METHODS OF INHIBITING GROWTH HORMONE EFFECTS

Abstract: A method of inhibiting effects of growth hormone comprising administering to a human in need thereof an effective amount of a compound having formula (I), wherein R<1> and R<3> are independently hydrogen, -CH3, (a), or (b), wherein Ar is optionally substituted phenyl; R<2> is selected from the group consisting of pyrrolidine, hexamethyleneimino, and piperidino; or a pharmaceutically acceptable salt of solvate thereof.

Description: METHODS OF INHIBITING GROWTH HORMONE EFFECTS Recent research concerning the effects of sex hormones on growth hormone secretion in males indicates that the stimulatory effect of testosterone upon the somatotropic axis is predicated upon its ability to be aromatized to estradiol. ( eissberger, J. Clin . Endocrm . , 76, 1993, 1407; Metzger, . Clir.. Endocrm . , 76, 1993, 1147' . For pre- pubertal, pubertal and adult males, it has been demonstrated that endogenous estrogens rathei than androgenε play a dominant role in regulating growth hormone secretions. 'Caruso-Nicoletti, J. Clin . Endocrm . , 6- , 1985, 896; Ho, J. Ci . Endocrm . , 64 , 1987, 51; see also references above It has recently been reported that the antiestrogen tamoxifen blocks the estradiol induced surge in growth hormone secretion in both adult and adolescent males. (Weissberger, J. Clin . Endocrm . , 76, 1993, 1407; Metzger, J. Clm . Endocrm . , 79, 1994, 513) . Current treatments for disorders associated with an excess of growth hormone are primarily restricted to surgical removal of all or part of the pituitary or irradiation thereof. One alternative is treatment with bromocriptme mesylate, a dopaminergic agonist, but siαe effects sucn as nausea, vomiting, postural hypotension, "cardiovascular collapse", visual ana auditor: nallucmations, and cutaneous livedo reticularis are problematic. This invention provides methods for inhibiting growth hormone effects comprising administering to a human in need therecf an effective amount of a compound of formula I (I) wherein P 1 and F- are independently hydrogen, -CH , C C II π -C- ( C -C alkyi. ^ or -C-Ar ^ whereιn Ar 1S opt i onally substituted phenyl; R 2 is selected from the group consisting of pyrrolidmo, nexamethyleneimmo, and piperidino,- and pharmaceutically acceptable salts and solvates thereof. The current invention concerns the discovery that a select group of 2-phenyl-3-aroylbenzothiophenes (benzothiophenes. , those of formula I, are useful for inhibiting growth hormone effects when present in elevated levels. Such effects include gigantisrr and acromega!: , and the delitorious effects on microvascuiar tissues, sucn as the retina. The methods of use provided βy this invention are practiced by administering to a numan in need thereof a dose of a compound of formula I or a acceptable salt or εolvate thereof, that ι e effective tc inhibit tne effects cf growth hormone. The term 'inhibit" includes its generall:" accepted meaning which includes p ohibiting, preventing, restraining, and slowing, stopping or reversing. As such, tne present etnod includes ooth medical therapeutic and/or prophylactic administration, as appropriate. Ralox fene, a compound of tr.is invention wnerein t is tne hvarocnioride salt cf comoound of formula M. , P 1 anc R 3 are hydrogen and R 2 is 1-pιperιdmyl, is a nuclear regulatory molecule. Raloxifene has been shown to bind to the estrogen receptor and was originally thought to be a molecule whose function and pharmacology was that of an anti- estrogen in that it blocked the ability of estrogen tc activate uterine tissue and estrogen dependent breast cancers. Indeed, raloxifene does block the action of estrogen in some cells; however m other cell types, raloxifene activates the same genes as estrogen does and displays the same pharmacology, e.g., osteoporosis, hyperlipidemia. As a result, raloxifene has been referred to as an anti-estrogen with mixed agonist-antagonist properties Tne unique profile which raloxifene displays and differs from that of estrogen is now thought to be due to the unique activation and/or suppression of various gene functions by the raloxifene-estrogen receptor complex as opposed tc the activation and/or suppression of genes by the estrogen- estrogen receptor complex. Therefore, although raloxifene and estrogen utilize and compete for the same receptor , the pharmacological outcome from gene regulation of the fΌ IS not easily predicted and is unique to each. As such, it is possible that raloxifene would also benefit a patient wno has lower than normal levels of growth hormone. Generally , the compound is formulated with common excipients, diluents or carriers, and compressed into tablets, or formulated as elixirs or solutions for convenient ora_. administration, or administered by the intramuscular or intravenous routes. The compounds can be administered transderrrally, and may be formulated as sustained release dosage forms and the like. The compounds used in the methods or the current invention can be made according to established procedures, sucn as tnose detailed in U.S. Patent Nos. 4,133,814, 4,418,06;, and 4,380,635 all of which are incorporated by reference herein. In general, the process starts icr. a oenzo[bj tr.iophene navmg a ό-nyαroxyl group ana a 2- ■ * - nyαroxypnenyl group Tne starting compound is protected, acyiated, and deprotected to form the rormula I compounds. Examples of the preparation of such compounds are provided in the U.S. patents discussed above. Optionally substituted phenyl includes phenyl and phenyl substituted once or twice 5 with -Cς alkyl, C 1 -C alkoxy, , nitro, chloro, fluoro, or tri (chloro or fluoro)methv1. The compounds used in the methods of this invention form pharmaceutically acceptable acid and base addition salts with a wide variety of organic and inorganic acids and bases 10 and include the physiologically acceptable salts which are often used in pharmaceutical . Such salts are also part of this invention. Typical inorganic acids used to form sucn εaitε include hydrocnlor c, hydrcoromic, hydroiodic, nitric, s lfunc, pnosphonc, nypophospnoric and the lικe. 15 Salts derived from organic acids, such as aliphatic mono and dicarboxylic acids, phenyl substituted alkanoic acids, hydroxyalkanoic and hydroxyalkandioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, may also be used. Such pharmaceutically acceptable salts thus include acetate, 20 phenylacetate, tπfluoroacetate, acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxyoenzoate, methylbenzoate, o-acetoxybenzoate, naphthaiene-2-benzoate, Promiαe, isobatyrate, phenylbutyrate, β-hydroxyoutyrate, outyne-1, -dιoat , nexyne-1, -dιoate, 25 caprate, caprylate, chloride, cinnamate, citrate, formate, fumarate, glycollate, heptanoate, hippurate, lactate, malate, maleate, hydroxymaieate, malonate, manαelate, mesylate, nicotmate, lsonicotmate, nitrate, cxalate, phthalate, teraphthalate, phosphate, mononyaroαenphosphate, ~ _n dihydrogenpnosphate, metapnosphate, ophospnate, propiolate, propionate, pnenyipropionate, salicylate, sebacate, succmate, suberate, sulfat- bisulfate, pyrosulfate, sulfite, bisulfite, sulfonate, cenzene- sulfonate, p-bromophenylsulfonate, ch._.orobenzenesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, metnanesulfonate, naDhtπalene-1-suifonate, napnthaiene---sulfonate, p- toluenesulfonate, xylenesulfonate, tartarate, and the like. A preferred salt is the hydrochloride salt. The pharmaceutically acceptable ac d addition salts are typically formed by reacting a compound cf formula I with an equimolar or excess amount of acid. The reactants are generally comoined in a mutual solvent sucn as diethyl ether or benzene. The salt normally precipitates out of solution within aDout one hour to 10 days and can be isolated by filtration or the solvent can be stripped off by conventional means. Bases commonly used for formation of salts include ammonium hydroxide and alkali and alkaline earth metal hydroxides, carbonates, as well as aliphatic and primary, secondary and tertiary amines, aliphatic diammes. Bases especially useful in the preparation of addition salts include ammonium hydroxide, potassium carbonate, methylamine, diethylamine, ethylene diamme and cyclohexyiamme. The pharmaceutically acceptable salts generally have ennanced solubility characteristics compared to the compound from which they are derived, and thus are often more amenable to formulation as liquids or emulsions. Pharmaceutical formulations can be prepared by procedures Known m the art. For examp_=>, t. ~ e compounds car. be formulated with common excipientε, diluen _? , or carriers, and formed into tablets, capsules, suspensions, powders, and the like. Examples of excipientε, diluents, and carriers that are suitable for such formulations include the following: fillers and extenders such as starch, sugars, mannitc-, and silicic derivatives; binding agents such as carboxymethyl cellulose and other cellulose derivatives, algmates, gelatin, and poiyvinyl pyrrclidone; moisturizing agents such as glycerol; disintegrating agents such as calcium carbonate and sodium bicarbonate; agents for retarding dissolution such as paraffin? resorption accelerators such as quaternary ammonium compounds; surface active agents sucn as cetyl alcohol, glycerol monostearate; aαsorpti"e carriers sucn as kaolin and bentcπite; and lubricants such as talc, calcium and magnesium stearate, ano solid polyethyl glycols. The compounds can also be formulated as elixirs or solutions for convenient oral administration or as solutions appropriate for parenteral administration, for instance by intramuscular, subcutaneous or intravenous routes. Additionally , the compounds are well suited to formulation as sustained release dosage forms and the like. The formulations can be so constituted that they release the active ingredient only or preferably m a particular part of the intestinal tract, possibly over a period of time. The coatings, envelopes, and protective matrices may be made, for example, from polymeric suoεtances or waxes. The particular dosage of a compound of formula I required to inhibit the effects of growth hormone according to this invention will depend upon the severity of the condition, the route of administration, and related factors that will be decided by the attending physician. Generally, accepted and effective daily doses will be from about 0.1 to about 1000 mg/day, and mo e typically from about 50 to about 200 mg/day. Such dosages will be administered to a sub ect in need tnereof from once to about tnree times each da^ , or more often as needed to effectively ιea r tne nαiome or at least one of its symptoms. It is usually preferred tc administer a compound :: formula I m the form of an acid addition salt, as is customary m the administration of pharmaceuticals bearing a basic group, such as the piperidino ring. It is also advantageous to administer such a compound by the orai route For such purposes the following oral acsage forms are available. In the formulations which rc low, "Active ingredient" means a compound of formula I. Formula-icr. 1: Gelatin Capsules Hard gelatin capsules are prepared using the following: Ingredient Quantity (mα/caρsule_ Active ingredient 0.1 - 1000 Starch, NF 0 - 650 Starch flo able powder 0 - 650 Sil cone fluid 350 centistokes 0 - 15 The ingredients are blended, passed through a No. 45 mesh U.S. sieve, and filled into hard gelatin capsules. Examples of specific capsule formulations of raloxifene that have been made include those shown below: Formulation 2: Raloxifene capsule Ingredient Quantity (mσ/capsulel Raloxifene 1 Starch, NF 112 Starch flowable powder 225.3 Silicone fluid 350 centistokes 1.7 Formulation 3 : Raloxifene capsule Ingredient Quantity (mg/ capsule) Raloxifene 5 Starch, NF 108 Starch flowable powdei 225.3 ilicone fluid 350 centistokes 1.7 Formulation 4: Raloxifene capsule Ingredient Quantity (mg/capsule. Raloxifene 10 Starch, NF 10. Starch flowable powdei 225. Silicone fluid 350 centistokes l.- Formul ion 5: Raloxifene capsule Ingredient Puantit,' (mg/capsule) Raloxifene 50 Starch, NF .5C Starch flowable powder Silicons fluid 3 C 0 centlstoke; The specific formulations above may be changed ii compliance with the reasonable variations provided. A tablet formulation is prepared using the ingredients below : Formulation 6 : Tablets Ingredient Quantity (mg tablet ) Active ingredient 0 . 1 100C Cellulose , microcrystalline 0 650 Silicon dioxide , fumed 0 650 Stearate acid 0 15 The components are blended and compressed tc form tablets . Alternat ively , tablets each containing 0 . 1 - 1000 mg of active ingredient are made up as follows : Formulation 7 : Tablets Ingredient Quantity img tablet ) Act ive ingredient 0.1 - 1000 Starch 45 Cellulose, microcrystalline 35 Polvvinylpyrrolidone 4 (as 1C. solution in v.atei > Sodium carboxymetny1 cellulose 4.Ε Magnesium stearate 0.5 Talc 1 The active ingredient, starch, and cellulose are passed through a No. 45 mesh U.S. sieve and mixed thoroughly. The solution of polvvinylpyrrolidone is mixed with the resultant powders which are then passed through a No. 14 mesh U.S. sieve. The granules so produced are dried at 50°-60° C and passed through a No. 13 mesh U.S. sieve. The sodium carboxymethyl starch, magnesium stearate, and talc, previously passed through a Nc. 60 U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets. Suspensions each containing 0.1 - 1000 mg of medicament per 5 mL dose are made as follows: Formulation 8: Suspensions Ingredient Quantl " (mg 5 ml > Active ingredient 0.1 1000 mg Sodium carooxymethyl cellulose 0 mg Syrup 1.25 mg Benzoic acid solution 0.10 mL Flavoi q.v. Coloi q.v. Purified water to 5 mL The medicament is passed through a No. 45 mesh U.S. sieve and mixed with the sodium carboxymethyl cellulose and syrup to form a smooth paste. The benzoic acid solution, flavor, and color are diluted with some of tne water and added, with stirring. Sufficient water is then added tc produce the required volume. TF.FT PΓDCEDΠPE Five to healtny , late puoerta. ma_es are selected for the cnnical study. The males are at Tanner genital stage IV or V, vitn testicu ar volumes _ 15 mL. The growth hormone concentrations are determined, as well as concentrations of other normoneε. The study nas a placebo control group, i.e., the males are di"ided into two groups, one of wπich receives tne active agent of tftiε invention ano tne otner receives a piaceoo. Males m the test group receive oetween 50-600 mg of tne actι ** e agent per day by the oral route. They continue this therap . v for 3- months. Accurate records are kept as to the concentrations of growtr. hormone and other hormones in botn αrou ε and at tne end of the study these results are compared. The results are compared both between members of each group and also the results for each patient are compared to the concentrations reported by each patient before the study began. Utility of the compounds of the invention is illustrated by the impact they have on the concentration cf growth hormone when used in a study as above.

Claims: i - We claim : 1. A method of inhibiting the effects of growth hormone comprising administering to a human in need thereof an effective amount of a compound having the formula (I) wherein R 1 and P. 3 are independently hydrogen, -CH 3 0 0 II -C-(C;-C alkyl) ( or -C-Ar , wherein Ar is optionally substituted phenyl; P. 2 is selected from the grcυr consisting of pyrrolidine, hexamethyleneimino, ana piperidino; or a pharmaceutically acceptable salt of soivate thereof. 2. The method of Claim 1 wherein said compound is the hvdrochloride εalt thereof. The method of Claim 1 wherein said compound is or its hvdrochloride salt. 4. The method of Claim 1 wherein said effects are gigantism or acromegaly.

Inventors: GRESE TIMOTHY ALAN, GRESE, TIMOTHY, ALAN
Applicants: GRESE TIMOTHY ALAN, LILLY CO ELI, ELI LILLY AND COMPANY, GRESE, TIMOTHY, ALAN
Application year: 1995
Main classification: A61K31
IPC codes: A61K31, A61P5, C07D333