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• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
  • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
  • C07D491/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/50—Pyridazines; Hydrogenated pyridazines
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
  • A61P15/06—Antiabortive agents; Labour repressants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
  • A61P15/18—Feminine contraceptives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
  • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P5/00—Drugs for disorders of the endocrine system
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
  • C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
  • C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
  • C07D237/36—Benzo-cinnolines

Definitions

• the present invention is directed to compounds represented by formula I:
• L is CO, CS or SO 2 ;
• R 1 and R 2 are independently selected from any of H, halogen , alkyl (C 1 -C 6 ), haioalkyl (C 1 -C 6 ), nitro, cyano, carboxyl, and carboalkoxyl (C 1 -C 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 in any substitution pattern: H, halogen, alkyl (C 1 -C 6 ), haloalkyl (C 1 -C 6 ), nitro, carboxyl or carboalkoxyl (C 1 -C 6 );
• X is a diradical of the formula (CH 2 ) n or Y-(CH 2 )n-1 where n is an integer from 1 to 3; and Y is O or S.
• alkyl is defined as 1 -6 carbon atoms which may be branched in which case there are at least 3 carbon atoms or unbranched.
• Halogen is defined as chlorine, bromine, fluorine or iodine.
• Alkoxy refers to groups derived from alcohols having 1-6 carbon atoms and haloalkyl is defined as containing an alkyl group having 1-3 carbon atoms, such as trifluoromethyl.
• the compounds of this invention are nonsteroidal heterocycles which can act as selective progestins and/or antiprogestins having a high i ⁇ -vitro affinity for either the uterine, breast or bone progestin receptor as well as biological activity by intravenous, subcutaneous and oral routes. As a result, they may be useful as therapeutics in connection with contraception, menopause,
• the present invention relates to a series of nonsteroidal heterocyclic derivatives, the activity of which mimics that of progestins and/or antiprogestins having a high in vitro affinity for either the uterine or breast or bone progestin receptor.
• the compounds of the present invention may be prepared by the following reaction Scheme 1 :
• an appropriately substituted benzocycloalkanone (II) is converted to the cyclic acyihydrazone (III) by a means known in the art such as the method of Holava and Partyka (J. Med. Chem, 14, 262, (1971)).
• this comprises conversion of II to an ⁇ unsaturated keto acid using glyoxylic acid and base, followed by the reduction of the unsaturation by heating with zinc in acetic acid and treatment of the reduced ketoacid with hydrazine to form III
• the substituted cyclic acyihydrazone (III) is then converted to the cyclic hydrazone (IV) by reaction with a reducing agent such as, for example, lithium aluminum hydride or diborane in a suitable solvent such as tetrahydrofuran (THF) by conventional means such as described by J-L. Aubagnac, J. Elguero, R. Jacquier and R. Robert in Bull. Chem. Soc. France 2859, (1972).
• a reducing agent such as, for example, lithium aluminum hydride or diborane in a suitable solvent such as tetrahydrofuran (THF)
• the resultant cyclic hydrazone (IV) is acylated with an appropriately substituted benzoyl halide or sulfonyl halide in a suitable solvent such as pyridine or in an organic solvent such as THF or toluene with a base such as triethylamine to form the nonsteroidal heterocyclic derivative (I).
• the product is isolated and purified by techniques known to those skilled in the art such as, for example, by pouring the reaction mixture into a dilute acid such as, for example, hydrochloric acid, and extracting the mixture with an organic solvent such as methylene chloride or ethyl acetate. The organic layer is concentrated and the residue is crystallized or purified by chromatography over silica gel. The fractions containing the product are evaporated and the residue recrystallized to afford the desired compounds.
• a dilute acid such as, for example, hydrochloric acid
• an organic solvent such as methylene chloride or ethyl acetate
• monohalobenzocycloalkanones can be halogenated with a different halogen to afford mixed substitutions such as for example: 6-bromo-5-chloro-1 -tetralone or 5-chloro-7- iodo-1-tetralone.
• the uteri are minced, 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 supernatant fraction is used as the receptor preparation.
• a competitive binding assay is performed by mixing 3 H-R5020 with the receptor preparation and adding a known amount of unlabelled compound. This mixture is incubated at 4°C for 18 h. The compounds bound to the receptor are separated from those free in solution using dextran coated charcoal and the amount of isotope bound to the receptor is determined. A depression of 20% or greater from control isotope binding is considered significant.
• a similar method may be used to determine binding affinities to progestin receptor derived from breast or bone tissue.
• T47-D cells The incorporation of 3 H-thymidine into T47-D cells was used to test the effect of compounds on T47-D cell proliferation.
• Compounds of the present invention have utility to treat in vivo progestin modulated biological conditions where they demonstrate a sufficient effect on the growth of T47-D cells.
• T47-D human breast line
• 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 using standard procedures.
• Cells were plated in 96-well microtiter plates by incubation in RPMI medium (phenol red-free, insulin-free, 5% charcoal treated fetal bovine serum) at 37°C in an atmosphere of 95% air/5% CO 2 . Approximately 48 hours later, spent medium was replaced by fresh medium containing test compounds dissolved in DMSO (0.1% final concentration) and the cells were incubated for approximately 22 hours. 3 H-Thymidine was added and the incubation allowed to proceed for another 4 hours. The test was then stopped with the addition of excess unlabeled thymidine. Cells were washed free of soluble thymidine, trypsinized and harvested by standard procedures.
• RPMI medium phenol red-free, insulin-free, 5% charcoal treated fetal bovine serum
• the amount of 3 H-thymidine incorporated into DNA was determined by liquid scintillation counting.
• the primary standards were promegestone, a potent synthetic progestin and RU486, an antiprogestin.
• Test compounds were generally screened at concentrations ranging from 0.1 to 1000 nM. A compound was considered active if it stimulated or inhibited thymidine incorporation. Results were expressed as the concentration of test compounds needed to increase proliferation 2 times over control (SC200) or the concentration needed to inhibit promegestone induced proliferation by 50% (EC50). A value less than 1000 nM was considered active.
• Table 1 shows examples of the invention with molecular formulas, melting points, the binding affinity expressed as the concentration of compound in nanomoles per liter ( x10 -9 M) required to displace 50% of H 3 labeled R5020 from the rabbit uterine cytosolic progestin receptor (PR)(IC 50 ), and the ability to proliferate or to inhibit the R5020 induced proliferation of T47D human breast carcinoma cells (T47D). If there is no value reported in the T47D column that particular compound was not tested.
• PR rabbit uterine cytosolic progestin receptor
• Tables 2 and 3 show several examples of the invention with molecular formulas, melting points, and activity expressed as the average increase in bone cell proliferation at 5 concentrations (CP) or as the concentration of compound in nanomoles per liter ( x10 -9 M) required to displace 50% of I 125 labeled vinyl nortestosterone (VNT) from the human bone progestin receptor (BPR) (IC 50 ). If there is no value reported in the CP column that particular compound was not tested.
• CP concentrations
• VNT vinyl nortestosterone
• compositions containing a compound of the present invention as the active ingredient in intimate admixture with a pharmaceutical carrier can be prepared according to conventional pharmaceutical
• the carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g.
• any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations (such as, for example, suspensions, elixirs and solutions), or carriers such as starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations (such as, for example, powders, capsules and tablets). Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed.
• tablets may be sugar-coated or enteric-coated by standard techniques.
• the carrier will usually comprise sterile water, though other ingredients may be employed, for example, to aid solubility or for preservative purposes; injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed.
• the pharmaceutical compositions of the present invention for use in the treatment of any of contraception, menopause, endometriosis, breast cancer, cyclesynchrony, pregnancy termination, labor induction or osteoporosis are possible indications, the most likely are endometriosis, contraception and osteoporosis will generally contain a dosage unit, e.g. tablet, capsule, powder and the like, from about 1 to about 500 mg/kg/day and preferably from about 10 to about 100 mg/kg/day of the active ingredient. The exact dose may vary depending upon the age and conditon of the patient and the particular condition being tested.
• Sections A, B and C contain a description of the preparation of certain starting materials and intermediates useful in the preparation of the compounds of the present invention.
• N-bromosuccinimide can be substituted for bromine and N-chlorosuccinimide or chlorine can be used to make the chloro compounds.
• N-iodosuccinimide affords the iodo analogs.
• Vllb 6-Bromoindan-1-one
• VIIa 4-bromoindan-1-one
• a 250 mL three-necked round bottom flask was equipped with a water cooled Liebig condenser, a mechanical stirrer and a pressure-equalized addition funnel protected by means of drying tubes.
• the flask was charged with anhydrous aluminum chloride (16.6 g, 0.125 moles) and stirred while 1-Indanone (VI) (6.60 g, 0.05 moles), which had been ground to a fine powder with a mortar and pestle was added in two portions over 3 minutes. Copious evolution of HCl gas was accompanied by a moderate exotherm and the mixture rapidly became a dark brown, homogenous slurry which was stirred for an additional 10 minutes.
• VI 1-Indanone
• Bromine (3.1 ml, 0.06 moles) was added dropwise to the well stirred mixture over a 10 minute period. After all the bromine had been added, the molten mixture was heated in a water bath to 80°C for 5 minutes. While still hot, the mixture was poured into 100 g of crushed ice and 20 mi of concentrated hydrochloric acid. The ice mixture was then stirred for 10 minutes, diluted with 100 ml of water and extracted with ether (2 ⁇ 200 mL). The combined ether extracts were washed with water (2 ⁇ 100 mL) and dried over anhydrous sodium sulfate and concentrated to give 10.6 g of a red oil which crystallized on standing at room temperature.
• the title compound was prepared by treating 5-Bromo-1-tetralone (IXb) (20 mmol) with glyoxylic acid (20 mmol), the product reduced with excess zinc in acetic acid and treated with excess hydrazine by conventional means as in Holava, H. M. and Partyka, R. A. J. Med. Chem. 14, 262, (1971 ) to give the title compound.
• the title compound was prepared by treating 5,6-Dibromo-1 -tetralone (Xlla) (10 mmol) with glyoxylic acid (10 mmol), the product reduced with excess zinc in acetic acid and thereafter treated with excess hydrazine as in Holava, H. M. and Partyka, R. A. J. Med. Chem. 14, 262, (1971) to give the title compound.
• Xlla 5,6-Dibromo-1 -tetralone
• the title compound was prepared by treating 6-Bromo-1-benzosuberone Xlb with glyoxylic acid, then reducing with excess zinc in acetic acid and thereafter treating with excess hydrazine as in Holava, H. M. and Partyka, R. A. J. Med. Chem. 14, 262, (1971) to give the titled compound.
• Example 1 8-Bromo-3,4,4a,5,6,7-hexahydro-2-(4-iodobenzenesulfonyl)-2H-benzo[6,7]cyclohepta[1 ,2c]pyridazine 8-Bromo-3,4,4a,5,6,7-hexahydro-2H-benzo[6,7]cyclohepta
• [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 turning a deep red color. The mixture was concentrated at reduced pressure and the pyridine solution poured into 6 M HCl and ice and extracted with dichloromethane.
• 3,4-diazo-1 ,2,3,9,10,10a-hexahydrophenanthrene (XIV) (1.83 g, 9.82 mmol) and 3,4-difluorobenzoylchloride (1.73 g, 9.82 mmol) were combined in 75 mL of dichloromethane and 5 mL of triethylamine added. The mixture was stirred at 22°C for 16 h and evaporated to dryness at reduced pressure.
• Example 12 3-(3,4-dichlorobenzoyl)-3,4-diazo-9-oxa-1 ,2,3,9,10,10a- hexahydrophenanthrene
• 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 of Example 10 (1.0 g, 3.06 mmol) and phosphorous pentasulfide (2.05g, 4.6 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 eluted with dichloromethane to give 0.8 g of yellow solid with mp 170-171oC.
• Example 14 (0.63 g, 1.8 mmol) and phosphorous pentasulfide (1.05g 2.3 mmol) were combined in 100 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 eluted with dichloromethane to give 0.5 g of yellow solid with mp 138-140°C. Calc for C 18 H 14 Cl 2 N 2 S: C, 59.84, H, 3.91 , N, 7.76; found C, 59.77, H, 3.97, N, 7.76.

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• 1996
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