MXPA97010075A - Melatonine agonists for the treatment in prostatic hyperplasia beni - Google Patents
Melatonine agonists for the treatment in prostatic hyperplasia beniInfo
- Publication number
- MXPA97010075A MXPA97010075A MXPA/A/1997/010075A MX9710075A MXPA97010075A MX PA97010075 A MXPA97010075 A MX PA97010075A MX 9710075 A MX9710075 A MX 9710075A MX PA97010075 A MXPA97010075 A MX PA97010075A
- Authority
- MX
- Mexico
- Prior art keywords
- ethyl
- methoxy
- methyl
- acetamide
- chloroindol
- Prior art date
Links
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- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 201000002327 urinary tract obstruction Diseases 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N β-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
Abstract
. The present invention provides a method for the treatment of benign prostatic hyperplasia using various melatoni agonists.
Description
AGONISTS OF ME ATONINA FOR THE TREATMENT IN BENIGN PROSTATIC HYPERPLASIA
Melatonin, N- [2- (5-methoxy-3-indolyl) ethyl] -acetamide, is a pineal glandular hormone which has inhibitory activity in ovulation, Chu et al. Endocrinology. 75, 238 (1964), as well as some contrary activity in human breast cancer cells MCF-7, Blask et al. J. Neural. Transm. [Supp.], 21, 433 (1986) and for the treatment of mammary carcinoma in mammals, Blask et al. f Neuroendocrinol. Lett .. 9 (2). 63 (1987). In addition, melatonin has been known to help the recovery of
"diarrheal syndrome", Arendt et al. f Ergonomicsf 30, 1379
(1987), to cause sleepiness, Waldhauser e_ £ al. ,
Psychopharmacology. ÍM, 222 (1990) and to minimize disturbances in the circadian rhythm of body action and function, U.S. Pat. Nos. 4,600,723 and 5,242,941. In addition, certain formulations containing melatonin have been indicated for the treatment of benign prostatic hyperplasia (EP 565296 A1 931013). Several melatonin agonists of the formula
REF: 26279
wherein R 1 is hydrogen, C 1 -C 4 alkyl or Ci-C * alkoxy; R2 is hydrogen or C ^ -C alkyl; R3 is hydrogen or methyl; R 4 is hydrogen, haloacetyl, Ci-C 3 alkanoyl, benzoyl or benzoyl substituted with halo or methyl, • R 5 and R 6 are individually hydrogen or halo, and R 7 is hydrogen or Ci-C alkyl; they have also been prepared and show to have inhibitory activity in ovulation (see U.S. Patent Nos. 4,997,845 and 4,614,807). Such analogs are also established to be active in the treatment of breast carcinomas with hormonal dependence in U.S. Pat. No. 5,196,435. However, none of these agonists were previously shown to possess activity in the treatment of benign prosthetic hyperplasia. Finally, European Patent Application 513,702 discloses that melatonin and components of the formula
wherein R1 and R5 are the same or different and are hydrogen or halogen can be used in treatment of sleep disturbance and in pre-anesthetic medication. Again, such an exposure does not indicate or suggest the use of melatonin agonist for the treatment of benign prosthetic hyperplasia. It is an object of this invention to provide a new method for the prevention and treatment of benign prosthetic hyperplasia (BPH) using certain known melatonin agonists. The following classes of melatonin agonists have been reported and are useful in the method of the present invention: 1) N- [2- (optionally substituted-3-indolyl) ethyl] amides (Flaugh, et al. J. Med. Chem .. 22, 63-69, (1979); Vakkuri et al .. Anal. Biochem. 142, 284-9,
(1984); Stankov, et al. Life Sci .. 51, 479-485 (1992)); 2)
N- [2- (heteroaryl) ethyl] substituted amines (EP 527,687 A2
130892); 3) N- [2 - (optionally substituted-1-naphthyl) ethyl] amides (Yous, et al. J: Chem .. med. 35, 1484-6
(1992); 4) N- [optionally substituted-1, 2, 3, 4-tetrahydronaphth-2-yl] amides (Copinga, et al .. J. Med. Chem. R
36, 2891-98 (1993); and 5) N- [(optionally substituted-1,2,3,4-tetrahydro-9H-carbazol-4-yl) methylamides (Garratt = £.,., Bioorg. Med. Chem. Lett. 4, 1559- 1564 (1994) .The instantaneous method is believed to provide a more effective meaning (in terms of activity, profile and duration of the side effect) for the BPH treatment previously shown.In addition, the melatonin agonists used in the instantaneous method are believed to be they are completely devoid of toxicity in the dosages required for treatment and, as such, a further objective of the present invention is to provide a safe, and effective method of treating BPH, since the present invention provides a new method for treating BPH in mammals. , suitable pharmaceutical formulations will be required for the new method. Therefore, a further objective of this invention is to provide pharmaceutical formulations suitable for use in the imminently claimed method.
Other objects, features and advantages of the present invention will be obvious from the subsequent description and appendix of claims. As noted above, the present invention provides a method of preventing or treating BPH in a male mammal suffering from or susceptible to such a disorder comprising administering to said male mammal an effective amount of a melatonin agonist. Such a melatonin agonist is a compound of formula (I)
wherein R 1 is hydrogen, C 1-6 alkyl or Cj.-C 4 alkoxy; RJ is hydrogen or Ci-; alkyl; R3 is hydrogen, alkyl -t, phenyl or substituted phenyl; R 4 is hydrogen, haloacetyl, Ci-C 3 alkanoyl, benzoyl or benzoyl substituted with halo or methyl;
R5 and R6 are individually each hydrogen or halo and R7 is hydrogen or CL-C4 alkyl. The following definitions refer to several terms used before and throughout the exhibition. The term "halo" refers to fluoro, chloro, bromo and iodo. The term "Ci-C 'alkyl" refers to straight and branched aliphatic radicals of 1-4 carbon atoms including methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. C 1 -C 6 alkoxy includes linear and branched aliphatic ether radicals of 1-4 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, and tert-butoxy. "refers to chloroacetyl, bromoacetyl, fluoroacetyl and iodoacetyl The term" CÍ-CJ alkanoyl "includes for example, formyl, acetyl, propionyl, butyryl, α-methylpropionyl, valeryl, Q! -methyl-butyryl, ß-methylbutyryl and pivaloyl The term "halo substituted benzoyl" defines mono- and di-halo benzoyl groups Specific mono-halo benzoyl groups are chlorobenzoyl, bromobenzoyl, fluorobenzoyl and iodobenzoyl The di-halo benzoyl groups include those in which both halo substituents are The di-halo benz groups Typical oylles include 2-dichlorobenzoyl, 3,4-dibromobenzoyl, 2,5-difluorobenzoyl and 2,6-diiodobenzoyl. The term "benzoyl substituted with methyl" contemplates methylbenzoyl, dimethylbenzoyl and trimethylbenzoyl. The term "substituted phenyl" refers to a phenyl ring which is substituted with one or two substituents selected from the group consisting of halo, C 1 -C 4 alkyl or C 1 -C 4 alkoxy. Examples of such terms, therefore, include 4-chlorophenyl, 2-fluorophenyl, 3-iodophenyl, 4-bromophenyl, 3,4-dibromophenyl, 4-methylphenyl, 2-ethylphenyl, 3-n-propylphenyl, 4-isopropyl- phenyl, 4-n-butylphenyl, 3-t-butylphenyl, 4-sec-butylphenyl, 3,4-dimethylphenyl, 4-methoxyphenyl, 3-ethoxyphenyl, 2-n-propylphenyl, 4-isopropoxyphenyl, 3-isobutoxyphenyl, 4- t-butoxyphenyl, 3-ethoxy-4-methoxyphenyl and the like. While all of the compounds of Formula I are reliable to be used for the prevention and treatment method of BPH presented herein, certain of these components are preferred for such use. Preferred compounds of Formula I for use in the imminently claimed method include the compounds wherein R1 is CL-C4 alkyl (especially methyl), R3 is hydrogen or Cx-C4 alkyl (especially methyl) and R4 is hydrogen. Of such preferred compounds, particularly preferred compounds include those wherein R 2 and R 7 are each independently C 1 C alkyl, (preferably methyl). More preferred compounds for use in the method of the present invention include N- [2-methyl-2- (5-methoxy-6-fluoroindol-3-yl) ethyl] acetamide, N- [2-ethyl-2- ( 5-methoxy-6-chloroindol-3-yl) ethyl] acetamide, N- [2-methyl-2- (5-methoxy-6,7-dichloroindol-3-yl] acetamide and N- [2-methyl-2] - (5-methoxy-6-chloroindol-3-yl) ethyl] acetamide The latter compound is especially preferred for the purposes of the present invention The compounds employed in the method of the present invention wherein R2 is C ^ C alkyl * have an asymmetric center on the carbon atom in which the substituent R2 is attached (eg., the carbon atom ß-). As such, substituted compounds R2 may exist as a racemic mixture or as individual stereoisomers. All of these types of compounds are contemplated for use in the method of the present invention. The following list illustrates representative compounds suitable for use in the present invention. N- [2-methyl-2- (5-methoxy-6-chloroindol-3-yl) ethyl] -acetamide N- [2-methyl-2- (5-methoxy-6-fluoroindol-3-yl) ethyl] -acetamide N- [2-ethyl-2- (5-methoxy-6-fluoroindol-3-yl) ethyl] -acetamide N- [2-ethyl-2- (5-methoxy-6-chloroindol-3-yl) ethyl] -acetamide N- [2-isopropyl -2- (5-methoxy-6-chloroindol-3-yl) ethyl] -acetamide N- [2-isopropyl-2- (5-methoxy-6-f-luoroindol-3 -yl) ethyl] -acetamide N- [2-methyl-2- (5-methoxy-6-bromoindol-3-yl) ethyl] -formamide
N- [2-butyl-2- (5-methoxy-6-bromoindol-3-yl) ethyl] -formamide N- [2-ethyl-2- (5-propoxy-6-chloroindol-3-yl) ethyl] -formamide N- [2-propyl-2- (5-isopropoxy-6-iodoindol-3-yl) ethyl] -formamide N- [2-methyl-2- (5-methoxy-6-chloroindol-3-yl) ethyl] -propionamide N- [2-ethyl-2- (5-methoxy-6-f-luoroindol-3-yl) ethyl] -propionamide N- [2-methyl-2- (5-ethoxy-6-bromo-nol) -3-yl) ethyl] -propionamide N- [2-methyl-2- (5-ethoxy-6-f-luoroindol-3-yl) ethyl] -abu i ramide N- [2-pro-il-2- (5 -butoxy-6-chloroindol-3-yl) ethyl] -butyramide N- [2-methyl-2- (5-methoxy-6-chloroindol-3-yl) ethyl] -but i ramide N- [2-methyl- 2- (5-methoxy-7-chloroindol-3-yl) ethyl] -acetamide N- [2-methyl-2- (5-methyl-oxy-7-fluoropro-indol-3-yl) ethyl] -acetamide N - [2-Ethyl-2- (5-methoxy-7-chloroindol-3-yl) ethyl] -acetamide N- [2-propyl-2- (5-methoxy-7-bromoindol-3-yl) ethyl] - acetamide N- [2-ethyl-2- (5-t-butoxy-7-chloroindol-3-yl) ethyl] -formamide N- [2-ethyl-2- (5-ethoxy-7-iodoindol-3-yl ) ethyl] -formamide
N- [2-methyl-2- (5-isopropoxy-7-chloroindol-3-yl) ethyl] -formamide N- [2-methyl-2- (5-methoxy-7-bromoindol-3-yl) ethyl] -propionamide N- [2-ethyl-2- (5-propoxy-7-chloroindol-3-yl) ethyl] -propionamide N- [2-methyl-2- (5-s-butoxy-7-fluoroindol- 3 - i1) ethyl] -propionamide N- [2-methyl-2- (5-methoxy-7-chloroindol-3-yl) ethyl] -butyramide N- [2-butyl-2- (5-ethoxy-7-chloroindol- 3-yl) ethyl] -butyramide
N- [2-ethyl-2- (5-methoxy-7-fluoro-indol-3-yl) -ethyl] -butyramide N- [2-methyl-2- (5-methoxy-6,7-dichloroindol-3-yl) ) ethyl] acetamide N- [2-ethyl-2- (5-methoxy-6,7-dichloroindol-3-yl) ethyl] acetamide N- [2-isopropyl-2- (5-methoxy-6,7-dichloroindole) -3-yl) ethyl] acetamide N- [2-methyl-2- (5-isopropoxy-6,7-dichloroindol-3-yl) ethyl] acetamide N- [2-methyl-2- (5-methoxy-6 , 7-difluoroindol-3-yl) ethyl] acetamide N- [2-propyl-2- (5-methoxy-6,7-difluoroindole-3-yl) ethyl] acetamide N * [2-ethyl-2- (5-Butoxy-6,7-difluoroindol-3-yl) ethyl] acetamide N- [2-methyl-2- (5-methoxy-6-chloro-7-fluoroindol-3-yl) ethyl] acetamide N- [2-methyl-2- (5-methoxy-6-chloro-7-bromoindol-3-yl) ethyl] acetamide N- [2-methyl-2- (5-methoxy-6-fluoro-7-chloroindol-3 -yl) ethyl] acetamide N- [2-methyl-2- (5-ethoxy-6-bromo-7-iodoindol-3-yl) ethyl] acetamide N- [2-ethyl-2- (5-ethoxy-6 -chloro-7-fluoroindol-3-iDethyl] acetamide N- [2-isopropyl-2- (5-t-butoxy-6-chloro-7-f-luoroindol-3-yl) ethyl] acetamide N- [2-ethyl] -2- (5 -butoxy - 6) -bromo- 7-chloroindol-3-diethyl] acetamide N- [2-methyl-2- (5-methoxy-6,7-dichloroindol-3-yl) ethyl] formamide N- [2-methyl-2- (5 -methoxy-6,7-dibromoindol-3-yl) ethyl] formamide N- [2-t-butyl-2- (5-methoxy-6-chloro-7-f-luoroindol-3-yl) ethyl] -formamide N- [2-Ethyl-2- (5-ethoxy-6-fluoro-7-bromo-nol-3-yl) ethyl] formamide N- [2-ethyl-2- (5-s-butoxy-6-f) 7-chloroindol-3-yl) ethyl] formamide N- [2-methyl-2- (5-methoxy-6,7-dichloroindol-3-yl) ethyl] propionamide N- [2-ethyl-2- (5- methoxy-6,7-dichloroindol-3-yl) ethyl] propionamide N- [2-propyl-2- (5-isopropoxy-6-chloro-7-f-luoroindol-3-yl) -eti] propionamide N- [2 -methyl-2- (5-methyl-oxy-6-bromo-7-iodoindol-3-yl) ethyl] propionamide N- [2-methyl-2- (5-ethoxy-6-bromo-7-chloroindole-3 -yl) ethyl] propionamide N- [2-methyl-2- (5-methoxy-6,7-difluoroindol-3-yl) ethyl] butyramide N- [2-ethyl-2- (5-methoxy-6- fluoro-7-chloroindol-3-yl) ethyl] butyramide N- [2-isopropyl-2- (5-me oxy-6,7-dibromo and dol-3-yl) ethyl] butyr amide N- [2-isopropyl-2- (5-butoxy-6-bromo-7-chloroindol-3-yl) ethyl] butyramide N- [2-ethyl-2- (5-methoxy-6,7-dichloro- 3-yl) ethyl] butyramide N- [2-methyl-2- (l-acetyl-5-methoxy-6-chloroindol-3-yl) ethyl] acetamide N- [2-butyl-2- (l-acetyl- 5-methoxy-6-fluoroindol-3-yl) ethyl] acetamide N- [2-ethyl-2- (l-acetyl-5-isopropoxy-6-chloro-7-fluoroindol-3-yl) ethyl] acetamide N- [2-methyl-2- (l-propionyl-5-methoxy-6-fluoroindol-3-yl) ethyl] acetamide N- [2-methyl-2- (1-propionyl-5-ethoxy-6,7-dichloroindole -3-yl) ethyl] acetamide N- [2-ethyl-2- (l-propionyl-5-butoxy-7-chloroindol-3-yl) ethyl] acetamide N- [2-methyl-2- (l-pivaloyl -5-ethoxy-6-bromoindol-3-yl) ethyl] formamide N- [2-propyl-2- (l-chloroacetyl-5-methoxy-6-bromo-7-fluoroindol-3-yl) ethyl] propionamide N - [2-methyl-2- (l-bromoacetyl-5-ethoxy-7-chloroindol -3-yl) ethyl] butyramide N- [2-ethyl-2- (l-valeryl-5-isopropoxy-6, 7-dichloroindol-3-yl) ethyl] acetamide N- [2-methyl-2- (l-butyryl-5-methoxy-6-chloroindol-3-yl) ethyl] acetamide N- [2-ethyl-2- (l-benzoyl-5-t-butoxy-7-bromoindol-3-yl) ethyl] formamide N- [[2-isopropyl-2- [1- (4-chlorobenzoyl) -5-methoxy-7-f-luoroindole - 3 -yl] ethyl]] formamide N- [[2-methyl-2- [l- (4-bromobenzoyl) -5-ethoxy-6,7-dichloroindol-3-yl] ethyl]] propionamide N- [[2 -ethyl-2- [1- (2,4-dichlorobenzoyl) -5-methoxy-7-bromoindol-3-yl] and yl]] propionamide N- [[2-methyl-2- [1- (2, 4 -dif luorobenzoyl) -5-propoxy-6-chloroindol-3-yl] ethyl]] formamide N- [[2-methyl-2- [1- (4-iodobenzoyl) -5-ethoxy-6-f-luoro-7 -chloroindol-3-yl] ethyl]] acetamide N- [[2-ethyl-2- [1- (2-methylbenzoyl) -5-methoxyindol-3-yl] ethyl]] ropionamide N- [[2-methyl- 2- [1- (4-f-luorobenzoyl) -5-ethoxyindol-3-yl] ethyl]] formamide N- [[2-methyl-2- [1- (2,6-dimethylbenzoyl) -5-methoxy-7 -fluoroindol-3-yl] ethyl]] formamide N- [[2-ethyl-2- [1- (2,6-dimethylbenzoyl) -5-ethoxyindol-3-yl] ethyl]] acetamide N- [[2-ethyl-2- [l- (2,4,6-trimethoxybenzoyl) -5-methoxy-6-chloroindol-3-yl] ethyl]] propionamide N- [[2-methyl-2- [ 1- (2,4,6-trimethoxybenzoyl) -5-methoxy-indol-3-yl] ethyl]] formamide N- [2-ethyl-2- (l-pivaloyl-5-isopropoxyindol-3-yl) ethyl] acetamide N- [2-methyl-2- (l-chloroacetyl-5-methoxy indol-3-yl) ethyl] butyramide N- [2-methyl-2- (2,5-methoxyindol-3-yl) ethyl] acetamide N- [2-ethyl-2- (5-methoxyindol-3-yl) ethyl] acetamide N- [2-ethyl-2- (5-methoxyindol-3-yl) ethyl] propionamide N- [2-methyl-2 - (5-propoxyindol-3-yl) ethyl] formamide N- [2-methyl-2- (5-s-butoxyindol-3-yl) ethyl] butyramide N- [2-ethyl-2- (5-ethoxyindol- 3-yl) ethyl] propionamide N- [2-methyl-2- (5-ethoxyindol-3-yl) ethyl] formamide N- [2-isopropyl-2- (5-methoxy-indol-3-yl) ethyl) ] acetamide N- [2-ethyl-2- (5-methoxyindol-3-yl) ethyl] formamide N- [2- (5-methoxy-6-chloroindol-3-yl) ethyl] acetamide N- [2- ( 5-methoxy-6-fluoroindol-3-yl) ethyl] acetamide N- [2- (5-methoxy-6-bromoindol-3-yl) ethyl] formamide N- [2- (5-methoxy -6-iodoindol-3-yl) ethyl] -propionamide N- [2- (5-methoxy-6-chloroindol-3-yl) ethyl] -n-butyramide N- [2- (2-methyl-5-methoxy -6-bromoindol-3-yl) ethyl] -acetamide N- [2- (2-ethyl-5-methoxy-6-chloroindol-3-yl) ethyl] -acetamide
N- [2- (2-n-propyl-5-methoxy-6-chloroindol-3-yl) ethyl] -formamide N- [2- (2-n-butyl-5-methoxy-6-chloroindol-3- il) ethyl] -formamide N- [2- (2-ethyl-5-methoxy-6-iodoindol-3-yl) ethyl] -propionamide N- [2- (2-isopropoxy-5-methoxy-6-f) luoroindole -3-yl) ethyl] -a-methylpropionamide N- [2- (2-phenyl-5-methoxy-6-chloroindol-3-yl) ethyl] -formamide N- [2- (2-phenyl-5-methoxy -6-bromoindol-3-yl) ethyl] -acetamide N- [2- (2-phenyl-5-methoxy-6-iodoindol-3-yl) ethyl] -propionamide N- [2- ((2- (4 -chlorofenyl) -5-methoxy-6-chloroindol-3-yl)) ethyl] formamide N- [2- ((2- (3-f luorofenyl) -5-methoxy-6-bromoindol-3-yl) ) ethyl] acetamide N- [2- ((2- (2-f luorofenyl) -5-methoxy-6-chloroindol-3-yl)) ethyl] propionamide N- [2- ((2- (4-methyl) enyl) -5-methoxy-6-bromoindol-3-yl)) ethyl] formamide N- [2- ((2- (3-ethylfenyl) -5-methoxy-6-f-luoroindol -3-yl)) ethyl ] utyramide N- [2- ((2- (4-n-propyl) enyl) -5-methoxy-6-chloroindol-3-yl)) ethyl] formamide N- [2- ((2- (3-isopropylphenyl)) -5-methoxy-6-f luoroindol-3-yl) ) ethyl] acetamide N- [2- ((2- (4-methoxyphenyl) -5-methoxy-6-chloroindol-3-yl)) ethyl] propionamide N- [2- ((2- (3-ethoxyphenyl- 5-methoxy -6-bromoindol -3-yl)) ethyl] acetamide N- [2- ((2- (3-n-propoxyphenyl) -5-methoxy-6-f-luoroindol-3-yl)) ethyl] acetamide N- [2- ((2- (4-t-butoxyphenyl) -5-methoxy-6-chloroindol-3-yl)) ethyl] formamide N- [2- ((2- (3-n-butoxyphenyl)) -5-methoxy-6-chloroindol-3-yl)) ethyl] acetamide N- [2- (l-acetyl-5-methoxy-6-chloroindol-3-yl) ethyl] acetamide N- [2- (l- propionyl-5-methoxy-6-fluoroindol-3-yl) ethyl] acetamide N- [2- (l-pivaloyl-5-methoxy-6-bromoindol-3-yl) ethyl] formamide N- [2- (l- chloroacetyl-5-methoxy-6-iodoindol-3-yl) ethyl] propionamide N- [2- (l-bromoacetyl-5-methoxy-6-chloroindol-3-yl) ethyl] -n-butyramide N- [2- (l-valeryl-2-methyl-5-methoxy-6-bromoindol-3-yl) ethyl] acetamide N- [2- (l-butyryl-2-ethyl-5-methoxy-6-chloroindol-3-yl) et il] acetamide N- [2- (l-benzoyl-2-n-propyl-5-methoxy-6-chloroindol-3-yl) ethyl] formamide N- [[2- [1- (4-chloroben zoil) -2-n-butyl-5-methoxy-6-chloroindol-3-yl] ethyl]] formamide N- [[2- [1- (4-bromobenzoyl) -2-ethyl-5-methoxy-6- iodoindol-3-yl] ethyl]] propionamide N- [[2- [l- (2,4-dichlorobenzoyl) -2-isopropyl-5-methoxy-6-fluoroindol-3-yl] ethyl]] -a -methylpropionamide N- [[2- [1- (2,4-difluorobenzoyl) -2-pheny1-5-methoxy-6-chloroindol-3-yl] ethyl]] formamide N- [[2- [1- (4-iodobenzoyl ) -2-phenyl-5-methoxy-6-bromoindol-3-yl] ethyl]] acetamide N- [[2- [1- (2-methylbenzoyl) -2-phenyl-5-methoxy-6-iodoindole-3 -yl] ethyl]] propionamide N- [[2- [1- (2,6-dimethylbenzoyl) -2- (4-chloro-phenyl) -5-methoxy-6-chloroindol-3-yl] ethyl]] formamide N- [[2- [1- (2,4,6-trimethylbenzoyl) -2- (3-fluorophenyl) -5-methoxy-6-bromoindol-3-yl] ethyl]] acetamide N- [2- (l -pivaloyl-5-methoxy-6-chloroindol-3-yl) ethyl] acetamide N- [2- (l-chloroacetyl-5-methoxy-6-chloroindol-3-yl) ethyl] -acetamide N- [[2- [1- (4-chlorobenzoyl) -5-methoxy-6-chloroindol-3-yl] ethyl]] acetamide N- [[2- [1- (2,4-dichlorobenzoyl) -5-methoxy-6-chloroin] dol-3-yl] ethyl]] acetamide N- [[2- [1- (2-methylbenzoyl) -5-methoxy-6-chloroindol-3-yl] ethyl]] acetamide N- [[2- [1- (2,6-dimethylbenzoyl) -5-methoxy-6-chloroindol-3-yl] ethyl]] acetamide N- [[2- [1- (2,4,6-trimethylbenzoyl) -5-methoxy-6-chloroindole] -3-yl] ethyl]] acetamide N- [2- (5-methoxy-6,7-dichloroindol-3-yl) ethyl] acetamide N- [2- (2-methyl-5-methoxy-6,7- difluoroindol-3-yl) ethyl] acetamide N- [2- (2-methyl-5-methoxy-6-fluoro-7-chloroindol-3-yl) ethyl] acetamide N- [2- (5-methoxy-6, 7-Dichloroindol-3-yl) ethyl] propionamide N- [2- (5-methoxy-6,7-difluoroindol-3-yl) ethyl] -isobutyramide N- [2- (5-methyl-5-methoxy-6 , 7-dichloroindol-3-yl) ethyl] -n-butyramide; and similar. The compounds employed in the method of this invention are known in the art or can be made by methods described in the art. Representative publications indicating the preparation of compounds of Formula I include U.S. Pat. Nos. 4,087,444; 4,614,807; and 4,997,845. What all these patents indicate is incorporated herein by reference. The agonists of melatonin, as used in this invention, are useful in the treatment of benign prosthetic hypertrophy (BPH) in male mammals. The diseases of the prostate are some of the most common in the human male. BPH occurs in an average of 80% of the male population before age 80 and 25% will require surgery at some time to alleviate the most common symptom, urinary obstruction. The cause of BPH is not well defined, but it is thought to be mediated by the effect of androgens and their metabolites, particularly dihydrotestosterone. While the role of melatonin in BPH is unknown, evidence of melatonin receptors in the human prostate has recently been reported (EP 565291 A1 931013). As discussed above, melatonin agonists are useful in the treatment of BPH in mammals. Such a method comprises administering to a mammal (preferably a human) in need of such treatment a sufficient amount of one or more melatonin agonists to achieve the desired therapeutic intervention. The compounds can be administered via a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular or intranasal routes. Oral and transdermal routes are preferred. Although the administration route is chosen, such administration is carried out by means of pharmaceutical compositions which are prepared by techniques well known in the pharmaceutical sciences. To make these compositions, one or more active ingredients will usually be mixed with a vehicle, or diluted by a vehicle, or included in a vehicle which may be in the form of a capsule, tablet, paper or other presentations.
When the vehicle serves as a diluent it can be a solid, semi-solid or liquid material which acts as a vehicle, excipient or medium for the active ingredient. In this way the compositions can be in the form of tablets, pills, powders, lozenges, pills, capsules, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid medium or a liquid medium), ointments containing for example up to 10% by weight of the active compound, soft or hard gelatine capsules, suppositories, sterile injectable solutions, and sterile packaged powders. Examples of suitable carriers, excipients, and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, starches, acacia gum, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, saline, syrup, methylcellulose, methyl- and propylhydroxybenzoates, talcum, magnesium stearate and mineral oil; The formulations may additionally include lubricating agents, wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents or flavoring agents. The compositions can be formulated to provide rapid, sustained or delayed release of the active ingredient after administration to the patient employing procedures well known in the art. The compositions are formulated, preferably in a unit dosage form, such that each dose contains about 0.1 to 100 mg, more usually about 10 to 50 mg, of the active ingredient. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined amount of calculated active material produces the desired therapeutic or prophylactic effect in association with one or more suitable diluents, excipients or pharmaceutical vehicles. The compounds employed in the method of the present invention are effective over a dosage range of about 0.1 mg / day to about 100 mg / day to prevent or treat BPH. Thus, as used herein, the term "effective amount" refers to a dosage range of about 0.1 to about 100 mg of active ingredient per day. In the treatment of adult humans, the range of about 10 to about 50 mg of active ingredient per day, in single or divided doses, is preferred. In some patients, the amount of melatonin agonists required to treat BPH could be greater than 100 mg / day. In these patients, who are commonly old in nature, the pineal gland is no longer able to secrete this major hormone, melatonin. The following formulation examples could employ as an active ingredient any melatonin agonist. The examples are illustrative only and are not intended to limit the scope of the invention in any way.
Example i
Suitable hard gelatin capsules were prepared to treat or prevent BPH using the following ingredients:
Quantity (mg / capsulph)
(±) -N- [2-methyl-2- (5-methoxy) -6-chloroindol-3-yl) ethyl] acetamide 100 Dry starch 200 Magnesium stearate 10
The above ingredients are mixed and filled into hard gelatin capsules in amounts of 310 mg.
BjempJ.Q 2_
A suitable tablet was prepared for treatment or prevention of BPH using the following ingredients: ntity (mg / tablet)
(-) -N- [2-methyl-2- (5-methoxy) -6-chloroindol-3-yl) ethyl] acetamide 5 Cellulose, microcrystalline 400 Silicon dioxide 100 Stearic acid 5
The compounds are mixed and compressed to form tablets each weighing 420 mg.
Example 3
A suitable aerosol solution was prepared to treat or prevent BPH using the following compounds:
Weight
(±) -N- [2-methyl-2- (5-methoxy) -6-fluoroindol-3-yl) ethyl] ketamide 0.25 Ethanol 29.75 Propellant 22 (Chlorodifluoromethane) 70.00
The active compound is mixed with ethanol and the mixture is added to a portion of the propellant 22, cooled to -30 ° C and transferred to a filling device. The required amount is then fed to a stainless steel container and diluted with the propellant residue. The unit valves are then fitted to the container.
Example 4
Suitable tablets were made to treat or prevent BPH, each containing 1 mg of active ingredient:
(+) -N- [2-methyl-2- (5-methoxy) -6-chloroindol-3-yl) ethyl] acetamide 1 mg Starch 44 mg Microcrystalline cellulose 35 mg Polyvinylpyrrolidone (as a 10% solution in water) 4 mg Carboxymethyl sodium starch 4.5 mg Magnesium stearate 0.5 mg Talc 1 mg Total 90 mg
The active ingredient, starch and cellulose are passed through a U.S. No. 45 mesh and mix thoroughly. The solution of polyvinylpyrrolidone is mixed with the resulting powders which are then passed through a U.S. No. of mesh 14. The granules thus produced are dried at 50-60 ° C and passed through a U.S. No. 18 mesh. Sodium carboxymethyl starch, magnesium stearate and talcum are passed through a U.S. 60 mesh, then added to the granules which, after mixing, are compressed into a tablet machine to produce tablets each weighing 90 mg.
Example 5
Suitable capsules are made to treat or prevent BPH, each containing 10 mg of drug, as follows:
(-) -N- [2-methyl-2- (5-methoxy) -6,7-dichloroindol-3-yl) ethyl] acetamide 50 mg Starch 59 mg Microcrystalline cellulose 59 mg Magnesium stearate 2 mg Total 170 mg
The active ingredient, cellulose, starch and magnesium stearate are mixed, passed through a U.S. No. 45 mesh, and filled into hard gelatin capsules in amounts of 170 mg.
gjeropio d
Suitable suppositories to treat or prevent BPH, each containing 20 mg of active ingredient, are made as follows:
(±) -N- [2-Ethyl-2- (5-methoxy) -6-chloroindol-3-yl) ethyl] acetamide 20 mg Saturated fatty acid glycerides up to 2,000 mg
The active ingredient is passed through a U.S. No. 60 mesh and suspended in saturated fatty acid glycerides previously melted using the minimum heat required. The mixture is then poured into a suppository mold of nominal 2 g capacity and allowed to cool.
Example 7
Suitable suspensions are made to treat or prevent BPH, each containing 5 mg of drug per 5 ml of dose, as follows: (±) -N- [2-methyl-2- (5-methoxy) -6-chloroindol- 3-yl) ethyl] acetamide 5 mg Sodium carboxymethyl cellulose 50 mg Syrup 1.25 ml Benzoic acid solution 0.10 ml Savoring qv Color q.v. Purified water up to 5 ml
The medication is passed through a U.S. No. 45 mesh and mixed with sodium carboxymethyl cellulose and syrup to form a cleaning paste. The benzoic acid, flavor and color solution is diluted with some water and added with agitation. Sufficient water is then added to produce the required volume.
Example S
Capsules suitable for use in the treatment or prevention of BPH are made, each containing 15 mg of medicament, as follows:
(±) -N- [2-methyl-2- (5-methoxy) -6,7-dichloroindol-3-yl) ethyl] acetamide 15 mg Starch 164 mg Microcrystalline cellulose 164 ml Magnesium stearate 22 ml Total 365 ml
The active ingredient, cellulose, starch and magnesium stearate are mixed, passed through a U.S. 45 mesh and are emptied into hard gelatin capsules in amounts of 365 mg.
Claims (10)
1. - A method for the treatment of benign prosthetic hyperplasia in mammals, characterized in that it comprises the administration to a mammal in need of such treatment an effective dose of melatonin agonist.
2. - The method of claim 1, characterized in that the mammal is a human.
3. - The method of claim 1 or 2, characterized in that the melatonin agonist is selected from N- [2- (substituted 3-indolyl) ethyl] amides; substituted N- [2- (heteroacetyl) ethyl] amines; N- [2 - (substituted 1-naphthyl) ethyl] amides; N- [(substituted 1, 2,3,4-tetrahydronaphth-2-yl] amides; or N- [(substituted 1, 2, 3,4-tetrahydro-9H-carbazol-4-yl) methyl] amides.
4. - The method of claim 3, characterized in that the melatonin agonist is an N- [2- (substituted 3-indolyl) ethyl] amide of Formula: wherein R 1 is hydrogen, Ci-Ci alkyl or C 1 -C 4 alkoxy; R2 is hydrogen or Ci-C alkyl; R 3 is hydrogen, C 1 -C 4 alkyl, phenyl or substituted phenyl; R 4 is hydrogen, haloacetyl, Ci-C 3 alkanoyl, benzoyl or benzoyl substituted with halo or methyl; R5 and Rs are each individually hydrogen or halo and; R7 is hydrogen or Cj-C4 alkyl.
5. - The method of claim 4, characterized in that R1 and R2 are independently C1- alkyl.
6. - The method of claim 5, characterized in that R1 and R2 are methyl.
1 . The method of claim 6, characterized in that the melatonin agonist is N- [2-methyl-2- (5-methoxy-6-chloroindol-3-yl) ethyl] acetamide.
8. - A pharmaceutical formulation for use in the treatment of benign prosthetic hyperplasia, characterized in that it contains an effective dose of melatonin agonist together with at least one pharmaceutically acceptable carrier, diluent or excipient.
9. - A formulation of claim 8, characterized in that the melatonin agonist is an N- [2- (substituted 3-indolyl) ethyl] amide of Formula: wherein R 1 is hydrogen, alkyl- or alkoxy Ci-C ,, - R2 is hydrogen or Ci-C4 alkyl; R 3 is hydrogen, C 1 -C 6 alkyl, phenyl or substituted phenyl; R 4 is hydrogen, haloacetyl, Cj.-C 5 alkanoyl, benzoyl or benzoyl substituted with halo or methyl; R5 and R6 are each individually hydrogen or halo; and R7 is hydrogen or CL-C4 alkyl.
10. The formulation of claim 9, characterized in that the melatonin agonist is N- [2-methyl-2- (methoxy-6-chloroindol-3-yl) ethyl] acetamide.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US61013595A | 1995-06-14 | 1995-06-14 | |
| US000203 | 1995-06-14 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| MX9710075A MX9710075A (en) | 1998-03-29 |
| MXPA97010075A true MXPA97010075A (en) | 1998-10-15 |
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