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Publication numberUS3580916 A
Publication typeGrant
Publication dateMay 25, 1971
Filing dateFeb 20, 1969
Priority dateFeb 20, 1969
Publication numberUS 3580916 A, US 3580916A, US-A-3580916, US3580916 A, US3580916A
InventorsWilliam L Garbrecht
Original AssigneeLilly Co Eli
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Hydroxyesters of hexa- and octahydroindoloquinolines
US 3580916 A
Abstract  available in
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Description  (OCR text may contain errors)

United States Patent 3,580,916 HYDROXYESTERS 0F HEXA- AND OCTAHYDROINDOLOQUINOLINES William L. Garbrecht, Indianapolis, Ind., assignor to Eli Lilly and Company, Indianapolis, Ind. No Drawing. Filed Feb. 20, 1969, Ser. No. 801,144 Int. Cl. C07d 43/20 US. Cl. 260-2855 13 Claims ABSTRACT OF THE DISCLOSURE Esters of lysergic and dihydrolysergic acids, including 4-alkyl, 4-alkenyl and 4-aralkyl derivatives thereof, in which the esterifying group is derived from a dihydroxy or trihydroxy alkyl alcohol having from two to eight carbon atoms or a C to C cycloalkyl dihydroxy alcohol, having from 5 to 8 ring carbon atoms, the esters having neurosedative activity in animals.

BACKGROUND OF THE INVENTION Extensive research in the field of mental health has uncovered a variety of therapeutic agents useful in the treatment of various mental conditions. The commonly used tranquilizers, psychic energizers, antidepressants and neurosedatives of today are a result of this research. Although significant advances have been made by the development of compounds having these activities, there remains the need for more effective agents.

This invention comprises novel compounds which possess desirable neurosedative properties.

SUMMARY OF THE INVENTION This invention relates to novel esters of certain indoloquinoline carboxylates. More particularly, this invention relates to polyhydric alcohol esters of lysergic and dihydrolysergic acids wherein the polyhydric alcohol is alkyl and has from two to eight carbon atoms or is a C to C cycloalkyl having from five to eight ring carbon atoms.

DETAILED DESCRIPTION The novel esters of this invention have the following structural formula wherein the numbering of the indoloquinoline ring system is indicated:

and wherein the 10, IOa-bond may be unsaturated, as shown, or saturated. In the above formula, R is hydro- 3,580,916 Patented May 25, 1971 gen, methyl, ethyl, propyl, isopropyl, allyl or benzyl and R is the residue of an alkyl polyhydric alcohol having from two to eight carbon atoms or a C to C cycloalkyl polyhydric alcohol having from five to eight ring carbon atoms. Also a part of the persent invention are the salts of the compounds of the above formula.

As employed herein, the term polyhydric alcoho refers to a dihydroxy or trihydoxy alcohol. Illustrative of such alcohols which can be employed in the preparation of the esters of this invention are ethylene glycol, propane-1,2-diol, propane-1,3-diol,

glycerol, 2,2-diethylpropane-1,3-diol, 2-ethyl-2-methylpropane-1,3-diol, butane-1,4-diol, 2-methylbutane-l,4-diol, butyne-1,4-diol, butane-1,3-diol, butane-2,3-diol, butane-1,2,4-triol, pentane-1,5-diol, pentane-1,4-diol, 2-methylpentane-2,4-diol, hexane-1,6-diol, hexane-2,5-diol, 2,5-dimethylhexane-2,S-diol, heptane-1,7-diol, octane-l,-8-diol and the like.

Illustrative of the cycloalkyl polyhydric alcohols which can be employed in the present invention are cyclopentane-l,3-diol, cyclohexane-l,4-diol, 5,5-dimethylcyclohexane-1,3-diol, Z-ethylcyclopentane-1,3-dio1, cycloheptane-1,2-diol, 4-rnethylcyc1oheptane-1,2-diol, cyclooctane-l,5-diol, 3-ethylcyclooctane-1,3-diol, 4-isopropylcycloheptane-1,2-diol, 3-propylcyclooctane-1,5-diol, 3-isopropylcyclooctane-1,5-diol and the like.

The polyhydric alcohols which can be employed in the preparation of the novel esters of this invention are available from commercial sources or they can be obtained by commonly known synthetic methods.

The compounds of the present invention are formally named as esters of 7-methyl-4,6,6a,7,8,*9-hexahydroindolo [4,3-fg]-quinoline-9-carboxylates and of 7-methyl-4,6,6a, 7,8,9,10,10a-octahydroindolo[4,3-fg]-quinoline 9 carboxylates. Informally, the compounds are designated as esters of lysergic acids or dihydrolysergic acids respectively.

The novel compounds disclosed herein can all be prepared from lysergic acid by procedures known in the art. As is illustrated by the following reaction sequence, wherein R and R have the previously assigned meanings, the compounds can be prepared by several alternative routes:

A=alkylation E=esterification H =hydrogenation R =C -C lower alkyl, allyl or benzyl R =mono or dihydroxy C -C alkyl and monohydroxy C -C cycloalkyl Dashed arrows=alternate routes Solid arrows=preferred routes It is readily apparent from the foregoing scheme that considerable choice is permitted with respect to the sequence in which the various process steps are carried out. This choice in reaction sequence is indicated in Flow Sheet I by means of solid and dashed arrows. Thus, for example, in the preparation of the esters of a 4-substituted lysergic acid, the esterification reaction can be performed either prior to or after the introduction of the substituent in the 4-position. Similarly, in the synthesis of the dihydrolysergic acid esters the introduction of the 4-substituent, the hydrogenation step and the esterification can be carried out in any sequence. When however, the desired 4-substituent of the dihydrolyser gic acid is unsaturated, as for example, 4-allyldihydrolysergic acid, the hydrogenation step is carried out on lysergic acid or a saturated ester thereof prior to alkylation in order to avoid hydrogenation of the desired 4-substituent. Likewise, when the desired ester function of the dihydrolysergic acid is unsaturated, for example, 4-hydroxy-2-butynyl dihydrolysergic acid carboxylate, hydrogenation is carriedout prior to the esterification step.

Generally speaking it is preferred to carry out the esterification procedure as the final step of the reaction sequence in either the lysergic or dihydrolysergic acid series. The esterification is conveniently eifected by adding the lysergic or dihydrolysergic acid to the desired polyhydric alcohol in the presence of a suitable acid at a temperature between about 0 and 75 C. The reaction mixture is stirred vigorously until solution is obtained and the product recovered by treating the reaction product mixture with three to four volumes of water containing an excess of base and extracting with a suitable water-immiscible solvent such as ethylene dichloride, chloroform, ether and the like. The polyhydric alcohol is desirably used in large excess and thus provides as well as suitable reaction C O OH I l A GHa i DIHYDROLYSERGIC ACID CH3 medium. When the polyhydric alcohol employed for esterification has a melting point above about 25 C. the warm melt of the alcohol can be used with success.

Among the acids which can be suitably employed in the esterification reaction are concentrated sulfuric acid and the alkyl and arylsulfonic acids such as benzenesulfonic acid, p-toluenesulfonic acid, p-chlorobenzenesulfonic acid, p-nitrobenzenesulfonic acid, methanesulfonic acid, ethanesulfonic acid and the like. The preferred acids are concentrated sulfuric acid and p-toluenesulfonic acid, although satisfactory yields of product can be obtained with the other acids listed. For best results when concentrated sulfuric acid is employed, it is preferable to carry out the esterification at a temperature between about 0 and 35 C., although significant yields of product can be obtained at higher temperatures. Small amounts of concentrated sulfuric acid suffice. For example, a convenient ratio of concentrated sulfuric acid to polyhydric alcohol is 5 ml. to ml. and a convenient ratio of concentrated sulfuric acid to the lysergic or dihydrolysergic acid employed is about 1 ml. to 1 gram or less.

The 4-substituted dihydrolysergic acids employed for esterification are conveniently prepared by the alkylation of dihydrolysergic acid in liquid ammonia in the presence of sodium amide according to the procedure described in US. Pat. No. 3,183,234. The 4-substituted lysergic acids are prepared by a procedure analogous to that employed in the dihydro series. Thus, for example, 4-methyllysergic acid is prepared by first forming sodium amide in liquid ammonia, adding lysergic acid thereto, and alkylating the sodio derivative of the lysergic acid so obtained with methyl iodide or methyl sulfate.

Those skilled in the art will recognize that when the polyhydric alcohol employed in the esterification is unsymmetrically substituted, it is probable that diastereoisomers are obtained, the number of such diastereoisomeric pairs being dependent upon the number of asymmetric carbon atoms present in the alcohol. Moreover, esterification can occur with any of the available hydroxy groups of the polyhydric alcohol, so that the possibility of forming position isomers also exists. In general, it can be said that in such cases the resulting product is a mixture of the various possible isomers.

If desired, salts of the novel esters of the invention can be prepared with physiologically acceptable acids by procedures well known in the art. Such acids may be either inorganic or organic and may include, among the latter such acids as maleic, fumaric, benzoic, p-toluenesulfonic, salicylic, mandelic, cinnamic, naphthoic, ascorbic, succinic, citric, tartaric, malic, pirnelic and like acids. In general, the salts with polycarboxylic organic acids are more readily obtained in crystalline form and are, therefore, preferred. An especially preferred acid is maleic acid.

The novel esters of this invention have interesting and valuable physiological properties. The compounds are potent serotonin antagonists in vitro tests with the isolated rat uterus and guinea pig ileum preparations. In animals, the compounds act as neurosedatives with a rapid onset of action and are therefore useful in calming domestic or agricultural animals. The activity of the compounds is demonstrated at doses as low as 5-25 mg./kg. when they are administered subcutaneously or intravenously and at doses from about 25-100 mg./kg. orally. The oral LD in mice is about 500 to 1000 mg./kg.

In order that the practice of this invention may be more clearly understood, the following non-limiting examples are provided by way of illustration.

EXAMPLE 1 To an ice-cold solution of 5 ml. of concentrated sulfuric acid in 100 ml. of ethylene glycol were added with stirring 7/g. of lysergic acid. The mixture was allowed to warm to room temperature and stirring was continued for about 72 hours, when solution was complete. About 4 volumes of water, to which had been added an excess of concentrated ammonium hydroxide, were added, and the resulting mixture was extracted with ethylene chloride. The combined extracts were dried and concentrated in vacuo. The residue was converted to the maleate salt in a methanol ether solvent mixture. The dried 2-hydroxyethyl 7-methyl-4,6,6a,7,8,9-hexahydroindolo [4,3-fg] quinoline-9-carboxylate maleate melted with decomposition at about 129-136 C.

By employing propane 1,3-dio1 in the foregoing procedure, the crystalline free base of 3-hydroxypropyl 7- methyl 4,6,6a,7,8,9 hexahydroindolo[4,3 fg]quinoline-9-carboxylate melting at about 128-129 C. is obtained.

EXAMPLE 2 The following compounds were prepared according to the procedure described in Example 1 when dihydrolysergic acid was reacted with the indicated polyhydric alcohol.

2 hydroxyethyl 7 methyl 4,6,6a,7,8,9,10,10a octahydroindolo [4,3 fg]quinoline 9 carboxylate maleate, M.P. (dec.) about 161l63 C., prepared with ethylene glycol.

3 hydroxypropyl 7 methyl 4,6,6a,7,8,9,10,la octahydroindolo [4,3 fg]quinoline 9 carboxylate, M.P. (dec.) about 155-156 C., prepared with propane-1,3- diol.

2 hydroxypropyl 7 methyl 4,6,6a,7,8,9,10,10aoctahydroindolo [4,3 fg]quinoline 9 carboxylate, M.P. (dec.) about l78l82 C., prepared with propane- 1,2-diol.

2,3 dihydroxypropyl 7 methyl 4,6,6a,7,8,9,10,10aoctahydroindolo [4,3 fg]quinoline 9 car-boxylate, M.P. (dec.) about ll51l7 C., prepared with glycerol.

4 hydroxybutyl 7 methyl 4,6,6a,7,8,9,10,l0a octahydroindolo[4,3 fg]quinoline 9 carboxylate, M.P. (dec.) about 163-165 C., prepared with butane-1,4-diol.

3 hydroxybutyl 7 methyl 4,6,6a,7,8,9,10,l0a octahydroindolo [4,3 fg]quinoline 9 carboxylate, M.P. (dec.) about 141144 C., prepared with butane-1,3-di0l.

5 hydroxypentyl 7 methyl 4,6,6a,7,8,9,10,10a-

6 octahydroindolo [4,3 fg] quinoline 9 carboxylate, M.P. (dec.) about 156-158 C., prepared with pentane- 1,5-diol.

EXAMPLE 3 When 4-methyllysergic acid was reacted with ethylene glycol in the procedure described in Example 1, 2-hydroxyethyl 4,7 dimethyl 4,6,6a,7,8,9 hexahydroindolo [4,3-fg]quinoline-9-carboxylate maleate was obtained melting at about -85 C. (dec.)

In an analogous manner, the compounds listed below were prepared from the indicated 4-substituted lysergic acid and the indicated polyhydric alcohol.

2 hydroxypropyl 4,7 dimethyl 4,6,6a,7,8,9 hexahydroindolo[4,3 fg]quinoline 9 carboxylate maleate, M.P. (dec.) about 7982 C., prepared from propane-1,2- diol and 4-methyllysergic acid.

3 hydroxypropyl 4,7 dimethyl 4,6,6a,7,8,9 hexahydrindolo [4,3 fg]quinoline 9 carboxylate maleate, M.P. (dec.) about -90" C., prepared from propane- 1,3-diol and 4-methyllysergic acid.

2 hydroxypropyl 4 isopropyl 7 methyl 4,6,6a,7 ,8, 9-hexahydroindolo[4,3 fg]quinoline 9 carboxylate maleate, M.P. (dec.) about 128-134" C., prepared from propane-1,2-diol and 4-isopropyllysergic acid.

3 hydroxypropyl-4-isopropyl 7 methyl-4,6,6a,7,8,9- hexahydroindolo [4,3 fg] quinoline 9 carboxylate maleate, M.P. (dec.) about -105 C., prepared from propane-1,3-diol and 41isopropyllysergic acid.

2 hydroxy l methylpropyl 4 isopropyl 7 methyl- 4,6,6a,7,8,9 hexahydroiudolo[4,3 fg] quinoline 9- carboxylate, M.P. (dec.) about 146-148 C., prepared from butane-2,3-diol and 4-isopropyllysergic acid.

2 hydroxyethyl 4 benzyl 7 methyl 4,6,6a,7,8,9- hexahydroindolo [4,3 fg]quinoline 9 canboxylate maleate, M.P. (dec.) about 100-105 C., prepared from ethylene glycol and 4-benzyllysergic acid.

EXAMPLE 4 When 4-methyldihydrolysergic acid was reacted with ethylene glycol according to the procedure described in Example 1 there was obtained 2-hydroxyethyl 4,7-dimeth' yl 4,6,6a,7,8,9,l0,l0a octahydroindolo[4,3 fg]quinoline-9-carboxylate melting at about 153-155 C.

In an analogous manner, the compounds listed below were prepared from the indicated 4-substituted dihydrolysergic acid and the indicated polyhydric alcohol.

3 hydroxypropyl 4,7 dimethyl 4,6,6a,7,8,9,10,10aoctahydroindolo[4,3 fg] quinoline 9 carboxylate maleate, M.P. (dec.) about 168173 C., prepared from propane-1,3-diol and 4-methyldihydrolysergic acid.

2 hydroxypropyl 4,7 dimethyl 4,6,6a,7,8,9,l0,l0aoctahydroindolo[4,3 fg]quinoline 9 carboxylate maleate, M.P. (dec.) about l73l76 C., prepared from propane-1,2-diol and 4-methyldihydrolysergic acid.

2,3 dihydroxypropyl 4,7 dimethyl 4,6,6a,7,8,9,10, 10a-octahdroindole[4,3 fg]quinoline 9 carboxylate maleate, M.P. (dec.) about 169-l74 C., prepared from glycerol and 4-methyldihydrolysergic acid.

4 hydroxybutyl 4,7 dimethyl 4,6,6a,7,8,9,l0,l0aoctahydroindolo [4,3 fg] quinoline 9 carboxylate, M.P. (dec.) about 131-133 C., prepared from butane-1,4-diol and 4-methyldihydrolysergic acid.

3 hydroxybutyl 4,7 dimethyl 4,6,6a,7,8,9,10,l0aoctahydroindolo[4,3 fg]quinoline 9 carboxylate maleate, M.P. (dec.) about 119-12l C., prepared from butane-1,3-diol and 4-methyldihydrolysergic acid.

2 hydroxypropyl 4 ethyl 7 methyl 4,6,6a,7,8, 9,10,10a octahydroindolo[4,3 fg]quinoline 9 carboxylate maleate, M.P. (dec.) about ISO-182 C., prepared from propane-1,2-diol and 4-ethyldihydrolysergic acid.

2,3 dihydroxypropyl 4 ethyl 7 methyl 4,6,6a,7,8, 9,10,10a octahydroindolo[4,3 fg]quinoline 9 carboxylate, M.P. (dec.) about 128129 C., prepared from glycerol and 4-ethyldihydrolysergic acid.

2 hydroxypropyl 4 n propyl 7 methyl 4,6,6a, 7,8,9,10,10a octahydroindolo[4,3 fg]quinoline 9 caroxylate maleate, M.P. (dec.) about 106-108" C., prepared from propane-1,2-diol and 4-n-propyldihydrolysergic acid.

2,3 dihydroxypropyl 4 n propyl 7 methyl 4,6, 6a,7,8,9,10,10a octahydroindolo[4,3 fg]quinoline 9- carboxylate, M.P. (dec.) about 138-140 C., prepared from glycerol and 4-n-propyldihydrolysergic acid.

2 hydroxyethyl 4 isopropyl 7 methyl 4,6,6a,7,8, 9,10,10a octahydroindolo[4,3 fg]quinoline 9 carboyxylate maleate, M.P. (dec.) about 135-140 C., prepared from ethylene glycol and 4-isopropyldihydrolysergic acid.

3 hydroxypropyl 4 isopropyl 7 methyl 4,6,6a, 7,8,9,l0,10a octahydroindolo[4,3 fg]quinoline 9- carboxylate, M.P. (dec.) about 135137 C., prepared from propane-1,3-diol and 4 isopropyldihydrolysergic acid.

2 hydroxypropyl 4 isopropyl 7 methyl 4,6,6a, 7,8,9,10,10a octahydroindolo[4,3 fg] quinoline 9 carboxylate maleate, M.P. (dec.) about l2l-124 C. prepared from propane-1,2-diol and 4-isopropyldihydrolysergic acid.

2,3 dihydroxypropyl 4 isopropyl 7 methyl 4,6, 6a,7,8,9,10,10a octahydroindolo[4,3 fg]quinoline 9- carboxylate, M.P. (dec.) about 165167 C., prepared from glycerol and 4-isopropyldihydrolysergic acid.

4 hydroxybutyl 4 isopropyl 7 methyl 4,6,6a,7, 8,9,10,10a octahydroindolo[4,3 fg]quinoline 9 carboxylate, M.P. (dec.) about 150-155 C., prepared from butane-1,4-diol and 4-isopropyldihydrolysergic acid.

3 hydroxybutyl 4 isopropyl 7 methyl 4,6,6a, 7,8, 9,10,10a octahydroindolo[4,3 fg]quinoline 9 carboxylate, M.P. (dec.) about 116120 C., prepared from butane-1,3-diol and 4-isopropyldihydrolysergic acid.

2 hydroxy 1 methylpropyl 4 isopropyl 7 methyl-4,6,6a,7,8,9,10,10a octahydroindolo[4,3 fg]quinoline 9 carboxylate, M.P. (dec.) about 166-168 C., prepared from butane-2,3-diol and 4-isopropyldihydrolysergic acid.

2,4 dihydroxybutyl 4 isopropyl 7 methyl 4,6,6a, 7,8,9,10,10a octahydrindo1o[4,3 fg]quinoline-9-carboxylate, M.P. (dec.) about 166170 C., prepared from butane-1,2,4-trio1 and 4-isopropyldihydrolyscrgic acid.

hydroxypentyl 4 isopropyl 7 methyl-4,6,6a,7,8,9, 10,10a octahydroindolo[4,3 fg]quinoline 9 carboxylate, M.P. (dec.) about 122-124 C., prepared from pentane-1,5-diol and 4-isopropyldihydrolysergic acid.

2,3 dihydroxypropyl 4 allyl 7 methyl 4,6,6a,7,8, 9,10,10a octahydroindolo[4,3 fg]quin0line 9 carboxylate, M.P. (dec.) about l24-130 C., prepared from glycerol and 4-allyldihydrolysergic acid.

2 hydroxyethyl 4 -al1yl 7 methyl 4,6,6a,7,8,9,10, a octahydroindolo[4,3 fg] quinoline 9 carboxylate, M.P. (dec.) about 55-60 C., prepared from ethylene glycol and 4-allyldihydr0lysergic acid.

3 hydroxypropyl 4 benzl 7 methyl 4,6,6a,7,8,9, 10,10a octahydroindolo[4,3 fg]quinoline 9 carboxylate maleate, M.P. (dec.) about l18120 C., prepared from propane-1,3-diol and 4-benzyldihydrolysergic acid.

2 hydroxyethyl 4 benzyl 7 methyl 4,6,6a,7,8,9, 10,10a octahydroindolo[4,3 fg]quinoline 9 carboxylate maleate, M.P. (dec.) about 156158 C., prepared from ethylene glycol and 4-benzyldihydrolysergic acid.

2,3 dihydroxypropyl 4 benzyl 7 methyl 4,6,6a, 7,8,9,10,10a-octahydroindolo[4,3 fgJquinoline 9 carboxylate, M.P. (dec.) 113-115 C., prepared from glycerol and 4-benzyldihydrolysergic acid.

EXAMPLE 5 A solution containing 50 g. of 4-isopropyldihydrolysergic acid and 50 g. of p-toluenesulfonic acid dissolved in 500 ml. of butane-2,3-diol was warmed at a temperature of about 50 C. for 24 hours. The reaction product mixture was diluted with four volume of water containing in A solution an excess of ammonium hydroxide and the resulting mixture extracted with ethylene chloride. The extract was washed with water, dried and concentrated by evaporation in vacuo to yield a light tan residue. The residue was crystallized from aqueous acetonitrile to yield 41 g. of 2-hydroxy-1-methylpropyl 4-isopropyl-7-methyl- 4,6,6a,7,8,9,10,10a octahydroindolo[4,3 fg]quinoline- 9-carboxylate melting at about 168170 C.

EXAMPLE 6 The following compounds are prepared according to the procedure of Example 6 when the indicated lysergic or dihydrolysergic acid is reacted with the specified polyhydric alcohol.

3-hydroxycyclopentyl 4,7-dimethyl-4,6,6a,7,8,9-hexahydro[4,3-fg]quinoline-9-carboxylate is prepared from 4- methyllysergic acid and cyclopentane-1,3-diol.

8-hydroxyoctyl 4,7-dimethyl-4,6,6a,7,8,9-hexahydro[4,3- fg]-quinoline-9-carboxylate is prepared from 4-methy1- lysergic acid and octaine-1,8-diol.

4-hydroxycyclohexyl 7-methyl-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinoline-9 carboxylate is prepared from dihydrolysergic acid and cyclohexane-1,4-diol.

2-hydroxycycloheptyl 4-isopropyl-7-methyl-4,6,6a,7,8,9, 1 0, lOa-octahydroindolo [4,3-fg] quinoline-9-carboxylate is prepared from 4-isopropyldihydrolysergic acid and cycloheptane-1,2-diol.

S-hydroxycyclooctyl 4-isopropyl-7-methyl-4,6,6a,7,8,9, 10,10a-octahydroindolo[4,3-fg] quinoline-9-carboxylate is prepared from 4-isopropyldihydrolysergic acid and cyclooctane-1,5-dio1.

5-hydr'oxy-3 (n-propyl) cyclooctyl 4,7-dimethyl-4,6,6a,7, 8,9,10,10a octahydroindolo[4,3-fg]quinoline 9 carboxylate is prepared from 4-methyldihydrolysergic acid and 3-(n-propyl) cyc1ooctane-1,5-diol.

2-hydroxy-4-methylcyclohepty1 4,7-dimethyl-4,6,6a,7,8, 9-hexahydroindolo[4,3-fg]quinoline-9-carboxylate is prepared from 4-methylsergic acid and 4-methylcycloheptane-l,2-diol.

4-ethyl-S-hydroxycyclooctyl 4-isopropyl-7-methyl-4,6,6a, 7,8,9,10,10a-octahydroindolo[4,3-fg]quinoline 9 carboxylate is prepared from 4-isopropyldihydrolysergic acid and 4-ethylcyclooctane-1,5-diol.

I claim:

1. A compound selected from the group consisting of compounds of the formula CH3 and the salts thereof with pharmaceutically acceptable acids, wherein R is hydrogen, C -C lower alkyl, allyl or benzyl and R is C C monohydroxyalkyl, C -C dihydroxyalkyl or C -C monohydroxycycloalkyl having from 5 to 8 ring carbon atoms.

2. The compound of claim 1 of the formula wherein R and R are defined as in claim 1.

6. The compound of claim 2, said compound being 2- 10 hydroxyethyl 4-al1yl-7-methyl-4,6,6a,7,8,9,l0,l0a-octahydroindolo [4,3-fg] quinoline-9-carboxylate.

7. The compound of claim 2, said compound being 2,3-dihydroxypropyl 4-ethyl-7-methyl-4,'6,6a,7,8,9,10,10aoctahydroindolo [4,3 -fg] quinoline-9-carb oxylate.

8. The compound of claim 1 of the formula ()OOR wherein R and R are defined as in claim 1.

9. The compound of claim 8, said compound being 25 2-hydroxy-1-methylpropyl 4-isopropy1-7-methyl-4,6,6a,7, 8,9-hexahydroindolo [4,3-fg] quinoline-9-carboxylate.

10. The compound of claim 8, said compound being 2-hydroxypropyl 4-isopropyl-7-methyl-4,6,6a,7,8,9-hexahydroindolo [4,3-fg] quinoline-9-carboxylate.

11. The compound of claim 8, said compound being 2- hydroxyethyl 4,7-dimethyl-4,6,6a,7,8,9-hexahydroindolo- [4, 3-fg'] quinoline-9-carboxylate.

12. The compound of claim 8, said compound being 2-hydroxyethyl 4-benzyl-7-methyl-4,6,6a,7,8,9-hexahydroindolo [4,3-fg] quinoline-9-carboxylate.

13. The compound of claim 8, said compound being 2- hydroxypropyl 4,7-dimethyl-4,6,6a,7,8,9-hexahydroindolo- [4,3-fg] quinoline-9-carboxy1ate.

References Cited UNITED STATES PATENTS 3,183,234 5/1965 Garbrecht et a1. 260-285.5 3,218,323 11/1965 Hormann et al. 260-2855 OTHER REFERENCES Stoll et al., Helv. Chem. Acta, vol. 32, pp. 506-21 (1949).

DONALD G. DAUS, Primary Examiner US. Cl. X.R.

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US4835159 *Aug 24, 1988May 30, 1989Eli Lilly And CompanyErgoline esters useful as serotonin antagonists
US4845224 *Apr 29, 1987Jul 4, 1989Eli Lilly And CompanyCycloalkanol esters of dihydrolysergic acid having peripheral serotonin antagonist properties
US4847261 *Sep 29, 1988Jul 11, 1989Eli Lilly And CompanyAlkoxy cycloalkanol esters of dihydrolysergic acid having peripheral serotonin antagonists properties
US4906639 *Apr 11, 1989Mar 6, 1990Eli Lilly And CompanyCycloalkanol esters of dihydrolysergic acid
US4908449 *Mar 27, 1989Mar 13, 1990Rhone-Poulenc SanteProcess for preparing N-methyl derivatives of lysergol and 10α-methoxylumilysergol
US4914107 *Jan 17, 1989Apr 3, 1990Eli Lilly And CompanyAdministering 1-isopropyldihydrolysergic acid
US4939258 *Jan 10, 1990Jul 3, 1990Eli Lilly And CompanyCycloalkanol esters of dihydrolysergic acid
US4968802 *Jan 10, 1990Nov 6, 1990Eli Lilly And CompanyEsterification with alkoxycycloalkyl sulfonate
US4981859 *Feb 20, 1990Jan 1, 1991 Sexual dysfunction
US5141944 *Jun 24, 1991Aug 25, 1992Eli Lilly And CompanySexual dysfunction, hypotensive, antiischemic agents, headache, psychological disorders
US5441961 *Aug 27, 1992Aug 15, 1995Eli Lilly And CompanySubstituted cyclo or bicycloalkylamides of (8β)-6-(substituted) ergolines
US5739146 *May 1, 1995Apr 14, 1998Eli Lilly And CompanySubstituted cyclo or bicycloalkylamides of (8β)-6-(substituted) ergolines
EP0122044A1 *Mar 9, 1984Oct 17, 1984Eli Lilly And CompanySelective method for blocking 5HT2 receptors
EP0218433A1 *Sep 29, 1986Apr 15, 1987Eli Lilly And CompanySelective method for blocking 5HT2 receptors
EP0219257A2 *Sep 29, 1986Apr 22, 1987Eli Lilly And CompanyEsters of dihydrolysergic acid
Classifications
U.S. Classification546/69
International ClassificationC07D457/04
Cooperative ClassificationC07D457/04
European ClassificationC07D457/04