KR19990082055A - Inhibition method of myofoskeletal fibrosis - Google Patents

Abstract

A method of inhibiting myofoskeletal fibrosis, comprising administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof to a mammal in need thereof.

<Formula I>

Where

R ¹ and R ³ are independently hydrogen, —CH ₃ , (a) Or (b) Wherein Ar is optionally substituted phenyl;

R ² is selected from the group consisting of pyrrolidino, hexamethyleneimino or piperidino.

Description

Inhibition method of myofoskeletal fibrosis

Most "puffoma" lesions are associated with skeletal muscle and associated fascia layers. It occurs most often in the abdominal wall in women who are pregnant or after pregnancy, but it is most common in the extra-abdominal area, including the head, neck, thighs and shoulders in men.

Lesions sometimes occur in surgical scars and mesentery, and familial morphology is associated with Gardner's syndrome. A wide range of resections involving the edges of normal tissue is recommended for therapy. However, the mesentery and the major blood vessels and nerves should remain, even if recurrence is likely to occur. Local recurrences often occur and often require resection. These lesions may also respond to radiation therapy. Some cases respond to treatment with tamoxifen. However, additional treatment is still needed.

Myopathofibromatosis is a group of nonmetastatic, dysplastic lesions of locally infiltrating connective tissue.

<Overview of invention>

The present invention provides a method of inhibiting myofodyngeal fibromatosis in a mammal by administering to a mammal in need thereof an effective amount of a compound of formula (I), and a pharmaceutically acceptable salt and solvate thereof: .

Where

R ¹ and R ³ are independently hydrogen, -CH ₃ , or Wherein Ar is optionally substituted phenyl;

R ² is selected from the group consisting of pyrrolidino, hexamethyleneimino and piperidino.

<Detailed Description of the Invention>

The present invention relates to the discovery that a specific group of 2-phenyl-3-aroylbenzothiophenes (benzothiophenes), which are compounds of formula I, are useful for inhibiting myofodystrofioma.

The method of use provided by the present invention is carried out by administering to a person in need of such treatment an amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof effective to inhibit myofoskeletal fibrosis. The term “inhibit” includes its generally accepted meanings, including preventing, preventing, inhibiting, inhibiting, stopping or reversing the symptoms or effects of progression, severity or outcome.

Hydrochloride of one of the compounds of the present invention, raloxyphene, ie, compounds of formula (I) wherein R ¹ and R ³ are hydrogen and R ² is 1-piperidinyl, is a nuclear regulatory molecule. Raloxyphene has been shown to bind to estrogen receptors and was originally thought to be the same molecule as the action and pharmacology of antiestrogens in blocking the ability of estrogens to activate uterine tissue and estrogen-dependent breast cancer. . Indeed, raloxifene blocks the action of estrogens in some cells, while in other types of cells raloxyphene activates the same genes that estrogens act on and exhibits the same pharmacology such as osteoporosis and hyperlipidemia. As a result, raloxyphene has been referred to as an antiestrogenic agent with a mixture of agonist-antagonists. The distinctive profile distinguished from the estrogens represented by raloxyphene is due to the unique activation of various gene functions by the raloxyphene-estrogen receptor complex as opposed to the activation and / or inhibition of genes by the estrogen-estrogen receptor complex. It is thought that it originates in (or) suppression. Thus, while raloxyphene and estrogens compete with the same receptors, the pharmacological consequences of the gene regulation of these two compounds are not easily predicted and unique to each other.

Generally, the compounds are formulated with conventional excipients, diluents or carriers, compressed into tablets, formulated with elixirs or solutions for convenient oral administration, or administered by the intramuscular or intravenous route. The compounds can be administered transdermally, and formulated in sustained release dosage forms and the like.

The compounds used in the methods of the present invention can all be prepared according to established methods as detailed in US Pat. Nos. 4,133,814, 4,418,068 and 4,380,635, which are incorporated herein by reference. In general, the process uses benzo [b] thiophene having 6-hydroxyl groups and 2- (4-hydroxyphenyl) groups as starting materials. The starting compound is protected, acylated and deprotected to form the compound of formula (I). Examples of preparation of such compounds are shown in the above-mentioned US patents. Optionally substituted phenyl replaces phenyl and phenyl substituted once or twice with C ₁ -C ₆ alkyl, C ₁ -C ₄ alkoxy, hydroxy, nitro, chloro, fluoro or tri (chloro or fluoro) methyl. Include.

The compounds used in the methods of the present invention form pharmaceutically acceptable acid addition salts and base addition salts with a wide variety of organic and inorganic acids and bases, and include physiologically acceptable salts often used in pharmaceutical chemistry. These salts also form part of the present invention. Typical inorganic acids used to form these salts include hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid and hypophosphorous acid, and the like. Salts derived from organic acids such as aliphatic monocarboxylic and dicarboxylic acids, phenyl substituted alkanoic acids, hydroxyalkanoic acids and hydroxyalkanoic acids, aromatic acids, aliphatic and aromatic sulfonic acids can also be used. Thus, such pharmaceutically acceptable salts include acetates, phenylacetates, trifluoroacetates, acrylates, ascorbates, benzoates, chlorobenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates , Methylbenzoate, o-acetoxybenzoate, naphthalene-2-benzoate, bromide, isobutyrate, phenylbutyrate, β-hydroxybutyrate, butyne-1,4-dirate, hexin-1, 4-Dirate, Caprynate, Caprylate, Chloride, Cinnamic Acid, Citrate, Formate, Fumarate, Glycolate, Heptanate, Hypurate, Lactate, Malate, Maleate, Hydroxy Maleate, malonate, mandelate, mesylate, nicotinate, isonicotinate, nitrate, oxalate, phthalate, terephthalate, phosphate, monohydrogen phosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, propiolate, Propionate, phenyl Cypionate, Salicylate, Sebacinate, Succinate, Suverinate, Sulfate, Bisulfate, Pyrosulfate, Sulfite, Bisulfite, Sulfonate, Benzene-sulfonate, P-bromophenylsulfonate, Chlorobenzenesulfonate , Ethane sulfonate, 2-hydroxyethane sulfonate, methane sulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, p-toluene sulfonate, xylene sulfonate, tartarate and the like. Preferred salts are hydrochlorides.

Pharmaceutically acceptable acid addition salts are typically formed by reacting a compound of formula (I) with an equimolar or excess acid. The reactions are generally mixed in a cosolvent such as diethyl ether or benzene. Salts generally precipitate out of solution within about 1 hour to 10 days and can be isolated by filtration or the solvent can be stripped by conventional methods.

Bases commonly used to form salts include ammonium hydroxide, and alkali and alkaline earth metal hydroxides, carbonates, as well as aliphatic and primary, secondary and tertiary amines, aliphatic diamines. Particularly useful bases for the preparation of addition salts include ammonium hydroxide, potassium carbonate, methylamine, diethylamine, ethylene diamine and cyclohexylamine.

Pharmaceutically acceptable salts generally have increased solubility compared to the parent compound from which they are derived and are therefore often easier to formulate in liquid or emulsion.

Pharmaceutical formulations may be prepared by methods known in the art. For example, the compounds may be formulated with common excipients, diluents or carriers to form tablets, capsules, suspensions, powders, and the like. Examples of excipients, diluents and carriers suitable for such formulations include fillers and extenders such as starch, sugars, mannitol and silicic acid derivatives; Binders such as carboxymethyl cellulose and other cellulose derivatives, alginates, gelatin and polyvinyl pyrrolidone; Humectants, such as glycerol; Disintegrants such as calcium carbonate and sodium bicarbonate; Dissolution retardants such as paraffin; Absorption accelerators such as quaternary ammonium compounds; Surfactants such as cetyl alcohol and glycerol monostearate; Adsorptive carriers such as kaolin and bentonite; And lubricants such as talc, calcium and magnesium stearate, and solid polyethyl glycols.

The compounds may also be formulated as elixirs or solutions for convenient oral administration or as solutions suitable for parenteral administration, for example, by the intramuscular, subcutaneous or intravenous route. In addition, the compounds are well suited for formulation into sustained release dosage forms and the like. The formulations may be formulated to release only the active ingredient or, preferably, at specific sites in the intestine, possibly over a long period of time. For example, coatings, envelopes and protective matrices can be made with polymeric materials or waxes.

The specific dosage of the compound of formula (I) necessary for inhibiting myofoskeletal fibrosis or for any other use described herein will depend on the severity of the disease, the route of administration and related factors, as determined by the attending physician. Will be decided. Generally, an acceptable and effective daily dose will be about 0.1 to about 1000 mg / day, and more typically about 50 to about 200 mg / day. These doses will be administered to patients in need of such treatment once to about three times daily, or more frequently, as necessary to effectively inhibit myofoskeletal fibromatosis.

As is typical for the administration of a medicament comprising a basic group such as a piperidino ring, it is generally preferred to administer the compound of formula (I) in acid addition salt form. In addition, such compounds are advantageously administered by the oral route. The following oral dosage forms are available for that purpose.

For external administration, the compounds can be formulated as known in the art for direct administration to the lesion. Conventional formulations for this purpose include ointments, lotions, pastes, jellies, sprays and aerosols. The weight percent of the compounds of the present invention present in the external formulation will depend on a variety of factors, but will generally be from 0.5 to 95% and typically from 1 to 25% by weight of the total weight of the formulation.

The composition may take the form of an aqueous or anhydrous solution or dispersion, or alternatively in the form of an emulsion or suspension.

These compositions may contain pharmaceutically acceptable vehicles and adjuvants known in the art. For example, besides water, glycol ethers, such as acetone, ethanol, isopropyl alcohol, products sold as "Dowanol", polyglycol and polyethylene glycol, C ₁ -C ₄ alkyl esters of short chain acids, preferably From a physiological point of view, preferably selected from solvents such as fatty acid triglycerides such as ethyl or isopropyl lactate, a product sold as "Miglyol", isopropyl myristate, homomul oil, mineral oil and vegetable oil and polysiloxane The solution may be prepared using one or more acceptable organic solvent (s).

The composition according to the invention may also contain thickening agents such as cellulose and / or cellulose derivatives. The compositions may also contain gums such as xanthan, guar or carob gum or gum arabic, or alternatively polyethylene glycol, benton and montmorillonite and the like.

Galenus formulation forms adapted primarily for external administration may be in the form of creams, milks, gels, dispersions or microemulsions, rather or more or less concentrated lotions, impregnated pads, ointments or sticks, or alternatively spray or foamed aerosol formulations. Take the form, or alternatively, the soap form.

Formulation example

In the following formulations, "active ingredient" means a compound of formula (I).

Formulation Example 1: Gelatin Capsule

Hard gelatin capsules were prepared using the following ingredients:

ingredient Amount (mg / capsules) Active ingredient 0.1-1000 Starch, NF 0-650 Fluid starch powder 0-650 Silicone Latex (Viscosity 350 Centistokes) 0-15

The ingredients are combined and 45 mesh U.S. After passing through a sieve, the hard gelatin capsules were filled.

Examples of specific capsule formulations of raloxyphene that are being prepared include those shown below:

Formulation Example 2: Raloxyphene Capsule

ingredient Amount (mg / capsules) Raloxyfen One Starch, NF 112 Fluid starch powder 225.3 Silicone Latex (Viscosity 350 Centistokes) 1.7

Formulation Example 3: Raloxyphene Capsule

ingredient Amount (mg / capsules) Raloxyfen 5 Starch, NF 108 Fluid starch powder 225.3 Silicone Latex (Viscosity 350 Centistokes) 1.7

Formulation Example 4: Raloxyphene Capsule

ingredient Amount (mg / capsules) Raloxyfen 10 Starch, NF 103 Fluid starch powder 225.3 Silicone Latex (Viscosity 350 Centistokes) 1.7

Formulation Example 5: Raloxyphene Capsule

ingredient Amount (mg / capsules) Raloxyfen 50 Starch, NF 150 Fluid starch powder 397 Silicone Latex (Viscosity 350 Centistokes) 3.0

The specific formulations may vary depending on the appropriate parameters provided.

Tablet formulations were prepared using the following ingredients:

Formulation Example 6: Tablet

ingredient Amount (mg / tablet) Active ingredient 0.1-1000 Cellulose (microcrystalline) 0-650 Silicon Dioxide (Smoke) 0-650 Stearic acid 0-15

The components were combined and compressed to form tablets.

Alternatively, tablets containing 0.1 to 1000 mg of active ingredient each were prepared as follows:

Formulation Example 7: Tablet

ingredient Amount (mg / tablet) Active ingredient 0.1-1000 Starch 45 Cellulose (microcrystalline) 35 Polyvinylpyrrolidone (10% solution in water) 4 Sodium carboxymethyl cellulose 4.5 Magnesium stearate 0.5 Talc One

The active ingredient, starch and cellulose were 45 mesh U.S. Pass through the sieve and mix well. A solution of polyvinylpyrrolidone was mixed with the resulting powder, which was then subjected to 14 mesh U.S. Passed through a sieve. The granules so produced are dried at 50-60 ° C. and 18 mesh U.S. Passed through a sieve. 60 mesh in advance U.S. Sodium carboxymethyl cellulose, magnesium stearate and talc passed through a sieve were added to the granules, mixed and compressed on a tableting machine to give tablets.

Suspensions containing 0.1 to 1000 mg of active ingredient per 5 ml dose each were prepared as follows:

Formulation Example 8: Suspension

ingredient Volume (mg / 5 ml) Active ingredient 0.1-1000 mg Sodium carboxymethyl cellulose 50 mg syrup 1.25 mg Benzoic acid solution 0.10 ml Spice Enough coloring agent Enough Purified water The total amount of 5 ml

The active ingredient is 45 mesh U.S. Passed through a sieve and mixed with sodium carboxymethyl cellulose and syrup to form a soft paste. The benzoic acid solution, flavor and colorant were diluted with a portion of water and added with stirring. Subsequently, a sufficient amount of water was added to fill the required volume.

The following external compositions were prepared:

Formulation Example 9

ingredient Volume (mg / 5 ml) Hydroxypropyl cellulose 1.5 g Active ingredient 1.5-30 g Sufficient amount of isopropanol 100 g

Formulation Example 10

ingredient Volume (mg / 5 ml) Hydroxypropyl cellulose 1.5 g Ethyl lactate 15.0 g Active ingredient 1.5-30 g Sufficient amount of isopropanol 100 g

Formulation Example 11

ingredient Volume (mg / 5 ml) Hydroxypropyl cellulose 1.0 g Butylated hydroxytoluene 0.02 g Active ingredient 1.5-25 g Enough ethanol 100 g

Formulation Example 12

ingredient Volume (mg / 5 ml) Hydroxypropyl cellulose 1.5 g Butylated hydroxytoluene 0.01 g C ₈ -C ₁₂ Fatty Acid Trisleyide 10.0 g Active ingredient 1.5-30 g Sufficient amount of isopropanol 100 g

Formulation examples 9 to 12 above take the form of a gel.

Formulation Example 13

ingredient Volume (mg / 5 ml) Isopropanol 46.0 g Active ingredient 1.0-15 g C ₈ -C ₁₂ Fatty Acid Trisleyide 49.0 g

Formulation Example 14

ingredient Volume (mg / 5 ml) ethanol 69.0 g Ethyl lactate 10.0 g Active ingredient 1.5-20 g C ₈ -C ₁₂ Fatty Acid Trisleyide 30.0 g

Formulation Example 15

ingredient Volume (mg / 5 ml) Isopropanol 47.0 g Acetone 10.0 g Ethyl lactate 10.0 g Active ingredient 1-15 g C ₈ -C ₁₂ Fatty Acid Trisleyide 30.0 g

Formulation Example 16

ingredient Volume (mg / 5 ml) ethanol 95.08 g Butylated hydroxytoluene 0.02 g Active ingredient 1.5-25 g

Formulation Examples 13, 14, 15 and 16 take the form of lotions.

Formulation Example 17

ingredient Volume (mg / 5 ml) White petrolatum 50.0 g Floating paraffin 15.0 g Refined paraffin wax 32.0 g Active ingredient 1-20 g

Formulation Example 18

ingredient Volume (mg / 5 ml) White petrolatum 50.0 g Floating paraffin 13.0 g Refined paraffin wax 32.0 g Active ingredient 1-20 g

Formulation examples 17 and 18 take the form of sticks.

The dry species is a nonmetastatic rare cancer of fibrous origin. Clinicians have suggested that steroid hormones may play an important role in the original history of these cancers: these cancers appear mainly in female patients of childbearing age, and the regression of these cancers is associated with menopause or antiestrogenic therapy.

The purpose of this study was to identify estrogen receptors in P. pylori primary cells and to evaluate the effects of compounds of formula (I) on P. pylori cells in primary culture.

Since vulgaroma develops in patients with familial adenocarcinoma polyposis (FAP), which can sometimes degenerate into colorectal or rectal cancer, we are concerned with cell growth of fibroblasts in adenocarcinoma cell lines (HCT8) and colon cancer biopsy specimens. The inhibitory effect of compound la was tested.

Compound Ia is a compound of Formula I wherein R ² is pyrrolidino and R ¹ and R ³ are hydrogen.

Binding studies were performed using the intact cells. Pyophiloma cells were placed in 6-well plates in growth medium [Coon modified Ham F12 supplemented with 10% FCS]. After 24 hours, growth medium was replaced with steady state medium without phenol red, and the cells were starved for 24 hours. Thereafter, a concentration of [ ³ H] 17βE ₂ was increased (0.05-10 nM) with 25 mM HEPES and 0.5% EtOH (binding buffer), with or without 500-fold excess of unlabeled 17βE ₂ and Compound Ia. Cells were incubated for 1 hour using 1 ml of medium without phenol red. After incubation, cells were washed twice with 800 μl binding buffer and lysed with 1N NaOH at 70 ° C. for 30 minutes. 4N HCl was then neutralized by addition to each well. Radioactivity was measured with a liquid scintillation spectrometer. ER binding affinity and binding capacity were assessed by Scatchard analysis.

All subsequent steps were performed at 0-4 ° C. The ground tissue was then in a polytron homogenizer in buffer [10 mM Tris-HCl, 5 mM EDTA, 10 mM sodium molybdate, 10 mM dithiothritol, 10% glycerol (v / v) (pH 7.4)]. Homogenized into two 10 second bursts divided by a 30 second cooler. The pellet was discarded by centrifugation of the homogenate at 7000 g for 20 minutes, and the supernatant was recentrifuged at 105000 g for 60 minutes to obtain a cytosol and used for estrogen receptor analysis. The cytosol was diluted with 1-2 mg protein / ml. Cytosol proteins were determined according to the Bradford method. For estrogen receptor evaluation, cytosol is incubated for 16 hours at 4 ° C. over a concentration range of 0.05 to 5 nM of [ ³ H] 17βE ₂ with or without a 500-fold excess of unlabeled 17βE ₂ and Compound Ia I was. ER binding affinity and binding capacity were assessed by Scatchard analysis.

Cells were placed in 6-well plates at a density of 8 × 10 ⁴ cells per well in growth medium. After 24 hours, cells were supplemented with 0.1% DMF, 0.1% EtOH, and different concentrations of Compound Ia (2 × 10 ⁻⁵ M, 10 ⁻⁵ M, 5 × 10 ⁻⁶ M, 10 ⁻⁶ M) Stimulation was done in growth medium without red.

Cells were incubated for 6 days, separated with trypsin / ethylenediamine tetraacetic acid solution, and then counted under a microscope to assess growth. The same method was used for colorectal cancer primary fibroblast cell line and HCT8 cell line (this cell line was cultured in RPMI and incubated for 4 days after stimulation).

Type I collagen in the culture medium and cell layer was measured using enzyme-linked immunoassay (ELISA). Briefly, cells were incubated for 24 hours in Coun Modified Ham F12 medium without supplements containing 50 μg / ml ascorbic acid and 100 μg / ml βaminopropionitrile fumarate.

The culture medium is recovered, diluted appropriately in 0.1 M carbonate / bicarbonate buffer (pH 9.6), and then used to coat the ELISA plate overnight at 4 ° C. and the ELISA plate containing PBS (PBS bloto) containing 5% milk powder. Incubate at 37 ° C. for 1.5 hours in saturation to saturate nonspecific binding sites, and in a PBS bloto containing specific polyclonal antibody for 2 hours at 37 ° C. and goat antirabbit IgG-alkali phosphatase complex complex (Sigma) Incubated at 37 ° C. for 1.5 hours in PBS bloto containing Chemical Company (Sigma Chemical Co., St. Louis, M.).

The samples were then exposed to 10% diethanolamine (pH 9.8) containing 50 μg / ml of Mg ⁺⁺ and 1 mg / ml of paranitrophenylphosphate as substrate for alkaline phosphatase at room temperature. Optical density was read at 405 nm and concentration was calculated based on the standard curve. Cell monolayers were recovered in 0.5N NaOH and sonicated to determine cellular type I collagen. Cell extracts were then diluted in 0.1 M carbonate / bicarbonate buffer (pH 9.6) and used to coat the ELISA plates. Standards and samples were analyzed in triplicate. The results are shown as μg protein / μg cell DNA. DNA content was measured with a spectrofluorometer.

Binding experiments were performed on frozen Pseudomonas spp. And frozen specimens of Pseudomonas spp. Using [ ³ H] 17βE ₂ as ligand.

In both experiments, [ ³ H] 17βE ₂ binding is slightly (about 10%) replaced by both 500-fold excess of unlabeled estrogen and Compound Ia. Using the computer binding program LIGAND to perform the scaven analysis of [ ³ H] 17βE ₂ binding data, Munson PJ, Rodard D. Anal. Biochem. 1980; 107: 220-39], which indicates the presence of ER in three different cultures and two different cytosolic formulations from the biopsy specimens of the vulgaris.

In the growth assay, Pseudomonas primary cells were stimulated when exposed to varying concentrations of Compound Ia. As a result, cell growth was inhibited by increasing the concentration of Compound Ia (Table 1). Similar results were obtained using HCT8 cell line (Table 2) and colorectal cancer fibroblast cell lines (Table 3).

Pylori species were inhibited in a dose dependent fashion by compound Ia at concentrations of 10 ⁻⁵ M, 5 × 10 ⁻⁶ M, and 10 ⁻⁶ M, with a maximum inhibitory effect at 10 ⁻⁵ M (Table 4).

Compound Ia can only replace 17βE ₂ that binds to driftwood tissue at very high concentrations (500-fold excess).

Compound Ia can significantly inhibit Pseudomonas cell proliferation at micromolar concentrations. In addition, at similar concentrations, the compounds inhibit the proliferation of endothelial cells and fibroblasts derived from human colon cancer.

Compound Ia also significantly reduced type I collagen production in Pyophiloma cells in primary culture.

All conditions (electroporation, Ca / P precipitation, liposomes) were tested for Pseudomonas cell infection by estrogen reactive components, and the cells were destroyed and consequently unsuitable for "in vitro" analysis.

Compound Ia (mol / L) Cell × 10 ^-4 Control 12.3 2.10 ^-5 0.1 10 ^-5 2.8 5.10 ^-6 7.0 10 ^-6 10.0

Compound Ia (mol / L) Cell × 10 ^-4 Control 150 2.10 ^-5 3 10 ^-5 71 5.10 ^-6 115

Compound Ia (mol / L) Cell × 10 ^-4 Control 7.6 2.10 ^-5 0.1 10 ^-5 5.4 5.10 ^-6 6.3 10 ^-6 7.6

DNA (O: D.) DNA (μg) Type I collagen (pg / well) Collagen Type I (μg / μg DNA) P value Control 4.85 ± 0.32 1.36 ± 0.06 47.82 ± 4.15 35.00 ± 1.41 Compound Ia 1 μM 8.20 ± 0.23 1.97 ± 0.05 43.78 ± 5.23 22.00 ± 1.46 P <0.005 Compound Ia 5 μM 6.90 ± 0.50 1.85 ± 0.24 38.01 ± 6.24 20.50 ± 0.61 P <0.005 Compound Ia 10 μM 7.90 ± 1.46 1.96 ± 0.29 35.16 ± 2.44 18.00 ± 1.41 P <0.005

Claims (4)

A method of inhibiting myofoskeletal fibrosis comprising administering to a mammal in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof. <Formula I> Where R ¹ and R ³ are independently hydrogen, -CH ₃ , or Wherein Ar is optionally substituted phenyl; R ² is selected from the group consisting of pyrrolidino, hexamethyleneimino or piperidino. The method of claim 1, wherein the mammal is a human. The method of claim 2 wherein said compound is a hydrochloride thereof. 4. The method of claim 3, wherein said compound is a compound of formula: