Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1995-09-07
1997-06-17
Haley, Jacqueline
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
548427, 548432, 548437, A61K 3133, C07D49104, C07D40912
Patent
active
056397780
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
This invention relates to novel 6,7,8,9-tetrahydro-3H-benz(e)indolamine derivatives, to therapeutically acceptable acid addition salts thereof, to processes for their preparation and intermediates used therein, to methods of using the derivatives and to pharmaceutical compositions of the derivatives. These derivatives exhibit dopamine-receptor stimulating activity in a mammal. Thus, they can be useful for treating hyperprolactinemia, glactorrhea, amenorrhea, impotence, schizophrenia, Parkinsonism, diabetes, acromegaly, hypertension and other central nervous system disorders which respond to dopamine-receptor stimulation.
A number of 6,7,8,9-tetrahydro-3H-benz(e)indolamine derivatives are known and described, for example, L. B. Shagalov et al., Chem. Abstr. 91, 56747 v (1979) for Khim. Geterotsikl. Siedin., (3), 360 (1979); L. B. Shagalov et al., Chem. Abstr. 89, 146703 r (1978) for Khim. Geterotsikl. Soedin., (5), 634 (1978); Derwent Publicatiions Ltd., Farmdoc 46000U for Netherlands Patent 7,300,871, published Jul. 30, 1973; and Derwent Publications Ltd., Farmdoc 24087B for German Offenlegungsschrift 2,740,836, published Mar. 22, 1979. The reported compounds lack the particular substitutents of the indole ring system which are characteristic of the compounds of this invention as well as the various placements of the indole ring structure. N. J. Bach and E. C. Kornfeld, U.S. Pat. No. 4,110,339, Aug. 29, 1978, disclose tricyclic tetrahydro-2H-benz(c)pyrroles which are dopamine agonist. These latter compounds are distinguished most readily from the compounds of this invention by having a perfused tricyclic ring system.
European Patent 0055043-B1 discloses 6,7,8,9-tetrahydro-3H-benz(e) indole compounds (see, also U.S. Pat. Nos. 4,510,157 and 4,470,990); however, they lack the indole and/or tertiary amine substitutents of this invention. Alternate placement of the indole ring is not disclosed by this reference.
SUMMARY OF THE INVENTION
In one aspect the subject invention is directed toward compounds of Formula I and pharmaceutically acceptable salts thereof: ##STR2## where Z is R.sub.3 and X and Y form (a), or X is R.sub.3 and Y and Z form (a), (b) or (c) ##STR3## R.sub.1 and R.sub.2 are independently hydrogen, C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, --CH.sub.2 --C.sub.3-7 cycloalkyl, phenyl (optionally substituted with halogen or C.sub.1-6 alkyl), -thiophenyl (optionally substituted with halogen or C.sub.1-6 alkyl), or C.sub.1-6 alkyl phenyl; C.sub.1-6 alkyl; alkyl, halogen, CON(R.sub.3).sub.2, --COCF.sub.3, --CO--C.sub.1-6 alkyl, --CO phenyl, oxygen, --CHO, CN except that when Y and Z form (b), R.sub.1 and R.sub.2 are hydrogen or a C.sub.1-6 alkyl and R.sub.3 is hydrogen, then at least one of R.sub.5 and R.sub.6 must be other than hydrogen or oxygen. These compounds and derivatives thereof predominantly exhibit dopamine-receptor stimulating activity in mammals.
DETAILED DESCRIPTION OF THE INVENTION
The compounds of this invention are represented by Formula I or a pharmaceutically acceptable salt thereof as shown above. The compounds provide a method for treating mammals, especially humans, suffering from dopamine generated central nervous system disorders by administering a therapeutically effective amount of Formula I.
In the structural Formula I, the carbon content of various hydrocarbon-containing moieties is indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety, i.e., the prefix C.sub.i -C.sub.j defines the number of carbon atoms present from the integer "i" to "j" inclusive. Thus, C.sub.1 -C.sub.6 alkyl refers to straight and branched alkyls of one to six carbon atoms, inclusive, including isomers thereof such as methyl, propyl, ethyl and isopropyl.
Cycloalkyl are three to seven carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
The term "halogen" includes fluoro, chloro, bromo and iodo.
Pharmaceutically acceptable salts means salts useful for administering the compounds of this invention or useful forms th
REFERENCES:
patent: 4060626 (1977-11-01), Hrstka et al.
patent: 4110339 (1978-08-01), Bach et al.
patent: 4470990 (1984-09-01), Asselin et al.
patent: 4510157 (1985-04-01), Asselin et al.
Nichols, D.E. et al, J. Med. Chem., 1989, 32, 2128-34.
Shagalov, L.B. et al., "Vilsmeier reaction in angular tetrahydrobenzindoles," Khim. Geterotsikl. Soedin. 3:360-65 (1979) (Russ.) - Chem. Abstr. 91:56747v.
Shagalov, L.B. et al., "Synthesis of angular tetrahydro[4,5]- and [6,7]benzindoles," Khim. Geterotsikl. Soedin. 5:634-40 (1978) (Russ.) - Chem. Abstr. 89:146703r.
Andersson Bengt R.
Carlsson Per A. E.
Haadsma-Svensson Susanne R.
Hansson Lars O.
Sonesson Clas A.
Corneglio Donald L.
Haley Jacqueline
Pharmacia & Upjohn Company
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