH 2) 3 3,4-diF 4.8 C20H18F2N2O 117-8 9 (CH 2) 3 3,4-diCl 123 107 C20H18Cl2N2O 136-7 10 (CH 2) 2 3,4-diF 112 19Hi ^c 6 ^ 2 ^ 20 146-7 11 (CH 2) 2 3,5-diCl 113 11.6 C19H16Cl2N2O 141-2 12 OCH2 3,4-diCl 107 3.6 C18H14Cl2N2O2 166-7 13 SCH2 3,4-diCl 50 C18H14Cl2N2OS 145-6 14 CH2 3,4-diCl 9.0 C18H14Cl2N2O 122-4

99 99 99 9999

9 9 9 9 9 9 99

9 9 9 9 999 9 999

11 «♦ ·« «« · ·

Table 3

THIOAMIDY

£ X— J ^R 3 X ( m Áx fiE N WITH BEB formula L.é. 15 Dec (CH 2) 3 3,5-diCl 109 23.3 C20H18Cl2N2S 149-50 16 (CH 2) 3 3,4-diF 111 C20H18F2N2S 134-6 17 (CH 2) 3 3,4-diCl 115 32 C20H18Cl2N2S 140-1 18 (CH 2) 2 3,4-diF C19H16F2N2S 170-1 19 Dec (CH 2) 2 3,4-diCl 87 44.3 C19H16Cl2N2S 110-1 20 May (CH 2) 2 3,5-diCl 103 10.2 C19H16Cl2N2S 162-3 21 OCH2 3,4-diCl 2.0 C18H14Cl2N2OS 187-8 22nd CH2 3,4-diCl 0.5 C18H14Cl2N2S 138-40

Pharmaceutical compositions containing the compound of the present invention as an active ingredient in intimate admixture with a pharmaceutical carrier may be prepared by conventional pharmaceutical compounding procedures. The carrier may take various kinds of forms depending on the form of preparation desired for administration, such as intravenous, oral or parenteral. Any conventional pharmaceutical media such as water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like can be used in the preparation of oral dosage forms for oral liquid preparations (such as suspensions, elixirs, and the like). Or carriers (such as starches, sugars, diluents, granulating agents) or carriers. , lubricants, binders, disintegrants and the like in the case of oral solid preparations (such as powders, capsules and tablets). Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case conventional solid pharmaceutical carriers are employed. If desired, tablets may be sugar or enteric coated by standard techniques. For parenteral administration, the carrier typically comprises sterile water, and other ingredients may be used, for example, to improve solubility or for preservative reasons; injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like are used. The pharmaceutical compositions of the present invention are for use in therapy for contraception, menopause, endometriosis, breast cancer, cyclesynchronia, termination of pregnancy, induction of labor or osteoporosis, as possible indications. Endometrosis, contraception, and osteoporosis are most likely wherein the dosage units, eg, tablets, capsules, powder and the like, contain from about 1 to about 500 mg / kg / day and preferably from about 10 to about 100 mg / kg / day of active ingredient. The exact dose will vary depending upon the age and condition of the patient and the particular conditions being tested.

Examples

I. Preparation of starting materials and intermediates used in the preparation of the final products of the invention

The following Chapters A, B and C contain a description of the preparation of some of the starting materials and intermediates useful in the preparation of the compounds of the present invention.

A. Preparation of halobenzocyclanones

In the following examples, N-bromosuccinimide may be

• · • ···

Bromine and N-chlorosuccinimide or chlorine can be used to prepare chlorinated compounds. N-iodosuccinimide assumes iodine analogs.

05 / About AICIs / Br ₂ - * ψΣ> Y 1-indanone (VI) Villa, X = Br; VIIb, Y = Br; Villa, X = Y = Br

6-Bromindan-1-one (VIIb) and 4-bromoindan-1-one (Villa)

The 250 ml three-necked round bottom flask was equipped with a water-cooled Liebig condenser, mechanical stirrer and pressure-balanced addition funnel protected by a drying tube. The flask was filled with anhydrous aluminum chloride (16.6 g, 0.125 mol) and stirred while 1-indanone (VI) (6.60 g, 0.05 mol) was added in two portions over 3 minutes, which was ground in Mortar and pestle on fine powder. The abundant evolution of HCl gas was terminated slightly exothermally and the mixture quickly darkened to a dark brown, homogeneous slurry, which was stirred for an additional 10 minutes.

To the well stirred mixture was added bromine (3.1 mL, 0.06 mol) dropwise over 10 minutes. When all bromine was added, the molten mixture was heated in a water bath at 80 ° C for 5 minutes. While still hot, the mixture was poured into 100 g of crushed ice and 20 ml of concentrated hydrochloric acid. The ice mixture was then stirred for 10 minutes, diluted with 100 mL of water and extracted with ether (2x200 mL). The combined ether extracts were washed with water (2x100 mL) and dried over anhydrous sodium sulfate and concentrated to give 10.6 g of a red oil which crystallized upon standing at room temperature.

Analysis of GC-MC showed a mixture of 1 = 1 monobromisomers. The material was subjected to silica gel column chromatography (45 x 10 cm) using n-hexane / THF (8: 1) to separate the isomers. The separated isomers were recrystallized from hexane to give 3.8 g of 6-bromoindan-1-one (VIIa) and 4.0 g.

4-bromoindan-1-one (VIIIb).

Vila'- Yield

37.7 prisms; IR (KBr)

1712 cm

mp 108-109 ° C, light yellow *; 1 H NMR (CDCl ₃ ) δ 2.70-2.74 (m,

2H), 3.08-3.12 (m,

7.35-7.38 (d, 1H), 7.66-7.70 (dd, 1H),

7.87-7.88 (d, 1H);

m / z 211;

Anal. calc. for

CgHyBrO: C,

51.22; H, 3.34.

Ma 1 ezeno · '

C, 51.10;

H, 3.25.

Vllb:

Yield

35, 8

m.p. 90-92 ° C, light yellow prisms;

IR (KBr)

1709 cm ^-1 ;

@ 1 H NMR (CDCl3) .delta. 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) m / z 211;

Anal. calc. for C 8 H 9 BrO: C, 51.22; H, 3.34.

Found: C, 50.38; H, 3.24.

7-Bromo-1-tetralone (IXa) and 5-bromo-1-tetralone (IXb)

IXa. X-ππ IXb, Y = Br

1-Tetralone; (VIII) 1-Tetralone (VIII) (7.3 g, 0.05 mol) was added dropwise to anhydrous aluminum chloride (16.6 g,

0.125 mol) za • ΦΦΦ · φ · φ · φ φ φ φ φ φ

125 * Intensive stirring for 3 minutes. Bromine (3.71 mL, 0.06 mol) was added to the sanded slurry for 10 minutes. The mixture was heated to 80 ° C for 45 minutes after bromine addition was complete, and the still molten mixture was poured into 150 g of crushed ice containing 20 mL of 12N HCl. In the same manner as in Example 1, 10.85 g of a brown oil is obtained. The oil was chromatographed on a silica gel column (45 x 10 cm) using hexane: THF (δ = 1). The separated isomers were recrystallized with 2 hexanes to give 4.2 g of 7-bromo-1-tetralone (IXa) and 4.5 g of 5-bromo-1-tetralone (IXb).

IXa: Yield 37.2 bt 74-75 ° C, light yellow prisms; IR (KBr) 1676 cm ^-1 ; 1 H 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); m / z 225;

Anal. calc. for C 10 H 9 BrO: C, 53.36; H, 4.03.

Found: C, 53.14; H, 3.96.

IXb: Yield 39.8%; mp 45-46 ° C, light yellow prisms; IR (KBr) 1679 cm ^-1 ; 1 H 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); m / z 225;

Anal. calc. for C 10 H 9 BrO · 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 9

99

4 · 9 9 99 9 9 9

-¼ ° · 9 · 9 · 99 · 99

Bromine (7.42 g, 0.12 mol) was added dropwise to a slurry formed from anhydrous aluminum chloride (16.6 g, 0.125 mol) and

1-tetralone (VIII) (0.05 mol) as in Example 1. The yield was 15.0 g of a brown oil which crystallized on standing. GC-MS showed a mixture of 87% dihrominated product and 13% 1: 1 tribrominated isomers. Chromatography and recrystallization from hexane gave 7.7 g.

IXc: Yield 51%> mp 60-61 ° C, light yellow prisms; IR (KBr) 1690 cm ^-1 ; 1 H NMR (CDCl ₃ ) δ 2.11-2.20 (m,

2H), 2.62-2.66 (dd, 2H), 2, 93-2.97 <t, 2H, J = 6.2 Hz), 17.88 (d, 1H, J = 2Hz) 8.13 (d, 1H, J = 2 Hz); 8.13 CD, 1 H, J = 2 Hz) ; ms m / z 304; Anal. calc. for CioHsBrO: C, 39.51; H, 2, 65. Found: C, 39.41; H, 2.49.

8-bromo-1-benzosuberone (XIa) and 6-bromo-1-benzosuberone (XL1)

X 1a, X = Br; X 1b, Y = Br; Xc, X »Y = Br

Following the general procedure detailed above for the preparation of bromotetralones, the yield is a mixture of benzosuberone (X) (8.01 g, 0.05 mol), aluminum chloride (16.6 g, 0.125 mol), and bromine (3.07 mL,

0.06 mol) after usual work-up 11.87 g of brown oil.

GC-MS showed a mixture of 1 = 1 monobromisomers containing 2% di-bromoisomer.

XIa = Yield 30% ’> m.p. 38-38.5 ° C, off-white powder; m / z 239;

Anal. Calcd for C 11 H 11 BrO: C, 55.25; H, 4.64.

Found: C, 54.83; H, 4.62.

························

X1b: Yield 320%; clear oil m.p.

• ·· ·· · · li ?. ”.

• · · · · · · · · · · · · · · · · · · · · · · · · ·

101-105 ° C, 0.12 mm Hg _; m / z 239;

Anal. Calcd for C 11 H 11 BrO: C, 55.25; H, 4.64.

Found: c, 55.32; H, 4.59.

5,6-dibromo-1-tetralone X11a and 6,7-dibromo-1-tetralone X11b

X 11a, Y = Br, X = H X 11b, X = Br, Y = H

Following the same procedures described in detail above for bromination of tetralone, a mixture of 6-bromo-1-tetralone XII (2 g, mmol), aluminum chloride (16.6 g, 0.125 mol), and bromine (3.07 mL, 0.06 mol) ) yielded 1.87 g of brown oil after usual work-up.

B. Preparation of cyclic acylhydrazones

3,4-diazo-1,2,3,9,9a-tetrahydrofluoren-2-one (XIII)

The title compound was prepared as described by Torna, L., Cignarella, G., Barlocco.D. and Ronchetti,

F. in J, Med. Chem., 33, 1591-4 (1990).

3,4-diazo-1,2,3,9,10,10a-hexahydrophenantren-2-one (XIV) The title compound was prepared according to the method of Holava, H.M. and Partyka, R.A. in J, Med. Chem. 14,262, (1971).

• · · · · · · · · • · · · • · • · φ · φ · φ · φ · φ · φ · ··

3,4,4a, 5,6,7-hexahydro-2H-benzo [6,7] cyclohepta [1,2c] pyridazin-2-one (XV)

The title compound was prepared as described by Holava, H.M. and Partyká, R.A. in J. Med. Chem. 14 262, (1971),

8-bromo-3,4-diazo-1,2,3,9,10,10a-hexahydrophenanthren-2-one (XVI)

Compound ^- The title compound was prepared by treating

5-bromo-1-tetraone (IXb) (20 mmol) with glyoxylic acid (20 mmol), the product was reduced with excess zinc in acetic acid and treated with excess hydrazine by conventional procedures as described by Holava, H.M. and Partyka, R.A, J. Med. Chem 14, 262, (1971) to give the title compound.

7,8-Dibromo-3,4-diazo-1,2,3,9,10,10a-hexahydrophenanthren-2-one (XVII)

The title compound was prepared by treating 5,6-dibromo-1-tetralone (XIIa) (10 mmol) with glyoxylic acid (10 mmol), reducing the product with excess zinc in acetic acid and treating with excess hydrazine as described by Holava, H.M. and Partyka, R.A, J. Med. Chem 14, 262, (1971) to give the title compound.

7-chloro-3,4-diazo-1,2,3,9,10,10a-hexahydrophenanthren-2-one (XVIII)

The title compound was prepared by workup

6-chloro-1-tetralone (Rosowsky, A., Chaykovsky, M., Yeager,

S.A., et al., J. Het.Chem. 8,809, (1971)) 50 mmol with glyoxylic acid 50 mmol, and the base was then reduced with an excess of zinc in acetic acid and then treated with an excess

hydrazine, as described Holava, Η. M. and Party, R. A, J.Med.Chem 14, 262, (1971) to give compounds listed in the title.

• · •>

8-bromo-3,4,4a, 5,6,7-hexahydro-2H-benzo [6,7] cycloheptal-1,2c] pyridaain-2-one (XIX)

The title compound was prepared by treating 8-bromo-1-benzosuberone (X1b) with glyoxylic acid, then reducing with excess zinc in acetic acid, and then treating with excess hydrazine as described by Holava, H.M. and Fartyka, R.A, J. Med. Chem 14, 262, (1971) to give the title compound.

C. Preparation of cyclic hydrazones

3,4-diazo-1,2,3,9,10,10a-hexahydrophenanthrene (XX)

3,4-diazo-1,2,3,9,10,10a-hexahydrophenantren-2-one (XIV) (2.5 g, 12.5 mmol) was dissolved in THF and 1 equivalent of aluminum hydride was added dropwise 1-lithium (21 mL, 1M solution in THF). After 30 minutes at 22 ° C, a 15% NaOH solution was added dropwise, and the gelatinous precipitate was filtered off. 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 further purification.

7-chloro-3,4-diazo-1,2,3,9,10,10a-hexahydrophenanthrene (XXI)

7-chloro-3,4-diazo-1,2,3,9,10,10a-hexahydrophenanthren-2-one (XVIII) was dissolved in THF and 1 equivalent of lithium aluminum hydride (1M solution) was added dropwise. in THF). After 30 minutes at 22 ° C, a 15% NaOH solution was added dropwise, and the precipitate was filtered off. 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 further purification.

8-bromo-3,4,4a, 5,6,7-hexahydro-2H-benzo [6,71-cycloheptai-1,2c] pyrimidine (XXII)

20 .. ·

5-Bromo-3,4,4a, 5,6,7-hexahydro-2H-benzo [6,7] cyclohepta [1,2c] pyridazi-2-one (XIX) (1 g, 3.4 mmol) dissolved in THF and 2 equivalents of diborane (1M solution in THF) were added dropwise. After 2 h 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 as such without further purification.

8-bromo-3,4-diazo-1,2,3,9,10,10a-hexahydrophenanthrene (XXIII)

8-bromo-3,4-diazo-1,2,3,9,10,10a-hexahydrophenanthren-2-one (XVI) (1.0 g, 3.6 mmol) was dissolved in THF and added dropwise 2 equivalents of diborane (1M solution in THF). After 1 h at 22 ° C, the reaction mixture was heated on a steam bath for 5 min and then quenched with 1 mL 6N 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 as such without further purification.

7,8-dibromo-3,4-diazo-1,2,3,9,10,10a-hexahydrophenanthrene (XXIV)

7,8-dibromo-3,4-diazo-1,2,3,9,10,10a-hexahydrophenantren-2-one (XVII) (0.71 g,

(1.98 mmol) was suspended in THF and 2 equivalents of diborane (3.96 mL in

1M solution in THF) at 22 ° C.

The mixture was briefly warmed to ° C to dissolve all solids

The mixture was stirred at room temperature for 60 h.

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 a starting material without 2 f.

3,4-diazo-1,2,3,9,9a-tetrahydrofluorene (XXV)

3,4-diazo-1,2,3,9,9a-tetrahydrofluoren-2-one (XIII) (3.5 g, 17.5 mmol) was dissolved in THF and an equivalent of lithium aluminum hydride was added dropwise ( 1M solution in THF). After 30 minutes at 22 ° C, a 15% NaOH solution was added dropwise, and the gelatinous precipitate was filtered off. 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 further purification.

3,4-diazo-9-oxa-1,2,3,9,10,10a-hexahydrophenanthrene (XXVI)

3,4-diazo-9-oxa-1,2,3,9,10,10a-hexahydrophenanthren-2-one (15 mmol) prepared as described (Cignarella, G .; Barlocco,

D.; Curzu, M.M. ; Pinna, G.A .; Cazzulani, P. ; Cassin.M .;

Lumachi.B. Eur.J. Copper. Chem. 25 (9): 749-56. (1990)) was reduced as above with 2 equivalents of diborane.

3,4-diazo-9-thia-1,2,3,9,10,10a-hexahydrophenanthrene (XXVII)

3,4-diazo-9-thia-1,2,3,9,10,10a-hexahydrophenantren-2-one (10 mmol) prepared as described (Nakao,

Tohru;

Tanaka, H i rosh i;

Mor imoto,

Yasuto;

Takehara, Shuzo; Demizu,

Ken i chi;

Tahara dating in Tetsuya

Yakugaku Zasshi 110 (12)

922-31, (1990)) was reduced as above with 2 equivalents of diborane.

The following examples are provided to illustrate the present invention but are not to be construed as limiting the scope of the invention.

Examples

Example 1: 8-bromo-3,4,4a, 5,6,7-hexahydro-2- (4-iodobenzene- sulfonyl) -2H-benzo [6,71-cycloheptat-1,2c] pyridazine

8-bromo-3,4,4a, 5,6,7-hexahydro-2H-benzo [6,7] cyclohexyl-1,2c] pyridazine (XIX) (1.0 g, 3.6 mmol) and 4-iodobenzenesulfonyl chloride (1.1 g, 3.6 mmol) were combined in a solution of 50 mL of dichloromethane and 50 mL of pyridine. The mixture was stirred at 22 ° C for 64 h to give a dark red color. The mixture was concentrated under reduced pressure and the pyridine solution was poured into 6 M 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

1.3 g of off-white solid which was recrystallized from isopropanol / chloroform to give a white solid, m.p. 180-181 ° C.

Calculated for: C 18 H 18 Br 1 N 2 O 2 S: C, 41.85, H, 3.33, N, 5.14.

Found: c,

H, 3.27; N, 5.03.

Example ___ 2:

8-bromo-3,4-diazo-1,2,3,9,10,10a-hexahydro-3- (4-iodobenzenesulfonyl) phenanthrene

8-bromo-3,4-diazo-1,2,3,9,9,10,10a-hexahydrophenanthrene (XXI) (1.0 g, 3.77 mmol) and 4-iodobenzenesulfonyl chloride (1.14 g, 3.77) mmol) were combined in 100 mL of pyridine. The mixture was stirred at 22 ° C for 16 h to give a deep red color. Then the mixture was poured into 6 M 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 material which was recrystallized from hexane to give 0.28 g of off-white solid, mp 197-198 ° C.

Calcd for C 18 H 16 BrIN ₂ O ₂ SC, 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-diazo-1,2,3,9,10,10a-hexahydro-3- (4-iodobenzenesulfonyl) phenanthrene

7,8-dibromo-3,4-diazo-1,2,3,9,10,10a-hexahydrophenanthrene (XVI)

(0.7 g, 1.9 mmol) and 4-iodobenzenesulfonyl chloride (0.65 g, 2.1 mmol) were combined in 100 mL pyridine. The mixture was stirred at ° C for 16 h to obtain a deep red color.

The mixture was then poured into 6 L

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 a crude material that was recrystallized from hexane to give 0.1 g of a white solid, mp 202-203 ° C.

H, 2.48; N, 4.59. Found: C, 35.44; H, 2.48;

Found: c, 35.54, H, 2.47, N, 4.61.

Example 4 ^: 7-Chloro-3,4-diazo-1,2,3,9,10,10a-hexahydro-3- (4-benzenesulfonyl) phenanthrene

7-chloro-3,4-diazo-1,2,3,9,10,10a-hexahydrophenanthrene (XXI) (1.1 g, 5.00 mmol) and 4-iodobenzenesulfonyl chloride (1.2 g, 3.9 mmol) were combined in a solution of 50 mL of dichloromethane and 50 mL of pyridine. The mixture was stirred at 22 ° C for 20 h to give a deep red color. Then the mixture was concentrated under reduced pressure and the pyridine solution was poured into 6 M 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 an off-white solid, which was recrystallized from hexane to give 0.5 g of a white solid, mp 194-196 ° C.

Calcd for C 18 H 10 ClN 2 O 6 S: 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-diazo-1,2,3,9,10,10a-hexahydro-3- (2,5-dichlorobenzenesulfonyl) phenanthrene

7-chloro-3,4-diazo-1,2,3,9,10,10a-hexahydrophenanthrene (XXI) (1.0 g, 4.7 mmol) and 2,5-dichlorobenzenesulfonyl chloride (1.2 g,

4.9 mmol) were combined in 100 mL pyridine. The mixture was stirred at 22 ° C for 16 h to give a deep red color. Then the mixture was poured into 6 M 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 material which was recrystallized twice from hexane / chloroform to give 0.25 g of an off-white solid, mp 186-187 ° C.

Calcd for C18H15Cl3N2O3S: 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-diazo-1,2,3,9,10,10ahexahydrophenanthrene

3,4-diazo-1,2,3,9,10,10a-hexahydrophenanthrene (XXI) (2.67 g,

14.3 mmol) and 3,4-dichlorobenzoyl chloride (3.0 g) were combined in 100 mL pyridine and stirred at 22 ° C for 16 h. 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 washed with dichloromethane to give 3.7 g of an off-white solid, mp 154-5 ° C.

Calculated for C18H10Cl5N2O = 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] cycloheptat 1,2c-1 pyridazine

3,4,4a, 5,5,7-hexahydro-2H-benzo [6,71-cycloheptat-1,2-pyridazazine (XV) (2.0 g, 10 mmol) and 3,5-dichlorobenzoyl chloride (2.1 g, 10 mmol) were combined in 75 mL of dichloromethane and 5 mL of triethylamine was added. The mixture was stirred at 22 ° C for 16 h and evaporated to dryness under reduced pressure. The rest was dissolved • ···

in dichloromethane and washed with dilute HCl, dried over magnesium sulfate, filtered and chromatographed on silica gel washed with dichloromethane to give 2.5 g of a white solid, m.p. 115-116 ° C.

Calcd. For C20H18Cl2N2O 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-benzol 6,7] cycloheptat-1,2c] pyridazine

3,4,4a, 5,5,7-hexahydro-2H-benzo [6,7] cycloheptat-1,2c] pyridazine (XV) (2.0 g, 10 mmol) and 3,4-difluorobenzoyl chloride (2.1 g) (10 mmol) were combined in 75 mL of dichloromethane and 5 mL of triethylamine was added. The mixture was stirred at 22 ° C for 16 h and evaporated to dryness under reduced in dichloromethane and washed with magnesium, filtered and pressure. The residue was dissolved with dilute HCl, dried over sulfate and chromatographed on silica gel eluting with dichloromethane to give 2.8 g of a light yellow solid, mp 117-118 ° C.

Calcd. For C20H15F2N2O: 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, 5,6,7hexahydro-2H-benzo [6,7] cycloheptat-1,2c] pyridazine

3,4,4a, 5,5,7-hexahydro-2H-benzot6,71-cycloheptat-1,2-c] pyridazine (XV) (2.24 g, 11.2 mmol) and 3,4-dichlorobenzoyl chloride (2.34 g,

11.2 mmol) were combined in 100 mL dichloromethane and 10 mL triethylamine was added. The mixture was stirred at 22 ° C for 16 h 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 washed with dichloromethane to give 2.0 g of a light yellow solid, m.p. 136-137 ° C.

• ♦ · φ · · • · • · • · • φ * φ

· .. · *

Calcd. For C 20 H 21 Cl 2 N 2 O: C, 64.35, Η, 4.86, Ν, 7.50.

Found: c, 64.29, H 4.80, N 7.39. Example 10 = 3- (3,4-Difluorobenzoyl) -3,4-diazo-1,2,3,9,10,10ahexahydrophenanthrene

3,4-diazo-1,2,3,9,9,10,10a-hexahydrophenanthrene (XIV) (1.83 g, 9.82 mmol) and 3,4-difluorobenzoyl chloride (1.73 g, 9.82 mmol) were combined in 75 mL of dichloromethane and 5 mL of triethylamine was added. The mixture was stirred at 22 ° C for 16 h and evaporated

to dryness under reduced pressure. The rest was dissolved

in dichloromethane and washed with dilute HCl, dried over sulfate

magnesium, filtered and chromatographed on silica gel

washed with dichloromethane to give 1.4 g of a white solid

with melting point 146-147 ° C.

Calcd for C19H16F2N2O: C, 69.93, H, 4.94, N, 8.58

Found: C, H, 4.72; N, 8.79. Example 11: 3- (3,5-dichlorobenzoyl) -3,4-diazo-1,2,3,9,10,10ahexahydrophenanthrene

3,4-diazo-1,2,3,9,9,10,10a-hexahydrophenanthrene (XIV) (2.67 g,

14.3 mmol) 3,5-dichlorobenzoyl chloride (3.0 g) was combined

in 250 ml of dichloromethane and 10 ml of triethylamine was added. The mixture was stirred at 22 ° C for 1 h 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, m.p. 141-142 ° C.

Calcd for C 19 H 16 Cl 2 N 2 O: C, 63.52, H, 4.49, N, 7.84.

Found: C, 63.45, H, 4.14, N, 7.70.

φ ·

ΦΦΦ • φ · φ φ φφ

ΦΦΦ

Example 12: 3- (3,4-dichlorobenzoyl) -3,4-diazo-9-oxa-1,2,3,9,10,10a-hexahydrophenanthrene

3,4-diazo-9-oxa-1,2,3,9,10,10a-hexahydrophenanthrene (XXVI) (1.73 g, 9.2 mmol) and 3,4-dichlorobenzoyl chloride (1.93 g) were were combined in 200 mL of dichloromethane and 150 mL of triethylamine was added. The mixture was stirred at 22 ° C for 14 h 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 washed with dichloromethane to give 1.2 g of an off-white solid, m.p. 166-167 ° C.

Calcd for C 18 H 14 Cl 2 N 2 O: 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-diazo-9-thi- -1,2,3,9,10,10a-hexahydrophenanthrene

3,4-diazo-9-thia-1,2,3,9,10,10a-hexahydrophenanthrene (XXVII) (1.33 g,

6.6 mmol) and 3,4-dichlorobenzoyl chloride (1.38 g, 6.6 mmol) were combined in 100 mL dichloromethane and added

100 ml of three ethylamines. The mixture was stirred at 22 ° C for 48 h 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

1.0 g of off-white solid which was recrystallized from benzene-hexane to give 0.84 g of white solid, m.p. 145-146 ° C.

Calcd for C 18 H 14 Cl 2 N 2 OS 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-diazo- -1,2,3,9,9a-tetrahydrofluorene

3,4-di azo-1,2,3,9,9a-tetrahydrofluorene (XXV) (1.6 g, 9.3 mmol) and 3,4-dichlorobenzoyl chloride (1.95 g, 9.3 mmol) were were combined in 100 mL of dichloromethane and 10 mL of triethylamine was added. The mixture was stirred at 22 ° C for 16 h 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 washed with dichloromethane to give 1.1 g of an off-white solid, mp 122-124 ° C.

Calcd for C 13 H 14 Cl 2 N 2 O: 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-benzol 6,7] cyclohepta [1,2c] pyridazine

2- (3,5-dichlorobenzoyl) -3,4,4a, 5,6,7-hexahydro-2H-benzol-6,7] cycloheptat-1,2c] pyridazine from Example 7 (1.22 g, 3.27 mmol) and phosphorus pentasulfide (2.14 g, 3.9 mmol) was combined in 200 mL toluene and heated to 100 ° C for 1 h. The mixture was cooled and filtered through a pad of silica gel and washed with dichloromethane. The filtrate was evaporated to dryness and purified by column chromatography washed with dichloromethane to give

1.2 g of a yellow solid which was recrystallized from ether to give the title compound (1.0 g), m.p. 149-150 ° C.

Calcd for C 20 H 15 Cl 2 N 2 S: 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] cyclohexyl-1,2c] pyridazine

2- (3,4-Difluorobenzoyl) -3,4,4a, 5,6,7-hexahydro-2H-benzo [6,7] cycloheptat-1,2-pyridazine from Example 8 (1.5 g, 4.4 mmol) and phosphorus pentasulfide (1.74 g, 5.3 mmol) were combined in

··

200 ml of toluene and heated at reflux for 1 h. The mixture was cooled and filtered through a pad of silica gel and washed with dichloromethane. The filtrate was evaporated to dryness and purified by column chromatography washed with dichloromethane to give

1.3 g of a yellow solid which was recrystallized from ether to give the title compound (0.83 g), m.p. 134-136 ° C.

Calcd for C20H18F2N2S: C, 67.40, H, 5.09, N, 7.86,

Found: C, H, 5.03; N, 7.94. Example 17 = 2- (3,4-dichlorothiobenzoyl) -3,4,4a, 5,6,7hexahydro-2H-benzo [6,71-cyclohepta [1,2c] pyridazine

2- (3,4-dichlorobenzoyl) -3,4,4a, 5,6,7-hexahydro-2H-benzole 6.71 cycloheptal-1,2c] pyridazine from Example 9 (1.5 g, 4.0 mmol) and phosphorus pentasulfide (2.7 g, 6 mmol) was combined in 150 mL toluene and heated to 100 ° C for 30 min. The mixture was cooled and filtered through a pad of silica gel and washed with dichloromethane. The filtrate was evaporated to dryness and purified by column chromatography washed with dichloromethane to give

1.3 g of a yellow solid which was recrystallized from ether to give the title compound (1.0 g), m.p. 140-141 ° C.

Calcd for C 20 H 18 Cl 2 N 2 S: 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-diazo- 1,2,3,9,10,10a-hexahydrophenanthrene

3- (3,4-difluorobenzoyl) -3,4-diazo-1,2,3,9,10,10a-hexahydrophenanthrene from Example 10 (1.0 g, 3.06 mmol) and phosphorus pentasulfide (2, 05 g (4.6 mmol) were combined in 150 mL toluene and heated to reflux for 1 h. The mixture was cooled and filtered through a pad of silica gel and washed with dichloromethane. The filtrate was evaporated to dryness and purified

Fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl Flash column chromatography eluting with dichloromethane 2a gave 0.8 g of a yellow solid, m.p. 170-171 ° C.

Calcd for C19H16F2N2S: C, 66.65, H, 4.71, N, 8.18. Found: C, 66.32, H, 4.76, N, 8.19.

Example 19: 3- (3,4-dichlorothiobenoyl) -3,4-diazo-1,2,3,9,10,10a-hexahydrophenanthrene

- (3,4-dichlorobenzoyl) -3,4-dia2O-1,2,3,9,10,10a-hexahydrophenanthrene 2 of Example 10 (1.06 g, 2.95 mmol) and phosphorus pentasulfide (1.17 g) (3.83 mmol) were combined in 150 mL of toluene and heated to reflux for 1.5 h. The mixture was cooled and filtered through a pad of silica gel and washed with dichloromethane. The filtrate was evaporated to dryness and purified by column chromatography washed with dichloromethane 2a to give 0.8 g of a yellow solid with a melting point of 110-111 ° C.

Calcd for C19H16Cl2N2S: C, 60.80, H, 4.30, N, 7.46. Found: C, 60.74, H, 4.11, N, 7.47.

Example 20: 3- (3,5-Dichlorothiobenoyl) -3,4-dia20- 1,2,3,9,10,10a-hexahydrophenanthrene

3- (3,5-dichlorobenzoyl) -3,4-diazo-1,2,3,9,10,10a-hexahydro-phenanthrene of Example 11 (

1,5 g,

4.2 mmol) and phosphorus pentasulfide (1.69 g,

4, 2 mmol) were combined in 150 mL of toluene and

2heated to 80 ° C after

h. The mixture was cooled and filtered through a pad of silica gel and washed with dichloromethane. The filtrate was evaporated to dryness and purified by column chromatography washed with dichloromethane and recrystallized with 2 ether / hexane 2a to give 1.1 g of a yellow solid, mp 162-163 ° C.

Calcd. For C19H16Cl2N2S: C, 60.80, H, 4.30, N, 7.46.

Found; C,

H, 4.26; N, 7.22.

Example 21:

- (3,4-dichlorothiobenzoyl) -3,4-diazo-9-oxa-1,2,3,9,10,10a-hexahydrophenanthrene phenanthrene from Example (0.6 g, mmol) and phosphorus pentasulfide (0.96)

2.1 mmol) were combined in 100 mL toluene and heated to reflux for 1 h

h.

The mixture was cooled and filtered through a pad of silica gel and washed with dichloromethane. The filtrate was evaporated to dryness and purified by column chromatography washed with dichloromethane to give

0.5 g of a yellow solid, m.p. 187-188 ° C.

Calcd. For C18H14Cl2N2OS: 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-diazo- 1,2,3,9,9a-tetrahydrofluorene

3- (3,4-Dichlorobenzoyl) -3,4-diazo-1,2,3,9,9a-tetrahydro-fluorene from Example (

0.63 g, 1.8 mmol) and phosphorus pentasulfide

1.05 g (2.3 mmol) were combined in 100 mL toluene and heated to reflux for 1.5 h.

The mixture was cooled and filtered through a pad of silica gel and washed with dichloromethane. The filtrate was evaporated to dryness and purified by column chromatography washed with dichloromethane to give 0.5 g of a yellow solid, mp 138-140 ° C.

Calculated for C ₂ N2S Hi4Cl _S: C, 59.84, H, 3.91, N, 7.76.

Found: C, 59.77, H, 3.97, N, 7.76.

··

Claims (16)

wherein L is selected from the group consisting of CO, CS and SO 2; wherein R 1 and R 2 are independently selected from the group consisting of hydrogen, halogen, alkyl (C 1 -C 6), haloalkyl (C 1-6), ni troskupiny, cyano, carboxyl, and carboalkoxy (Ct_e); with that though L is SO 2, R 1 and R 2 they are not simultaneously hydrogen; where R 3 is independently selected from 1 to 3-member groups consisting of of hydrogen, halogen, alkyl (C 1-6), haloalkyl (C 1-6), nitro, carboxyl and carboalkoxy (C 1-6); and wherein X is selected from (CH2) n or Y (CH2) n-i, wherein Y is O or S and n is an integer from 1 to 3. The compound of claim 1, wherein L is SO 2, at least one of R 1 and R 2 is halogen, R 3 is independently selected from halogen or CF 3, and X is (CH 2) η where n is 1 to 3. The compound of claim 1, wherein L is CO or CS, R 1 and R 2 are each hydrogen, R 3 is 3,4-dichloro, and X is (CH 2) n wherein n is 1 to 3. ♦ · · · · · · 99 ·· A compound according to claim 1, selected from the group consisting of: 8-bromo-3,4,4a, 5,6,7-hexahydro-2- (4-iodobenzenesulfonyl) -2Hbenzo [6,7] cycloheptat-1,2c] pyridazine; 8-bromo-3,4-diazo-1,2,3,9,10,10a-hexahydro-3- (4-iodobenzenesulfonyl) phenanthrene; 7,8-dibromo-3,4-diazo-1,2,3,10,10a-hexahydro-3- (4-iodobenzenesulfonyl) phenanthrene; 3- (3,4-dichlorobenzoyl) -3,4-diazo-1,2,3,9,10,10a-hexahydro-phenanthrene; and, 2- (3,5-dichlorobenzoyl) -3,4,4a, 5,6,7-hexahydro-2H-benzo [6,71-cycloheptat-1,2c] pyridazine. A compound according to claim 1, selected from the group consisting of: 2- (3,4-difluorothiobenzoyl) -3,4,4a, 5,6,7-hexahydro-2H-benzo [6,7] cyclohepta [1,2c] pyridazine; 2- (3,4-dichlorobenzoyl) -3,4,4a, 5,6,7-hexahydro-2H-benzo [6,7] cycloheptai 1,2c] pyridazine; 3- (3,4-difluorobenzoyl) -3,4-diazo-1,2,3,9,10,6a-hexahydro-phenanthrene; 3- (3,5-dichlorobenzoyl) -3,4-diazo-1,2,3,9,10,10a-hexahydro-phenanthrene; and 3- (3,4-dichlorobenzoyl) -3,4-diazo-9-oxa-1,2,3,9,10,10a-hexahydrophenanthrene. The compound of claim 1, selected from the group consisting of 3- (3,4-dichlorobenzoyl) -3,4-diazo-9-thi-1,2,3,9,10,10a-hexahydrophenanthrene; 3- (3,4-dichlorobenzoyl) -3,4-diazo-1,2,3,9,9a-tetrahydrofluorene; 2- (3,5-dichloro-thiobenzoyl) -3,4,4a, 5,6,7-hexahydro-2H-benzo [6,7] cycloheptat-1,2c] pyridazine; 2- (3,4-difluorothiobenzoyl) -3,4,4a, 5,6,7-hexahydro-2H-benzo [6,7] cyclohepta [1,2c] pyrimidine; and 2- (3,4-Dichlorothiobenzoyl) -3,4,4a, 5,6,7-hexahydro-2H-benzo [6,7] cyclohepta [1,2c] pyrimidine. A compound according to claim 1 selected from the group consisting of ξ ^: 3- (3,4-difluorothiobenzoyl) -3,4-diazo-1,2,3,9,10,10a-hexahydro-phenanthrene; . 3- (3,4-dichlorothiobenzoyl) -3,4-diazo-1,2,3,9,10,10a-hexahydrophenanthrene; 3- (3,5-dichlorothiobenzoyl) -3,4-diazo-1,2,3,9,10,10a-hexahydrophenanthrene; 3- (3,4-dichlorothiobenzoyl) -3,4-diazo-9-oxa-1,2,3,9,10,10ahexahydrophenanthrene; 7-chloro-3,4-diazo-1,2,3,9,10,10a-hexahydro-3- (4-iodobenzenesulfonyl) -phenanthrene; 7-chloro-3,4-diazo-1,2,3,9,10,10a-hexahydro-3- (2,5-dichlorobenzene sulfonyl) phenanthrene; and 3- (3,4-dichlorothiobenzoyl) -3,4-diazo-1,2,3,9,9a-tetrahydrofluorene. A process for preparing a compound of the formula: wherein R 1, R 2, R 3, 1 and X are as defined in claim 1 which comprises (a) reacting a benzocycloalkanone of the formula: with a glyoxylic acid, reducing the formed product with a reducing agent, and treating the formed reducing product with hydrazine to form a cyclic acylhydrazone of the formula: reacting the cyclic acylhydrazone with a second reducing agent to form a cyclic hydrazone of the formula: and reacting the cyclic hydrazone with an acylating agent and, if L is CS, (b) reacting the formed amide with a reagent selected from Laweson's reagent or P2S5. The process of claim 8 wherein the first reducing agent is zinc in acetic acid. 10. The process of claim 8 wherein the second reducing agent is selected from 1-lithium aluminum hydride and diborane. 11. The method of claim 8 ₅ characterized in that the acylating agent is selected from halide and sulfonyl halide benzoy1. 12. The process of claim 11 wherein the acylating agent is benzenesulfonyl chloride. 13. The method of claim 11 wherein the acylating agent is benzoyl chloride. 14. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 in association with a pharmaceutically acceptable carrier. 15. A method of treating contraception, menopause, endometriosis, breast cancer, cyclesynchronia, termination of pregnancy, induction of labor, or osteoporosis, comprising administering to a patient a compound of claim 1 in a therapeutically effective amount for treating any of the contraceptives, menopause, endometriosis, breast cancer, cyclesynchronia, termination of pregnancy, induction of labor and osteoporosis. φ * i ΦΦ ΦΦ • Φ • Φ Φ • ΦΦ Φ Φ φ · • Φ φ Φ ΦΦ * · ·· φ · · φ φ φ φ · · 16. The method of claim 15, wherein the amount is from about 1 to about 500 mg / kg / day.