WO2003082336A1 - Female birth control method - Google Patents

Female birth control method Download PDF

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Publication number
WO2003082336A1
WO2003082336A1 PCT/CA2003/000493 CA0300493W WO03082336A1 WO 2003082336 A1 WO2003082336 A1 WO 2003082336A1 CA 0300493 W CA0300493 W CA 0300493W WO 03082336 A1 WO03082336 A1 WO 03082336A1
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WIPO (PCT)
Prior art keywords
aromatase inhibitor
contraceptive
amount equivalent
norethindrone
progestin
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PCT/CA2003/000493
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French (fr)
Inventor
Robert F. Casper
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Jencap Research Ltd.
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Publication date
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Priority to AU2003213958A priority Critical patent/AU2003213958A1/en
Publication of WO2003082336A1 publication Critical patent/WO2003082336A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/566—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol having an oxo group in position 17, e.g. estrone
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
    • A61K31/569—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone substituted in position 17 alpha, e.g. ethisterone
    • 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

Definitions

  • This invention relates to an improved female birth control method which substantially reduces breakthrough bleeding and mood or emotional disorders in women, and more particularly, to a contraceptive unit comprising at least one aromatase inhibitor combined with a combination of a substance exhibiting estrogen activity, or a substance exhibiting progestin activity, or both substances in amounts required to prevent pregnancy in females.
  • Oral contraceptives for women have been available commercially since the early 1960's.
  • Oral contraceptives generally comprise an estrogen active substance and a progestin active substance administered in regimens comprising various combinations of dosage levels.
  • Early pill formulations contained up to 100 to 150 ⁇ g of estrogen, but later studies revealed that far less hormone was needed to prevent conception. Thus as the technology has evolved, decreasing amounts of estrogen and progestin have been included in contraceptive formulations.
  • a progestin only pill was introduced for contraceptive purposes which relied on norethindrone, with one preferred formulation comprising 350 ⁇ g of norethindrone.
  • multiphasic pill formulations were introduced which are referred to as biphasics and triphasics.
  • the original combination preparations are generally referred to as monophasics.
  • All of these regimens are described as continuous combined regimens.
  • There are also interrupted or cyclophasic regimens which comprise consecutively administrable phases of unit doses comprising estrogen and progestin and phases of unit doses comprising estrogen and higher amounts of progestin.
  • oral contraceptives are among the most popular, many other forms of administration are available such as implants, injections, gels, transdermal patches, suppositories and the like.
  • the pill has become the most popular reversible method of birth control in the Western World. In the United States, approximately 80% of females have used the pill at one point during their reproductive lives, and women are now staying on the pill longer than ever before.
  • OCs oral contraceptives
  • Mood disturbances such as depression and loss of libido may be related to suppression of androgens in OC users.
  • Plasma free testosterone and other measures of androgenicity were substantially lower in women taking oral contraceptives compared to a control group of non-users (Bancroft et al, 1991 ).
  • a lower free testosterone level was associated with a lower frequency of sexual intercourse (Bancroft et al, 1991 ).
  • the testosterone secretion rate was diminished and sex hormone binding globulin was increased by OC use, resulting in lowered free testosterone.
  • N.E.E.1/35 s N.E.E.1/50- Nelova 0.5/35E - Nelova1/35E ⁇ Nelova1/50M
  • Demulen 30 2 Demulen 50 2 Loestrin 1.5/30 - Marvelon 1 Minestrin 1/20 4 Min-Ovral - Norinyl 1/50 ⁇ Ortho 0.5/35 - Ortho 1/35 5 Ortho 7/7/7 -
  • the numbers refer to the hormones present in each brand name formulation.
  • the progestins are numbered to match the corresponding brand names.
  • the Casper cyclophasic regimens seek to induce higher levels of progestin and estrogen receptors by an estrogen-induced increase in receptor production.
  • the greater concentration of steroid receptors increases the sensitivity of the target organs to progestin and estrogen and allows the use of lower doses of exogenous steroids.
  • the cyclophasic or interrupted regimens of Casper upregulate the estrogen and progestin receptors in an estrogen-dominant phase and then down-regulate the same receptors in a progestin-dominant phase.
  • the estrogen dose is constant while the progestin dose is varied to produce relatively progestin-dominant or estrogen-dominant effects.
  • the present invention is useful for substantially reducing mood or emotional disorders such as preventing depression and loss of libido associated with oral contraceptive use.
  • the combination of at least one aromatase inhibitor with contraceptive levels of estrogen and progestin will increase endogenous androgen concentrations (testosterone and androstenedione) by prevention of peripheral aromatization of these androgen substrates to estrogen in muscle, fat and other tissues as described in Nelson LR, Bulun SE. J Am Acad Dermatol 2001; 45:S116-24.
  • the increase in androgen levels in the presence of adequate estrogen administration will improve well-being and libido.
  • the blockade of aromatization will prevent endogenous estrogen production, and estrogen fluctuations, thereby reducing the incidence of breakthrough bleeding.
  • the benefits of the new aromatase inhibitor/estrogen/progestin contraceptive regimen include: 1 ) Increased endogenous androgen concentrations into the physiologic range without the need for exogenous testosterone treatment by injection or skin patch. 2) Improved well being and libido as a result of increased endogenous androgen. 3) Decreased risk of breast cancer by inhibition of breast aromatase activity, and local estrogen production in breast tissue. 4) Decreased incidence of BTB by preventing endogenous fluctuations in estrogen levels that result from peripheral aromatization of adrenal androgens to estrogen.
  • the present invention provides in a first aspect a method for preventing pregnancy in females wherein breakthrough bleeding is substantially reduced, which comprises administering to such females from at or about 20 to at or about 28 consecutive daily unit doses or an equivalent thereof, of a substance exhibiting estrogen activity, or a substance exhibiting progestin activity or both such substances, or combinations of such unit doses in amounts sufficient to prevent pregnancy in such females together with at least one aromatase inhibitor-followed by from at or about 2 to at or about 10 days where no such substance is administered.
  • the invention provides a method for preventing pregnancy in females wherein mood disorders and/or emotional disorders are substantially reduced, which comprises administering to such females from at or about 20 to at or about 28 consecutive daily unit doses or an equivalent thereof of a substance exhibiting estrogen activity, or a substance exhibiting progestin activity or both such substances, in amounts sufficient to prevent pregnancy in such females, together with at least one aromatase inhibitor, followed by from at or about 2 to at or about 10 days where no such substance is administered.
  • the invention provides a contraceptive unit having at or about 20 to at or about 28 separate dosage units or an equivalent thereof, adapted for consecutive daily administration, the daily dosage units each comprising a substance exhibiting estrogen activity, or a substance exhibiting progestin activity, or both such substances or combinations of such units in amounts sufficient to prevent pregnancy in females, together with at least one aromatase inhibitor, and a pharmaceutically acceptable carrier therefor, and wherein breakthrough bleeding is substantially reduced in such females.
  • the invention provides a contraceptive unit having from at or about 20 to at or about 28 separate daily dosage units or an equivalent thereof, adapted for successive daily administration, each daily dosage unit comprising a substance exhibiting estrogen activity or a substance exhibiting progestin activity or both such substances, or combinations of such units, in amounts sufficient to prevent pregnancy in such females together with at least one aromatase inhibitor and a pharmaceutically acceptable carrier therefor, wherein mood disorder or emotional disorder symptoms are substantially reduced in such females.
  • this invention provides for the inclusion of at least one aromatase inhibitor for administration in conjunction with the usual birth control hormones and in accordance with any of the various regimens known to those skilled in the art.
  • the preferred hormone combinations for use in the contraceptive method of this invention may be selected from the following combinations:
  • the preferred progestin for use on its own as the contraceptive hormone may be selected from
  • the amounts of hormones for use in the method of this invention are clearly set out in the literature and prior patents.
  • the combinations and amounts may be easily selected by the person skilled in the art in accordance with the specific hormone(s) and type of regimen.
  • the amount and choice of the aromatase inhibitor is again selected to ensure that the desired reduction in breakthrough bleeding and/or mood/emotional disorders are achieved.
  • the mood/emotional disorders preferably encompass loss of libido and/or depression.
  • Any conventional estrogen may be employed as a suitable component in the contraceptive regimen of this invention.
  • Preferred estrogens are 17 ⁇ -ethinylestradiol, esters and ethers of 17 ⁇ -ethinylestradiol such as, for example, 17 ⁇ -ethinylestradiol 3-dimethylamino propionate, 17 ⁇ - ethinylestradiol e-cyclopentyl ether (quienestrol) and 17 ⁇ -ethinylestradiol 3-methyl ether (mestranol) may also be employed as the estrogen component.
  • Natural estrogens such as estrone, estrone sulfate, estrone sulfate piperazine salt, estradiol and estriol, and their esters, as well as other synthetic estrogens, may be employed.
  • the preferred estrogen is 17 ⁇ -ethinylestradiol or 17 ⁇ -ethinylestradiol 3-methyl ether.
  • Any progestationally active compound may be employed in this method. These compounds are classified, in agreement with their structure, in various groups which include progesterone, retroprogesterones, 17alpha-hydroxyprogesterones, 19- norprogesterones, 17alpha-hydroxyprogesterone derivatives, androstane and estrane derivatives.
  • Progestins which may be employed as a component in the present invention include progesterone and its derivatives such as, for example, 17-hydroxyprogesterone esters and 19-nor-17-hydroxyprogesterone esters, 17 ⁇ -ethinyltestosterone, 17 ⁇ -ethinyl- 19-nortestosterone and derivatives thereof, norethindrone, D-norgestrel, ⁇ 15 levonorgestrel, ⁇ 15 levonorgestrel acetate, ⁇ 15 levonorgestrel acetate oxime, D-17 ⁇ - acetoxy- ⁇ -ethyl- 7 ⁇ -ethinylgon-4-en-3-one oxime (norgestimate), desogestrel, ethynodiol diacetate, dydrogesterone, medroxyprogesterone acetate, norethynodrel, allylestrenol, lynoestrenol, qu
  • the literature contains descriptions of numerous progestins and based on the criteria set out above, the person skilled in the art may make a suitable choice.
  • the amount(s) of estrogen is dependent on the type of hormone and the regimen of administration and the art provides clear guidance to the person skilled therein.
  • the daily unit doses comprise estrogen in an amount equivalent to at or about 0.02 mg to at or about 0.05 mg 17 ⁇ -ethinylestradiol and progestin in an amount equivalent to at or about 0.5 mg to at or about 2.0 mg of norethindrone, and the at least one aromatase inhibitor is present in an amount equivalent to at or about 0.25 mg to at or about 10.0 mg per day of anastrazole.
  • the daily unit doses comprise estrogen in an amount equivalent to at or about 0.02 mg to at or about 0.05 mg 17 ⁇ -ethinylestradiol and progestin in an amount equivalent to at or about 0.5 mg to at or about 1.0 mg of norethindrone, and the at least one aromatase inhibitor is present in an amount equivalent to at or about 0.25 mg to at or about 10.0 mg per day of anastrazole.
  • the daily unit doses comprise estrogen in an amount equivalent to at or about 0.02 mg to at or about 0.05 mg 17 ⁇ -ethinylestradiol and progestin in an amount equivalent to at or about 0.5 mg to at or about 1.0 mg of norethindrone, and the at least one aromatase inhibitor is present in an amount equivalent to at or about 0.25 mg to at or about 10.0 mg per day of anastrazole.
  • the daily unit doses comprise estrogen in an amount equivalent to at or about 0.02 mg to at or about 0.035 mg 17 ⁇ -ethinylestradiol and progestin in an amount equivalent to at or about 0.35 mg to at or about 1.0 mg of norethindrone, and the at least one aromatase inhibitor is present in an amount equivalent to at or about 0.25 mg to at or about 10.0 mg per day of anastrazole.
  • Aromatase inhibitors may have a non-steroidal or a steroidal chemical structure. According to the present invention, both non-steroidal aromatase inhibitors and steroidal aromatase inhibitors can be used.
  • aromatase inhibitors there are to be understood especially those substances that in a determination of the in vitro inhibition of aromatase activity exhibit IC 50 values of 10 "5 M or lower, especially 10 "6 M or lower, preferably 10 "7 M or lower and most especially 10 "8 M or lower.
  • IC 50 values for aromatase inhibition can be obtained, for example, in vitro by a direct product isolation method relating to inhibition of the conversion of 4- 14 C- androstenedione to 4- 14 C-estrone in human placental microsomes.
  • aromatase inhibitors there are to be understood most especially substances for which the minimum effective dose in the case of in vivo aromatase inhibition is 10 mg/kg or less, especially 1 mg/kg or less, preferably 0.1 mg/kg or less and most especially 0.01 mg/kg or less.
  • in vivo aromatase inhibition can be determined, for example, by the following method [see J. Enzyme Inhib. 4, 179 (1990)]: androstenedione (30 mg/kg subcutaneously) is administered on its own or together with a compound of the invention (orally or subcutaneously) to sexually immature female rats for a period of 4 days. After the fourth administration, the rats are sacrificed and the uteri are isolated and weighed. The aromatase inhibition is determined by the extent to which the hypertrophy of the uterus induced by the administration of androstenedione alone is suppressed or reduced by the simultaneous administration of the compound according to the invention.
  • aromatase inhibitors The following groups of compounds are listed as examples of aromatase inhibitors. Each individual group forms a group of aromatase inhibitors that can be used successfully in accordance with the present invention.
  • R-i is hydrogen, lower alkyl; lower alkyl substituted by hydroxy, lower alkoxy, lower alkanoyloxy, lower alkanoyl, amino, lower alkylamino, di-lower alkylamino, halogen, sulfo, carboxy, lower alkoxycarbonyl, carbamoyl or by cyano; nitro, halogen, hydroxy, lower alkoxy, lower alkanoyloxy, phenylsulfonyloxy, lower alkylsulfonyloxy, mercapto, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, lower alkanoylthio, amino, lower alkylamino, di-lower alkylamino, lower alkyleneamino, N-morpholino, N-thiomorphoIino, N- piperazino that is unsubstituted or lower alkyl-substituted in the 4-
  • n 0, 1 , 2, 3 or 4; and R ⁇ and R 2 are as defined above for formula I; it being possible for the phenyl ring in the radicals phenylsulfonyloxy, phenyliminomethyl, benzoyl, phenyl-lower alkyl, phenyl-lower alkylthio and phenylthio to be unsubstituted or substituted by lower alkyl, lower alkoxy or by halogen; it being possible in a compound of formula I* for the two substituents C 6 H 4 -R_ and R 2 to be linked to each of the saturated carbon atoms of the saturated ring, either both to the same carbon atom or both to different carbon atoms, and pharmaceutically acceptable salts thereof.
  • R and R 0 independently of one another, are each hydrogen or lower alkyl, or R and R 0 at adjacent carbon atoms, together with the benzene ting to which they are bonded, form a naphthalene or tetrahydronaphthalene ring;
  • Ri is hydrogen, lower alkyl, aryl, aryl-lower alkyl or lower alkenyl;
  • R 2 is hydrogen, lower alkyl, aryl, aryl-lower alkyl, (lower alkyl, aryl or aryl-lower alkyl)-thio or lower alkenyl, or wherein Ri and R 2 together are lower alkylidene or C 4 -C 6 alkylene;
  • W is 1-imidazolyl, 1 -(1 ,2,4 or 1 ,3,4)-triazolyl, 3-pyridyl or one of the mentioned heterocyclic radicals substituted by lower alkyl; and aryl within the context of the above definitions
  • Tetr is 1- or 2-tetrazolyl that is unsubstituted or substituted in the 5-position by lower alkyl, phenyl-lower alkyl or by lower alkanoyl
  • R and R 2 independently of one another, are each hydrogen; lower alkyl that is unsubstituted or substituted by hydroxy, lower alkoxy, halogen, carboxy, lower alkoxycarbonyl, (amino, lower alkylamino or di- lower alkylamino)-carbonyl or by cyano; lower alkenyl, aryl, heteroaryl, aryl-lower alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyl-lower alkyl, lower alkylthio, arylthio or aryl-lower alkylthio; or Ri and R 2 together are straight-chained C 4 -C 6 alkylene that is unsubstituted or substituted by lower alky
  • X is halogen, cyano, carbamoyl, N-lower alkylcarbamoyl, N-cycloalkyl-lower alkylcarbamoyl, N,N-di-lower alkylcarbamoyl, N-arylcarbamoyl, hydroxy, lower alkoxy, aryl-lower alkoxy or aryloxy, wherein aryl is phenyl or naphthyl, each of which is unsubstituted or substituted by lower alkyl, hydroxy, lower alkoxy, halogen and/or by.
  • Y is a group -CH 2 -A wherein A is 1-imidazolyl, 1-(1 ,2,4-triazolyl), 1- (1 ,3,4-triazolyl), 1-(1 ,2,3-triazolyl), 1-(1 ,2,5-triazolyl), 1 -tetrazolyl or 2-tetrazolyl, or Y is hydrogen, R ⁇ and R 1f independently of one another, are each hydrogen, lower alkyl or a group -CH 2 -A as defined for Y, or R ⁇ and R 2 together are --(CH 2 ) n - wherein n is 3, 4 or 5, with the proviso that one of the radicals Y, Ri and R 2 is a group -CH 2 -A, with the further proviso that in a group -CH 2 ⁇ A as a meaning of Ri or R 2 , A is other than 1- imidazolyl when X is bromine, cyano or carbamoyl, and
  • dotted line denotes an additional bond or no additional bond
  • Az is imidazolyl, triazolyl or tetrazolyl bonded via a ring nitrogen atom, each of those radicals being unsubstituted or substituted at carbon atoms by lower alkyl or by aryl-lower alkyl
  • Z is carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl, N,N-di-lower alkylcarbamoyl, N-arylcarbamoyl, cyano, halogen, hydroxy, lower alkoxy, aryl-lower alkoxy, aryloxy, lower alkyl, trifluoromethyl or aryl-lower alkyl
  • Ri and R 2 independently of one another, are each hydrogen, lower alkyl, lower alkoxy, hydroxy, halogen or trifluoromethyl; aryl being phenyl or naphthyl each of
  • Z is a five-membered nitrogen-containing heteroaromatic ting selected from the group 5-isothiazolyl, 5-thiazolyl, 5-isoxazolyl, 5-oxazolyl, 5-(1 ,2,3-thiadiazolyl), 5-(1 ,2,3- oxadiazolyl), 3-(1 ,2,5-thiadiazolyl), 3-(1 ,2,5-oxadiazolyl), 4-isothiazolyl, 4-isoxazolyl, 4- (1 ,2,3-thiadiazolyl), 4-(1 ,2,3-oxadiazolyl), 2-(1 ,3,4-thiadiazolyl), 2-(1 ,3,4-oxadiazolyl), 5- (1,2,4-thiadiazolyl) and 5-(1,2,4-oxadiazolyl); R and R 0 are hydrogen; or R and R 0 together are a benzo group that is unsubstituted or substituted by lower alkyl, lower alkoxy,
  • Z is a five-membered nitrogen-containing heteroaromatic ring selected from the group 5-isothiazolyl, 5-thiazolyl, 5-isoxazolyl, 5-oxazolyl, 5-(1 ,2,3-thiadiazolyl). 5-(1 ,2,3- oxadiazolyl) 3-(1 ,2,5-thiadiazolyl), 3-(1 ,2,5-oxadiazolyl), 4-isothiazolyl.
  • R and R 0 are each hydrogen; or R and R 0 together are a benzo group that is unsubstituted or substituted by lower alkyl, lower alkoxy, hydroxy, halogen or by trifluoromethyl;
  • Ri is hydrogen, hydroxy, chlorine or fluorine;
  • R 3 is hydrogen;
  • R 2 is hydrogen, lower alkyl or phenyl that is unsubstituted or substituted by lower alkyl, lower alkoxy, hydroxy, halogen, trifluoromethyl, aryl-lower alkoxy or by aryloxy; or R-i and R 2 together are methylidene, and W 2 is
  • Z is imidazolyl, triazolyl, tetrazolyl, pyrrolyl, pyrazolyl, indolyl, isoindolyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl.
  • RT and R 2 independently of one another, are each hydrogen or lower alkyl; or R !
  • R 2 together are C 3 -C 4 alkylene, or a benzo group that is unsubstituted or substituted as indicated below for aryl;
  • R is hydrogen, lower alkyl, aryl or heteroaryl, and
  • X is cyano, carbamoyl, N-lower alkylcarbamoyl, N,N-di-lower alkylcarbamoyl, N, N-lower alkylenecarbamoyl; N, N-lower alkylenecarbamoyl interrupted by -0-, -S-- or --NR"-, wherein R" is hydrogen, lower alkyl or lower alkanoyl; N- cycloalkylcarbamoyl, N-(lower alkyl-substituted cycloalkyl)-carbamoyI, N-cycIoalkyl-lower alkylcarbamoyl, N-(lower alkyl-substitute
  • Those compounds are especially the compounds of formula I whereto Z is 1-imidazolyl, 1- (1 ,2,4-triazolyl), 1-(1 ,3,4-triazolyl), 1-(1 ,2,3-triazolyl), 1 -tetrazolyl, 2-tetrazoIyl, 3-pyridyl, 4- pyridyl, 4-pyrimidyl, 5-pyrimidinyl or 2-pyrazinyl; Ri and R 2 , independently of one another, are each hydrogen or lower alkyl; or R.-i and R 2 together are 1 ,4-butylene or a benzo group; R is lower alkyl; phenyl that is unsubstituted or substituted by cyano, carbamoyl, halogen, lower alkyl, trifluoromethyl, hydroxy, lower alkoxy or by phenoxy; or benzotriazolyl or benzo[b]furanyl, the last two radicals being unsubstituted or substituted by
  • R 1 is hydrogen
  • R 2 is hydrogen, sulfo, Ci -C 7 alkanoyl or Ci -C 7 alkanesulfonyl
  • R 3 is hydrogen, or wherein R-, is Ci -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 7 alkynyl, C 3 -C ⁇ 0 cycloalkyl, C 3 -C 10 cycloalkenyl, C 3 3 -C 6 cycloalkyl-Ci -C 4 alkyl, C 3 -C 6 cycloalkyl-C 2 -C 4 alkenyl or C 3 -C 6 cycloalkenyl-C-) -C 4 alkyl
  • R 2 is hydrogen, C-, -C 7 alkyl, sulfo, Ci -C 7 alkanoyl or C ⁇ -C 7 alkanesulfonyl
  • R 3 is hydrogen or ⁇ -C 7 al
  • Ri is hydrogen, alkyl having from 1 to 12 carbon atoms, alkenyl having from 2 to 12 carbon atoms, lower alkynyl, cycloalkyl or cycloalkenyl each having from 3 to 10 carbon atoms, cycloalkyl-lower alkyl having from 4 to 10 carbon atoms, cycloalkyl-lower alkenyl having from 5 to 10 carbon atoms, cycloalkenyl-lower alkyl having from 4 to 10 carbon atoms, or aryl having from 6 to 12 carbon atoms or aryl-lower alkyl having from 7 to 15 carbon atoms, each of which is unsubstituted or substituted by lower alkyl, hydroxy, lower alkoxy, acyloxy, amino, lower alkylamino, di-lower alkylamino, acylamino amino or by halogen
  • R 2 is hydrogen, lower alkyl, sulfo, lower alkanoyl or lower alkan
  • W ( ⁇ ) is a 2-naphthyl or 1-anthryl radical, wherein each benzene ring is unsubstituted or substituted by a substituent selected from halogen, hydroxy, carboxy, cyano and nitro; or (.beta.) is 4-pyridyl, 2-pyrimidyl or 2-pyrazinyl, each of those radicals being unsubstituted or substituted by a substituent selected from halogen, cyano, nitro, C, -C 4 alkoxy and C 2 -C 5 alkoxycarbonyl; and pharmaceutically acceptable salts thereof.
  • R-i is hydrogen, methyl, ethyl, propyl, propenyl, isopropyl, butyl, hexyl, octyl, decyl, cyclopentyl, cyclohexyl, cyclopentylmethyl, cyclohexylmethyl or benzyl
  • R 2 is benzyloxy, 3-bromo-, 4-bromo-, 4-chloro-, 2,3-, 2,4-, 4,5- or 4,6-dichloro-benzyloxy
  • R 3 is cyano
  • C 2 -C 10 alkanoyl that is unsubstituted or mono- or poly-substituted by halogen, methoxy, amino, hydroxy and/or by cyano
  • benzoyl that is unsubstituted or substituted by one or more substituents from the group halogen, CT -C alkyl, methoxy, amino, hydroxy and cyano; carb
  • Ri is hydrogen, methyl, ethyl, propyl, propenyl, isopropyl, butyl, hexyl, octyl, decyl, cyclopentyl, cyclohexyl, cyclopentylmethyl, cyclohexylmethyl or benzyl
  • R 2 is hydrogen, halogen, cyano, methyl, hydroxymethyl, cyanomethyl, methoxymethyl, pyrrolidinylmethyl, carboxy, (methoxy, ethoxy or butoxy)-carbonyl, carbamoyl, N- isopropylcarbamoyl, N-phenylcarbamoyl, N-pyrroIidylcarbonyl; C 2 -C 10 alkanoyl that is unsubstituted or mono- or poly-substituted by halogen, methoxy, ethoxy, amino, hydroxy and/or by cyano; or benzoy
  • Ri is hydrogen, methyl, ethyl, propyl, propenyl, isopropyl, butyl, hexyl, octyl, decyl, cyclopentyl, cyclohexyl, cyclopentylmethyl, cyclohexylmethyl or benzyl
  • R 2 is a radical from the group methyl, ethyl, propyl, benzyl, phenyl and ethenyl that is substituted by hydroxy, cyano, methoxy, butoxy, phenoxy, amino, pyrrolidinyl, carboxy, lower alkoxycarbonyl or by carbamoyl; or R 2 is formyl or derivatised formyl that can be obtained by reaction of the formyl group with an amine or amine derivative from the group hydroxylamine, O-methylhydroxylamine, O-ethylhydroxylamine, O-allylhydroxylamine, O- benzylhydroxyl
  • A is an N-atom or a CH radical and W is a radical of the formula
  • W' is a cyclopentylidene, cyclohexylidene, cycloheptylidene or 2-adamantylidene radical
  • Y and Z independently of one another, are each a methine group (CH) or a nitrogen atom, and their pharmaceutically acceptable addition salts with acids.
  • X is CH or N
  • R-i and R 2 are identical or different and are each phenyl or halophenyl
  • R 3 is C -C 4 alkyl
  • a C 5 -C cycloalkyl group that is optionally condensed by benzene, or is thienyl, pyridyl or 2- or 3-indolyl; and acid addition salts thereof.
  • phenyl is phenyl, substituted phenyl, naphthyl, pyridyl, aminopyridyl, imidazolyl, triazolyl, thienyl, halothienyl, furanyl, C-, -C 6 alkylfuranyl, halofuranyl or thiazolyl; wherein Ar 2 is phenyl, substituted phenyl or pyridyl; and wherein "substituted phenyl” is phenyl that is substituted by up to 3 substituents in each case selected independently of one another from the group consisting of halogen, hydroxy, hydroxymethyl, trifluoromethyl, Ci -C 6 alkyl, Ci -C 6 alkoxy, C-i -C 6 alkoxycarbonyl, carboxy, formyl, hydroxyiminomethyl, cyano, amino, mono- and di-(C! -C 6 aIkyl)amino and nitro
  • the compounds of formula I as defined in EP-A-354 689 especially (1) 4-[2-(4-cyanophenyl)-3-(1 ,2,4-triazol-1-yl)propyl]benzonitrile, (2) 4-[1-(4-chIorobenzyl)-2-(1 ,2,4-triazol-1-yl)ethyl]benzonitrile, (3) 4-[2-(1 ,2,4-triazol-1-yl)-1-(4-trifluoromethyl]benzyl)ethyl]benzonitrile,
  • the compounds of formula (1 ) as defined in EP-A-354 683 especially (1) 6-[2-(4-cyanophenyl)-3-(1,2,4-triazol-1-yl)-propyl]nicotinonitrile, (2) 4-[1 -(1 ,2,4-triazol-1 -yl-methyl)-2-(5-[trifluoromethyl]pyrid-2-yl)ethyl]benzonitrile.
  • steroidal aromatase inhibitors that may be mentioned are:
  • R is hydrogen, acetyl, heptanoyl or benzoyl.
  • An individual compound from that group that may be given special mention is: (1 ) 4-hydroxy-4-androstene-3,17-dione.
  • Organic radicals designated by the term “lower” contain up to and including 7, preferably up to and including 4, carbon atoms.
  • Acyl is especially lower alkanoyl.
  • Aryl is, for example, phenyl or 1- or 2-naphthyl, each of which is unsubstituted or substituted by lower alkyl, hydroxy, lower alkoxy, lower alkanoyloxy, amino, lower alkylamino, di-lower alkylamino, lower alkanoylamino or by halogen.
  • compositions are, for example, pharmaceutically acceptable acid addition salts or pharmaceutically acceptable metal or ammonium salts.
  • Pharmaceutically acceptable acid addition salts are especially those with suitable inorganic or organic acids, for example strong mineral acids, such as hydrochloric acid, sulfuric acid or phosphoric acid, or organic acids, especially aliphatic or aromatic carboxylic or sulfonic acids, for example formic, acetic, propionic, succinic, glycolic, lactic, hydroxysuccinic, tartaric, citric, maleic, fumaric, hydroxymaleic, pyruvic, phe ⁇ ylacetic, benzoic, 4-aminobenzoic, anthranilic, 4-hydroxybenzoic, salicylic, 4-aminosalicylic, pamoic, gluconic, nicotinic, methanesulfonic, ethanesulfonic, halobenzenesulfonic, p- toluenesulfonic, naphthalenesulfonic, sulfanilic or cyclohexylsulfamic acid; or with other acid
  • Compounds containing acid groups can also form pharmaceutically acceptable metal or ammonium salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium, magnesium or calcium salts, also ammonium salts derived from ammonia or suitable organic amines.
  • pharmaceutically acceptable metal or ammonium salts such as alkali metal or alkaline earth metal salts, for example sodium, potassium, magnesium or calcium salts, also ammonium salts derived from ammonia or suitable organic amines.
  • Special compounds include aliphatic, cycloaliphatic, cycloaliphatic-aliphatic or araliphatic primary, secondary or tertiary mono-, di- or poly-amines, such as lower alkylamines, for example di- or tri-ethylamine, hydroxy-lower alkylamines, for example 2-hydroxyethylamine, bis(2- hydroxyethyl)amine or tris(2-hydroxyethyl)amine, basic aliphatic esters or carboxylic acids, for example 4-aminobenzoic acid 2-diethylaminoethyl ester, lower alkyleneamines, for example 1-ethylpiperidine, cycloalkylamines, for example dicyclohexylamine, benzylamines, for example N,N'-dibenzylethylenediamine; also heterocyclic bases, for example of the pyridine type, for example pyridine, collidine or quinoline.
  • lower alkylamines for
  • Compounds according to the invention having an acidic and a basic group may also be in the form of internal salts, i.e. in the form of zwitterions and another part of the molecule in the form of a normal salt.
  • the pharmaceutically acceptable salts are included in each case insofar as the individual compound is capable of salt formation.
  • the compounds listed, including the individual compounds mentioned, both in free form and in salt form, may also be in the form of hydrates, or their crystals may include, for example, the solvent used for crystallisation.
  • the present invention relates also to all those forms.
  • the amount of the at least one aromatase inhibitor may be an amount equivalent to between at or about 0.25 mg to at or about 10.0 mg per day of anastrazole.
  • a preferred amount may be at or about 0.5 mg per day of anastrazole.
  • the aromatase inhibitors have a half-life of about 8 hours to about 4 days, more preferably a half-life of about 2 days.
  • the inhibitor may be selected from non- steroidal and reversible and from steroidal irreversible aromatase inhibitors. More preferably the aromatase inhibitor is non-steroidal and reversible.
  • Aromatase inhibitors such as anastrazole, ZN 1033, (Arimidex®), ietrozole, CGS 20267, (Femara®) and vorozole (Rivizor®) are selective Als, available for clinical use in North America and other parts of the world for treatment of postmenopausal breast cancer. These triazole (antifungal) derivatives are reversible, competitive Als, which are highly potent and selective.
  • an aromatase inhibitor (Al) is present in each daily unit dosage, although it may be administered separately.
  • the Al may comprise an equivalent in a range from at or about 0.25 mg to at or about 10 mg per day of anastrazole. More preferably the amount is from at or about 0.5 mg per day to at or about 1 mg per day of anastrazole or its equivalent. Most preferably the amount is at or about 0.5 mg per day of anastrazole or its equivalent.
  • the total number of days during which the progestin and estrogen combinations are administered daily is preferably 21. These are followed by 4 to 8 days which are free of hormone administration to approximate the natural 28-day menstrual cycle of the female.
  • Day one of the cycle is defined as the first day of menstruation and the days are numbered sequentially thereafter until menstruation occurs again.
  • the cycle usually lasts 28 days but it may be slightly longer or shorter.
  • the placebo or any of the hormone containing tablets might contain nutritional supplements such as, for example, iron supplements, folic acid, calcium, etc.
  • phase one would commence sometime between day 1 and day 7 of the menstrual cycle and last 5 to 8 days but preferably 7 days, phase two would last 7 to 11 days, preferably 7 days, while phase three would last 3 to 7 days, preferably 7 days.
  • the contraceptive composition employed in the present invention comprises separate daily dosage units which are adapted for successive daily oral ingestion.
  • the composition consists essentially of, as the first phase, 5 to 8 dosage units containing, in admixture with a pharmaceutically acceptable carrier, a combination of an estrogen in combination with a progestin and an aromatase inhibitor, followed by, as the second phase, 7 to 11 dosage units containing, a combination of estrogen and a progestin, and an aromatase inhibitor, followed by, as the third phase, 3 to 7 dosage units containing a combination of an estrogen and a progestin and an aromatase inhibitor, optionally followed by 4 to 8 dosage units free of estrogen and progestin.
  • the estrogen daily dosage is kept constant in all three phases.
  • the daily dosage should be equal in contraceptive activity in each phase to a daily dosage of about 23 to 28 ⁇ g of 1 ⁇ -ethinylestradiol.
  • the preferred dosage is one equal to a daily dosage of at or about 25 ⁇ g of 17 ⁇ -ethinylestradiol.
  • the progestin is preferably administered in a daily dosage in the first phase corresponding in progestogen activity to 0.25-0.75 mg of norethindrone per day, during the second phase a daily dosage corresponding in progestin activity to 0.25- 1.0 mg of norethindrone per day and during the third phase a daily dosage corresponding in progestin activity to 0.35-2.0 mg of norethindrone per day. It is an aspect of the present invention that the progestin dose should substantially increase from the first phase to the second phase to the third phase.
  • the progestin is more preferably administered in a daily dosage in the first phase corresponding in progestin activity to 0.25-0.65 mg of norethindrone per day and most preferably 0.40-0.60 mg of norethindrone per day, during the second phase a daily dosage corresponding in progestin activity to 0.35-0.9 mg of norethindrone per day and most preferably 0.65-0.85 mg norethindrone per day, and during the third phase a daily dosage corresponding in progestin activity to 0.50-1.50 mg of norethindrone per day and most preferably 0.9-1.1 mg norethindrone per day.
  • An example dose of norethindrone in the first phase is 0.50 mg, in the second phase is 0.75 mg and in the third phase is 1.0 mg.
  • the progestin is norgestimate, it is preferably administered in a daily dosage in the first phase of 0.03-0.25 mg per day, during the second phase a daily dosage of 0.1-0.35 mg per day and during the third phase a daily dosage of 0.15-0.50 mg per day.
  • Norgestimate is more preferably administered in a daily dosage in the first phase of 0.1- 0.22 mg per day and most preferably 0.15-0.20 mg per day, during the second phase a preferred daily dosage of 0.15-0.30 mg per day and most preferably 0.2-0.23 mg per day, and during the third phase a daily dosage of 0.20-0.40 mg per day and most preferably 0.23-0.3 mg per day.
  • An example dose of norgestimate in the first phase is 0.180 mg
  • in the second phase is 0.215 mg
  • in the third phase is 0.250 mg.
  • the estrogen and progestin components are preferably administered together orally in a pharmaceutically acceptable nontoxic carrier, but they can also be administered separately or parenterally.
  • the effective agents are processed, together with the usual additives, vehicles and/or flavour-ameliorating agents normally employed in Galenic pharmacy, in accordance with generally accepted pharmaceutical practices.
  • tablets, dragees, capsules, pills, suspensions or solutions are particularly suitable;
  • oily solutions such as, for example, sesame oil or castor oil solutions which can optionally additionally contain a diluent such as, for example, benzyl benzoate or benzyl alcohol.
  • the at least one aromatase inhibitor may be included in the daily dosage units or it can be administered separately.
  • the three-phase combination-type contraceptives are preferably packaged in the form of a pharmaceutical kit or package in which the daily dosages are arranged for proper sequential administration.
  • This invention also relates, therefore, to a pharmaceutical unit which contains combination-type contraceptives in dosage units in a synchronized, fixed sequence, wherein the sequence or arrangement of the dosage units corresponds to the stages of daily administration.
  • the pharmaceutical unit can be, e.g., in the form of a transparent package having dosage units arranged sequentially and consisting of the tablets for the first phase, followed by the tablets for the second phase, followed by the tablets for the third phase, and finally optionally followed by the placebos.
  • a single tablet is to be taken each day over the period of the cycle.
  • Triphasic regimen wherein the first phase comprises a tablet containing 0.180 mg of norgestimate, 25 ⁇ g EE, and an aromatase inhibitor at a daily dosage equivalent to from at or about 0.25 mg to at or about 5 mg of anastrazole, once a day for 7 days; in the second phase a tablet containing 0.215 mg of norgestimate, 25 ⁇ g EE, and an aromatase inhibitor at a daily dosage equivalent to from at or about 0.25 mg to at or about 5 mg of anastrazole once a day for 7 days; and in the third phase a tablet containing 0.250 mg of norgestimate, 25 ⁇ g EE, and an aromatase inhibitor at a daily dosage equivalent to from at or about 0.25 mg to at or about 5 mg of anastrazole; followed by 7 days of placebo tablets.
  • the aromatase inhibitor may be selected from those described previously and a suitable amount is incorporated into each dosage in accordance with the guidance provided earlier.
  • This regimen is a two-stage oral contraceptive system in which an unopposed estrogenic compound and an aromatase inhibitor is administered during a terminal portion of the first 7 day segment of the menstrual cycle, counting as day 1 the onset of menses.
  • an estrogenic compound at a daily dosage equivalent in estrogenic activity to about 0.01 to about 0.04 mg of 17 ⁇ -ethinylestradiol and an aromatase inhibitor at a daily dosage equivalent to at or about 0.25 mg to at or about 5 mg of anastrazole, is administered to a female of childbearing age for contraception purposes.
  • a second stage of this contraceptive regimen is commenced comprising daily administration of a dosage comprising a progestin alone or in combination with an estrogenic compound, which is continued to about day 28 of the menstrual cycle.
  • the amount and type of aromatase inhibitor is selected in accordance with the earlier specified guidelines.
  • Twenty-eight tablets of an oral contraceptive regimen containing 0.15 mg desogestrel (13- ethyl-11-methylene-18,19-dinor-17 ⁇ -pregn-4-en-20-yn-17-ol) and 0.03 mg ethinylestradiol (19-nor-17 ⁇ -pregna-1 ,3,5(10)-trien-20-yne-3,17,diol) are prepared.
  • Inactive ingredients included in these tablets comprised Vitamin E, comstarch, pulvodone, cearic acid, collodoil silicon dioxide, lactose, hydroxypropyl methylcellulose, polyethylene glycol, titanium dioxide, talc and ferric oxide.
  • the non-hormone containing green tablets comprise inactive ingredients consisting of lactose, pregelatinized starch, magnesium stearate, F.D. and C. Blue No. 1 Aluminum Lake, ferric oxide, hydroxypropyl methylcellulose, polyethylene glycol, titanium dioxide and talc.
  • an additional dosage of aromatase inhibitor is added to the daily dosage of hormone described or it may be administered separately.
  • the amount of aromatase inhibitor and the particular aromatase inhibitor are selected in accordance with the guidelines previously set out.
  • Twenty-eight tablets, each containing norethinedrone, ethinylestradiol, and at least one aromatase inhibitor are prepared.
  • each tablet contains 0.5 mg of norethindrone and 0.035 mg of ethinylestradiol.
  • Inactive ingredients include lactose, magnesium stearate and pregelatinized starch.
  • the next phase of tablets comprise 0.75 mg of norethindrone and 0.035 mg of ethinylestradiol.
  • Inactive ingredients include F.D. & C. Yellow No. 6, lactose, magnesium stearate and pregelatizined starch.
  • the third set of tablets comprising unit dosages of 1 mg of norethindrone and 0.035 mg of ethinylestradiol are prepared.
  • Inactive ingredients include F.D. & C. Yellow No. 6, lactose, magnesium stearate and pregelatinized starch.
  • a set of placebo tablets containing inert ingredients only comprise D. and C. Yellow No. 10 Aluminum Lake, F.D. & C. Blue No. 2 Aluminum Lake, lactose, magnesium stearate, microcrystalline cellulose and pregelatinized starch.
  • an additional dosage of aromatase inhibitor is added to the daily dosage of hormone described or it may be administered separately.
  • the amount of aromatase inhibitor and the particular aromatase inhibitor are selected in accordance with the guidelines previously set out.
  • the first set of tablets contains 0.5 mg of norethindrone and 0.035 mg of ethinylestradiol.
  • Inactive ingredients in these tablets include lactose, magnesium stearate and pregelatinized starch.
  • the next set of tablets comprises 1 mg of norethindrone and 0.035 mg of ethinylestradiol.
  • Inactive ingredients include F.D. & C. Yellow No. 6, lactose, magnesium stearate and pregelatinized starch.
  • the next set of tablets contains only inert ingredients, having the formulation as described above.
  • an additional dosage of aromatase inhibitor is added to the daily dosage of hormone described or it may be administered separately.
  • the amount of aromatase inhibitor and the particular aromatase inhibitor are selected in accordance with the guidelines previously set out.
  • Twenty-one tablets are prepared, each containing 1 mg of norethindrone and 0.035 mg of ethinyl estradiol.
  • Inactive ingredients include F.D. & C. Yellow No. 6, lactose, magnesium stearate and pregelatinized starch.
  • a set of placebo tablets similar to those described above is also prepared.
  • an additional dosage of aromatase inhibitor is added to the daily dosage of hormone described or it may be administered separately.
  • the amount of aromatase inhibitor and the particular aromatase inhibitor are selected in accordance with the guidelines previously set out.
  • a set of twenty-one tablets, each tablet containing 0.5 mg of norethindrone and 0.35 mg of ethinylestradiol is prepared.
  • Inactive ingredients include lactose, magnesium stearate and pregelatinized starch.
  • a set of placebo tablets similar to those described above are also prepared.
  • the above regimen includes the addition of an aromatase inhibitor to every daily dosage unit, with the amount of inhibitor and specific choice being determined in accordance with the guidelines set out previously.
  • Twenty-one tablets containing the active ingredients 0.01 mg of levonorgestrel and 0.02 mg of ethinylestradiol are prepared.
  • the inactive ingredients present in the tablets comprise cellulose, hydroxypropyl methylcellulose, iron oxide, lactose, magnesium stearate, polacrillin potassium, polyethylene glycol, titanium dioxide and wax E.
  • placebo or inert tablets are prepared, each containing cellulose, F.D. & C. Blue No. 1 , hydroxypropyl methylcellulose, iron oxide, lactose, magenesium stearate, polacrillin potassium, polyethylene glycol, titanium dioxide and wax E.
  • the unit dosages each include an aromatase inhibitor in an amount and the specific inhibitor is selected in accordance with the previously mentioned guidelines.
  • the following regimen represents a new class of formulations called estrophasic.
  • the estrophasic oral contraceptive phases in gradually increasing doses of estrogen, e.g., 20, 30, 35 meg ethinylestradiol with a low, constant dose of progestin (1 mg norethindrone acetate).
  • the first low step comprises unit dosages for the first 5 days
  • the next step comprises unit dosages for the next 7 days
  • the last step comprises unit dosages for the last 9 days, for a total of 21 days. Seven days of no estrogen or progestin or aromatase inhibitor are then administered to the patient.
  • Transdermal forms of administration for contraceptives are well known and there are many commercial products available in the market.
  • An example is that sold under the trade-mark Orthoevra.
  • Orthoevra is a combination transdermal contraceptive patch with a contact surface area of 20 cm 2 . It contains 6.00 mg norelgestromin and 0.75 mg ethinylestradiol and releases 150 ⁇ g of norelgestromin and 20 ⁇ g of ethinylestradiol to the bloodstream per 24 hours.
  • the patch comprises three layers.
  • the backing layer is composed of a flexible film consisting of low density pigmented polyethylene outer layer and a polyester inner layer. This provides structural support and protects the middle adhesive layer from the environment.
  • the middle layer contains polyisobutylene/polybutene adhesive, crospovidone, non-woven polyester fabric and laurel lactate as inactive components.
  • the active components in this layer are the hormones norelgestromin and ethinylestradiol.
  • the third layer is the release liner which protects the adhesive layer during storage and is removed just prior to application. It is a transparent polyethylene terethalate film with a polydimethyl cyloxane coating on the side that is in contact with the middle adhesive layer.
  • This regimen provides a 28 day cycle. A new patch is applied each week for three weeks providing a total of 21 total days. Week 4 is patchfree.
  • the patch is normally applied the first day of the woman's menstrual period or the first Sunday after the menstrual period begins.
  • the patch is applied to clean, dry, intact healthy skin on the buttock, abdomen, upper outer arm or upper torso, in a place where it won't be rubbed by tight clothing.
  • the patch cannot be placed on skin that is red, irritated or cut, nor should it be placed on the breasts.
  • the aromatase inhibitor in this regimen can be administered in oral form and taken every day when a patch is in place or it may be incorporated into the patch.
  • the choice and amount are as stated above.
  • Two-day phases (unit dosages of EE 0.035 mg and NET 0.5 mg) alternating with three- day phases of EE 0.035 mg and NET 0.35 mg, beginning and ending with the 0.5 mg combination are prepared for administration. Twenty-one days of unit doses are provided and the at least one aromatase inhibitor is administered simultaneously. Placebo or no pills are to be administered for 7 days thereafter.
  • Two-day phases of unit dosages of EE 0.035 mg alternating with unit dosages of EE 0.035 mg and NET 0.75 mg, beginning and ending with the first unit dosage ' and running for 22 days total are prepared for administration. Twenty-two days of unit doses are provided and the at least one aromatase inhibitor is administered simultaneously. Placebo or no pills are to be administered for 6 days thereafter.
  • the at least one aromatase inhibitor is administered each day and the 24 pills may be followed by 4 days of no pills or with placebo pills.
  • Example 17 Three-day phases and four-day phases of each of the above combinations as set forth in Examples 15 and 16, starting with either three or four-day phases and ending with the other are prepared for a total of 21 days, each including a suitable amount of the at least one aromatase inhibitor and ending with 7 days of no pills or placebo pills.
  • Three-day and four-day phases of formulations starting with a three-day phase of 0.035 mg NET with 0.035 mg EE and ending with a four-day phase of 0.5 mg NET and 0.035 mg EE are prepared for a total of 21 days, each including a suitable amount of the at least one aromatase inhibitor and ending with 7 days of no pills or placebo pills.
  • Two-day phases of daily unit dosages comprising EE 0.025 mg and levonorgestrel (D- norgestrel) 0.05 mg alternating with two-day phases of daily unit dosages comprising EE
  • Each daily unit dose includes at least one aromatase inhibitor. There follows 6 days of placebo or no pills.
  • Two-day phases of daily unit dosages comprising EE 0.025 mg and norgestimate 0.05 mg alternating with daily unit dosages comprising EE 0.025 mg and norgestimate 0.180 mg are prepared for administration for 21 days.
  • Each daily unit dose includes at least one aromatase inhibitor.
  • Example 23 Three-day phases of daily unit dosages comprising EE 0.025 mg and norgestimate 0.09 mg alternating with daily unit dosages comprising EE 0.035 and norgestimate 0.05 mg are prepared for administration for 21 days. Each daily unit dose includes at least one aromatase inhibitor. There follows 7 days of placebo or no pills.
  • an aromatase inhibitor is included in every unit dosage, its selection being determined in accordance with the guidelines set out previously.
  • Twenty-tablets are prepared, each containing 0.1 mg levonorgestrel and 0.02 mg ethinylestradiol.
  • Other substances present in the tablets include lactose monohydrate, maize starch, maize starch (modified), polyvidone 25,000, magnesium stearate, sucrose, polyvidone 700,000, macrogal 6,000, calcium carbonate, talc, glycerol 85%, ferric oxide pigment yellow, ferric oxide pigment red, titanium dioxide, montanglycol wax.
  • an aromatase inhibitor selected in accordance with the guidance previously provide is included for administration with each of the 21 unit dosages.
  • the regimen does not include the 7 days of placebo.
  • the 21 pills are consumed and 7 days of no unit dosage is part of the regimen.
  • Twenty-one tablets are prepared as follows: 6 tablets each with 0.05 mg gestodene and 0.03 mg ethinylestradiol, 5 tablets each with 0.07 mg gestodene and 0.04 mg ethinylestradiol, 10 tablets each with 0.10 mg gestodene and 0.03 mg ethinylestradiol.
  • Other substances included in the pills comprise the following: lactose monohydrate, maize starch, polyvidone 25,000, sodium calcium edetate, magnesium stearate, sucrose, polyvidone 700,000, macrogal 6,000, calcium carbonate, talc, glycerol 85%, titanium dioxide, ferric oxide pigment yellow, ferric oxide pigment chocolate brown, montanglycol wax.
  • This formulation does not involve a placebo and 7 days are observed when no unit dosage containing active ingredient is taken.
  • an aromatase inhibitor the selection of which is determined by the guidance previously provided.
  • Continuous Combined Monophasic Oral Contraceptive Regimen Twenty-one tablets are prepared, each containing 0.15 mg desogestrel and 0.02 mg ethinylestradiol. A set of 2 green pills are prepared comprising placebo and an additional 5 pills are prepared comprising 0.01 mg ethinylestradiol.
  • the placebo tablets comprise inert ingredients of the type set out above. The last set of tablets containing ethinylestradiol also include such ingredients.
  • an aromatase inhibitor is included for administration on each of the days when a tablet comprising an active ingredient is administered. The selection and amount is determined in accordance with the guidelines previously set out.
  • the active ingredients are usually compounded with the chosen carrier and in for example the case of a tablet form, placed in a tablet molding apparatus to form the tablets which are subsequently packaged in accordance with the chosen regimen.
  • the package In the oral form of the formulation, the package would have the daily dosages arranged for proper sequential administration.
  • Data indications may be provided on the packaging.
  • the packaging may be a tube or box or a strip.
  • the box may be circular, square, or otherwise shaped with the tablets for example being accommodated separately therein for ease of administration.
  • Date indications may appear adjacent each tablet corresponding with the days on which each tablet is to be taken. Some indication of the sequence in which the tablets are to be taken preferably appears on the packaging regardless of its form.
  • compositions for enteral such as peroral or rectal administration, also for transdermal or sublingual administration, and for parenteral, for example intravenous, subcutaneous and intramuscular, administration.
  • Suitable unit dose forms, especially for peroral and/or sublingual administration, for example dragees, tablets or capsules, comprise preferably from approximately 0.01 mg to approximately 20 mg, especially from approximately 0.1 mg to approximately 10 mg, of the combination of the above-mentioned compounds or of a pharmaceutically acceptable salt thereof, together with pharmaceutically acceptable carriers.
  • the preferred form of administration is oral.
  • the proportion of active ingredient in such pharmaceutical compositions is generally from approximately 0.001 % to approximately 60%, preferably from approximately 0.1 % to approximately 20%.
  • Suitable excipients for pharmaceutical compositions for oral administration are especially fillers, such as sugars, for example lactose, saccharose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, and binders, such as starches, for example corn, wheat, rice or potato starch, gelatin, tragacanth, methylcellulose and/or hydroxypropylcellulose, disintegrators, such as the above-mentioned starches, also carboxymethyl starch, cross- linked polyvinylpyrrolidone, agar, alginic acid or a salt thereof, such as sodium alginate, and/or cellulose, for example in the form of crystals, especially in the form of microcrystals, and/or flow regulators and lubricants, for example silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, cellulose and/or polyethylene glycol
  • Dragee cores can be provided with suitable, optionally enteric, coatings, there being used inter alia concentrated sugar solutions which may comprise gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, or coating solutions in suitable solvents or solvent mixtures, or, for the preparation of enteric coatings, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate.
  • suitable, optionally enteric, coatings there being used inter alia concentrated sugar solutions which may comprise gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, or coating solutions in suitable solvents or solvent mixtures, or, for the preparation of enteric coatings, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate.
  • compositions are dry-filled capsules consisting of gelatin, and also soft sealed capsules consisting of gelatin and a plasticiser, such as glycerol or sorbitol.
  • the dry-filled capsules may contain the active ingredient in the form of granules, for example in admixture with fillers, such as lactose, binders, such as starches, and/or glidants, such as talc or magnesium stearate, and, if desired, stabilisers.
  • the active ingredient is preferably dissolved or suspended in suitable oily excipients, such as fatty oils, paraffin oil or liquid polyethylene glycols, to which stabilisers and/or anti-bacterial agents may also be added.
  • suitable oily excipients such as fatty oils, paraffin oil or liquid polyethylene glycols, to which stabilisers and/or anti-bacterial agents may also be added.
  • suitable oily excipients such as fatty oils, paraffin oil or liquid polyethylene glycols, to which stabilisers
  • Suitable rectally or transvaginally administrable pharmaceutical compositions are, for example, suppositories that consist of a combination of the active ingredient with a suppository base.
  • Suitable suppository bases are, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols.
  • gelatin rectal capsules which contain a combination of the active ingredient with a base material.
  • Suitable base materials are, for example, liquid triglycerides, polyethylene glycols or paraffin hydrocarbons.
  • Suitable formulations for transdermal administration comprise the active ingredient together with a carrier.
  • Advantageous carriers include absorbable pharmacologically acceptable solvents that serve to facilitate the passage through the skin of the host.
  • Transdermal systems are usually in the form of a bandage that comprises a support, a supply container containing the active ingredient, if necessary together with carriers, optionally a separating device that releases the active ingredient onto the skin of the host at a controlled and established rate over a relatively long period of time, and means for securing the system to the skin.
  • Suitable for parenteral administration are especially aqueous solutions of an active ingredient in water-soluble form, for example in the form of a water-soluble salt, and also suspensions of active ingredient, such as corresponding oily injection suspensions, there being used suitable lipophilic solvents or vehicles, such as fatty oils, for example sesame oil, or synthetic fatty acid esters, for example ethyl oleate, or triglycerides, or aqueous injection suspensions that comprise viscosity-increasing substances, for example sodium carboxymethylcellulose, sorbitol and/or dextran, and, optionally, stabilisers.
  • suitable lipophilic solvents or vehicles such as fatty oils, for example sesame oil, or synthetic fatty acid esters, for example ethyl oleate, or triglycerides
  • viscosity-increasing substances for example sodium carboxymethylcellulose, sorbitol and/or dextran, and, optionally, stabilisers.
  • Dyes or pigments may be added to the pharmaceutical compositions, especially to the tablets or dragee coatings, for example for identification purposes or to indicate different doses of active ingredient.
  • compositions containing compounds of the invention may further comprise pharmaceutically acceptable carriers and be in either solid or liquid form.
  • Solid preparations include powders, tablets, dispersible granules, capsules, etc.
  • the carrier may also be one or more substances, which act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, or tablet disintegrating agents as well as encapsulating materials.
  • Suitable carriers include magnesium carbonate, magnesium stearate, talc, lactose, sugar, peptin, dextrin, starch, methylcellulose, sodium carboxylmethylcellulose, and the like.
  • Liquid form preparations include solutions, which are suitable for oral or parenteral administration, or suspensions and emulsions suitable for oral administration.
  • Aqueous solutions for oral administration can be prepared by dissolving the active compound in water and adding suitable flavorants, coloring agents, stabilizers and thickening agents as required.
  • Aqueous suspensions for oral use can be made by dispersing the active component in • water together with a viscous material such as a natural or synthetic gum, methylcellulose, sodium carboxymethyl-cellulose, and other suspending agents known to the pharmaceutical formulation art.
  • solid dosage forms include topical dosage forms which include solutions, powders, fluid emulsions, fluid suspensions, semi-solids, ointments, pastes, creams, gels or jellies and foams; and parenteral dosage forms which include solutions, suspensions, emulsions or dry powder comprising an effective amount of estrogen and an aromatase inhibitor or estrogen and progestin and an aromatase inhibitor as taught in this invention.
  • compositions including solutions, suspensions, tablets or caplets
  • solutions, suspensions, tablets or caplets can be employed, as would be known to those skilled in the art and as is disclosed for example by Remington's Pharmaceutical Sciences, Mack Publishing Co., Part 8, Chapters 76-93, Pharmaceutical Preparations and Their Manufacture, pp. 1409-1677 (1985).
  • the pharmaceutical formulations may be provided in kit form containing preferably multiples of three unit dosages, each constituting a relatively dominant estrogenic activity phase and in a suitable form, for example, caplets or tablets.
  • the kit may comprise a dial package or a foil strip as is well known in the art.
  • the kit would typically contain an even number of doses for each phase arranged in an even number of relatively dominant estrogenic activity phases.
  • the unit dosages would be arranged in each package in multiples of six so that an even number of phases would be present in each package.
  • unit dosage form refers to physically discrete units suitable as unit dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • doses as used herein broadly encompasses the term unit dosage form or dosage units as well as continuous dosing of compositions by depot or other methods.
  • compositions of the present invention can be prepared in a manner known per se, for example by means of conventional mixing, granulating, confectioning, dissolving or lyophilising processes.
  • pharmaceutical compositions for oral administration can be obtained by combining the active ingredient with solid carriers, optionally granulating a resulting mixture, and processing the mixture or granules, if desired or necessary after the addition of suitable excipients, to form tablets or dragee cores.
  • the daily doses of the present invention may be administered in any convenient form.
  • Preferred, as set out earlier is a single daily tablet, but any other suitable form may be employed.
  • the single tablet is preferred as it reduces the likelihood that the patient will get confused.
  • the words "an equivalent thereof are meant to cover administrative forms that do not comprise daily doses, for example a transdermal form.
  • the formulations are prepared according to conventionally known procedures in accordance with the desired method of administration. Different amounts of the active ingredients may be required in different types of formulations but it is essential that the amount of estrogenically active substance and progestationally active substance be selected so as to provide the dose equivalency for the regimen as described above.
  • the percentage of active ingredients may vary according to the potency of the hormone, the delivery system or method of administration and is chosen in accordance with conventional methods known in the art.
  • the estrogen and progestin compositions can be administered by way of any art recognized means as practiced in the pharmaceutical arts.
  • the estrogen and progestin alone or in combination may be so formulated so that it can be administered orally, via a skin patch for transdermal absorption, by intramuscular injection, contained within an inert matrix which is implanted within the body and in a depot state, or intravaginally in a matrix that slowly releases the active compositions (such implants are taught for example in U.S. Patents Nos. 4,957,119 and 5,088,505).

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Abstract

This invention relates to an improved female birth control method which substantially reduces breakthrough bleeding and mood or emotional disorders in women, and more particularly, to a contraceptive unit comprising at least one aromatase inhibitor combined with a combination of a substance exhibiting estrogen activity, or a substance exhibiting progestin activity, or both substances in amounts required to prevent pregnancy in females.

Description

FEMALE BIRTH CONTROL METHOD
FIELD OF THE INVENTION
This invention relates to an improved female birth control method which substantially reduces breakthrough bleeding and mood or emotional disorders in women, and more particularly, to a contraceptive unit comprising at least one aromatase inhibitor combined with a combination of a substance exhibiting estrogen activity, or a substance exhibiting progestin activity, or both substances in amounts required to prevent pregnancy in females.
BACKGROUND OF THE INVENTION
Oral contraceptives for women have been available commercially since the early 1960's. Oral contraceptives generally comprise an estrogen active substance and a progestin active substance administered in regimens comprising various combinations of dosage levels. Early pill formulations contained up to 100 to 150 μg of estrogen, but later studies revealed that far less hormone was needed to prevent conception. Thus as the technology has evolved, decreasing amounts of estrogen and progestin have been included in contraceptive formulations. In the early 1970's, a progestin only pill was introduced for contraceptive purposes which relied on norethindrone, with one preferred formulation comprising 350 μg of norethindrone.
In the 1980's, multiphasic pill formulations were introduced which are referred to as biphasics and triphasics. In these formulations, the level of progestin changes during the monthly cycles. The original combination preparations are generally referred to as monophasics. All of these regimens are described as continuous combined regimens. There are also interrupted or cyclophasic regimens which comprise consecutively administrable phases of unit doses comprising estrogen and progestin and phases of unit doses comprising estrogen and higher amounts of progestin. While oral contraceptives are among the most popular, many other forms of administration are available such as implants, injections, gels, transdermal patches, suppositories and the like.
In the late 1980's, further developments allowed the introduction of formulations comprising one-third of the original dose of estrogen and one-twentieth the original amount of progestin. These preparations still maintain a 99% effectiveness rate as a method of preventing pregnancy..
The pill has become the most popular reversible method of birth control in the Western World. In the United States, approximately 80% of females have used the pill at one point during their reproductive lives, and women are now staying on the pill longer than ever before. The acceptability of oral contraceptives (OCs) is often influenced by the side effect profile. One of the most common side effects, and a common reason for discontinuing OCs, is breakthrough bleeding (BTB) as described in Thomeycroft IH. Cycle control with oral contraceptives: A review of the literature. Am J Obstet Gynecol 1999;180:280-287. Other less common, but disturbing, side effects include decreased libido (see Glick ID and Bennet SE, Psychiatric complications of progesterone and oral contraceptives. J Clin Psychopharmacol 1981 ;1 (6):350-67; Frey H, Aakvaag A. The treatment of essential hirsutism in women with cyproterone acetate and ethinyl estradiol. Clinical and endocrine effects in 10 cases. Acta Obstet Gynecol Scand 1981 ;60(3):295-300; Erkkola R, et al. Ovulation inhibitors containing cyproterone acetate or desogestrel in the treatment of hyperandrogenic symptoms. Acta Obstet Gynecol Scand 1990;69(1 ):61-5; Graham CA, Sherwin BB. The relationship between mood and sexuality in women using an oral contraceptive as a treatment for premenstrual symptoms. Psychoneuroendocrinology 1993;18(4):273-81) and depression (see Glick ID and Bennet SE, Psychiatric complications of progesterone and oral contraceptives. J Clin Psychopharmacol 1981 ;1 (6):350-67; Frey H, Aakvaag A. The treatment of essential hirsutism in women with cyproterone acetate and ethinyl estradiol. Clinical and endocrine effects in 10 cases. Acta Obstet Gynecol Scand 1981 ;60(3):295-300). The cause of breakthrough bleeding remains unclear but generally cycle control and BTB is worse with the use of OCs containing the lowest doses of ethinyl estradiol and progestin. It is possible that fluctuations in endogenous estrogen produced by aromatization of androgens (especially adrenal androgens that may be increased by emotional stress) to estrogen in peripheral tissues such as fat, liver and muscle, as described in Nelson LR. et al., J Am Acad Dermatol 2001 ; 45:S116-24, could result in endometrial instability and breakthrough bleeding. In addition, there is evidence that progesterone or progestin administration will increase aromatase activity in the endometrium as described in Tseng, J.K. et al., J Steroid Biochem, 1988, 29, 9-13 and Tseng, L, Endocrinology, 1984, 115, 833-5, suggesting a tissue specific effect of progestin modulation of aromatase. The increase in endometrial aromatase could result in increased local estrogen production in the endometrium. Fluctuating endogenous estrogen from both these sources could cause BTB.
Mood disturbances such as depression and loss of libido may be related to suppression of androgens in OC users. Plasma free testosterone and other measures of androgenicity were substantially lower in women taking oral contraceptives compared to a control group of non-users (Bancroft et al, 1991 ). A lower free testosterone level was associated with a lower frequency of sexual intercourse (Bancroft et al, 1991 ). In another study of women with hirsutism who were treated with oral contraceptives, the testosterone secretion rate was diminished and sex hormone binding globulin was increased by OC use, resulting in lowered free testosterone. Although the great majority of women had improvement in their unwanted hair growth, side effects of the OC treatment included loss of libido and mental depression (Frey and Aakvaag, 1981 ). Both estrogen and androgen are thought to be required for normal sexual function and libido in the female, as described in Gelfand MM, Davis S. J Reprod Med 2001 ; 46:291-6; Rako S., J Womens Health Gend Based Med 2000; 9:917-23, and Sherwin BB., Exp Gerontol 1994; 29:423-30. Oral contraceptives, by reducing pituitary gonadotropins, subsequently decrease ovarian thecal cell androgen production. In addition, the estrogen component of OCs stimulates hepatic production of SHBG, a circulating protein to which testosterone binds with high affinity, thereby reducing the amount of biologically active free testosterone.
There are a number of patents relating to contraceptive methods and many different commerical formulations available in the marketplace. Some commonly used brand names for estrogen and progestin containing oral contraceptives are as follows. The superscript numbers refer to the hormones present in the contraceptives which are identified hereafter.
Alesse - Brevicon - Demulen 1/35 -
Demulen 1/502
Desogen - Estrostep - Estrostep Fe :
Genora 0.5/35 -
Genora 1/35 §
Genora 1/50 -
Intercon 0.5/35 -
Intercon 1/35 -
Intercon 1/50 -
Jenest 5
Levlen -
Levlite 2
Levora 0.15/30 -
Loestrin 1/20 -
Loestrin Fe 1/20 -
Loestriη 1.5/30 -
Loestrin Fe 1.5/30 -
Lo/Ovral - Mircette λ ModiCon - Necon 0.5/35 § Necon 1/35 § Necon 1/50- Necon 10/11 -
N.E.E.1/35 s N.E.E.1/50- Nelova 0.5/35E - Nelova1/35E§ Nelova1/50MS
Nelova 10/11 - Nordette - Norethin 1/35E- Norethin1/50M§ Norinyl1+35§
Norinyl 1+50s Ortho-Cept 1 Ortho-Cyclen z Ortho-Novum 1/35 Ortho-Novum 1/50
Ortho-Novum 7/7/7 Ortho-Novum 10/11 Ortho Tri-Cyclen z Ovcon-35 - Ovcon-50 -
Ovral - Tri-Levlen s Tri-Norinyl - Triphasil - Trivora 2
Zovia1/35E2 Zovia1/50E2 Brevicon 0.5/355 Brevicon 1/35 § Cyclen z
Demulen 302 Demulen 502 Loestrin 1.5/30 - Marvelon 1 Minestrin 1/204 Min-Ovral - Norinyl 1/50 ~ Ortho 0.5/35 - Ortho 1/35 5 Ortho 7/7/7 -
Ortho 10/11 5 Ortho-Cept 1 Ortho-Novum 1/50 ! Ovral ~ Select 1/35 -
Synphasic - Tri-Cyclen z Triphasil -
Triquilar 2
The numbers refer to the hormones present in each brand name formulation.
1. Desogestrel and Ethinyl Estradiol 2 Ethynodiol Diacetate and Ethinyl Estradiol 3 Levonorgestrel and Ethinyl Estradiol 4 Norethindrone Acetate and Ethinyl Estradiol 5 Norethindrone and Ethinyl Estradiol 6 Norethindrone and Mestranol 7. Norgestimate and Ethinyl Estradiol 8 Norgestrel and Ethinyl Estradiol
Some commonly used brand names for progestin for contraceptive use are as follows. The superscript numbers refer to the hormones present in the contraceptives which are identified hereafter.
Depo-Provera Contraceptive Injection - Micronor -
NORPLANT System 1
Nor-QD -
Ovrette -
Plan B 1
The progestins are numbered to match the corresponding brand names.
1. Levonorgestrel
2. Medroxyprogesterone
3. Norethindrone 4. Norgestrel Examples of patents covering interrupted regimens include Robert F. Casper's US Patents Nos. 5,276,022 issued January 4, 1994 and 5,585,370 issued December 17, 1996.
The continuous combined regimens are described in the prior art which is exemplified by the following patents. US 2001/0044429A to Shangold, et al published November 22, 2001 for a method of contraception in which an estrogen and desogestrel are administered daily in a three phase sequence for 21 days followed by no hormones for from 4 to 8 days. US 6,312,722 B1 to Schmidt-Gollwitzer, et al granted November 6,
2001 describes a biphasic or two-stage combined preparation containing at least 30 daily unit doses. US 6,245,804 B1 to Lehmann, et al granted June 12, 2001 described nonsteroidal gestagens which can be used alone or in combination with estrogens for contraceptives. US 6,214,815 B1 to Shangold, et al granted April 10, 2001 describes a method of contraception wherein an estrogen and a progestin are administered in a three-phase sequence for 21 days followed by 4 to 8 days without an estrogen or progestin.
Other patents which cover triphasic formulations include US 6,133,251 issued October 17, 2000 to Dittgen et al; US 5,858,405 issued January 12, 1999 to Gast; US 4,962,098 issued October 9, 1990 to Boissonneault; US 4,378,356 issued March 19, 1983 to DeJager; US 4,143,136 to DeJager et al; and US 3,795,734 issued March 5, 1974 to Rochefort.
Other biphasic formulations are described in US 6,312,722 B1 issued November 6, 2001 to Schmidt-Gollwitzer et al; US 6,027749 issued February 22, 2000 to Schmidt-Gollwitzer et al; US 5,756,490 issued May 26, 1998 to Lachnit et al; and US 3,568,828 issued March 9, 1971 to Lerner. US 5,762,956 issued June 9, 1998 to Chien et al covers a transdermal contraceptive.
The Casper cyclophasic regimens (mentioned earlier) seek to induce higher levels of progestin and estrogen receptors by an estrogen-induced increase in receptor production. The greater concentration of steroid receptors increases the sensitivity of the target organs to progestin and estrogen and allows the use of lower doses of exogenous steroids. The cyclophasic or interrupted regimens of Casper upregulate the estrogen and progestin receptors in an estrogen-dominant phase and then down-regulate the same receptors in a progestin-dominant phase. In both phases of the Casper regimen, the estrogen dose is constant while the progestin dose is varied to produce relatively progestin-dominant or estrogen-dominant effects. All patents and literature references referred to herein are incorporated herein in their entirety by reference.
SUMMARY OF THE INVENTION The present invention is useful for substantially reducing mood or emotional disorders such as preventing depression and loss of libido associated with oral contraceptive use. The combination of at least one aromatase inhibitor with contraceptive levels of estrogen and progestin will increase endogenous androgen concentrations (testosterone and androstenedione) by prevention of peripheral aromatization of these androgen substrates to estrogen in muscle, fat and other tissues as described in Nelson LR, Bulun SE. J Am Acad Dermatol 2001; 45:S116-24. The increase in androgen levels in the presence of adequate estrogen administration will improve well-being and libido. In addition, the blockade of aromatization will prevent endogenous estrogen production, and estrogen fluctuations, thereby reducing the incidence of breakthrough bleeding.
The benefits of the new aromatase inhibitor/estrogen/progestin contraceptive regimen include: 1 ) Increased endogenous androgen concentrations into the physiologic range without the need for exogenous testosterone treatment by injection or skin patch. 2) Improved well being and libido as a result of increased endogenous androgen. 3) Decreased risk of breast cancer by inhibition of breast aromatase activity, and local estrogen production in breast tissue. 4) Decreased incidence of BTB by preventing endogenous fluctuations in estrogen levels that result from peripheral aromatization of adrenal androgens to estrogen.
The present invention provides in a first aspect a method for preventing pregnancy in females wherein breakthrough bleeding is substantially reduced, which comprises administering to such females from at or about 20 to at or about 28 consecutive daily unit doses or an equivalent thereof, of a substance exhibiting estrogen activity, or a substance exhibiting progestin activity or both such substances, or combinations of such unit doses in amounts sufficient to prevent pregnancy in such females together with at least one aromatase inhibitor-followed by from at or about 2 to at or about 10 days where no such substance is administered.
In another aspect, the invention provides a method for preventing pregnancy in females wherein mood disorders and/or emotional disorders are substantially reduced, which comprises administering to such females from at or about 20 to at or about 28 consecutive daily unit doses or an equivalent thereof of a substance exhibiting estrogen activity, or a substance exhibiting progestin activity or both such substances, in amounts sufficient to prevent pregnancy in such females, together with at least one aromatase inhibitor, followed by from at or about 2 to at or about 10 days where no such substance is administered.
In another aspect, the invention provides a contraceptive unit having at or about 20 to at or about 28 separate dosage units or an equivalent thereof, adapted for consecutive daily administration, the daily dosage units each comprising a substance exhibiting estrogen activity, or a substance exhibiting progestin activity, or both such substances or combinations of such units in amounts sufficient to prevent pregnancy in females, together with at least one aromatase inhibitor, and a pharmaceutically acceptable carrier therefor, and wherein breakthrough bleeding is substantially reduced in such females.
In another aspect, the invention provides a contraceptive unit having from at or about 20 to at or about 28 separate daily dosage units or an equivalent thereof, adapted for successive daily administration, each daily dosage unit comprising a substance exhibiting estrogen activity or a substance exhibiting progestin activity or both such substances, or combinations of such units, in amounts sufficient to prevent pregnancy in such females together with at least one aromatase inhibitor and a pharmaceutically acceptable carrier therefor, wherein mood disorder or emotional disorder symptoms are substantially reduced in such females.
General and particular descriptions of these regimens are described in the Background section previously. The present invention is believed to have application to all of these regimens and formulations.
In effect, this invention provides for the inclusion of at least one aromatase inhibitor for administration in conjunction with the usual birth control hormones and in accordance with any of the various regimens known to those skilled in the art.
The preferred hormone combinations for use in the contraceptive method of this invention may be selected from the following combinations:
Desogestrel and Ethinyl Estradiol,
Ethynodiol Diacetate and Ethinyl Estradiol,
Levonorgestrel and Ethinyl Estradiol,
Norethindrone Acetate and Ethinyl Estradiol, Norethindrone and Ethinyl Estradiol,
Norethindrone and Mestranol,
Norgestimate and Ethinyl Estradiol, and
Norgestrel and Ethinyl Estradiol. The preferred progestin for use on its own as the contraceptive hormone may be selected from
Levonorgestrel, Medroxyprogesterone, Norethindrone, and Norgestrel.
The amounts of hormones for use in the method of this invention are clearly set out in the literature and prior patents. The combinations and amounts may be easily selected by the person skilled in the art in accordance with the specific hormone(s) and type of regimen. The amount and choice of the aromatase inhibitor is again selected to ensure that the desired reduction in breakthrough bleeding and/or mood/emotional disorders are achieved. The mood/emotional disorders preferably encompass loss of libido and/or depression.
Definitions a substance exhibiting estrogen activity
Any conventional estrogen may be employed as a suitable component in the contraceptive regimen of this invention.
Preferred estrogens are 17α-ethinylestradiol, esters and ethers of 17α-ethinylestradiol such as, for example, 17α-ethinylestradiol 3-dimethylamino propionate, 17α- ethinylestradiol e-cyclopentyl ether (quienestrol) and 17α-ethinylestradiol 3-methyl ether (mestranol) may also be employed as the estrogen component. Natural estrogens such as estrone, estrone sulfate, estrone sulfate piperazine salt, estradiol and estriol, and their esters, as well as other synthetic estrogens, may be employed. The preferred estrogen is 17α-ethinylestradiol or 17α-ethinylestradiol 3-methyl ether. The selection of the estrogen and the dose level will generally follow from the literature, which is well known to the person skilled in the art.
a substance exhibiting progestin activity
The discussion that follows about the selection of a progestin and its dose level may be used as a guide in the selection of a suitable dose of estrogen, as discussed above.
Any progestationally active compound may be employed in this method. These compounds are classified, in agreement with their structure, in various groups which include progesterone, retroprogesterones, 17alpha-hydroxyprogesterones, 19- norprogesterones, 17alpha-hydroxyprogesterone derivatives, androstane and estrane derivatives. Progestins which may be employed as a component in the present invention include progesterone and its derivatives such as, for example, 17-hydroxyprogesterone esters and 19-nor-17-hydroxyprogesterone esters, 17α-ethinyltestosterone, 17α-ethinyl- 19-nortestosterone and derivatives thereof, norethindrone, D-norgestrel, Δ15 levonorgestrel, Δ15 levonorgestrel acetate, Δ15 levonorgestrel acetate oxime, D-17β- acetoxy-β-ethyl- 7α-ethinylgon-4-en-3-one oxime (norgestimate), desogestrel, ethynodiol diacetate, dydrogesterone, medroxyprogesterone acetate, norethynodrel, allylestrenol, lynoestrenol, quingestranol acetate, medrogestone, norgestrienone, dimethisterone, ethisterone, cyproterone acetate, chlormadinone acetate, and magestrol acetate. Preferred progestins are norethindrone, desogestrel and norgestimate.
Corresponding progestin activity between progestins in general and norethindrone in particular is well reported in the literature. Table 1 below is taken from the literature and is reported herein for convenience.
Table 1
Figure imgf000011_0001
The literature contains descriptions of numerous progestins and based on the criteria set out above, the person skilled in the art may make a suitable choice. The amount(s) of estrogen is dependent on the type of hormone and the regimen of administration and the art provides clear guidance to the person skilled therein. When the method of the invention involves a continuous combined monophasic contraceptive method, the daily unit doses comprise estrogen in an amount equivalent to at or about 0.02 mg to at or about 0.05 mg 17α-ethinylestradiol and progestin in an amount equivalent to at or about 0.5 mg to at or about 2.0 mg of norethindrone, and the at least one aromatase inhibitor is present in an amount equivalent to at or about 0.25 mg to at or about 10.0 mg per day of anastrazole.
When the methods of the invention involve a continuous combined biphasic regimen, the daily unit doses comprise estrogen in an amount equivalent to at or about 0.02 mg to at or about 0.05 mg 17α-ethinylestradiol and progestin in an amount equivalent to at or about 0.5 mg to at or about 1.0 mg of norethindrone, and the at least one aromatase inhibitor is present in an amount equivalent to at or about 0.25 mg to at or about 10.0 mg per day of anastrazole.
When the methods of the invention involve a continuous combined triphasic contraceptive method, the daily unit doses comprise estrogen in an amount equivalent to at or about 0.02 mg to at or about 0.05 mg 17α-ethinylestradiol and progestin in an amount equivalent to at or about 0.5 mg to at or about 1.0 mg of norethindrone, and the at least one aromatase inhibitor is present in an amount equivalent to at or about 0.25 mg to at or about 10.0 mg per day of anastrazole.
When the methods of the invention involve an interrupted contraceptive method, the daily unit doses comprise estrogen in an amount equivalent to at or about 0.02 mg to at or about 0.035 mg 17α-ethinylestradiol and progestin in an amount equivalent to at or about 0.35 mg to at or about 1.0 mg of norethindrone, and the at least one aromatase inhibitor is present in an amount equivalent to at or about 0.25 mg to at or about 10.0 mg per day of anastrazole.
aromatase inhibitors By "aromatase inhibitors" there are to be understood substances that inhibit the enzyme aromatase (=estrogen synthetase), which is responsible for converting androgens to estrogens.
Aromatase inhibitors may have a non-steroidal or a steroidal chemical structure. According to the present invention, both non-steroidal aromatase inhibitors and steroidal aromatase inhibitors can be used.
By aromatase inhibitors there are to be understood especially those substances that in a determination of the in vitro inhibition of aromatase activity exhibit IC50 values of 10"5 M or lower, especially 10"6 M or lower, preferably 10"7 M or lower and most especially 10"8 M or lower.
The in vitro inhibition of aromatase activity can be demonstrated, for example, using the methods described in J. Biol. Chem. 249, 5364 (1974) or in J. Enzyme Inhib. 4, 169 (1990). In addition, IC50 values for aromatase inhibition can be obtained, for example, in vitro by a direct product isolation method relating to inhibition of the conversion of 4-14 C- androstenedione to 4-14 C-estrone in human placental microsomes.
By aromatase inhibitors there are to be understood most especially substances for which the minimum effective dose in the case of in vivo aromatase inhibition is 10 mg/kg or less, especially 1 mg/kg or less, preferably 0.1 mg/kg or less and most especially 0.01 mg/kg or less.
In vivo aromatase inhibition can be determined, for example, by the following method [see J. Enzyme Inhib. 4, 179 (1990)]: androstenedione (30 mg/kg subcutaneously) is administered on its own or together with a compound of the invention (orally or subcutaneously) to sexually immature female rats for a period of 4 days. After the fourth administration, the rats are sacrificed and the uteri are isolated and weighed. The aromatase inhibition is determined by the extent to which the hypertrophy of the uterus induced by the administration of androstenedione alone is suppressed or reduced by the simultaneous administration of the compound according to the invention.
The following groups of compounds are listed as examples of aromatase inhibitors. Each individual group forms a group of aromatase inhibitors that can be used successfully in accordance with the present invention.
The compounds of formulae I and I* as defined in EP-A-165 904. These are especially the compounds of formula I
Figure imgf000013_0001
wherein R-i is hydrogen, lower alkyl; lower alkyl substituted by hydroxy, lower alkoxy, lower alkanoyloxy, lower alkanoyl, amino, lower alkylamino, di-lower alkylamino, halogen, sulfo, carboxy, lower alkoxycarbonyl, carbamoyl or by cyano; nitro, halogen, hydroxy, lower alkoxy, lower alkanoyloxy, phenylsulfonyloxy, lower alkylsulfonyloxy, mercapto, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, lower alkanoylthio, amino, lower alkylamino, di-lower alkylamino, lower alkyleneamino, N-morpholino, N-thiomorphoIino, N- piperazino that is unsubstituted or lower alkyl-substituted in the 4-position, tri-lower alkylammonio, sulfo, lower alkoxysulfonyl, sulfamoyl, lower alkylsulfamoyl, di-lower alkylsulfamoyl, formyl; iminomethyl that is unsubstituted or substituted at the nitrogen atom by hydroxy, lower alkoxy, lower alkanoyloxy, lower alkyl, phenyl or by amino; C2 -C7 alkanoyl, benzoyl, carboxy, lower alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl, di- lower alkylcarbamoyl, cyano, 5-tetrazolyl, unsubstituted or lower alkyl-substituted 4,5- dihydro-2-oxazolyl or hydroxycarbamoyl; and R2 is hydrogen, lower alkyl, phenyl-lower alkyl, carboxy-lower alkyl, lower alkoxycarbonyl-lower alkyl, halogen, hydroxy, lower alkoxy, lower alkanoyloxy, mercapto, lower alkylthio, phenyl-lower alkylthio, phenylthio, lower alkanoylthio, carboxy, lower alkoxycarbonyl or lower alkanoyl; the 7,8-dihydro derivatives thereof; and the compounds of formula I*
Figure imgf000014_0001
wherein n is 0, 1 , 2, 3 or 4; and R^ and R2 are as defined above for formula I; it being possible for the phenyl ring in the radicals phenylsulfonyloxy, phenyliminomethyl, benzoyl, phenyl-lower alkyl, phenyl-lower alkylthio and phenylthio to be unsubstituted or substituted by lower alkyl, lower alkoxy or by halogen; it being possible in a compound of formula I* for the two substituents C6 H4 -R_ and R2 to be linked to each of the saturated carbon atoms of the saturated ring, either both to the same carbon atom or both to different carbon atoms, and pharmaceutically acceptable salts thereof.
Individual compounds that may be given special mention here are: (1 ) 5-(p-cyanophenyl)imidazo[1 ,5-a]pyridine,
(2) 5-(p-ethoxycarbonylphenyl)imidazo[1 ,5-a]pyridine,
(3) 5-(p-carboxyphenyI )imidazo[1 ,5-a]pyridine,
(4) 5-(p-tert-butylaminocarbonylphenyl)imidazo[1 ,5-a]pyridine, (5) 5-(p-ethoxycarbonylphenyl)-5,6,7,8-tetrahydroimidazo[1 ,5-a]pyridine,
(6) 5-(p-carboxyphenyl)-5,6,7,8-tetrahydroimidazo[1 ,5-a]pyridine, (7) 5-(p-carbamoylphenyl)-5,6,7,8-tetrahydroimidazo[1 ,5-a]pyridine, (8) 5-(p-tolyl)-5,6,7,8-tetrahydroimidazo[1 ,5-a]pyridine, (9) 5-(p-hydroxymethylphenyl)imidazo[1 ,5-a]pyridine,
(10) 5-(p-cyanophenyl)-7,8-dihydroimidazo[1 ,5-a]pyridine,
(11 ) 5-(p-bromophenyl)-5,6,7,8-tetrahydroimidazo[1 ,5-a]pyridine,
(12) 5-(p-hydroxymethylphenyl)-5,6,7,8-tetrahydroimidazo[1 ,5-a]pyridine,
(13) 5-(p-formylphenyl)-5,6,7,8-tetrahydroimidazo[1 ,5-a]pyridine, (14) 5-(p-cyanophenyl)-5-methylthio-5,6,7,8-tetrahydroimidazo[1 ,5-a]pyridine,
(15) 5-(p-cyanophenyl)-5-ethoxycarbonyl-5,6J,8-tetrahydroimidazo[1 ,5-a]pyridine,
(16) 5-(p-aminophenyl)-5,6,7,8-tetrahydroimidazo[1 ,5-a]pyridine,
(17) 5-(p-formylphenyl)imidazo[1 ,5-a]pyridine,
(18) 5-(p-carbamoylphenyl)imidazo[1 ,5-a]pyridine, (19) 5H-5-(4-tert-butylaminocarbonylphenyl)-6,7-dihydropyrrolo[1 ,2-c]imidazole,
(20) 5H-5-(4-cyanophenyl)-6,7-dihydropyrrolo[1 ,2-c]imidazole,
(21 ) 5H-5-(4-cyanophenyl)-6,7,8,9-tetrahydroimidazo[1 ,5-a]azepine,
(22) 5-(4-cyanophenyl)-6-ethoxycarbonylmethyl-5,6,7,8-tetrahydroimidazo[1 ,5-a]pyridine,
(23) 5-(4-cyanophenyl)-6-carboxymethyl-5,6,7,8-tetrahydroimidazo[1 ,5-a]pyridine (24) 5-benzyl-5-(4-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1 ,5-a]pyridine,
(25) 7-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1 ,5-a]pyridine,
(26) 7-(p-carbamoylphenyl)-5,6,7,8-tetrahydroimidazo[1 ,5-a]pyridine,
(27) 5-(p-cyanophenyl)-5,6J,8-tetrahydroimidazo[1 ,5-a]pyridine (=Fadrozol).
The compounds of formula I as defined in EP-A 236 940. These are especially the compounds of formula I
Figure imgf000015_0001
wherein R and R0, independently of one another, are each hydrogen or lower alkyl, or R and R0 at adjacent carbon atoms, together with the benzene ting to which they are bonded, form a naphthalene or tetrahydronaphthalene ring; wherein Ri is hydrogen, lower alkyl, aryl, aryl-lower alkyl or lower alkenyl; R2 is hydrogen, lower alkyl, aryl, aryl-lower alkyl, (lower alkyl, aryl or aryl-lower alkyl)-thio or lower alkenyl, or wherein Ri and R2 together are lower alkylidene or C4 -C6 alkylene; wherein W is 1-imidazolyl, 1 -(1 ,2,4 or 1 ,3,4)-triazolyl, 3-pyridyl or one of the mentioned heterocyclic radicals substituted by lower alkyl; and aryl within the context of the above definitions has the following meanings: phenyl that is unsubstituted or substituted by one or two substituents from the group lower alkyl, lower alkoxy, hydroxy, lower alkanoyloxy, nitro, amino, halogen, trifluoromethyl, cyano, carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl, N,N-di-lower alkylcarbamoyl, lower alkanoyl, benzoyl, lower alkylsulfonyl, sulfamoyl, N- lower alkylsulfamoyl and N,N-di-lower alkylsulfamoyl; also thienyl, indolyl, pyridyl or furyl, or one of the four last-mentioned heterocyclic radicals monosubstituted by lower alkyl, lower alkoxy, cyano or by halogen; and pharmaceutically acceptable salts thereof.
Individual compounds from that group that may be given special mention are:
( ) 4-[alpha-(4-cyanophenyl)-1-imidazolylmethyl]-benzonitrile,
(2) 4-[alpha-(3-pyridyl )-1-imidazolyImethyl]-benzonitrile,
(3) 4-[alpha-(4-cyanobenzyl)-1 -imidazolylmethylj-benzonitrile, (4) 1-(4-cyanophenyl)-1-(1-imidazolyl)-ethylene,
(5) 4-[alpha-(4-cyanophenyl)-1 -(1 ,2,4-triazolyl)methyl]-benzonitrile, (6) 4-[alpha-(4-cyanophenyl)-3-pyridylmethyl]-benzonitrile.
The compounds of formula I as defined in EP-A-408 509. These are especially the compounds of formula I
Figure imgf000016_0001
wherein Tetr is 1- or 2-tetrazolyl that is unsubstituted or substituted in the 5-position by lower alkyl, phenyl-lower alkyl or by lower alkanoyl; R and R2, independently of one another, are each hydrogen; lower alkyl that is unsubstituted or substituted by hydroxy, lower alkoxy, halogen, carboxy, lower alkoxycarbonyl, (amino, lower alkylamino or di- lower alkylamino)-carbonyl or by cyano; lower alkenyl, aryl, heteroaryl, aryl-lower alkyl, C3 -C6 cycloalkyl, C3 -C6 cycloalkyl-lower alkyl, lower alkylthio, arylthio or aryl-lower alkylthio; or Ri and R2 together are straight-chained C4 -C6 alkylene that is unsubstituted or substituted by lower alkyl, or are a group -(CH 2)m -1 ,2-phenylene-(CH2)n - wherein m and n, independently of one another, are each 1 or 2 and 1 ,2-phenylene is unsubstituted or substituted in the same way as phenyl in the definition of aryl below, or are lower alkylidene that is unsubstituted or mono- or di-substituted by aryl; and R and R0, independently of one another, are each hydrogen or lower alkyl; or R and R0 together, located at adjacent carbon atoms of the benzene ring, are a benzo group that is unsubstituted or substituted in the same way as phenyl in the definition of aryl below; aryl in the above definitions being phenyl that is unsubstituted or substituted by one or more substituents from the group consisting of lower alkyl, lower alkoxy, hydroxy, lower alkanoyloxy, nitro, amino, halogen, trifluoromethyl, carboxy, lower alkoxycarbonyl, (amino, lower alkylamino or di-lower alkylamino)-carbonyl, cyano, lower alkanoyl, benzoyl, lower alkylsulfonyl and (amino, lower alkylamino or di-lower alkylamino)-sulfonyl; heteroaryl in the above definitions being an aromatic heterocyclic radical from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, tria.zolyl, tetrazolyl, furanyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, triazinyl, indolyl, isoindolyl, benzimidazolyl, benzotriazolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzoxadiazolyϊ, benzothiadiazolyl, quinolyl and isoquinolyl that is unsubstituted or substituted in the same way as phenyl in the definition of aryl above; and pharmaceutically acceptable salts thereof.
Individual compounds from that group that may be given special mention are: (1 ) 4-(2-tetrazolyl)methyl-benzonitrile, , (2) 4-[α-(4-cyanophenyl )-(2-tetrazolyl )methyl]-benzonitrile, .
(3) 1 -cyano-4-(1 -tetrazolyl)methyl-naphthalene,
(4) 4-[α-(4-cyanophenyl)-(1 -tetrazolyl)methyl]-benzonitrile.
The compounds of formula I as defined in European Patent Application No. 91810110.6. These are especially the compounds of formula I
Figure imgf000017_0001
wherein X is halogen, cyano, carbamoyl, N-lower alkylcarbamoyl, N-cycloalkyl-lower alkylcarbamoyl, N,N-di-lower alkylcarbamoyl, N-arylcarbamoyl, hydroxy, lower alkoxy, aryl-lower alkoxy or aryloxy, wherein aryl is phenyl or naphthyl, each of which is unsubstituted or substituted by lower alkyl, hydroxy, lower alkoxy, halogen and/or by. trifluoromethyl; Y is a group -CH2 -A wherein A is 1-imidazolyl, 1-(1 ,2,4-triazolyl), 1- (1 ,3,4-triazolyl), 1-(1 ,2,3-triazolyl), 1-(1 ,2,5-triazolyl), 1 -tetrazolyl or 2-tetrazolyl, or Y is hydrogen, R^ and R1f independently of one another, are each hydrogen, lower alkyl or a group -CH2 -A as defined for Y, or R^ and R2 together are --(CH2)n - wherein n is 3, 4 or 5, with the proviso that one of the radicals Y, Ri and R2 is a group -CH2 -A, with the further proviso that in a group -CH2 ~A as a meaning of Ri or R2, A is other than 1- imidazolyl when X is bromine, cyano or carbamoyl, and with the proviso that in a group CH.2 -A as a meaning of Y, A is other than 1-imidazolyl when X is halogen or lower alkoxy, Ri is hydrogen and R2 is hydrogen or lower alkyl, and pharmaceutically acceptable salts thereof.
Individual compounds from that group that may be given special mention are: (1) 7-cyano-4-[1-(1 ,2,4-triazoIyl)methyl]-2,3-dimethylbenzofuran, (2) 7-cyano-4-(1-imidazolylmethyl)-2,3-dimethylbenzofuran,
(3) 7-carbamoyl-4-(1 -imidazolylmethyl)-2,3-dimethylbenzofuran,
(4) 7-N-(cyclohexyImethyl)carbamoyl-4-(1-imidazolylmethyl)-2,3-dimethyIbenzofuran.
The compounds of formula I as defined in Swiss Patent Application 1339/90-7.
These are especially the compounds of formula
Figure imgf000018_0001
wherein the dotted line denotes an additional bond or no additional bond, Az is imidazolyl, triazolyl or tetrazolyl bonded via a ring nitrogen atom, each of those radicals being unsubstituted or substituted at carbon atoms by lower alkyl or by aryl-lower alkyl, Z is carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl, N,N-di-lower alkylcarbamoyl, N-arylcarbamoyl, cyano, halogen, hydroxy, lower alkoxy, aryl-lower alkoxy, aryloxy, lower alkyl, trifluoromethyl or aryl-lower alkyl, and Ri and R2, independently of one another, are each hydrogen, lower alkyl, lower alkoxy, hydroxy, halogen or trifluoromethyl; aryl being phenyl or naphthyl each of which is unsubstituted or substituted by one or two substituents from the group consisting of lower alkyl, lower alkoxy, hydroxy, halogen and trifluoromethyl; with the proviso that neither Z nor R2 is hydroxy in the 8-position, and pharmaceutically acceptable salts thereof.
Individual compounds from that group that may be given special mention are: (1) 6-cyano-1-(1-imidazolyl)-3,4-dihydronaphthalene, (2) 6-cyano-1 -[1 -(1 ,2,4-triazoIyl)]-3,4-dihydronaphthalene, (3) 6-chloro-1-(1-imidazoIyl)-3,4-dihydronaphthalene, (4) 6-bromo-1 -(1 -imidazolyI)-3,4-dihydronaphthalene. The compounds of formula I as defined in Swiss Patent Application 3014/90-0.
These are especially the compounds of formula I
Figure imgf000019_0001
wherein Z is a five-membered nitrogen-containing heteroaromatic ting selected from the group 5-isothiazolyl, 5-thiazolyl, 5-isoxazolyl, 5-oxazolyl, 5-(1 ,2,3-thiadiazolyl), 5-(1 ,2,3- oxadiazolyl), 3-(1 ,2,5-thiadiazolyl), 3-(1 ,2,5-oxadiazolyl), 4-isothiazolyl, 4-isoxazolyl, 4- (1 ,2,3-thiadiazolyl), 4-(1 ,2,3-oxadiazolyl), 2-(1 ,3,4-thiadiazolyl), 2-(1 ,3,4-oxadiazolyl), 5- (1,2,4-thiadiazolyl) and 5-(1,2,4-oxadiazolyl); R and R0 are hydrogen; or R and R0 together are a benzo group that is unsubstituted or substituted by lower alkyl, lower alkoxy, hydroxy, halogen or by trifluoromethyl; Ri is hydrogen, hydroxy, chlorine or fluorine; R3 is hydrogen; R2 is hydrogen, lower alkyl or phenyl that is unsubstituted or substituted by lower alkyl, lower alkoxy, hydroxy, halogen, trifluoromethyl or by cyano; or RT and R2 together are methylidene; or R2 and R3 together are -(CH2)3 --; or Ri and R2 and R3 together are a group =CH-(CH2)2~ wherein the single bone is linked to the benzene ring; X is cyano; and X may also be halogen when R2 and R3 together are — (CH2)3 - or R-i and Ri and R3 together are a group =CH-(CH2)2 --; and pharmaceutically acceptable salts thereof.
Individual compounds from that group that may be given special mention are: (1) 4-[α-(4-cyanophenyl)-α-hydroxy-5-isothiazolylmethyl]-benzonitrile. (2) 4-[α-(4-cyanophenyl)-5-isothiazolylmethyl]-benzonitrile, (3) 4-[ -(4-cyanophenyl)-5-thiazolylmethyl]-benzonitrile,
(4) 1 -(4-cyanophenyl)-1 -(5-thiazolyI)-ethylene,
(5) 6-cyano-1 -(5-isothiazolyl )-3,4-dihydronaphthalene,
(6) 6-cyano-1 -(5-thiazolyl)-3,4-dihydronaphthalene.
The compounds of formula VI as defined in Swiss Patent Application 3014/90-0.
These are especially the compounds of formula VI
Figure imgf000020_0001
wherein Z is a five-membered nitrogen-containing heteroaromatic ring selected from the group 5-isothiazolyl, 5-thiazolyl, 5-isoxazolyl, 5-oxazolyl, 5-(1 ,2,3-thiadiazolyl). 5-(1 ,2,3- oxadiazolyl) 3-(1 ,2,5-thiadiazolyl), 3-(1 ,2,5-oxadiazolyl), 4-isothiazolyl. 4-isoxazolyl, 4- (1 ,2,3-thiadiazolyl), 4-(1 ,2,3-oxadiazolyI), 2-(1 ,3,4-thiadiazolyI), 2-(1 ,3,4-oxadiazolyI), 5- (1 ,2,4-thiadiazolyl) and 5-(1 ,2,4-oxadiazolyl); R and R0 are each hydrogen; or R and R0 together are a benzo group that is unsubstituted or substituted by lower alkyl, lower alkoxy, hydroxy, halogen or by trifluoromethyl; Ri is hydrogen, hydroxy, chlorine or fluorine; R3 is hydrogen; R2 is hydrogen, lower alkyl or phenyl that is unsubstituted or substituted by lower alkyl, lower alkoxy, hydroxy, halogen, trifluoromethyl, aryl-lower alkoxy or by aryloxy; or R-i and R2 together are methylidene, and W2 is halogen, hydroxy, lower alkoxy, aryl-lower alkoxy or aryloxy; aryl in each case being phenyl that is unsubstituted or substituted by lower alkyl, lower alkoxy, hydroxy, halogen or by trifluoromethyl; and pharmaceutically acceptable salts thereof.
Individual compounds from that group that may be given special mention are: bis(4,4'-bromophenyl)-(5-isothiazolyl)methanol, bis(4,4'-bromophenyl)-(5-isothiazolyl)methane, bis(4,4'-bromophenyl)-(5-thiazoIyl)methanol, bis(4,4'-bromophenyl)-(5-thiazolyl)methane. The compounds of formula I as defined in Swiss Patent Application 3923/90-4.
These are especially the compounds of formula
Figure imgf000020_0002
wherein Z is imidazolyl, triazolyl, tetrazolyl, pyrrolyl, pyrazolyl, indolyl, isoindolyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl. triazinyl, quinolinyl or isoquinolinyl, all those radicals being bonded via their heterocyclic rings and all those radicals being unsubstituted or substituted by lower alkyl, hydroxy, lower alkoxy, halogen or by trifluoromethyl: RT and R2, independently of one another, are each hydrogen or lower alkyl; or R! and R2 together are C3 -C4 alkylene, or a benzo group that is unsubstituted or substituted as indicated below for aryl; R is hydrogen, lower alkyl, aryl or heteroaryl, and X is cyano, carbamoyl, N-lower alkylcarbamoyl, N,N-di-lower alkylcarbamoyl, N, N-lower alkylenecarbamoyl; N, N-lower alkylenecarbamoyl interrupted by -0-, -S-- or --NR"-, wherein R" is hydrogen, lower alkyl or lower alkanoyl; N- cycloalkylcarbamoyl, N-(lower alkyl-substituted cycloalkyl)-carbamoyI, N-cycIoalkyl-lower alkylcarbamoyl, N-(lower alkyl-substituted cycloalkyl)-lower alkylcarbamoyl, N-aryl-lower alkylcarbamoyl, N-arylcarbamoyl, N-hydroxycarbamoyl, hydroxy, lower alkoxy, aryl-lower alkoxy or aryloxy; and wherein X is also halogen when Z is imidazolyl, triazolyl, tetrazolyl, pyrrolyl, pyrazolyl, indolyl, isoindolyl, benzimidazolyl, benzopyrazolyl or benzotriazolyl; wherein aryl is phenyl or naphthyl, these radicals being unsubstituted or substituted by from 1 to 4 substituents from the group consisting of lower alkyl, lower alkenyl, lower alkynyl, lower alkylene (linked to two adjacent carbon atoms), C3 -C8 cycloalkyl, phenyl- lower alkyl, phenyl; lower alkyl that is substituted in turn by hydroxy, lower alkoxy, phenyl- lower alkoxy, lower alkanoyloxy, halogen, amino, lower alkylamino, di-lower alkylamino, mercapto, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl, N,N-di-lower alkylcarbamoyl and/or by cyano; hydroxy; lower alkoxy, halo-lower alkoxy, phenyl-lower alkoxy, phenoxy, lower alkenyloxy, halo-lower alkenyloxy, lower alkynyloxy, lower alkylenedioxy (linked to two adjacent carbon atoms), lower alkanoyloxy, phenyl-lower alkanoyloxy, phenylcarbonyloxy, mercapto, lower alkylthio, phenyl-lower alkylthio, phenylthio, lower alkylsulfinyl, phenyl- lower alkylsulfinyl, phenylsulfinyl, lower alkylsulfonyl, phenyl-lower alkylsulfonyl, phenylsulfonyl, halogen, nitro, amino, lower alkylamino, C3 -C8 cycloalkylamino, phenyl- lower alkylamino, phenylamino, di-lower alkylamino, N-lower alkyl-N-phenylamino, N- lower alkyl-N-phenyl-lower alkylamino; lower alkyleneamino or lower alkyleneamino interrupted by -0-, -S- or ~NR"~ (wherein R" is hydrogen, lower alkyl or lower alkanoyl); lower alkanoylamino, phenyl-lower alkanoylamino, phenylcarbonylamino, lower alkanoyl, phenyl-lower alkanoyl, phenylcarbonyl, carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl, N,N-di-Iower alkylcarbamoyl, N, N-lower alkylenecarbamoyl; N, N-lower alkylenecarbamoyl interrupted by -0-, -S-- or ~NR"~, wherein R" is hydrogen, lower alkyl or lower alkanoyl; N-cycloalkylcarbamoyl, N-(lower alkyl-substituted cycloalkyl)-carbamoyl, N-cycloalkyl-Iower alkylcarbamoyl, N-(lower alkyl- substituted cycloalkyl)-lower alkylcarbamoyl, N-hydroxycarbamoyl, N-phenyl-lower alkylcarbamoyl, N-phenylcarbamoyl, cyano, sulfo, lower alkoxysulfonyl, sulfamoyl, N- lower alkylsulfamoyl, N,N-di-lower alkylsulfamoyl and N-phenylsuIfamoyl; the phenyl groups occurring in the substituents of phenyl and naphthyl in turn being unsubstituted or substituted by lower alkyl, lower alkoxy, hydroxy, halogen and/or by trifluoromethyl; wherein heteroaryl is indolyl, isoindolyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzo[b]furanyl, benzo[b]thienyl, benzoxazolyl or benzothiazolyl, those radicals being unsubstituted or substituted by from 1 to 3 identical or different substituents selected from lower alkyl, hydroxy, lower alkoxy, halogen, cyano and trifluoromethyl; and pharmaceutically acceptable salts thereof.
Those compounds are especially the compounds of formula I whereto Z is 1-imidazolyl, 1- (1 ,2,4-triazolyl), 1-(1 ,3,4-triazolyl), 1-(1 ,2,3-triazolyl), 1 -tetrazolyl, 2-tetrazoIyl, 3-pyridyl, 4- pyridyl, 4-pyrimidyl, 5-pyrimidinyl or 2-pyrazinyl; Ri and R2, independently of one another, are each hydrogen or lower alkyl; or R.-i and R2 together are 1 ,4-butylene or a benzo group; R is lower alkyl; phenyl that is unsubstituted or substituted by cyano, carbamoyl, halogen, lower alkyl, trifluoromethyl, hydroxy, lower alkoxy or by phenoxy; or benzotriazolyl or benzo[b]furanyl, the last two radicals being unsubstituted or substituted by from 1 to 3 identical or different substituents selected from lower alkyl, halogen and cyano; and X is cyano or carbamoyl; and wherein X is also halogen when Z is 1- imidazolyl, 1-(1 ,2,4-triazolyl), 1-(1 ,3,4-triazoIyl), 1-(1 ,2,3-triazolyl), 1-tetrazolyl 2-tetrazolyl; and pharmaceutically acceptable salts thereof.
Individual compounds that may be given special mention here are:
(1 ) 4-[α-4-cyanophenyl)-α-fluoro-1-(1 ,2,4-triazolyl)methyl]-benzonitrile,
(2) 4-[α-(4-cyanophenyI)-α-fluoro-(2-tetrazolyl)methyl]-benzonitrile, (3) 4-[ -(4-cyanophenyl)-α-fluoro-(1 -tetrazolyl)methyl]-benzonitrile,
(4) 4-[α-(4-cyanophenyl)-α-fluoro-(1-imidazolyl)methyl]-benzonitrile,
(5) 1 -methyI-6-[α-(4-chlorophenyl)-α-fluoro-1 -(1 ,2,4-triazolyl)methyl]-benzotriazole,
(6) 4-[ -(4-cyanophenyl)- -fIuoro-1 -(1 ,2,3-triazolyl)methyl]-benzo nitrile, (7) 7-cyano-4-[α-(4-cyanophenyl)-α-fluoro-1 -(1 ,2,4-triazolyl)methy l]-2,3-dimethylbenzo[b]furan,
(8) 4-[α-(4-bromophenyl)-α-fluoro-1 -(1 ,2,4-triazolyl)methyl]-benzo nitrile,
(9) 4-[ -(4-cyanophenyl)-α-fluoro-(5-pyrimidyl)methyl]-benzonitrile, (10) 4-[α-(4-bromophenyl)-α-fluoro-(5-pyrimidyl)methyl]-benzonitrile,
(11 ) 4-[α-(4-cyanophenyl)- -fluoro-(3-pyridyl)methyl]-benzonitrile,
(12) 7-bromo-4-[α-(4-cyanophenyl)-α-fluoro-(1 -imidazolyl)methyl]-2, 3- dimethylbenzo[b]furan,
(13) 7-bromo-4-[ -(4-cyanophenyl)- -fluoro-1 -(1 ,2,4-triazolyl)methyl]-2,3- dimethylbenzo[b]furan,
(14) 4-[α-(4-cyanophenyI)-α-fluoro-(5-pyrimidyl)methyl]-benzonitrile, (15) 4-[α-(4-bromophenyl)-α-fluoro-(5-pyrimidyl)methyl]-benzonitrile,
(16) 4-[ -(4-cyanophenyl)-1 -(1 ,2,3-triazolyl)methyl]-benzonitrile,
(17) 2,3-dimethyl-4-[α-(4-cyanophenyl)-1 -(1 ,2,4-triazolyl)methyl]-7-cyano-benzo[b]furan, (18) 4-[ -(4-cyanophenyl)-(5-pyrimidyl)methyl]-benzonitrile,
(19) 4-[α-(4-bromophenyl)-(5-pyrimidyl)methyl]-benzonitrile,
(20) 2,3-dimethyl-4-[α-(4-cyanophenyl)-(1-imidazolyl)methyl]-7-bromo-benzo[b]furan,
(21 ) 2,3-dimethyl-4-[α-(4-cyanophenyl)-1-(1 ,2,4-triazoIyl)methyl]-7-bromo-benzo-[b]furan.
The compounds of formula I as defined in EP-A-114 033. These are especially the compounds of formula I
Figure imgf000023_0001
wherein R1 is hydrogen, R2 is hydrogen, sulfo, Ci -C7 alkanoyl or Ci -C7 alkanesulfonyl and R3 is hydrogen, or wherein R-, is Ci -C12 alkyl, C2 -C12 alkenyl, C2 -C7 alkynyl, C3 -Cι0 cycloalkyl, C3 -C10 cycloalkenyl, C33 -C6 cycloalkyl-Ci -C4 alkyl, C3 -C6 cycloalkyl-C2 -C4 alkenyl or C3 -C6 cycloalkenyl-C-) -C4 alkyl, R2 is hydrogen, C-, -C7 alkyl, sulfo, Ci -C7 alkanoyl or CΪ -C7 alkanesulfonyl and R3 is hydrogen or ^ -C7 alkyl, and salts of those compounds.
Individual compounds from that group that may be given special mention are: (1) 1-(4-aminophenyl)-3-methyl-3-azabicycIo[3.1.0]hexane-2,4-dione, (2) 1-(4-aminophenyl)-3-n-propyl-3-azabicyclo[3.1.0]hexane-2,4-dione,
(3) 1-(4-aminophenyl)-3-isobutyl-3-azabicyclo[3.1.0]hexane-2,4-dione,
(4) 1-(4-aminophenyl)-3-n-heptyl-3-azabicyclo[3.1.0]hexane-2,4-dione,
(5) 1-(4-aminophenyl)-3-cyclohexylmethyl-3-azabicyclo[3.1.0]hexane-2,4-dione.
The compounds of formula I as defined in EP-A-166 692. These are especially the compounds of formula I
Figure imgf000023_0002
wherein Ri is hydrogen, alkyl having from 1 to 12 carbon atoms, alkenyl having from 2 to 12 carbon atoms, lower alkynyl, cycloalkyl or cycloalkenyl each having from 3 to 10 carbon atoms, cycloalkyl-lower alkyl having from 4 to 10 carbon atoms, cycloalkyl-lower alkenyl having from 5 to 10 carbon atoms, cycloalkenyl-lower alkyl having from 4 to 10 carbon atoms, or aryl having from 6 to 12 carbon atoms or aryl-lower alkyl having from 7 to 15 carbon atoms, each of which is unsubstituted or substituted by lower alkyl, hydroxy, lower alkoxy, acyloxy, amino, lower alkylamino, di-lower alkylamino, acylamino amino or by halogen, R2 is hydrogen, lower alkyl, sulfo, lower alkanoyl or lower alkanesulfonyl, sulfonyl, R3 is hydrogen or lower alkyl and R4 is hydrogen, lower alkyl, phenyl or phenyl substituted by ~N(R2)(R3), and salts thereof, radicals described as "lower" containing up to and including 7 carbon atoms.
Individual compounds from that group that may be given special mention are: (1 ) 1-(4-aminophenyl)-3-n-propyl-3-azabicyclo[3.1.1 ]heptane-2,4-dione, (2) 1-(4-aminophenyl)-3-methyl-3-azabicyclo[3.1.1 ]heptane-2,4-dione,
(3) 1-(4-aminophenyl)-3-n-decyl-3-azabicyclo[3.1.1 ]heptane-2,4-dione,
(4) 1-(4-aminophenyl)-3-cyclohexyl-3-azabicyclo[3.1.1 ]heptane-2,4-dione,
(5) 1-(4-aminophenyl)-3-cyclohexylmethyl-3-azabicyclo[3.1.1 ]heptane-2,4-dione.
The compounds of formula I as defined in EP-A-356 673. These are especially the compounds of formula I
Figure imgf000024_0001
wherein W (α) is a 2-naphthyl or 1-anthryl radical, wherein each benzene ring is unsubstituted or substituted by a substituent selected from halogen, hydroxy, carboxy, cyano and nitro; or (.beta.) is 4-pyridyl, 2-pyrimidyl or 2-pyrazinyl, each of those radicals being unsubstituted or substituted by a substituent selected from halogen, cyano, nitro, C, -C4 alkoxy and C2 -C5 alkoxycarbonyl; and pharmaceutically acceptable salts thereof.
Individual compounds from that group that may be given special mention are:
(1) 5-(2'-naphthyl)-5,6,7,8-tetrahydroimidazo[1 ,5-a]pyridine,
(2) 5-(4'-pyridyI)-5,6,7,8-tetrahydroimidazo[1 ,5-a]pyridine. The compounds of formula I or la as defined in EP-A-337 929. These are especially the compounds of formula l/la
Figure imgf000025_0001
wherein R-i is hydrogen, methyl, ethyl, propyl, propenyl, isopropyl, butyl, hexyl, octyl, decyl, cyclopentyl, cyclohexyl, cyclopentylmethyl, cyclohexylmethyl or benzyl, R2 is benzyloxy, 3-bromo-, 4-bromo-, 4-chloro-, 2,3-, 2,4-, 4,5- or 4,6-dichloro-benzyloxy, and R3 is cyano; C2 -C10 alkanoyl that is unsubstituted or mono- or poly-substituted by halogen, methoxy, amino, hydroxy and/or by cyano; benzoyl that is unsubstituted or substituted by one or more substituents from the group halogen, CT -C alkyl, methoxy, amino, hydroxy and cyano; carboxy, (methoxy, ethoxy or butoxy)-carbonyl, carbamoyl, N- isopropylcarbamoyl, N-phenylcarbamoyl, N-pyrrolidylcarbonyl, nitro or amino; and salts thereof.
Individual compounds from that group that may be given special mention are:
1 ) 4-(2,4-dichlorobenzyloxy)-3-[1 -(1 -imidazolyl)-butyl]-benzonitrile,
2) (4-(4-bromobenzyloxy)-3-[1 -(1-imidazolyl )-butyl]-phenyl pentyl ketone, 3) 4-(4-bromobenzyIoxy)-3-[1-(1-imidazolyl)-butyl]-benzanilide, 4) 4-(4-bromobenzyloxy)-3-[1-(1-imidazolyl)-butyl]-benzoic acid,
5) 3-(2,4-dichlorobenzyloxy)-4-[1 -(1 -imidazolyl)-butyl]-benzonitrile,
6) 3-(2,4-dichlorobenzyloxy)-4-[1-(1-imidazolyl)-butyl]-benzoic acid methyl ester, 7) 3-(2,4-dichlorobenzyloxy)-4-[1-(1-imidazolyl)-butyl]-benzoic acid,
8) 3-(3-bromobenzyloxy)-4-[1 -(1 -imidazolyl )-butyl]-benzonitrile, 9) 4-(3-bromobenzyloxy)-3-[1-(1-imidazolyl)-butyl]-benzonitrile,
10) 3-(4-bromobenzyIoxy)-4-[1 - midazolyl)-butyl]-benzoic acid,
11) 3-(4-bromobenzyloxy)-4-[1- midazolyl)-butyl]-benzanilide,
12) 3-(4-bromobenzyloxy)-4-[1- midazolyl)-butyl]-phenyI pentyl ketone,
13) 4-(4-bromobenzyloxy)-3-[1- midazolyl)-butyl]-benzonitrile,
14) 3-(4-bromobenzyIoxy)-4-[1- midazolyl)-butyl]-benzonitrile,
15) 4-nitro-2-[1-(1-imidazolyl)-butyl]-phenyl-(2,4-dichlorobenzyl) ether,
16) 4-amino-2-[1-(1-imidazolyl)-butyl]-phenyl-(2,4-dichlorobenzyI) ether,
17) (2,4-dichlorobenzyl)-[2-(1-imidazolyl-methyl)-4-nitrophenyl]ether.
The compounds of formula I as defined in EP-A-337 928. These are especially the compounds of formula I
Figure imgf000026_0001
wherein Ri is hydrogen, methyl, ethyl, propyl, propenyl, isopropyl, butyl, hexyl, octyl, decyl, cyclopentyl, cyclohexyl, cyclopentylmethyl, cyclohexylmethyl or benzyl, R2 is hydrogen, halogen, cyano, methyl, hydroxymethyl, cyanomethyl, methoxymethyl, pyrrolidinylmethyl, carboxy, (methoxy, ethoxy or butoxy)-carbonyl, carbamoyl, N- isopropylcarbamoyl, N-phenylcarbamoyl, N-pyrroIidylcarbonyl; C2 -C10 alkanoyl that is unsubstituted or mono- or poly-substituted by halogen, methoxy, ethoxy, amino, hydroxy and/or by cyano; or benzoyl that is unsubstituted or substituted by one or more substituents from the group halogen, Ci -C4 alkyl, methoxy, ethoxy, amino, hydroxy and cyano, R3 is hydrogen, benzyloxy, 3-bromo-, 4-bromo-, 4-chloro-, 2,3-, 2,4-, 4,5- or 4,6- dichlorobenzyloxy, and X is ~CH=N~; -CH=N(~0)-or --S-; and salts thereof.
Individual compounds from that group that may be given special mention are: -imidazolyl)-butyl]-thiophene-2-carbonitrile, -imidazolyl)-butyl]-thiophene-4-carbonitrile, -imidazolyl )-butyl]-4-bromo-thiophene, -imidazolyl)-butyl]-5-bromo-thiophene, -imidazolyl)-butyl]-2-thienyl pentyl ketone,
Figure imgf000026_0003
-imidazolyl)-butyl]-2-thienyl ethyl ketone,
7) 5-(4-chlorobenzyloxy)-4-[1 -(1 -imidazolyl)-pentyl]-pyridine-2-carbonitrile,
8) 3-(4-chlorobenzyloxy )-4-[1-(1-imidazolyl)-pentyl]-pyridine-2-carbonitrile,
9) 3-(4-chlorobenzyloxy)-4-[1 -(1 -imidazoiyl)-pentyl]-pyridine-N-oxide,
10) 3-(4-chlorobenzyloxy)-4-[1 -(1 -imidazolyl)-pentyl]-pyridine.
The compounds of formula I as defined in EP-A-340 153. These are especially the compounds of formula I
Figure imgf000026_0002
wherein Ri is hydrogen, methyl, ethyl, propyl, propenyl, isopropyl, butyl, hexyl, octyl, decyl, cyclopentyl, cyclohexyl, cyclopentylmethyl, cyclohexylmethyl or benzyl, and R2 is a radical from the group methyl, ethyl, propyl, benzyl, phenyl and ethenyl that is substituted by hydroxy, cyano, methoxy, butoxy, phenoxy, amino, pyrrolidinyl, carboxy, lower alkoxycarbonyl or by carbamoyl; or R2 is formyl or derivatised formyl that can be obtained by reaction of the formyl group with an amine or amine derivative from the group hydroxylamine, O-methylhydroxylamine, O-ethylhydroxylamine, O-allylhydroxylamine, O- benzylhydroxylamine, O-4-nitrobenzyloxyhydroxylamine, 0-2,3,4,5,6- pentafluorobenzyloxyhydroxylamine, semicarbazide, thiosemicarbazide, ethylamine and aniline; acetyl, propionyl, butyryl, valeryl, caproyl; benzoyl that is unsubstituted or substituted by one or more substituents from the group halogen, Ci -C4 -alkyl, methoxy, amino, hydroxy and cyano; carboxy, (methoxy, ethoxy or butoxy)carbonyl, carbamoyl, N- isopropylcarbamoyl, N-phenylcarbamoyl or N-pyrrolidylcarbonyl; and salts thereof.
Individual compounds from that group that may be given special mention are:
(1) 4-(1-(1-imidazolyl)-butyl)-benzoic acid methyl ester,
(2) 4-(1-(1-imidazolyI)-butyl)-benzoic acid butyl ester, (3) 4-(1-(1-imidazolyl)-butyl)-phenyl-acetonitrile,
(4) 4-(1-(1-imidazolyl)-butyl)-benzaldehyde, (5) 4-(1-(1-imidazolyl)-buty!)-benzyl alcohol, {4-[1-(1-imidazolyl)-butyl]-phenyl }-2-propyl ketone, (7) 4-[1-(1-imidazolyl)-butyl]-phenyl propyl ketone, (8) 4-[1-(1-imidazolyl)-butyl]-phenyl butyl ketone, (9) 4-[1-(1-imidazolyl)-butyl]-phenyl pentyl ketone, (10) 4-[1 -(1 -imidazolyl)-butyl]-phenyl hexyl ketone.
The compounds of formula I as defined in DE-A-4 014 006. These are especially the compounds of formula I
Figure imgf000027_0001
wherein A is an N-atom or a CH radical and W is a radical of the formula
Figure imgf000028_0001
wherein X is an oxygen or a sulfur atom or a -CH=CH- group and Y is a methylene group, an oxygen or a sulfur atom and Z is a ~(CH2)n - group wherein n=1 , 2 or 3 and either R3 in W is a hydrogen atom and Ri and R2, independently of one another, are each a hydrogen atom, a Ci - to C-ι0 alkyl group or a C3 - to C7 cycloalkyl group, or R2 is as defined under a) and Ri together with R3 forms a ~(CH2)m - group wherein m=2, 3, or 4, and their pharmaceutically acceptable addition salts with acids.
Individual compounds from that group that may be given special mention are:
(1 ) 5-[1 -(1 -imidazolyl)-butyl]-1 -indanone,
(2) 7-[1 -(1 -imidazolyl)-butyl]-1 -indanone,
(3) 6-[1-(1-imidazolyl)-butyl]-1 -indanone,
(4) 6-(1 -imidazoIyl)-6,7,8,9-tetrahydro-1 H-benz[e]inden-3(2H)-one, (5) 2-[1 -(1 -imidazolyl)-butyl]-4,5-dihydro-6-oxo-cyclopenta[b]-thiophene, (6) 6-[1-(1-imidazolyl)-butyl]-3,4-dihydro-2H-naphthaIen-1-one, (7) 2-[1-(1-imidazolyl)-butyl]-6,7-dihydro-5H-benzo[b]thiophen-4-one,
(8) 6-[1 -(1 -imidazolyl)-butyl]-2H-benzo[b]furan-3-one,
(9) 5-[cyclohexyl-(1 -imidazolyI)-methyl]-1 -indanone, (10) 2-[1-(1-imidazolyl)-butyl]-4,5-dihydro-6H-benzo[b]thiophen-7-one, (11 ) 5-[1 -(1 -imidazo!yl)-1 -propyl-butyl]-1 -indanone, (12) 2-[1-(1-imidazolyl)-butyl]-4,5-dihydro-6H-benzo[b ]thiophen-7-one,
(13) 2-[1 -(1 -imidazolyl)-butyl]-4,5-dihydro-6-oxo-cyclopenta[b]-thiophene,
(14) 5-(1-imidazolylmethyl)-1 -indanone, (15) 5-[1 -(1 ,2,4-triazolyl)-methyl]-1 -indanone.
The compounds of formula I as disclosed in DE-A-3 926 365. These are especially the compounds of formula I
Figure imgf000029_0001
wherein W' is a cyclopentylidene, cyclohexylidene, cycloheptylidene or 2-adamantylidene radical, X is the grouping -CH=CH--, an oxygen or a sulfur atom, and Y and Z, independently of one another, are each a methine group (CH) or a nitrogen atom, and their pharmaceutically acceptable addition salts with acids.
Individual compounds from that group that may be given special mention are:
(1 ) 4-[1-cyclohexylidene-1-(imidazolyl)-methyl]-benzonitrile,
(2) 4-[1-cyclopentylidene-1-(imidazolyl)-methyl]-benzonitrile,
(3) 4-[1-cycloheptylidene-1 -(imidazolyl )-methyl]-benzonitrile,
(4) 4-[2-adamantylidene-1-(imidazolyl)-methyl]-benzonitrile,
(5) 4-[1 -cyclohexylidene-1 -(1 ,2,4-triazolyl)-methyl]-benzonitrile, (6) 4-[1-cyclopentylidene-1-(1 ,2,4-triazolyl)-methyl]-benzonitrile,
(7) 4-[1 -cycloheptylidene-1 -(1 ,2,4-triazolyl)-methyl]-benzonitrile,
(8) 4-[2-adamantylidene-1-(1 ,2,4-triazolyl )-methyl]-benzonitrile,
(9) 4-[1 -cyclohexylidene-1 -(1 , 2, 3-triazolyl)-methyl]-benzonitrile,
(10) 4-[1 -cyclopentylidene-1 -(1 ,2,3-triazolyl)-methyl]-benzonitrile,
(11 ) 5-[cyclohexylidene-1-imidazolylmethyl]-thiophene-2-carbonitrile.
The compounds of formula I as defined in DE-A-3 740 125. These are especially the compounds of formula I
Figure imgf000029_0002
wherein X is CH or N, R-i and R2 are identical or different and are each phenyl or halophenyl, and R3 is C -C4 alkyl; Ci -C4 alkyl substituted by CN, Ci -C4 alkoxy, benzyloxy or by C1 -C alkoxy-(mono-, di- or tri-)ethyleneoxy; Ci -C4 alkoxy, phenyl; phenyl that is substituted by halogen or by cyano; a C5 -C cycloalkyl group that is optionally condensed by benzene, or is thienyl, pyridyl or 2- or 3-indolyl; and acid addition salts thereof.
An individual compound from that group that may be given special mention is: 2,2-bis(4-chlorophenyl)-2-(1 H-imidazol-1 -yl)-1 -(4-chIorobenzoyI-amino) ethane.
The compounds of formula I as defined in ΞP-A-293 978. These are especially the compounds of formula I
Figure imgf000030_0001
pharmaceutically acceptable salts and stereochemically isomeric forms thereof, wherein - -A-, =A2 -A3 =A4 - is a divalent radical selected from «CH=N--CH=CH~, -CH=N-CH=N- and -CH=N-N=CH~, R is hydrogen or Ci -C6 alkyl; Ri is hydrogen, C -C10 alkyl, C3 -C7 cycloalkyl, Ar-t, Ar
Figure imgf000030_0002
alkyl, C2 -C6 alkenyl or C2 -C6 alkynyl: R2 is hydrogen; Ci -C10 alkyl that is unsubstituted or substituted by Aη ; C3 -C7 cycloalkyl, hydroxy, C-i -C6 alkoxy, Ar1f C2 -C6 alkenyl, C2 -C6 alkynyl, C3 -C7 cycloalkyl, bicyclo[2.2.1]heptan-2-yl, 2,3- dihydro-1 H-indenyl, 1,2,3,4-tetrahydronaphthyl, hydroxy; C2 -C6 alkenyloxy that is unsubstituted or substituted by Ar2 ; C2 -C6 alkynyloxy; pyrimidyloxy; di(Ar2)methoxy, (1- Ci -C4 alkyl-4-piperidinyl)oxy, Ci -C10 alkoxy; or C-i -C10 alkoxy that is substituted by halogen, hydroxy, C-i -C6 alkyloxy, amino, mono- or di-(C1 -C6 alkyl)amino, trifluoromethyl, carboxy, d -C6 alkoxycarbonyl, Ar.sub.I, Ar2 -0-, Ar2 ~S~, C3 -C7 cycloalkyl, 2,3- dihydro-1 ,4-benzodioxinyl, 1H-benzimidazolyl, Ci -C4 alkyl-substituted 1 H-benzimidazolyl, (1 ,1'-biphenyl)-4-yl or by 2,3-dihydro-2-oxo-1 H-benzimidazolyl; and R3 is hydrogen, nitro, amino, mono- or di-(C1 -C6 alkyl)amino, halogen, d -C6 alkyl, hydroxy or d -C6 alkoxy; wherein Ar! is phenyl, substituted phenyl, naphthyl, pyridyl, aminopyridyl, imidazolyl, triazolyl, thienyl, halothienyl, furanyl, C-, -C6 alkylfuranyl, halofuranyl or thiazolyl; wherein Ar2 is phenyl, substituted phenyl or pyridyl; and wherein "substituted phenyl" is phenyl that is substituted by up to 3 substituents in each case selected independently of one another from the group consisting of halogen, hydroxy, hydroxymethyl, trifluoromethyl, Ci -C6 alkyl, Ci -C6 alkoxy, C-i -C6 alkoxycarbonyl, carboxy, formyl, hydroxyiminomethyl, cyano, amino, mono- and di-(C! -C6 aIkyl)amino and nitro.
Individual compounds from that group that may be given special mention are: (1 ) 6-[(1 H-imidazol-1 -yl)-phenylmethyl]-1 -methyl-1 H-benzotriazole,
(2) 6-[(4-chlorophenyl)(1 H-1 , 2,4-triazol-1-yl)methyl]-1 -methyl-1 H-benzotriazole.
The compounds of formula II as defined in EP-A-250 198, especially (1 ) 2-(4-chlorophenyl)-1 ,1-di(1 ,2,4-triazol-1-ylmethyl)ethanol, (2) 2-(4-fluorophenyl)-1 ,1-di(1 ,2,4-triazol-1-ylmethyl)ethanol,
(3) 2-(2-fluoro-4-trifluoromethylphenyl)-1 ,1-di(1 ,2,4-triazol-1-ylmethyl)ethanol, (4) 2-(2,4-dichlorophenyl)-1 ,1-di(1 ,2,4-triazol-1-ylmethyl)ethanol,
(5) 2-(4-chlorophenyl)-1 ,1-di(1 ,2,4-triazol-1-ylmethyl)-ethanol, (6) 2-(4-fluorophenyl)-1 ,1-di(1 ,2,4-triazol-1-yl-methyl)ethanol.
The compounds of formula I as defined in EP-A-281 283, especially
(1 R*2R*)-6-fluoro-2-(4-fluorophenyl)-1 ,2,3,4-tetrahydro-1 -(1 H-1 ,2,4-triazo 1-1 -yl- methyl)naphthalene, (1 R *,2R * )-6-fluoro-2-(4-fluorophenyl)-1 ,2,3,4-tetrahydro-1 -(1 H-imidazolylmethyl)- . naphthalene,
(1 R*,2R*)- and (1 R*,2S*)-2-(4-fluorophenyl)-l,2,3,4-tetrahydro-1 -(1 H-1 ,2,4-triazol-1 - yimethyl)naphthalene-6-carbonitrile,
(1 R*,2R*)- and (1 R*,2S*)-2-(4-fluorophenyl)-l,2,3,4-tetrahydro-1-(1H- imidazolylmethyl)naphthalene-6-carbonitrile,
(1 R*,2R*)- and (1 R*,2S*)-1 ,2,3,4-tetrahydro-1-(1 H-1 ,2,4-triazol-1 -ylmethyl)-naphthalene-
2,6-dicarbonitrile,
(1 R*,2R*)- and (1 R*,2S*)-1 ,2,3,4-tetrahydro-1-(1 H-imidazol-1 -ylmethyl)naphthalene-2,6- dicarbonitrile, (1 R*,2S*)-2-(4-fluorophenyl)-1 ,2,3,4-tetrahydro-1-(5-methyl-1 H-imidazolyl-methyl
)naphthalene-6-carbonitrile.
The compounds of formula I as defined in EP-A-296 749, especially
2,2'-[5-(1 H-1 ,2,4-triazol-1-ylmethyl)-1 ,3-phenylene]di(2-methylpropiononitrile), 2,2'-[5-(imidazol-1-ylmethyl)-1 ,3-phenylene]di(2 methylpropiononitrile),
(3) 2-[3-(1-hydroxy-1-methylethyl)-5-(5H-1 ,2,4-triazol-1-yImethyl)phenyl]-2- methylpropiononitrile,
2,2'-[5-dideuterio(1 H-1 ,2,4-triazol-1 -yl)methyl-1 ,3-phenylene]di(2-trideuteriomethyl-3,3,3- trideuteriopropiononitrile), 2,2'-[5-dideuterio(1 H-1 ,2,4-triazoI-1-yl)methyl-3-phenylene]di(2methylpropiononitrile).
The compounds of formula I as defined in EP-A-299 683, especially (Z)-α-(1 ,2,4-triazol-1 -ylmethyl)stilbene-4,4'-dicarbonitrile, (Z)-4'-chloro-α-(1 ,2,4-triazol-1-ylmethyl)stilbene-4-carbonitrile, (Z)-α-(1 ,2,4-triazol-1 -ylmethyl)-4'-(trifluoromethyl)stilbene-4-carbonitrile, (E)-.beta.-fluoro-α-(1 ,2,4-triazol-1-ylmethyl)stilbene-4,4'-dicarbonitrile, (Z)-4'-fluoro-α-(imidazoI-1-ylmethyI)stilbene-4-carbonitrile, (Z)-2\ 4'-dichIoro-α-(imidazol-1-ylmethyl)stilbene-4-carbonitrile, (Z)-4'-chloro-α-(imidazol-1 -ylmethyl )stilbene-4-carbonitrile, (Z)-α-(imidazol-l -ylmethyl)stilbene-4,4'dicarbonitrile,
(Z)-α-(5-methylimidazol-1-ylmethyl)stilbene-4,4'-dicarbonitrile, (Z)-2-[2-(4-cyanophenyl)-3-(1 ,2,4-triazol-1-yl)propenyl]pyridine-5-carbonitrile.
The compounds of formula I as defined in EP-A-299 684, especially (1) 2-(4-chlorobenzyl)-2-fluoro-1 ,3-di(1 ,2,4-triazol-1-yl)propane,
(2) 2-fluoro-2-(2-fluoro-4-chIorobenzyl)-1 ,3-di(1 ,2,4-triazol-1 -yI)propane,
(3) 2-fluoro-2-(2-fluoro-4-trifluoromethyIbenzyl)-1 ,3-di(1 ,2,4-triazol-1-yl)propane, (4) 3-(4-chlorophenyl)-1-(1 ,2,4-triazol-1-yl)-2-(1 ,2,4-triazol-1-ylmethyl)butan-2-ol, (5) 2-(4-chloro-α-fluorobenzyl)-1 ,3-di(1 ,2,4-triazol-1 -yl)propan-2-ol, (6) 2-(4-chlorobenzyl)-1 ,3-bis(1 ,2,4-triazol-1 -yl)propane,
(7) 4-[2-(4-chlorophenyl)-1 ,3-di(1 ,2,4-triazol-1-ylmethyl)ethoxymethyl]-benzonitrile,
(8) 1-(4-fluorobenzyl)-2-(2fluoro-4-trifluoromethylphenyl)-1 ,3-di(1 ,2,4-triazol-1-yl)-propan- 2-ol,
(9) 2-(4-chlorophenyl)-1-(4-fluorophenoxy)-1 ,3-di(1 ,2,4-triazoI-1-yl)propan-2-ol, (10) 1-(4-cyanobenzyl )-2-(2,4-difluorophenyl)-1 ,3di(1 ,2,4-triazol-1-yl)propan-2-ol,
(11) 2-(4-chlorophenyl)-1 -phenyl-1 ,3-di(1 ,2,4-triazol-1 -yl)propan-2-ol.
The compounds as defined in claim 1 of EP-A-316 097, especially
1,1-dimethyl-8-(1H-1,2,4-triazol-1-ylmethyl)-2(1 H)-naphtho[2,1-b]furanone, 1 ,2-dihydro1 ,1-dimethyl-2-oxo-8-(1 H-1 ,2,4-triazol-1-yImethyl)naphtho[2,1-b]-furan-7- carbonitrile,
1 ,2-dihydro-1 ,1-dimethyl-2-oxo-8-(1 H-1 ,2,4-triazol-1-ylmethyl)naphtho[2,1-b]-furan-7- carboxamide,
1 ,2-dihydro-1 , 1 -dimethyl-2-oxo-8-[di(1 H-1 ,2,4-triazol-1 -yl)methyl]naphtho[2, 1 -b]-furan-7- carbonitrile.
The compounds of formula I as defined in EP-A-354 689, especially (1) 4-[2-(4-cyanophenyl)-3-(1 ,2,4-triazol-1-yl)propyl]benzonitrile, (2) 4-[1-(4-chIorobenzyl)-2-(1 ,2,4-triazol-1-yl)ethyl]benzonitrile, (3) 4-[2-(1 ,2,4-triazol-1-yl)-1-(4-trifluoromethyl]benzyl)ethyl]benzonitrile,
(4) 4-[2-(1 ,2,4-triazol-1-yl)-1-(4-[trifluoromethoxy]benzyl)ethyl]benzonitrile .
The compounds of formula (1 ) as defined in EP-A-354 683, especially (1) 6-[2-(4-cyanophenyl)-3-(1,2,4-triazol-1-yl)-propyl]nicotinonitrile, (2) 4-[1 -(1 ,2,4-triazol-1 -yl-methyl)-2-(5-[trifluoromethyl]pyrid-2-yl)ethyl]benzonitrile. Examples of steroidal aromatase inhibitors that may be mentioned are:
The compounds of formula I as defined in EP-A-181 287. These are especially the compounds of formula I
Figure imgf000033_0001
wherein R is hydrogen, acetyl, heptanoyl or benzoyl. An individual compound from that group that may be given special mention is: (1 ) 4-hydroxy-4-androstene-3,17-dione.
(ab) The compounds as defined in the claims of U.S. Pat. No. 4,322,416, especially 10- (2-propynyl )-oestr-4-ene-3,17-dione.
(ac) The compounds as defined in the claims of DE-A-3 622 841, especially 6- methyleneandrosta-1 ,4-diene-3,17-dione.
(ad) The compounds as defined in the claims of GB-A-2 17 1100, especially 4-amino- androsta-1 ,4,6-triene-3, 17-dione.
Also: (ae) androsta-1 ,4,6-triene-3,17-dione.
The content of the patent applications mentioned under (a) to (z) and (aa) to (ad), especially the subgroups of compounds disclosed therein and the individual compounds disclosed therein as examples, have been incorporated by reference into the disclosure of the present application.
The general terms used hereinbefore and hereinafter to define the compounds have the following meanings:
Organic radicals designated by the term "lower" contain up to and including 7, preferably up to and including 4, carbon atoms.
Acyl is especially lower alkanoyl. Aryl is, for example, phenyl or 1- or 2-naphthyl, each of which is unsubstituted or substituted by lower alkyl, hydroxy, lower alkoxy, lower alkanoyloxy, amino, lower alkylamino, di-lower alkylamino, lower alkanoylamino or by halogen.
Pharmaceutically acceptable salts of the above-mentioned compounds are, for example, pharmaceutically acceptable acid addition salts or pharmaceutically acceptable metal or ammonium salts.
Pharmaceutically acceptable acid addition salts are especially those with suitable inorganic or organic acids, for example strong mineral acids, such as hydrochloric acid, sulfuric acid or phosphoric acid, or organic acids, especially aliphatic or aromatic carboxylic or sulfonic acids, for example formic, acetic, propionic, succinic, glycolic, lactic, hydroxysuccinic, tartaric, citric, maleic, fumaric, hydroxymaleic, pyruvic, pheηylacetic, benzoic, 4-aminobenzoic, anthranilic, 4-hydroxybenzoic, salicylic, 4-aminosalicylic, pamoic, gluconic, nicotinic, methanesulfonic, ethanesulfonic, halobenzenesulfonic, p- toluenesulfonic, naphthalenesulfonic, sulfanilic or cyclohexylsulfamic acid; or with other acidic organic substances, for example ascorbic acid. Pharmaceutically acceptable salts may also be formed, for example, with amino acids, such as arginine or lysine.
Compounds containing acid groups, for example a free carboxy or sulfo group, can also form pharmaceutically acceptable metal or ammonium salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium, magnesium or calcium salts, also ammonium salts derived from ammonia or suitable organic amines. Special compounds include aliphatic, cycloaliphatic, cycloaliphatic-aliphatic or araliphatic primary, secondary or tertiary mono-, di- or poly-amines, such as lower alkylamines, for example di- or tri-ethylamine, hydroxy-lower alkylamines, for example 2-hydroxyethylamine, bis(2- hydroxyethyl)amine or tris(2-hydroxyethyl)amine, basic aliphatic esters or carboxylic acids, for example 4-aminobenzoic acid 2-diethylaminoethyl ester, lower alkyleneamines, for example 1-ethylpiperidine, cycloalkylamines, for example dicyclohexylamine, benzylamines, for example N,N'-dibenzylethylenediamine; also heterocyclic bases, for example of the pyridine type, for example pyridine, collidine or quinoline. If several acidic or basic groups are present, mono- or poly-salts can be formed. Compounds according to the invention having an acidic and a basic group may also be in the form of internal salts, i.e. in the form of zwitterions and another part of the molecule in the form of a normal salt.
In the case of the above-mentioned individual compounds the pharmaceutically acceptable salts are included in each case insofar as the individual compound is capable of salt formation. The compounds listed, including the individual compounds mentioned, both in free form and in salt form, may also be in the form of hydrates, or their crystals may include, for example, the solvent used for crystallisation. The present invention relates also to all those forms.
Many of the above-mentioned compounds, including the individual compounds mentioned, contain at least one asymmetric carbon atom. They can therefore occur in the form of R- or S-enantiomers and as enantiomeric mixtures thereof, for example in the form of a racemate. The present invention relates to the use of all those forms and to the use of all further isomers, and of mixtures of at least 2 isomers, for example mixtures of diastereoisomers or enantiomers which can occur when there are one or more further asymmetric centres in the molecule. Also included are, for example, all geometric isomers, for example cis- and trans-isomers, that can occur when the compounds contain one or more double bonds. The amount of the at least one aromatase inhibitor may be an amount equivalent to between at or about 0.25 mg to at or about 10.0 mg per day of anastrazole. A preferred amount may be at or about 0.5 mg per day of anastrazole. Preferably the aromatase inhibitors have a half-life of about 8 hours to about 4 days, more preferably a half-life of about 2 days. The inhibitor may be selected from non- steroidal and reversible and from steroidal irreversible aromatase inhibitors. More preferably the aromatase inhibitor is non-steroidal and reversible. Aromatase inhibitors such as anastrazole, ZN 1033, (Arimidex®), ietrozole, CGS 20267, (Femara®) and vorozole (Rivizor®) are selective Als, available for clinical use in North America and other parts of the world for treatment of postmenopausal breast cancer. These triazole (antifungal) derivatives are reversible, competitive Als, which are highly potent and selective.
DETAILED DESCRIPTION OF THE INVENTION
The following examples are included to illustrate the present invention and should not be •used to limit the claims. In every instance, an aromatase inhibitor (Al) is present in each daily unit dosage, although it may be administered separately. The Al may comprise an equivalent in a range from at or about 0.25 mg to at or about 10 mg per day of anastrazole. More preferably the amount is from at or about 0.5 mg per day to at or about 1 mg per day of anastrazole or its equivalent. Most preferably the amount is at or about 0.5 mg per day of anastrazole or its equivalent.
Example 1
Low Dose Triphasic Oral Contraceptive Formulation
The total number of days during which the progestin and estrogen combinations are administered daily is preferably 21. These are followed by 4 to 8 days which are free of hormone administration to approximate the natural 28-day menstrual cycle of the female. Day one of the cycle is defined as the first day of menstruation and the days are numbered sequentially thereafter until menstruation occurs again. The cycle usually lasts 28 days but it may be slightly longer or shorter. In actual practice, the placebo or any of the hormone containing tablets might contain nutritional supplements such as, for example, iron supplements, folic acid, calcium, etc. Thus, in a preferred regimen, phase one would commence sometime between day 1 and day 7 of the menstrual cycle and last 5 to 8 days but preferably 7 days, phase two would last 7 to 11 days, preferably 7 days, while phase three would last 3 to 7 days, preferably 7 days.
The contraceptive composition employed in the present invention comprises separate daily dosage units which are adapted for successive daily oral ingestion. The composition consists essentially of, as the first phase, 5 to 8 dosage units containing, in admixture with a pharmaceutically acceptable carrier, a combination of an estrogen in combination with a progestin and an aromatase inhibitor, followed by, as the second phase, 7 to 11 dosage units containing, a combination of estrogen and a progestin, and an aromatase inhibitor, followed by, as the third phase, 3 to 7 dosage units containing a combination of an estrogen and a progestin and an aromatase inhibitor, optionally followed by 4 to 8 dosage units free of estrogen and progestin. The estrogen daily dosage is kept constant in all three phases.
In this particular regimen, the daily dosage should be equal in contraceptive activity in each phase to a daily dosage of about 23 to 28 μg of 1 α-ethinylestradiol. The preferred dosage is one equal to a daily dosage of at or about 25 μg of 17α-ethinylestradiol.
As the progestin component, the progestin is preferably administered in a daily dosage in the first phase corresponding in progestogen activity to 0.25-0.75 mg of norethindrone per day, during the second phase a daily dosage corresponding in progestin activity to 0.25- 1.0 mg of norethindrone per day and during the third phase a daily dosage corresponding in progestin activity to 0.35-2.0 mg of norethindrone per day. It is an aspect of the present invention that the progestin dose should substantially increase from the first phase to the second phase to the third phase. The progestin is more preferably administered in a daily dosage in the first phase corresponding in progestin activity to 0.25-0.65 mg of norethindrone per day and most preferably 0.40-0.60 mg of norethindrone per day, during the second phase a daily dosage corresponding in progestin activity to 0.35-0.9 mg of norethindrone per day and most preferably 0.65-0.85 mg norethindrone per day, and during the third phase a daily dosage corresponding in progestin activity to 0.50-1.50 mg of norethindrone per day and most preferably 0.9-1.1 mg norethindrone per day. An example dose of norethindrone in the first phase is 0.50 mg, in the second phase is 0.75 mg and in the third phase is 1.0 mg. Where the progestin is norgestimate, it is preferably administered in a daily dosage in the first phase of 0.03-0.25 mg per day, during the second phase a daily dosage of 0.1-0.35 mg per day and during the third phase a daily dosage of 0.15-0.50 mg per day. Norgestimate is more preferably administered in a daily dosage in the first phase of 0.1- 0.22 mg per day and most preferably 0.15-0.20 mg per day, during the second phase a preferred daily dosage of 0.15-0.30 mg per day and most preferably 0.2-0.23 mg per day, and during the third phase a daily dosage of 0.20-0.40 mg per day and most preferably 0.23-0.3 mg per day. An example dose of norgestimate in the first phase is 0.180 mg, in the second phase is 0.215 mg and in the third phase is 0.250 mg.
The estrogen and progestin components are preferably administered together orally in a pharmaceutically acceptable nontoxic carrier, but they can also be administered separately or parenterally. In general, the effective agents are processed, together with the usual additives, vehicles and/or flavour-ameliorating agents normally employed in Galenic pharmacy, in accordance with generally accepted pharmaceutical practices. For the preferred oral administration, tablets, dragees, capsules, pills, suspensions or solutions are particularly suitable; for parenteral application, oily solutions such as, for example, sesame oil or castor oil solutions which can optionally additionally contain a diluent such as, for example, benzyl benzoate or benzyl alcohol. The at least one aromatase inhibitor may be included in the daily dosage units or it can be administered separately.
In the case of the preferred oral application, the three-phase combination-type contraceptives are preferably packaged in the form of a pharmaceutical kit or package in which the daily dosages are arranged for proper sequential administration. This invention also relates, therefore, to a pharmaceutical unit which contains combination-type contraceptives in dosage units in a synchronized, fixed sequence, wherein the sequence or arrangement of the dosage units corresponds to the stages of daily administration.
The pharmaceutical unit can be, e.g., in the form of a transparent package having dosage units arranged sequentially and consisting of the tablets for the first phase, followed by the tablets for the second phase, followed by the tablets for the third phase, and finally optionally followed by the placebos. A single tablet is to be taken each day over the period of the cycle.
The following is a more specific example of a suitable triphasic continuous combined oral contraceptive regimen. Triphasic regimen wherein the first phase comprises a tablet containing 0.180 mg of norgestimate, 25 μg EE, and an aromatase inhibitor at a daily dosage equivalent to from at or about 0.25 mg to at or about 5 mg of anastrazole, once a day for 7 days; in the second phase a tablet containing 0.215 mg of norgestimate, 25 μg EE, and an aromatase inhibitor at a daily dosage equivalent to from at or about 0.25 mg to at or about 5 mg of anastrazole once a day for 7 days; and in the third phase a tablet containing 0.250 mg of norgestimate, 25 μg EE, and an aromatase inhibitor at a daily dosage equivalent to from at or about 0.25 mg to at or about 5 mg of anastrazole; followed by 7 days of placebo tablets.
The aromatase inhibitor may be selected from those described previously and a suitable amount is incorporated into each dosage in accordance with the guidance provided earlier.
Example 2
Biphasic Oral Contraceptive Regimen
This regimen is a two-stage oral contraceptive system in which an unopposed estrogenic compound and an aromatase inhibitor is administered during a terminal portion of the first 7 day segment of the menstrual cycle, counting as day 1 the onset of menses. From day 2 to day 7, inclusive, of the menstrual cycle, an estrogenic compound at a daily dosage equivalent in estrogenic activity to about 0.01 to about 0.04 mg of 17α-ethinylestradiol and an aromatase inhibitor at a daily dosage equivalent to at or about 0.25 mg to at or about 5 mg of anastrazole, is administered to a female of childbearing age for contraception purposes. A second stage of this contraceptive regimen is commenced comprising daily administration of a dosage comprising a progestin alone or in combination with an estrogenic compound, which is continued to about day 28 of the menstrual cycle. The amount and type of aromatase inhibitor is selected in accordance with the earlier specified guidelines.
Example 3
Continuous Combined Monophasic Regimen
Twenty-eight tablets of an oral contraceptive regimen containing 0.15 mg desogestrel (13- ethyl-11-methylene-18,19-dinor-17α-pregn-4-en-20-yn-17-ol) and 0.03 mg ethinylestradiol (19-nor-17 α-pregna-1 ,3,5(10)-trien-20-yne-3,17,diol) are prepared. Inactive ingredients included in these tablets comprised Vitamin E, comstarch, pulvodone, cearic acid, collodoil silicon dioxide, lactose, hydroxypropyl methylcellulose, polyethylene glycol, titanium dioxide, talc and ferric oxide. The non-hormone containing green tablets comprise inactive ingredients consisting of lactose, pregelatinized starch, magnesium stearate, F.D. and C. Blue No. 1 Aluminum Lake, ferric oxide, hydroxypropyl methylcellulose, polyethylene glycol, titanium dioxide and talc.
In every instance, an additional dosage of aromatase inhibitor is added to the daily dosage of hormone described or it may be administered separately. The amount of aromatase inhibitor and the particular aromatase inhibitor are selected in accordance with the guidelines previously set out.
Example 4 Continuous Combined Triphasic Oral Contraceptive Regimen
Twenty-eight tablets, each containing norethinedrone, ethinylestradiol, and at least one aromatase inhibitor are prepared. In the first phase, each tablet contains 0.5 mg of norethindrone and 0.035 mg of ethinylestradiol. Inactive ingredients include lactose, magnesium stearate and pregelatinized starch. The next phase of tablets comprise 0.75 mg of norethindrone and 0.035 mg of ethinylestradiol. Inactive ingredients include F.D. & C. Yellow No. 6, lactose, magnesium stearate and pregelatizined starch. The third set of tablets comprising unit dosages of 1 mg of norethindrone and 0.035 mg of ethinylestradiol are prepared. Inactive ingredients include F.D. & C. Yellow No. 6, lactose, magnesium stearate and pregelatinized starch. A set of placebo tablets containing inert ingredients only comprise D. and C. Yellow No. 10 Aluminum Lake, F.D. & C. Blue No. 2 Aluminum Lake, lactose, magnesium stearate, microcrystalline cellulose and pregelatinized starch.
In every instance, an additional dosage of aromatase inhibitor is added to the daily dosage of hormone described or it may be administered separately. The amount of aromatase inhibitor and the particular aromatase inhibitor are selected in accordance with the guidelines previously set out.
Example 5
Continuous Combined Biphasic Oral Contraceptive Regimen Twenty-eight tablets are prepared as follows:
The first set of tablets contains 0.5 mg of norethindrone and 0.035 mg of ethinylestradiol. Inactive ingredients in these tablets include lactose, magnesium stearate and pregelatinized starch.
The next set of tablets comprises 1 mg of norethindrone and 0.035 mg of ethinylestradiol. Inactive ingredients include F.D. & C. Yellow No. 6, lactose, magnesium stearate and pregelatinized starch.
The next set of tablets contains only inert ingredients, having the formulation as described above.
In every instance, an additional dosage of aromatase inhibitor is added to the daily dosage of hormone described or it may be administered separately. The amount of aromatase inhibitor and the particular aromatase inhibitor are selected in accordance with the guidelines previously set out. Example 6
Monophasic Continuous Combined Oral Contraceptive Regimen
Twenty-one tablets are prepared, each containing 1 mg of norethindrone and 0.035 mg of ethinyl estradiol. Inactive ingredients include F.D. & C. Yellow No. 6, lactose, magnesium stearate and pregelatinized starch. A set of placebo tablets similar to those described above is also prepared.
In every instance, an additional dosage of aromatase inhibitor is added to the daily dosage of hormone described or it may be administered separately. The amount of aromatase inhibitor and the particular aromatase inhibitor are selected in accordance with the guidelines previously set out.
Example 7
Monophasic Continuous Combined Oral Contraceptive Regimen
A set of twenty-one tablets, each tablet containing 0.5 mg of norethindrone and 0.35 mg of ethinylestradiol is prepared. Inactive ingredients include lactose, magnesium stearate and pregelatinized starch. A set of placebo tablets similar to those described above are also prepared.
The above regimen includes the addition of an aromatase inhibitor to every daily dosage unit, with the amount of inhibitor and specific choice being determined in accordance with the guidelines set out previously.
Example 8
Monophasic Continuous Combined Oral Contraceptive Regimen
Twenty-one tablets containing the active ingredients 0.01 mg of levonorgestrel and 0.02 mg of ethinylestradiol are prepared. The inactive ingredients present in the tablets comprise cellulose, hydroxypropyl methylcellulose, iron oxide, lactose, magnesium stearate, polacrillin potassium, polyethylene glycol, titanium dioxide and wax E. In addition 7 placebo or inert tablets are prepared, each containing cellulose, F.D. & C. Blue No. 1 , hydroxypropyl methylcellulose, iron oxide, lactose, magenesium stearate, polacrillin potassium, polyethylene glycol, titanium dioxide and wax E.
In every instance, the unit dosages each include an aromatase inhibitor in an amount and the specific inhibitor is selected in accordance with the previously mentioned guidelines.
Example 11
The following regimen represents a new class of formulations called estrophasic. The estrophasic oral contraceptive phases in gradually increasing doses of estrogen, e.g., 20, 30, 35 meg ethinylestradiol with a low, constant dose of progestin (1 mg norethindrone acetate). The first low step comprises unit dosages for the first 5 days, the next step comprises unit dosages for the next 7 days and the last step comprises unit dosages for the last 9 days, for a total of 21 days. Seven days of no estrogen or progestin or aromatase inhibitor are then administered to the patient.
Every active unit dosage contains an aromatase inhibitor, the selection being made in accordance with the guidelines previously set out. Example 12
Transdermal Contraceptive Regimen
Transdermal forms of administration for contraceptives are well known and there are many commercial products available in the market. An example is that sold under the trade-mark Orthoevra. Orthoevra is a combination transdermal contraceptive patch with a contact surface area of 20 cm2. It contains 6.00 mg norelgestromin and 0.75 mg ethinylestradiol and releases 150 μg of norelgestromin and 20 μg of ethinylestradiol to the bloodstream per 24 hours. The patch comprises three layers. The backing layer is composed of a flexible film consisting of low density pigmented polyethylene outer layer and a polyester inner layer. This provides structural support and protects the middle adhesive layer from the environment. The middle layer contains polyisobutylene/polybutene adhesive, crospovidone, non-woven polyester fabric and laurel lactate as inactive components. The active components in this layer are the hormones norelgestromin and ethinylestradiol. The third layer is the release liner which protects the adhesive layer during storage and is removed just prior to application. It is a transparent polyethylene terethalate film with a polydimethyl cyloxane coating on the side that is in contact with the middle adhesive layer.
This regimen provides a 28 day cycle. A new patch is applied each week for three weeks providing a total of 21 total days. Week 4 is patchfree.
The patch is normally applied the first day of the woman's menstrual period or the first Sunday after the menstrual period begins. The patch is applied to clean, dry, intact healthy skin on the buttock, abdomen, upper outer arm or upper torso, in a place where it won't be rubbed by tight clothing. The patch cannot be placed on skin that is red, irritated or cut, nor should it be placed on the breasts.
Application of makeup, creams, lotions, powders to other topical products should not be applied to the skin where the patch is to be placed.
The aromatase inhibitor in this regimen can be administered in oral form and taken every day when a patch is in place or it may be incorporated into the patch. The choice and amount are as stated above.
Example 13
Cyclophasic Oral Contraceptive Regimen
Three-day phases of unit dosages of 17α-ethinylestradiol (EE) 0.035 mg, and norethindone (NET) 0.35 mg. Alternating with three-day phases of unit dosages ,of EE 0.035 mg and NET 0.75 mg for a total of 7 phases (21 days or 21 unit dosages) beginning and ending with the NET 0.5 mg combination. These phases are followed by a placebo for 7 days. The aromatase inhibitor is included in each unit dosage as set out earlier.
Example 14
Two-day phases (unit dosages of EE 0.035 mg and NET 0.5 mg) alternating with three- day phases of EE 0.035 mg and NET 0.35 mg, beginning and ending with the 0.5 mg combination are prepared for administration. Twenty-one days of unit doses are provided and the at least one aromatase inhibitor is administered simultaneously. Placebo or no pills are to be administered for 7 days thereafter.
Example 15
Two-day phases of unit dosages of EE 0.035 mg alternating with unit dosages of EE 0.035 mg and NET 0.75 mg, beginning and ending with the first unit dosage'and running for 22 days total are prepared for administration. Twenty-two days of unit doses are provided and the at least one aromatase inhibitor is administered simultaneously. Placebo or no pills are to be administered for 6 days thereafter.
Example 16
Two-day phases of unit dosages of EE 0.035 mg and NET 0.15 mg alternating with EE 0.035 and NET 0.35 mg and running for 24 days total followed by 4 days of placebo or no pills. The at least one aromatase inhibitor is administered each day and the 24 pills may be followed by 4 days of no pills or with placebo pills.
Example 17 Three-day phases and four-day phases of each of the above combinations as set forth in Examples 15 and 16, starting with either three or four-day phases and ending with the other are prepared for a total of 21 days, each including a suitable amount of the at least one aromatase inhibitor and ending with 7 days of no pills or placebo pills.
Example 18
Four-day and three-day phases are prepared, starting with a four-day unit dosage of 0.5 mg NET and 0.035 mg EE and ending with 0.75 mg NET and 0.035 mg EE are prepared for a total of 21 days, each including a suitable amount of the at least one aromatase inhibitor and ending with 7 days of no pills or placebo pills. Example 19
Three-day and four-day phases of formulations starting with a three-day phase of 0.035 mg NET with 0.035 mg EE and ending with a four-day phase of 0.5 mg NET and 0.035 mg EE are prepared for a total of 21 days, each including a suitable amount of the at least one aromatase inhibitor and ending with 7 days of no pills or placebo pills.
Example 20
Two-day alternating phases ending or beginning with a single three-day phase, using the unit dosage formulations set forth in Examples 13 and 14.
Example 21
Two-day phases of daily unit dosages comprising EE 0.025 mg and levonorgestrel (D- norgestrel) 0.05 mg alternating with two-day phases of daily unit dosages comprising EE
0.025 mg and levonorgestrel 0.075 mg are prepared for administration for 22 days. Each daily unit dose includes at least one aromatase inhibitor. There follows 6 days of placebo or no pills.
Example 22
Two-day phases of daily unit dosages comprising EE 0.025 mg and norgestimate 0.05 mg alternating with daily unit dosages comprising EE 0.025 mg and norgestimate 0.180 mg are prepared for administration for 21 days. Each daily unit dose includes at least one aromatase inhibitor. There follows 7 days of placebo or no pills..
Example 23 Three-day phases of daily unit dosages comprising EE 0.025 mg and norgestimate 0.09 mg alternating with daily unit dosages comprising EE 0.035 and norgestimate 0.05 mg are prepared for administration for 21 days. Each daily unit dose includes at least one aromatase inhibitor. There follows 7 days of placebo or no pills.
In the above examples, an aromatase inhibitor is included in every unit dosage, its selection being determined in accordance with the guidelines set out previously.
Example 24
Continuous Combined Monophasic Oral Contraceptive Regimen Twenty-one tablets are prepared comprising 0.075 mg gestodene and 0.020 mg ethinylestradiol. Other substances present in the tablets comprise lactose monohydrate, maize starch, polyvidone 25,000 magnesium stearate, sucrose, polyvidone 700,000, macrogal 6,000, calcium carbonate, talc and montanglycol wax. No placebo or non- hormone containing tablets are provided as part of this regimen. An aromatase inhibitor is included on each day that the 21 tablets containing the active ingredients are taken. The selection of the aromatase inhibitor is determined in accordance with the guidelines set out previously.
Example 25 Continuous Combined Monophasic Oral Contraceptive Regimen
Twenty-tablets are prepared, each containing 0.1 mg levonorgestrel and 0.02 mg ethinylestradiol. Other substances present in the tablets include lactose monohydrate, maize starch, maize starch (modified), polyvidone 25,000, magnesium stearate, sucrose, polyvidone 700,000, macrogal 6,000, calcium carbonate, talc, glycerol 85%, ferric oxide pigment yellow, ferric oxide pigment red, titanium dioxide, montanglycol wax.
In addition, an aromatase inhibitor selected in accordance with the guidance previously provide is included for administration with each of the 21 unit dosages. The regimen does not include the 7 days of placebo. The 21 pills are consumed and 7 days of no unit dosage is part of the regimen.
Example 26
Triphasic Continuous Combined Oral Contraceptive Regimen
Twenty-one tablets are prepared as follows: 6 tablets each with 0.05 mg gestodene and 0.03 mg ethinylestradiol, 5 tablets each with 0.07 mg gestodene and 0.04 mg ethinylestradiol, 10 tablets each with 0.10 mg gestodene and 0.03 mg ethinylestradiol.
Other substances included in the pills comprise the following: lactose monohydrate, maize starch, polyvidone 25,000, sodium calcium edetate, magnesium stearate, sucrose, polyvidone 700,000, macrogal 6,000, calcium carbonate, talc, glycerol 85%, titanium dioxide, ferric oxide pigment yellow, ferric oxide pigment chocolate brown, montanglycol wax. This formulation does not involve a placebo and 7 days are observed when no unit dosage containing active ingredient is taken. On every day when a tablet is taken, there is also provided an aromatase inhibitor the selection of which is determined by the guidance previously provided.
Example 27
Continuous Combined Monophasic Oral Contraceptive Regimen Twenty-one tablets are prepared, each containing 0.15 mg desogestrel and 0.02 mg ethinylestradiol. A set of 2 green pills are prepared comprising placebo and an additional 5 pills are prepared comprising 0.01 mg ethinylestradiol. The placebo tablets comprise inert ingredients of the type set out above. The last set of tablets containing ethinylestradiol also include such ingredients. In addition to the above, an aromatase inhibitor is included for administration on each of the days when a tablet comprising an active ingredient is administered. The selection and amount is determined in accordance with the guidelines previously set out.
The active ingredients are usually compounded with the chosen carrier and in for example the case of a tablet form, placed in a tablet molding apparatus to form the tablets which are subsequently packaged in accordance with the chosen regimen.
In the oral form of the formulation, the package would have the daily dosages arranged for proper sequential administration. Data indications may be provided on the packaging. The packaging may be a tube or box or a strip. The box may be circular, square, or otherwise shaped with the tablets for example being accommodated separately therein for ease of administration. Date indications may appear adjacent each tablet corresponding with the days on which each tablet is to be taken. Some indication of the sequence in which the tablets are to be taken preferably appears on the packaging regardless of its form.
pharmaceutical formulations
The pharmaceutical compositions that can be prepared according to the invention are compositions for enteral, such as peroral or rectal administration, also for transdermal or sublingual administration, and for parenteral, for example intravenous, subcutaneous and intramuscular, administration. Suitable unit dose forms, especially for peroral and/or sublingual administration, for example dragees, tablets or capsules, comprise preferably from approximately 0.01 mg to approximately 20 mg, especially from approximately 0.1 mg to approximately 10 mg, of the combination of the above-mentioned compounds or of a pharmaceutically acceptable salt thereof, together with pharmaceutically acceptable carriers. The preferred form of administration is oral. The proportion of active ingredient in such pharmaceutical compositions is generally from approximately 0.001 % to approximately 60%, preferably from approximately 0.1 % to approximately 20%.
Suitable excipients for pharmaceutical compositions for oral administration are especially fillers, such as sugars, for example lactose, saccharose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, and binders, such as starches, for example corn, wheat, rice or potato starch, gelatin, tragacanth, methylcellulose and/or hydroxypropylcellulose, disintegrators, such as the above-mentioned starches, also carboxymethyl starch, cross- linked polyvinylpyrrolidone, agar, alginic acid or a salt thereof, such as sodium alginate, and/or cellulose, for example in the form of crystals, especially in the form of microcrystals, and/or flow regulators and lubricants, for example silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, cellulose and/or polyethylene glycol.
Dragee cores can be provided with suitable, optionally enteric, coatings, there being used inter alia concentrated sugar solutions which may comprise gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, or coating solutions in suitable solvents or solvent mixtures, or, for the preparation of enteric coatings, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate.
Other orally administrable pharmaceutical compositions are dry-filled capsules consisting of gelatin, and also soft sealed capsules consisting of gelatin and a plasticiser, such as glycerol or sorbitol. The dry-filled capsules may contain the active ingredient in the form of granules, for example in admixture with fillers, such as lactose, binders, such as starches, and/or glidants, such as talc or magnesium stearate, and, if desired, stabilisers. In soft capsules, the active ingredient is preferably dissolved or suspended in suitable oily excipients, such as fatty oils, paraffin oil or liquid polyethylene glycols, to which stabilisers and/or anti-bacterial agents may also be added. There may also be used capsules that are easily bitten through, in order to achieve by means of the sublingual ingestion of the active ingredient that takes place as rapid an action as possible.
Suitable rectally or transvaginally administrable pharmaceutical compositions are, for example, suppositories that consist of a combination of the active ingredient with a suppository base. Suitable suppository bases are, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols. There may also be used gelatin rectal capsules, which contain a combination of the active ingredient with a base material. Suitable base materials are, for example, liquid triglycerides, polyethylene glycols or paraffin hydrocarbons.
Suitable formulations for transdermal administration comprise the active ingredient together with a carrier. Advantageous carriers include absorbable pharmacologically acceptable solvents that serve to facilitate the passage through the skin of the host. Transdermal systems are usually in the form of a bandage that comprises a support, a supply container containing the active ingredient, if necessary together with carriers, optionally a separating device that releases the active ingredient onto the skin of the host at a controlled and established rate over a relatively long period of time, and means for securing the system to the skin.
Suitable for parenteral administration are especially aqueous solutions of an active ingredient in water-soluble form, for example in the form of a water-soluble salt, and also suspensions of active ingredient, such as corresponding oily injection suspensions, there being used suitable lipophilic solvents or vehicles, such as fatty oils, for example sesame oil, or synthetic fatty acid esters, for example ethyl oleate, or triglycerides, or aqueous injection suspensions that comprise viscosity-increasing substances, for example sodium carboxymethylcellulose, sorbitol and/or dextran, and, optionally, stabilisers.
Dyes or pigments may be added to the pharmaceutical compositions, especially to the tablets or dragee coatings, for example for identification purposes or to indicate different doses of active ingredient.
Pharmaceutical compositions containing compounds of the invention may further comprise pharmaceutically acceptable carriers and be in either solid or liquid form. Solid preparations include powders, tablets, dispersible granules, capsules, etc. The carrier may also be one or more substances, which act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, or tablet disintegrating agents as well as encapsulating materials. Suitable carriers include magnesium carbonate, magnesium stearate, talc, lactose, sugar, peptin, dextrin, starch, methylcellulose, sodium carboxylmethylcellulose, and the like. Liquid form preparations include solutions, which are suitable for oral or parenteral administration, or suspensions and emulsions suitable for oral administration.
Sterile water solutions of the active component or sterile solutions of the active components in solvents comprising water, ethanol, or propylene glycol are examples of liquid preparations suitable for parenteral administration. Aqueous solutions for oral administration can be prepared by dissolving the active compound in water and adding suitable flavorants, coloring agents, stabilizers and thickening agents as required. Aqueous suspensions for oral use can be made by dispersing the active component in • water together with a viscous material such as a natural or synthetic gum, methylcellulose, sodium carboxymethyl-cellulose, and other suspending agents known to the pharmaceutical formulation art. Other solid dosage forms include topical dosage forms which include solutions, powders, fluid emulsions, fluid suspensions, semi-solids, ointments, pastes, creams, gels or jellies and foams; and parenteral dosage forms which include solutions, suspensions, emulsions or dry powder comprising an effective amount of estrogen and an aromatase inhibitor or estrogen and progestin and an aromatase inhibitor as taught in this invention.
Various conventional techniques for preparing pharmaceutical compositions including solutions, suspensions, tablets or caplets can be employed, as would be known to those skilled in the art and as is disclosed for example by Remington's Pharmaceutical Sciences, Mack Publishing Co., Part 8, Chapters 76-93, Pharmaceutical Preparations and Their Manufacture, pp. 1409-1677 (1985).
The pharmaceutical formulations may be provided in kit form containing preferably multiples of three unit dosages, each constituting a relatively dominant estrogenic activity phase and in a suitable form, for example, caplets or tablets. The kit may comprise a dial package or a foil strip as is well known in the art. The kit would typically contain an even number of doses for each phase arranged in an even number of relatively dominant estrogenic activity phases. Thus the unit dosages would be arranged in each package in multiples of six so that an even number of phases would be present in each package.
The term "unit dosage form" as used herein refers to physically discrete units suitable as unit dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The term "doses" as used herein broadly encompasses the term unit dosage form or dosage units as well as continuous dosing of compositions by depot or other methods.
The pharmaceutical compositions of the present invention can be prepared in a manner known per se, for example by means of conventional mixing, granulating, confectioning, dissolving or lyophilising processes. For example, pharmaceutical compositions for oral administration can be obtained by combining the active ingredient with solid carriers, optionally granulating a resulting mixture, and processing the mixture or granules, if desired or necessary after the addition of suitable excipients, to form tablets or dragee cores.
daily doses or an equivalent thereof
The daily doses of the present invention may be administered in any convenient form. Preferred, as set out earlier is a single daily tablet, but any other suitable form may be employed. The single tablet is preferred as it reduces the likelihood that the patient will get confused. The words "an equivalent thereof are meant to cover administrative forms that do not comprise daily doses, for example a transdermal form. Generally speaking, the formulations are prepared according to conventionally known procedures in accordance with the desired method of administration. Different amounts of the active ingredients may be required in different types of formulations but it is essential that the amount of estrogenically active substance and progestationally active substance be selected so as to provide the dose equivalency for the regimen as described above. The percentage of active ingredients may vary according to the potency of the hormone, the delivery system or method of administration and is chosen in accordance with conventional methods known in the art.
The estrogen and progestin compositions can be administered by way of any art recognized means as practiced in the pharmaceutical arts. For example, the estrogen and progestin alone or in combination may be so formulated so that it can be administered orally, via a skin patch for transdermal absorption, by intramuscular injection, contained within an inert matrix which is implanted within the body and in a depot state, or intravaginally in a matrix that slowly releases the active compositions (such implants are taught for example in U.S. Patents Nos. 4,957,119 and 5,088,505).
While the invention has been described with particular reference to certain embodiments thereof, it will be understood that changes and modifications may be made by those of ordinary skill in the art within the scope and spirit of the following claims. In the claims, the word "comprising" means "including the following elements (in the body), but not excluding others".

Claims

Claims:
1. A method for preventing pregnancy in females wherein breakthrough bleeding is substantially reduced in such females, which comprises administering to such females from at or about 20 to at or about 28 consecutive daily unit doses or an equivalent thereof, of a substance exhibiting estrogen activity, or a substance exhibiting progestin activity or both such substances, or combinations of such unit doses in amounts sufficient to prevent pregnancy in such females together with at least one aromatase inhibitor, followed by from at or about 2 to at or about 10 days where no such substance or aromatase inhibitor is administered.
2. A method for preventing pregnancy in females wherein mood disorders and/or emotional disorders are substantially reduced in such females, which comprises administering to such females from at or about 20 to at or about 28 consecutive daily unit doses or an equivalent thereof of a substance exhibiting estrogen activity, or a substance exhibiting progestin activity or both such substances, in amounts sufficient to prevent pregnancy in such females, together with at least one aromatase inhibitor, followed by from at or about 2 to at or about 10 days where no such substance or aromatase inhibitor is administered.
3. A contraceptive unit having at or about 20 to at or about 28 separate dosage units or an equivalent thereof, adapted for consecutive daily administration to a female wishing to prevent pregnancy, the daily dosage units each comprising a substance exhibiting estrogen activity, or a substance exhibiting progestin activity, or both such substances or combinations of such units in amounts sufficient to prevent pregnancy in females, together with at least one aromatase inhibitor, and a pharmaceutically acceptable carrier therefor, and wherein breakthrough bleeding is substantially reduced in such females.
4. A contraceptive unit having from at or about 20 to at or about 28 separate daily dosage units or an equivalent thereof, adapted for successive daily administration to a female wishing to prevent pregnancy, each daily dosage unit comprising a substance exhibiting estrogenic activity or a substance exhibiting progestin activity or both such substances, or combinations of such units, in amounts sufficient to prevent pregnancy in such females together with at least one aromatase inhibitor and a pharmaceutically acceptable carrier therefor, wherein mood disorder or emotional disorder symptoms are substantially reduced in such females.
5. A method as claimed in claim 1 or 2, wherein the estrogen is selected from 17α- ethinylestradiol, and esters and ethers thereof, natural estrogens and their esters, other synthetic estrogens and the progestin is selected from 17-hydroxyprogesterone esters and 19-nor-17-hydroxyprogesterone esters, 17α-ethinyltestosterone, 17α-ethinyl-19- nortestosterone and derivatives thereof, norethindrone, norethindrone acetate, D- norgestrel, Δ15 levonorgestrel, Δ15 levonorgestrel acetate, Δ15 levonorgestrel acetate oxime, D-17β-acetoxy-β-ethyl-17α-ethinylgon-4-en-3-one oxime (norgestimate), desogestrel, ethynodiol diacetate, dydrogesterone, medroxyprogesterone acetate, norethynodrel, allylestrenol, lynoestrenol, quingestranol acetate, medrogestone, norgestrienone, dimethisterone, ethisterone, cyproterone acetate, chlormadinone acetate, and magestrol acetate.
6. A method as claimed in claim 1 or 2, wherein the method comprises a continuous combined contraceptive method and the hormone combinations are selected from
Desogestrel and Ethinyl Estradiol, Ethynodiol Diacetate and Ethinyl Estradiol, Levonorgestrel and Ethinyl Estradiol, Norethindrone Acetate and Ethinyl Estradiol, Norethindrone and Ethinyl Estradiol, Norethindrone and Mestranol, Norgestimate and Ethinyl Estradiol, and Norgestrel and Ethinyl Estradiol.
7. A method as claimed in claim 1 or 2, wherein the progestin for use on its own as the contraceptive hormone may be selected from
Levonorgestrel, Medroxyprogesterone acetate, Norethindrone, and Norgestrel.
8. A method as claimed in claim 1 or 2, wherein the aromatase inhibitor(s) is present in each daily dose in an amount equivalent to between at or about 0.25 mg to at or about
10.0 mg of anastrazole.
9. A method as claimed in claim 1 or 2, wherein the aromatase inhibitor(s) is present in each daily dose in an amount equivalent to at or about 0.5 mg of anastrazole.
10. A method as claimed in claim 1 or 2, wherein the aromatase inhibitor is selected from aromatase inhibitors having a half-life of about 8 hours to about 4 days.
11. A method as claimed in claim 8, wherein the aromatase inhibitor is selected from aromatase inhibitors having a half-life of about 2 days.
12. A method as claimed in claim 8, wherein the aromatase inhibitor is selected from non-steroidal and reversible and from steroidal and irreversible aromatase inhibitors.
13. A method as claimed in claim 9, wherein the aromatase inhibitor is non-steroidal and reversible.
14. A method as claimed in claim 1 or 2, wherein the aromatase inhibitor is selected from anastrazole, vorozole, letrozole, fadrozole and xemestane.
15. A method as claimed in claim 1 or 2, wherein the method is a continuous combined monophasic contraceptive method and the daily unit doses comprise estrogen in an amount equivalent to at or about 0.02 mg to at or about 0.05 mg 17α-ethinylestradiol and progestin in an amount equivalent to at or about 0.5 mg to at or about 2.0 mg of norethindrone, and the at least one aromatase inhibitor is present in an amount equivalent to at or about 0.25 mg to at or about 10.0 mg per day of anastrazole.
16. A method as claimed in claim 1 or 2, wherein the method is a continuous combined biphasic regimen and the daily unit doses comprise estrogen in an amount equivalent to at or about 0.02 mg to at or about 0.05 mg 17α-ethinylestradiol and progestin in an amount equivalent to at or about 0.5 mg to at or about 1.0 mg of norethindrone, and the at least one aromatase inhibitor is present in an amount equivalent to at or about 0.25 mg to at or about 10.0 mg per day of anastrazole.
17. A method as claimed in claim 1 or 2, wherein the method is a continuous combined triphasic contraceptive method and the daily unit doses comprise estrogen in an amount equivalent to at or about 0.02 mg to at or about 0.05 mg 17α-ethinylestradiol and progestin in an amount equivalent to at or about 0.5 mg to at or about 1.0 mg of norethindrone, and the at least one aromatase inhibitor is present in an amount equivalent to at or about 0.25 mg to at or about 10.0 mg per day of anastrazole.
18. A method as claimed in claim 1 or 2, wherein the method is an interrupted contraceptive method and the daily unit doses comprise estrogen in an amount equivalent to at or about 0.02 mg to at or about 0.035 mg 17α-ethinylestradiol and progestin in an amount equivalent to at or about 0.35 mg to at or about 1.0 mg of norethindrone, and the at least one aromatase inhibitor is present in an amount equivalent to at or about 0.25 mg to at or about 10.0 mg per day of anastrazole.
19. A contraceptive unit as claimed in claim 3 or 4, wherein the estrogen is selected from 17α-ethinylestradiol, and esters and ethers thereof, natural estrogens and their esters, other synthetic estrogens and the progestin is selected from 17- hydroxyprogesterone esters and 19-nor-17-hydroxyprogesterone esters, 17α- ethinyltestosterone, 17α-ethinyl-19-nortestosterone and derivatives thereof, norethindrone, norethindrone acetate, D-norgestrel, Δ15 levonorgestrel, Δ15 levonorgestrel acetate, Δ15 levonorgestrel acetate oxime, D-17β-acetoxy-β-ethyI-17α- ethinylgon-4-en-3-one oxime (norgestimate), desogestrel, ethynodiol diacetate, dydrogesterone, medroxyprogesterone acetate, norethynodrel, allylestrenol, lynoestrenol, quingestranol acetate, medrogestone, norgestrienone, dimethisterone, ethisterone, cyproterone acetate, chlormadinone acetate, and magestrol acetate.
20. A contraceptive unit as claimed in claim 3 or 4, wherein the method comprises a continuous combined contraceptive method and the hormone combinations are selected from
Desogestrel and Ethinyl Estradiol, Ethynodiol Diacetate and Ethinyl Estradiol, Levonorgestrel and Ethinyl Estradiol, Norethindrone Acetate and Ethinyl Estradiol, Norethindrone and Ethinyl Estradiol, Norethindrone and Mestranol, Norgestimate and Ethinyl Estradiol, and Norgestrel and Ethinyl Estradiol.
21. A contraceptive unit as claimed in claim 3 or 4, wherein the progestin for use on its own as the contraceptive hormone may be selected from
Levonorgestrel,
Medroxyprogesterone acetate, Norethindrone, and Norgestrel.
22. A contraceptive unit as claimed in claim 3 or 4, wherein the aromatase inhibitor(s) is present in each daily dose in an amount equivalent to between at or about 0.25 mg to at or about 10.0 mg of anastrazole.
23. A contraceptive unit as claimed in claim 3 or 4, wherein the aromatase inhibitor(s) is present in each daily dose in an amount equivalent to at or about 0.5 mg of anastrazole.
24. A contraceptive unit as claimed in claim 3 or 4, wherein the aromatase inhibitor is selected from aromatase inhibitors having a half-life of about 8 hours to about 4 days.
25. A contraceptive unit as claimed in claim 22, wherein the aromatase inhibitor is selected from aromatase inhibitors having a half-life of about 2 days.
26. A contraceptive unit as claimed in claim 22, wherein the aromatase inhibitor is selected from non-steroidal and reversible and from steroidal and irreversible aromatase inhibitors.
27. A contraceptive unit as claimed in claim 23, wherein the aromatase inhibitor is non-steroidal and reversible.
28. A contraceptive unit as claimed in claim 3 or 4, wherein the aromatase inhibitor is selected from anastrazole, letrozole, fadrozole, vorozole and xemestane.
29. A contraceptive unit as claimed in claim 3 or 4, wherein the method is a continuous combined monophasic regimen and the daily unit doses comprise estrogen in an amount equivalent to at or about 0.02 mg to at or about 0.05 mg 17α-ethinylestradiol and progestin in an amount equivalent to at or about 0.5 mg to at or about 2.0 mg of norethindrone, and the at least one aromatase inhibitor is present in an amount equivalent to at or about 0.25 mg to at or about 10.0 mg per day of anastrazole.
30. A contraceptive unit as claimed in claim 3 or 4, wherein the method is a continuous combined biphasic regimen and the daily unit doses comprise estrogen in an amount equivalent to at or about 0.02 mg to at or about 0.05 mg 17α-ethinylestradiol and progestin in an amount equivalent to at or about 0.5 mg to at or about 1.0 mg of norethindrone, and the at least one aromatase inhibitor is present in an amount equivalent to at or about 0.25 mg to at or about 10.0 mg per day of anastrazole.
31. A contraceptive unit as claimed in claim 3 or 4, wherein the method is a continuous combined triphasic regimen and the daily unit doses comprise estrogen in an amount equivalent to at or about 0.02 mg to at or about 0.05 mg 17α-ethinylestradiol and progestin in an amount equivalent to at or about 0.5 mg to at or about 1.0 mg of norethindrone, and the at least one aromatase inhibitor is present in an amount equivalent to at or about 0.25 mg to at or about 10.0 mg per day of anastrazole.
32. A contraceptive unit as claimed in claim 3 or 4, wherein the method is an interrupted contraceptive regimen and the daily unit doses comprise estrogen in an amount equivalent to at or about 0.02 mg to at or about 0.035 mg 17α-ethinylestradioI and progestin in an amount equivalent to at or about 0.35 mg to at or about 1.0 mg of norethindrone, and the at least one aromatase inhibitor is present in an amount equivalent to at or about 0.25 mg to at or about 10.0 mg per day of anastrazole.
PCT/CA2003/000493 2002-04-03 2003-04-03 Female birth control method WO2003082336A1 (en)

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