CA1046519A - Trycyclic acetic acid derivatives - Google Patents
Trycyclic acetic acid derivativesInfo
- Publication number
- CA1046519A CA1046519A CA234,428A CA234428A CA1046519A CA 1046519 A CA1046519 A CA 1046519A CA 234428 A CA234428 A CA 234428A CA 1046519 A CA1046519 A CA 1046519A
- Authority
- CA
- Canada
- Prior art keywords
- formula
- hydrogen
- compound
- ethyl
- methyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Tricyclic Acetic Acid Derivatives Abstract of the Disclosure Tetrahydrocyclopent[b]indole-3-acetic acid, tetrahydrocarbazole-1-acetic acid and hexahydrocyclohept[b]-indole-6-acetic acid derivatives in which the carbon bearing the acetic acid residue is further substituted with a lower alkyl, lower alkenyl or lower cycloalkyl are disclosed. The compounds are useful antiinflammatory agents and methods for their preparation and use are described. The compounds are represented by the following formula in which R1 is lower alkyl, lower alkenyl or lower cycloalkyl, R2 is hydrogen or lower alkyl, R3 is hydrogen, lower alkyl, halo, hydroxy, lower alkoxy, lower alkanoyloxy or trihalomethyl, R4 is hydrogen or lower alkyl and n is an integer from two to four.
Description
. AHP'6154-1-CI
S Backqroun(l of the Invention (a~ Field of Invenlion .
This invsntion relates to tricyclic acetic acid derivatives, to their preparation and use, and to .intermediates used for their preparalion.
More specifically, this invention relates to tricyclic acid derivatives in which the tricyclic portion thereof is characterized by hàving an indole portion ~ -fused to a cyclopentane, cyclohexane or cycloheptane ring.
Still more specifically, the compounds of this invention are characterized as derivatives of one of the following tricyclic acetic acid systems~
a) Ir2,3,4-tetrahydrocyclopent[b~indole-3-acetic acid, :
b) 1,2,3,4-tetrahydrocarbazole-1-acetic acid, or c) 5,6,7,8,9,10-hexahydrocyclol:eDt[b]indole-6-acetic acid, in which the carbon bearin9 the acetic acid residue is further substituted with a lower alkyl, lower alkenyl or lower cycloalkyl.
~. ..
S Backqroun(l of the Invention (a~ Field of Invenlion .
This invsntion relates to tricyclic acetic acid derivatives, to their preparation and use, and to .intermediates used for their preparalion.
More specifically, this invention relates to tricyclic acid derivatives in which the tricyclic portion thereof is characterized by hàving an indole portion ~ -fused to a cyclopentane, cyclohexane or cycloheptane ring.
Still more specifically, the compounds of this invention are characterized as derivatives of one of the following tricyclic acetic acid systems~
a) Ir2,3,4-tetrahydrocyclopent[b~indole-3-acetic acid, :
b) 1,2,3,4-tetrahydrocarbazole-1-acetic acid, or c) 5,6,7,8,9,10-hexahydrocyclol:eDt[b]indole-6-acetic acid, in which the carbon bearin9 the acetic acid residue is further substituted with a lower alkyl, lower alkenyl or lower cycloalkyl.
~. ..
-2-., , ~ ' ' ~ , : , , , The tricyclic acetic acid compounds of this inventlon possess useful pharmacologic properties; for instance, they exhibit antiinflammatory activity at dose levels which do not elicit undesirable side effects.
The foregoing combination of attributes renders the compounds of this invention useful for the treatment of inflammatory conditions. ~;
b) Prior Art -Apparently the closest prior art to the present invention is a report by H. Sakakibara and T. Kobayashi, Tetrahedron~ 22, 2475 (1966), describing the preparation of 1,2,3,4-tetrahydrocarbazole-1-acetic acid. Pharmacologic properties for the compound are not mentioned. The latter compound is distinguished from the compounds of the present invention by its structural arrangement and its pharmacologic properties. More particularly, it is distinguished readily by the fact that it lacks a fully substituted carbon atom at positior I of the carbazole-l-.
acetic acid system and secondly the compound lacks antiinflammatory activity when tested in standard pharmacologic tests, see below, ~ -i in which the compounds of this invention exhibit substantial antiinflammatory effects.
, ~ Other prior art, although structurally further . - . . . . ~; .
removed, includes a report by G.R. Allen, Jr., J. Heterocycl.
Chem., 7, 239 (1970), describing the preparation of 1,2,3,4-tetrahydrocarbazole-2-carboxylic ac7d and its corresponding 6-methoxy derivative (see also Belgian Patent No. 771598, issued February 21, 1972).
, '
The foregoing combination of attributes renders the compounds of this invention useful for the treatment of inflammatory conditions. ~;
b) Prior Art -Apparently the closest prior art to the present invention is a report by H. Sakakibara and T. Kobayashi, Tetrahedron~ 22, 2475 (1966), describing the preparation of 1,2,3,4-tetrahydrocarbazole-1-acetic acid. Pharmacologic properties for the compound are not mentioned. The latter compound is distinguished from the compounds of the present invention by its structural arrangement and its pharmacologic properties. More particularly, it is distinguished readily by the fact that it lacks a fully substituted carbon atom at positior I of the carbazole-l-.
acetic acid system and secondly the compound lacks antiinflammatory activity when tested in standard pharmacologic tests, see below, ~ -i in which the compounds of this invention exhibit substantial antiinflammatory effects.
, ~ Other prior art, although structurally further . - . . . . ~; .
removed, includes a report by G.R. Allen, Jr., J. Heterocycl.
Chem., 7, 239 (1970), describing the preparation of 1,2,3,4-tetrahydrocarbazole-2-carboxylic ac7d and its corresponding 6-methoxy derivative (see also Belgian Patent No. 771598, issued February 21, 1972).
, '
-3-, .
.: .
: ~ . :
: . .
~ AHP-6154-1-CI :
,-''' " .
Summary_of the Invent ion The compounds of this invention are represented by formula 1~ R2 ` , R3 ~ ~ )n CH2COOH . ;~
in~ Which Rl iS lower alkyl, lower alkenyl or lower cycloalkyl, R- is hydrogen or lower alky.l, . . :~
lU .K3 is hydrogen, lower alkyl, halo, hydroxy, lower alkoxy, ~
lower alkanoyloxy or trihalomethyl, R4 is hydrogen or lower alkyl :- :
and n Ts an integer from two to four, With the~proviso that Rl is I
othar than methyl when R2 and R3 are both hydrogen. : ..... . ~:
.. . . . . , , .. .. .. - . : , ..
The compounds Of this invention are prepared by a .
process in Which the hydrazine Of tormula 2, ~ ` ~ NR ~H2 in Which R3 and R 3re as defined herein iS condeosed ' .: ~ .
wi~h a compound Of formula 3, ' ~ ~ .
2 ~ I ` .
~ (CH2)n 3 Rl CH2CoOR
in whiCh R , R and n are as de~ined herein and R iS hydrrgen or lower '.
. '" ' 1~ ~. . .
--~
' ~ -alkyl to give the corresponding hydrazone of formula 4, `~
R3 ~ CH2 ~ ` ;:
l (CH21n in which R , R , R3, R , R5~ and n are as defined herein, The hydrazone is then cyclized by treatment with a ~ ~
cyclizing agent to give the corresponding tricyclic compound ; . . .
..
of formula 5~ R2 . -R3 - ~ (CH2)n 5 . R ~ CH COOR
. 2 .
ln which Rl, R2, R3, R , R5 and n are as defined herein;
. followed,when said compound of formula 5 îs other than s~d compound of formula 1, by subjecttng the compound of formuia 5 to hydrolysis conditions to give the desired corresponding ~ ~ 20 compound of formula 1. -- In other words, when R of said compound of formula 5 is hydrogen, the compound is the desired compound of formula I and when R of said compound of formula 5 is ~:
~ ~.
Iower alkyl, the compounds of formula 5 is treated with a ' bydrolyz7ng agent to give the desired correspond7ng compound ;~
of formula 1.
. .
1 :-,.~. : -: :, , :
:;: , . - : . ' A~IP-6154-l-CI
~0~ 19 Detalled Descriptlon of the Invention The term "lower alkyl" as used herein contemplates straight chain alkyl radicals containing from one to six carbon atoms and branched chain alkyl radical containing from three to four carbon atoms and includes methyl, efhyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl and the :
like.
.. . , . .
The term "lower alkenyl" as used herein contemplates straight chain alkenyl radicals containing from two to six 0 carbon atoms and branched chain alkenyl radicals containing . I -~
from three to four carbon atoms and includes vinyl, allyl, I-propenyl, isopropenyl, 2-methyipropenyl and the like.
- The tsrm "lower cycloalkyl" as used herein contemplates saturated cyclic hydrocarbon radicals containing from three ~ i to six carbon atoms and includes cyclopropyl, cyclobutyl, ~;
cyclopenty! and cyclohexyl.
The term "lower alkoxy" as used herein contemplates both straight and branched chain alkoxy radicals containing from one to four carbon atoms and includes methoxy, ethoxy, isopropoxy, t-butoxy and the like.
.~ , .
The term "lower alkanoyloxy" as used herein - ;~
contemplates both straight and branched chain alkanoyloxy ~;
radicals containing from two to six carbon atoms and includes acetoxy, propionyloxy, pivaloyloxy, hexanoyloxy and the li~e.
The term "halo" as used herein contemplates halogens and includes fluorine, chlorine, bromine and iodine.
The term "trihalomethyl" as used herein contemplates trifluoromethyl, trichloromethyl and tribromomethyl. ¦, ,1 ::
` AHP-615~ -I-CI
L9 :
:' ;, The compounds of formula I form salts with suitable pharmaceutically acceptable inorganic and organic bases. These derived salts possess the same activity as the ;
parent acid and are included within the scope of thls invention. The acid is transformed in excellent yield into the corresponding pharmaceutically acceptable salts by neutralization of said acid with the appropriate inorganic ;~
or organic base. The salts are administered in the same manner as the parent acid compounds. Suitable inorganic bases to form these salts include, for example, the ;~
hydroxides, carbonates, bicarbonates or alkoxides of the alkali metals or alkaline earth metals, for example, sodium, - potassium, magnesium, calcium and the like. Suitable organic bases include the following amines; lower mono-, dt- and trialkylamines, the alkyl radicals of which contain up to three carbon atoms, such as methylamine, dimethylamine, ~ ~
trimethylamine, ethylamine, di- and triethylamine, methylethylamine, ~ ~ ;
and the like; mono-; di and trialkanolamines, the alkanol ~:, radicals of which contain up to three carbon atoms, such as mono-, di- and triethanolamine;~alkylene-diamines which contain up to six carbon atoms, such as hexamethylenediamine;
: . ~
cyclic saturated or unsaturated bases containing up to six . ~ ~ - I
carbon atoms, such as pyrrolidine, piperidine, morpholine, piperazine and their N-alkyl and N-hydroxyalkyl derivatives, ¦ ~-such as N-methyl-morpholine and N-(2-hydroxyethyl~piperidine, as wèll as pyridine. Furthermore, there may be mentioned ~;
-. .
": ~' . . ` ' "
.
. . ~ , , ~ A~1P-~154-1-CI
;S~g the corresponding quaternary salts, such as the tetraalkyl (for example tetramethyl), alkyl-alkanol (for example methyl-trimethanol and trimeihyl-monoethanol) and cyclic ammonium sal-ts, for example the N-methyl-pyridinium, N-me-thyl-N~
(2-hydroxyethyl)-morpholinium, N,N-dimethyl-morpholir,ium, N-methyl-N~2-hydroxyethyl)-morpholinium, N,N-dimethyl-piperidinium salts, which are characterized by a good water-solubility. In principle, hcwever, there can be used all the ammonium salts which are physiologically compatible.
The transformations to the salts can be carried out by a variety of methods known in the art. For example, in the case of the inorganic salts, it is preferred to dissolve the selected acid in wa;er containing at least one equivalent amount of a hydroxide, carbonate, or bicarbonate corresponding to the inorganic salt desired. Advantageously, -the reaction is performed in a water-miscible, inert organic solvent, for example~ methanol, ethanol, dioxane, and the like in the presence of water. For example, such use of sodium hydroxide, sodium carbonate or sodium bicarbonate gives a solution of the sodium salt. Evaporation of the solution or addition of a water-miscible solvent of a more moderate polarity, for example, a lower alkanol, for instance, butanol, or a lower alkanone, for instance, ethyl methyl ketone, gives the solid inorganic salt if that form is desir~d. ~
: ``:
, .. . .
.. ,,.~, .
., .
, ~ , , , ~
,,j To produce an amine salt, the selected acid is dissolved in a suitable solvent of either moderate or low ~-polarity, for example, ethanol, acetone, ethyl acetate, ~ ;
d7ethyl ether and benzene. At least an equivalent amount ` - ' of the amine corresponding to the'desired cation is then '~ '~
added to that solution. If the resulting sait does not precipitate, it can usually be obtained in solid form by addition of a miscible diluent of low polarity, for example, benzene or petroleum ether, -or by evaporation. If the amine is relatively volatile, any : .
excess can easily be removed by evaporation. It is preferred to use substantially equivalent amounts of the less volatile amines.
Saits wherein the cation is quaternary ammonium are produced by mixing the selected acid with an equivalent amount of the corresponding quaternary ammonium hydroxide in water solution, followed by evaporation of the water. ;
~ ~ Also included within the scope of this inveniion ;~ are the isomers of the compounds of formula I resulting from - the asymmetric centers contained therein. ; -AntiinflammatorY Activit~Y ' - , ~
- The useful antiinflammatory activities of the tricYclic acetic acid derivatives are demonstrated in standard pharmacologic tests, for example, the tests described by R.A. Turner in i ~ "Screening Methods in Pharmacology", Academic Press, New York and'London, 1965, pp. 152 - 163.
. More particularly exemplIfied the antiinflammatory , ¦
, ~ "
. . 9~
' :'' . :', ' '~ ' ' ' ' ,' .
AHP-6154-1-CI ~-., , ~
. .
effect for the compounds of this invention is demonstrated readily in a modification of the established arthritis test in rats described by B.B. Newbould, Br. J. Pharmac., 35, 487 (1969). In this test rats are made arthritic by treating them with an injection of Freund's adjuvant into the left hind pa~. After 14 days (day 0 of test) a chronic arthritis is established. At this point the rats are treated with a uniform daily dose of the test compound ;
from day 0 to day 8 of the test. Results are expressed as the change in volume of the injected paw from day 0. Untreated arthritic rats show an increased ..
paw size whereas active compounds cause a reduction in ~
. .
the volume of the injected paw. ~;
Typical results obtained for the compounds of -~
the present invention in the aforementioned test are as ~ ~ .
~ ~ follows: ~ --- , :~
Compound Daily Dose Reduction of ~ (mg/kg/p.o.) Paw Size (ml) I-ethyl-1,2,3,4-tetra- 10 0.88 hydrocarbazole-l-aceti~c acid (Example 51) ~;
I-ethyl-8-isopropyl- 10 1.53 ~ i~
1,2,3,4-tetrahydro- ;
carb zole-l-acetic acid (Example 58) -1,8-diethyl-1,2,3,4tetra- 10 1.19 ~1 hydrocarbazole~l-acetic acid (Example 56) In contrast the compo~nd of the prtor art, 1,2,3,4 1-tetrahydrocarbæ ole-l-acetic acid, showed no reduction of paw size at a daily dose of 10 or even 100 mg/kg/pOo. under the conditions of this test. ¦ ~`~
' ' ' - 1 0-!
:',.'. ' : , ; ~.. ' ,, ,' :' o 4 ~ 5 ~, 9 ¦ ¦ -- :: ~
The lack of side effects for the compounds of this invention i ara demonstrated by standard acute toxicity tests (see Turner cTted i ~`
l above) and by prolonged administra-iion of the compound to warm-blooded anlmals.
~,5 When the compounds of this invention are employed as antiinflammatory agents in-- _ I' I .
warm-blooded animals, e.g., rats, they are administered orally, alone or in dosage forms, i.e., capsules or tablets, combined with pharmacologically acceptable excipients, or they are .
administered orally in the form of soiutions in suitab~e ; vehicles such as vegetable oils or water.
The dosage of the indole derivatives of this inventlon will vary with the particular compound chosen and form -~ ~ of administration. Furthermore~ it will vary with the `~ !`
i~l5 parficular host under treatment. Generally, the compounds ;``~
of this invention are administered at a concentration ievel that affords protective effects without any deleterious side ~ `
effects. These antiinflammatorily effective ~
concentration levels are usually obtalned within a therapeutic ~ ;~ ; ;
20~1 range of l.O mg to SOO mg/kg per day, with a preferred ; -~ range of IO to IOO mg/kg per day.
The compounds of thTs invention also possess analgesTc and antipyretic act7vities.
~ The requisite starting materials of formula 2 ,~ 25 phenyihydrazine or subsiituted phenylhydrazines are known or are prepared according to known methods~ A convenient method for preparing the substituted phenylhydrazines involves the diazotizat~on of the appropiately substituted anil?ne to give the corresponding diazo derivative. The ~O la1ter compound is then reduced with stannous chloride or sodium sulfite to give the corresponding phenylhydrazine, -~
see L.F. Fieser and M Fieser, Advanced Organic Chemistry , ,~
: ~, - . , - . , , ~ .
.,,~
~S'~5~ :
' Reinhold Publishins Corporation, New York, 1961, p. 734. 1 The requisite starting mater7als of formula 3 .
are prepared by several methods. Three of these methods l .~ are illustrated in the following flow diagram in ~hlch ~.
Rl, R2, and R5 and n are as deftned herein, R6 ts ~
. hydroxy or butylthio and R7 is lower alkyl: ~;;
' '' ; ,;".
,~ ' : `~
"~ , ' ' ':~' '`'' "' :~
'''i ' - ; ~ ~
' ' ~
-12- 1, ~
.'; . . . ~. . .. .
, AHP-6154-l-CI
,~ ~
~Z~ il9 6~ R CH~ ~ ~
J ~ ~ 1~' R I R 1 CH2CH=CH2 I
6 ~ ~/ 6 ~ ~
~CH2 ) n - ~ :
. ' ~ ' ' ',' . ~ ~ .
R I ~H2COOR5 .,Z . .- . . ~: .
1~ 3 S . .
Y R2 R l~<CCH2)n ~CH2 ) n IX~/CH2 ) n J3 7 CH2COOR :
- 1~\ 7 Rl (CH2)2c R (CH2 )2COOR
.~ , . I
~, 9 10 'I ~ ~ ' ~j - ' . Z
. ~
,. .
.', , .
: - I 3 ,1 ' .~ ,, .
~,' :
9~9 : `
With reference to the first process for preparing the starting material, the substituted cycloalkanone of formula 6 is transformed into its corresponding hydroxymethylene derivative of formula 7 in which Rl, ~i R2 and n are as defined in the first instance and R
is hydroxy by treatment with ethyl formate in the presence i of sodium hydride. In turn the hydroxymethylene derivative s reacts readily with butanethiol to afford the corresponding i butylthiomethylene derivative of formula 7 in which Rl, R2 and n are as defined in the first instance and R
is butylthio. The latter compound is then subjected to .
alkylation with allyl bromide or allyl chloride in the ~-presence of a proton acceptor, preferably sodium tert- ;~
;~ amylate or potassium tert-butoxide, to give the ~_ corresponding butylthiomethylene derivative of the ketone ~ -~
of formula 8. Subsequent removal of the butylthiomethylene ~ -blocking group by heating the latter derivative in aqueous diethyleneglycol with sodium or potassium hydroxide ~
,~ . , . -see R.E. Ireland and J~A. Marshall, J. Amer. Chem. Soc., 81, l I
6336 (1959)] ~ields the corresponding ketone of formula 8.
The ketone of formula 8 is obtained alternatively by reacti;ng the appropriate substituted cycloalkanone o~
~; formula 6 directly with allyl bromide or chloride in the F~!' presence of a strong proton acceptor, for example, sodium terf t~ amylate, potassium tert-butoxide, sodamide, sodium hydride ahd the like, according to the method of J.M. Conia and F. Leyendecker, Bull. Soc. Chem. Fr., 830 (1967~.
~ ~ .
~ !
,~
~,,,~ , ': ' AHP-6154 -I-CI ~ ~
5~9 I I
., . . '' I' Oxidation of the ketone of formula 8 with ruthenium tetroxide-sodium metaperiodate according to the method of S.C. Welch and R.Y. Wong, Tetrahodron Letters, 1853 (1972) gives the desired starting material of formula 3 in which R5 is hydrogen. Thereafter, if desired, the latter compound, a cycloalkanoneacetic acid ;
derivative, is converted to its corresponding lower alkyl ester derivative of formula 3 by standard esterification methods; for example, by treatment with a lower alkanol in the presence of an acid, for instance, methanol and hydrogen chloride, or by treatment w;th an alkyl halide in the presence of a proton acceptor, for ,~ , , .
instance, methyl iodide and potassium carbonate.
`.~f. Alternatively the desired starting material is ., .
obtained by condensing the aforementioned substituted cycloalkanone of formula 6 with methyl acrylate in the presence of potassium tert-butoxide according to the method of H. House and M. Schellenbaum, J. Org. Chem , ;
~, 28, 34 (1963) to obtain the cycloalkanonepropionic acid , ~20 - lower alkyl ester of formula 9 in which Rl, R2, and n are as defined hereinbefore and R is lower alkyl. After , cdnversion of the latter compound to its corresponding ¦
ethylene ketal derivative of formula 10 with ethylene I
glycol and an acid catalyst, preferably p-toluenesulfonic t ~25 - acld, the ketal derivative is subjected to a Barbier-Wieland degredation according to the method of G. Stork, et 1., ~15~
. ,, "' .
;~ :, .. .
~ AHP-6154 -I-CI
~ t~
i7 J. Amer. Chem. Soc.,85, 3419 (1953). Mors specifically, the ketal 10 is first treated with an excess of phenyl magnesium bromide or chloride to give the corresponding diphenyl tertiary alcohol which on simultaneous deketalization and dehydration with aqueous acetic acid, and subsequent ;, oxidation of the resulting keto olefin with ruthenium tetroxide-sodium metaperiodate in the same manner as ' described above gives the corresponding desired starting material of formuia 3 in which R5 is hydrogen. If desired ~10 the latter compound is converted to its ccrresponding ~
Iower alkyl ester by esterification in the manner ~ ;
described previously to give the desired starting material , ~ of formula 3 in which R5 is lower alkyl.
3 Again alternatively a third method for preparing the starting material comprises the direct alkylation of the corresponding cycloalkanoneacetic acid lower alkyl ester of formula 11 in which R2 and n are as defined above and R is lower alkyl with the appropriate lower alkyl, ..
i lower alkenyl or lower cycloalkyl bromide, chloride or iodide Tn the prese~nce of a suitable proton acceptor preferably sodium tert-amylate or potassium tert-butoxide, according to the ¦~
method of Conia and Leyendecker, cited above, followed again by optional esterification as described above.
- The subsititued cycloalkanone utilized for ,~5 the first two processess for preparing the starting material ~are either known, for example, 2-methylcyclohexanone and , I .
,1, ' 'i ,, , , , ~ .. . . ............................. .. . . .
' ' ' ~ .'." , , AHP-6154-1-CI
~046~9 .,~ ' , , . .~' . 2-ethylcyclohexanone or are prepared by known methods, :~
. for example, see "Rodd's Chemistry of Carbon Compounds", . .
` 2nd Ed., S. Coffey, Ed., Elsevier Publishing.Company, .~ Amsterdam, Vol. 2A, 1967, pp. 64 - 168 and Vol. 2B, 1968, pp.92 - 113.
, ~ Likewise the cycloalkanoneacetic acid lower alkyl esters of formula 11, required for tbe aforementioned ~ .
methods are also known, for example, 1,4-dimethyl-2-cyclohexanone-l-acetic acid ethyl ester, see Welch and l : I
` 10 Wong, cited above, or they are prepared by known method, :
for example, see "Chemistry of Carbon Compounds", E.Ho .~ Rodd, Ed.. , Elsevier Publishing Co~, Amsterdam, Vol. 2A, ;
``~ 1953, pp. 220 - 248.
. Still another preparation of the compound of formula 3 is realized by subjecting an appropriately substituted 2-keto- .:
cycloa kaneacetoDitri i f formula 12 - ~C ~ H2) . 2 :
tn which R and n are as defined in the first instance to alkylation :~ ~ with the appropriate lower àlkyl, lower alkenyl or lower I cyclaalkyl bromide,chloride or iodide in the presence of a suitable proton acceptor, preferably sodium tert-amylate or potassium tert-butoxide, according to Ihe method of Conia ,.. ~ . . . ~1:;
. ~ I
,; .. 1~
~ -17- :~
;,~ ~1 AHP-6154 -i-CI
3~ ~ ~
and Leyendecher, cited above, to g7ve the corresponding compound of formula 13 R
~ l3 ~H2 ~ n Rl ~ H2CN
~, :
, , ,i in which R , R2 and n are as defined in the ftrst instance. Thereafter i the latter compound is subject to basic hydrolysis, prsferably - using sodium or potassium hydroxide as the base to give the ? 10 corresponding starting material of formula 3. -Tha requisite 2-ketocycloalkaneacetonitriles are elther known or are prepared by the method of G. Stork, et al., . Amer. Chem. Soc., 85, 207 (1963).
~: .
The above starting materials of formula 2 and , 15 formula _ are used to prepare the compounds of this ;
.~ .
-invention in the following manner: ~
; The starting material of formula 2 is condensed ;
with substantially one molar equivalent of the starting material of formula 3 to give the corresponding hydrazone of formula 4 in which R to R inclusive and n are as , ~ ~
si ~ defined in this first instance.
Generally speaking,the condensation is performed preferably in an inert atmosphere, for example, nitrogen ;
~t 25 or argon. Although not essential it is convenient to ~
effect the condensation in an inert solvent. Suitable ;
solvents include the lower alkanols such as methano, and ~
,, ' ~ ' ' ,; - 18 -., , - ~ ' : , - ,,~ ' .; . ; ; : ::
i :. , `,,:
'~ ethanol, aromatics such as benzene and toluene; the ethers, such as tetrahydrofuran, diethyl etner, dioxane, bis(2-methoxyethyl)-ether and 1he like; and the halogenated hydrocarbons, methylene chloride, chloroform and the like. Methanol and ethanol are especially convenient and practical solvents. Times and temperatures for the condensation generally range from 5 minutes to two ` or three days at 0 to 100C~ Convenient time and temperature ranges include 20C to the boiling point of the mixture and i~ 15 minutes to 24 hours.
The resulting hydrazone 4 is then cyclized to the tricyclic ester of formula 5 by the action of a suitable cyclization agent according to the conditions of the "Fischer Indole Synthesis", for example, see B. Robinson, Chem. Rev. 63, 373 tl963~.
A variety of cyclization agents are effective for this cyclylization; some of the agents suitable for this cyclization include ~-toluenesulfonic acid, hydrogen chloride, : ., -hydrogen bromide, phosphoric acid, sulturic acid, aluminum chloride, zinc chloride, hydrogen bromide in acetic acid, boron trifluoride-etherate, trifluoroacetic acid, cationic ion exchange resins such as Amberlite*lR-120, phenyl or ~¦ ethyl magnesium bromide and aniline salts. In other words ~ the usual catalysts employed for the "Fischer l-dole Synthesis"
`~ are efficacious; however, the preferred cyclization agents are aqueous solutions of strong acids, for example, 10 to 20 ~1 aqùeous sulfuric acid, concentrated hydrochloric acid or ...
~ *Trade Mark . .
~ J
~3 ,~
I g à
` :~ AHP-6154-1-CI
' ' .
L9 `
,~ .
., , , .
10% phosphoric acid.
In practice the isolation of the hydrazone 4 from the condensatlon reaction mixture is optional. Accordingly, the cyclization agent is added either to the above condensation reaction mixture containing the hydrazone, or to the isolated ;~
hydrazone optionally dissolved in one of the above inert i~
solvents, whereby the hydrazone then cyclizes to give the corresponding tricyclic ester of formula 5 in which R to R5 inclusive and n are as defined hereinbefore The cyclization usually proceeds smoothly and rapidly.
Convenient reaction times for the cyclization include five mTnutes to two hours, preferably five to 30 minutes. Convenient temperatures include 20 to 200C, preferably 120 to 180C.
`~ In practice a most convenient and practical procedure for effscting the above cyclization comprises evaporating solvent from the condensation reaction mixture containing the hydrazone, andthen heating the hydrazone at 120 to 200C
in one of the aforementioned solutions of strong acids; the ' use of an inert solvent during the cyclization being , omitted. Incidentally, by follo~wing this latter procedure the formation of a by-product of formula 14 ~: ,, , :
,` .~ ,. .
,:
: ' ' .
' , , ,' ~` '" ' ,, . . ,: . . .
; ~ AHP-6154 -I-CI
,., .
in which Rl, R2, R3 and n are as defined in the first instance, occurring when R of the hydrazone involved represents h~drogen, is substantially reduced by the use of the higher reaction temperatures and strong acid solutions.
As noted previously the starting material of formula 3 m3y be either a cycloalkanoneacetic acid derivative (R = hydrogen) or its corresponding lower alkyl ester (R5 = lower alkyl). Accordingly, when R of the starting material is hydrogen the above process yields the tricyclic compound of formula 5 in which R5 is hydrogen, this compound being identical to the desired compound of formula l;and when R5 of the starting material is lower alkyl the above process yields the tricyclic compound of formula 5 in which R5 is lower alkyl.
The subsequent conversion of the tricyclic compound of formula 5 in which R is lower alkyl to the corresponding compound of formula I is effected readily by subjecting the tricyclic compc,und to hydrolysis. Generally speaking, this conversion is most convsniently performed by employing a base as the hydroly2ing agentO The hydrolysis is performed in the presence of sufficient water, followed by acidification of the reaction mixture to yield the desired compound of formula 1. However, the manner of hydrolysis is not intended to be limited to basic hydrolysis since hydrolysis under acidic conditions and other variations, for example, treatment with lithium iodide in collidine (S~e L.F. Fieser and M. Fieser, "Reagents for Organic Synthesis", John '~iley and Sons, Inc., New York, 1967, pp. 615 - 617) zre also applicable.
For basic hydrolysis a preferred embodiment involves subjecting the tricyclic ester to the action of a base, for example, ,;,. , ~ .
:, . .
.:i :
, ':~., ~ . : ,, .Y
. . . . .
~ ~ AHP-615~ -I-CI
,~i 5~ .
:,. ' ;:
?; sodium or po-~assium carbonate, in the presence of sufficient water to effect hydrolysis of the ester. The hydrolysis is performed using a suitable 50 Ivent, for example, methanol or ethanol.
The reaction mixture is maintained at a temperature ~ of from 25C to the reflux temperature until hydrolysis ? occurs. Usually from lO minutes to 48 hours is sufficient for this hydrolysis. The reaction mixture is then rendered acidic with an acid, for example, acetic acid, hydrochloric acid, sulfuric acid and the like, to release the free acid ~ as a solid.
e Alternatively, the tricyclic ester is hydrolyzed by subjecting the ester to the action of a hydrolyzing agent - which is a strong organic or inorganic acid, for example, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric -~
acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid and the like in a suitable inert solvent at a temperature of at least 60C and preferably from 90C to the boiling point of the mixture until the hydrolysis occurs.
~ 20 Usually from 5 to 24 hours àre required for this hydrolysis.
.~ Suitable solvents include water, acetic acid, aqueous ~
~ alcohols and the like. If acid hydrolysis is used, the free ~ ?
?, . acid is formed directly. If necessary, the reaction mixture ~ can be diluted with water to precipitate the product. ~i ;~ 25 -Finally, it is the intention to cover all changes ~j and modifications of the embodiment of the invention chosen h~rein for the purpose of disclosure which are within the : 3 - ~ ~
, ` ~ ~; , .
:`' . ~ :
:~ :
-22- ~
:! ` . . . .: . .
:.~ ', - . '' ,,, . "' , ~, ' ' " ' , ' ' A~IP-6154-1-CI
seope and spiri~ cl this iUVol~iO~ r ~x~n~ , it wlll be obvious to those skilled in ~he art thal il is not critical to start with a compound of forrnula 2 in which R is lower alkyl in order to prepare a cornpound of forrnula I
in which R is lower alkyl. More specifically exemplified, the preceding process readily lends itseIf to an efficacious modification in which the tricyclic compound of formula 5 in which R is hydrogen is subjected to N-alkylâtion with the appropriate alkyl halide in the presence of one of the aforementioned proton acceptors, preferably sodium hydride, followed by hydrolysis, as described above, of the resulting ' N-alkylated tricyclic compound of formula 5 to give the corresponding compound of formula I in which R is lower alkyl. Likewise the preparation of the same compound 1~ of formula I (R = lower alkyl) by a similar N-alkylation ¦ of the corresponding compound of formula i in which R
is hydrogen is also intended to be included within the scope and spirit of this invention.
In a related aspect of this invention the tricyclic acetic `'~ acid compounds of tormula I as defined in the first instance as well ~ as the compounds of formula I in which Rl is methyl and R2 and R3 -1' are both hydrogen can be converted to corresponding amine derivatives of formula I in which the acetic acid residue is replaced by a ~onoalkylamino or dialkylamino residue and R4 is methyl, ethyl or i;
`3 propyl, This conversion can be effected by the methods described in U.S.Patent No. 3,852,285 of Demerson, et al., issued Dec. 3,1974, and its corresponding Canadian Patent Application, Serial No.
s 161,128 filed Jan.12, 1973, now Canadlan Patent No. 978,526, . _ .
issued November 25, 1975. For example, the tricyclic acetic acid ~ -compound of formula I can be reacted with methyl or ethyl chloroformate ~; in the presence of triethylamine to afford the corresponding mixed anhydrirJe which in turn is transforrned into the corresponding amide ', i,~,,) ,-.
.~ , .
... .
~ AHP-~154-1-CI
.,^ .
., , by treatment wlth the appropriate primary or secondary amine;
thereafter, the amide is reduced to the corresponding indolic amine with a complex metal hydride such as lithium aluminum hydride and said indolic amine is alkylated on the indolic nitrogen by standard methods to yield said corresponding amine. Such corresponding amines include:
1-[2-tdimethylamino)ethyl~-1,2,3,4-tetrahydro-1,9-dimethyl-carbazo1e, nmr (CDC13) ~ 1.4 (s, 3H), 2.19 (s, 6H), 3.8 (s, 3H), corresponding hydrochloride salt has m.p. 223 - 226C (dec), 1-~2-(dimethylamino)ethyl~-9-ethyl-1,2,3,4-tetrahydro-1-methyl- ` ~ ?
carbazole, nmr (CDC13) ~ 1.4 (t, J = 7, 3H), 1.4 (s, 3H), 2.2 ~s, 6H), corresponding hydrochloride salt has m.p. 206 - 209C, 9-ethyl-1,2,3,4-tetrahydro-1-methyl-1-[2-(methylamino)ethyl]- ! .
carbazole, nmr (CDC13) ~ 1.39 (t, J = 7, 3H), 1.41 ts, 3H), ~ -2.37 (s, 3H), corresponding hydrochloride salt has m.p. 213 - 216C, l-r2-(dimethylamino)ethyl]-lJ2~3~4-tetrahydro-l-methyl-9-pr carbazole, nmr (CDC13) ~ 1.0 (t, J = 7, 3H), 1.4 (s, 3H), ~
2.2 (s, 6H), corresponding hydrochloride sait has m.p. 230 - 233C, ~ ;
1-~2-(dimethylamino)ethyl~-8,9-diethyl-1,2,3,4-tetrahydro-1-methyl-carbazole, nmr (CDC13) ~ 1.18 (t, J = 7, 3H), 1.3 (t, J = 7, 3H), 1.47 (s, 3H), corresponding maleate has m.p. 80 - 90C, and 1-~2~dimethylamino)ethyl]-1,9-diethyl-1,2,3,4-tetrahydrocarbazole nmr (CDC13) ~ 0.85 (t, 3H), 1.45 (t, 3H), 2.2 (s, 6H), corresponding hydrobromide has m.p. 207 - 210C (dec).
The said corresponding amines are antidepressant agents and are used for this therapeutic purpose in the same manner as described for the amine antidepressants in said co-pending appl1cation S.N.217,627.
Preferred said amines are those corresponding to thecompound of formula I
in which Rl is methyl and R is methyl, ethyl or propyl.
The following examples illustrate further this invention.
.,, ' ,.
- 23a -:
AHP-615~ -I-CI
' ~0~51~
EXAMP~E I -2-lsopropYlPhenYlhYdrazine (2, R3 = 2-CH(C~13)2 and R = H) A mixture of the substituted aniline, 2-isopropylaniline (279, 0.2 mole), concentrated hydrochloric acid (150 ml) and water ~160 ml) is stirred mechanically for 30 minutes at !~ room temperature. After cooling to 0C, the mixture is diazotized by adding dropwise a solution of sodium nitrife ,~ (14 9, 0.203 mole) in water (140 ml) over a period of 20 minutes.
Stirring is continued for an additional one hour at 0C.
The diazo solution is reduced by adding dropwise a solution of stannous chloride dihydrate (112 9, 0.497 mole) in concentrated h~drochloric acid (90 ml) over a period of 30 minutes at -10C
to -15C. The reaction rnixture is stirred for an additional 1.5 hour at -10C to -15C. The precipitate is collected by filtration to give the hydrochloric acid addition salt of the title compound. The salt is purified further by dissolving ;it in ethanol, concentrating the solution and adding a saturated solution of hydrochloric acid in ether to give the hydrochloride salt with mp 206 - 210C.
~! By following the procedure of this example and USillg the appropriate substituted an~iline then other substituted hydrazines of formula 2, for example those described as starting i material`s in Examples 12 - 50, are obtained. More specifically - exemplified, the replacement of 2-isopropylaniline with anequivalent amount of 2-propylaniline gives 2-propylphenyl- ¦
hydrazine hydrochloride, mp 182 - 184C. Sirnilarily, replacement with 2-ethylaniline gives 2-ethylphenylhydrazine hydrochloride, mp j 181- 183C. ``
fl ~1 -24~
,s, , ` .
,_ . , : , , ,. . .
~ AHp-6l54-l-cl 5~L9 , .' 1:
EXA~PLE 2 2-Ethyl-6-(hydroxymethylene)cyclohexanone~7, Rl - C2H5, R2 = H, ;
R6 = OH and n = 3) To a stirred suspension of sodium hydride (18.2 9 of 53% ~
oil d7spersion, 0.4 mole) in dry ether cooled to 5 under nitrogen, I
absolute ethanol (2 ml) is added dropwise to initiate the reaction.
A solution of the substituted cycloalkanone, 2-ethylcyclohexanone t50.48 9, 0.4 mole), and ethyl formate (48.0 9, 0.6 mole) is ~hen added dropwise over a period of one hr. The mixture is stirred overnight at room temperature. To the stirred yellow suspension absolute ethanol (8 ml) in dry ether (80 ml) is added dropwise. Stirring is continued for one hr, then water ! ~ ' ~' . ~ ~ ' j (80 ml) is added. The mixture is transferred to separatory ~ -funnel, shaken well and the organic layer separated. The organic layer is washed once with waterO The aqueous layers are combined, washed once with ether and rendered acidic by the -~
careful addition of 6N HCI.
The acidic solution is extracted with ether (3 x).
- The ether extracts are washed once with brine, dried (MgS04) and concentrated.~The residue (57.2 9) is distilled to give the title compound, bp 82 - 84Cj8mm, nmr (CDC13) a 8.65 (59 IH), ~ ;
14.70 (broad s, IH). ~ I
,~ ' .
.1 . ' .;, . ' , . '~
. . ~ .
.;j '- . ::
, ~, .:
'i "' ' ' ' ' ' , :~ AHP-6154-1-CI
9 ' '~ i .~ I
`s EXAMPLE 3 ¦
2-[(gutylthio)methylene]-6-ethylcyclohexanone (7, ~ = C2H5, R2 = H, R = n-C4HgS and n - 3) A solution of 2-elhyl-6-(hydroxymethylene)cyclo-hexanone (43.0 9, 0.277 mole), described in Example 2, butylmercaptan (28.6 9, 0.318 mole) and ~-toluenesulfonic acid (50 mg) in dry benzene (200 ml) is heated at reflux under nitrogen for 4 hr using a Dean-Stark water separator.
The reaction mixture is cooled and washed with saturated aqueous ' ~i sodium bicarbonate (50 ml), water and brine, then dried ~MgS043. After removal of the solvent at reduced pressure the ~ residue is distilled to give the title compound, ;~
:~ bp 110 - 115C/1.5 mm, nmr (CDC13) ~ 0.92 (6H), 7.5 (m,lH). ~
.~ , . '' ~:
,~, , ~
,' ' . ~ :, - ' , ' ~ :
.
-'s ~ '; ' ', ~
,1 ~ ' , , . .
' ~, ." ' .
; - 26 -::
~ A~IP-6154-1-CI
;'' . -, ~65~
,` . .
~-~llyl-2-ethylcyclohexanone (8, Rl - C2H5, R2 = H and n = 3) Procedure A: .
To a well stirred solution of potassium ~ -butoxide (17.95 9, 0.16 mole) in dry redistilled tert-butanol (160 ml) under nitrogen, 2-[~butylthio)methylene]-6-ethylcylcohexanone (9.05 9, 0.04 mole), described in 1 Example 3, is added slowly. The mixture is stirred at '~ room temperature for 5 minutes and then chilled in an ice bath. AlIyl bromide (21.8 9, 0.18 mole) is added :
I rapidly to the chilled mixture. The mixture is then stirred at room temperature for 48 hr. Most OT the solvent is then ~;
~ ~ removed under reduced pressure and water (about 150 ml) is -i Hd ' added. The aqueous solution is extracted with ether (3 x).
, 15 The combined ether extracts are washed with brine, dried `~ (MgSO~) and concentrated to yield oil. The oil is subJected to chromotography on silica gel (320 9) using 4%
` ether in hexane as eluant. Concentration of the eluate gives 2-allyl-6-[(butylthio)methylene]-2-ethylcyclohexanone, nmr~CDC13) ~ 0,.85 (t, J=7, 3H), 2.85 (t, J=7, 2H), 4.80 - 6.0 (m, 3H), 7.5 (t, J=2, IH).
,j ; A solution of the latter compound (5.23 9, 0.0196 1 mole) in 25% NaOH (15 ml) and diethylene glycol (15 ml) 1~
, is heated at reflux overnight under nitrogen. The camphor ~ -~! 25 smelling mixture is steam distilled and about 250 ml of distillate is collected. The distillate is saturated with ~;
~?
~ ,i ~., -27~
.:, , ,. ~
,. .~ , .
, ~ . , .
, ~ .
. .
AHP-6154-1-CI ~
., ' .
,~ .
NaCI and ex-iracted with ether (4 x 60 ml). The combined ether extracts are washed with 25% aqueous KOH (2 x 10 m!), :1 then brine (2 x 40 ml) and dried (MgS04). Concentration of the extract affords the title compound as an oil, nmr (CDC13) ~ 0.78 (t, J~7, 3H), 2.15 - ~.4 trn, 4H), 4.8 - 6.1 (m, 3H).
Procedure B:
,ï To a suspension of sodium hydride (55% oil dispersion, 1.74 9, 0.04 mole) in dry dimethoxyethane(75 ml) cooled to ,.
5C, 2-ethylcyclohexanone (5.04 9, 0.04 mole) is added dropwise over a period of 10 minutes. The reaction mixture is allowed to reach room temperature and then heated to 80C for 1/2 hr. The mixture is cooled again at 5C and ;~
allyl bromide (3.45 ml, 4.489, 0.04 mole) is added dropwise.
The mixture is stirred at room temperature for I 1/2 hr. ~ -Water (10 ml) is added dropwise and the mixture transferred to a separatory funnel. It is extracted with ether twice. The ~ -`~ ether extracts are dried (MgS04) and concentrated to give `~ a yellow oil. The oil is subjected to chromatography on ~ -i~ si~ica gel (150 9) using 3~ ether in pentane as eluant.
The second main product to be eluted is the desired title compound identical to the product obtained by Procedure A.
In a manner similar to that described above under "B", , I~
2-methylcyclopentanone (6.6 9, 0.067 mole) and alIyl bromide (9.24 9, 0.07 mole) treated in anhydrous ether under nitrogen with sodium tert.-amylate (0.07 mole),worked up as above and purified by~ distillation, yield 2-alIyl-2-methylcyclopentanone as a colourless oil, b.p. 69-72C/12 mm ~1CmHacl3 1733, 925 cm 1, nmr (CDC13) ~ 1.05 (s), 4.85-6.15 (m).
.~
. , .:
s ~ AHP-6154-1-CI
.''' .
~ 4~ 9 , ~ EXAMPLE 5 -; I-Ethyl-2-oxocyclohexaneacetic Acid ~3, Rl = C2H5, R2 and R5 = H- _ ., and n = 3) A solution of 2-allyl-2-ethylcyclohexanone ~61 9, 0.37 mole), described in Example 4, in reagent acetone ~ is added dropwise under nitrogen to a solutTon of ruthenium J tetroxide (yellow) in carbon tetrachloride prepared as follows:
To ruthenium dioxide (4.7 9) in carbon tetrachloride (600 ml) stirred and cooled (ice bath) under nitrogen, add rapidly sodium metaperiodate (35 9) in water 250 ml. The yellow carbon tetrachloride layer is separated and used as such.
! I
' As the addition proceeds, the reaction mixture turns ¦ brown, then black as ruthenium dioxide precipitates. Reoxidation3, to yellow tetroxide is achieved by intermittent addition of sodium metaperiodate in aqueous solution or neat. Total ~ ;
~ weight of NalO4 used up: 375 9 in about 2 litres of water.
; Some acetone is added to keep the mixture homogeneous. The ;` temperature rises to 45C and some cooling is necessary to ' këep it around 30C.
The reaction is over after about 4.5 hours. Some isopropanol (50 ml) is added to destroy excess tetroxide.
` - The mixture is fiItered through a layer of diatomaceous ¦ -earth (Celite). The fiIter cake is thoroughly washed with 1 ~``i acetone. The organic layer of the fiItrate (CC14)is concentratedunder reduced pressure; the aqueous layer is saturated with sodium chloride and extracted with ether (4x)~ The combined organic fractions are washed with saturated aqueous sodium ~ ! :
.. ~ -... .
~:.$ : ~:
i'':~ ' ' ' ,, ~ , .
AHP~6154-1-CI
J~
s Z ' bicarbonate (7x~. The basic solution is rendered acidic by the careful addition of conc. HCI saturated wTth sodium chloride and then extracted with ether (4x).
The ether extracts are washed once with brine, drted (MgS04) and concentrated to afford the title compound, 3 3400, 1770, 1715 cm;l.
. In the same manner, but replacing 2-allyl-2-qthylcyclo-hexanone by 2-allyl-2-methylcyclopentanone described in Example 4 (6.01 9, 0.045 mole), treating the latter compound with ruthenium ~, 10 tetroxide prepared from 2.6 9 ruthenium dioxide and working up asdescribed above, there is obtained l-methyl-2-oxocyclopentane-acetic acid, m.p. 70-72C after recrystallization from ether-i - - hexane.
The corresponding ethyl ester is obtained by treating the above acid with ethy! bromide and anhydrous potassium carbonate in acetone solution under nitrogen and purifying by distiliafion.
~, - I-Methyl-2-oxocyclopentaneacetlc acid ethyl ester is obtained as ~`
a co!ourless oil, b.p. 63-64C/0.5 mm, vCHxC13 1730 cm ~, nmr - (CDC13) ~ 1.05 (5), 1.22 (t, J=7), 2.36 (d, J=17.5), 2.72 i- . - . : - ~
(d, J=17.5), 4.1 (q, J-7), identical with the compound described 5~ by L.E. King and R. Robinson in J. Chem. Soc. (1941), 465-470. -'ir' ;~ r ,, ;, ' . ' .
t~
, ~ :
.;., .: , .
~ ~IP-~154-1-CI
.
, ! -MathYI-2-ox~cYclohexanepropionic Acid Methyl Este _(9! Rl and R = CH3, R = H and n = 3) The substituted cycloalkanone, 2-methylcyclohexanone-(160 9. 1.27 mole), is added dropwise to a stirred solution of potassium tert-butoxide (7.0 9, 0.062 mole) in redistilled tert-butanol (325 ml) under nitrogen, followed by the addition ~ -of methyl acrylate (102.4 9, 1.20 mole). The temperature is kept below 30C by intermittent use of a cooling bath. Thereafter ~ -the mixture is stirred at room temperature for 2 hr. Dilute sulfuric acid (200 ml) is then added slowly. The aqueous phase ~ Ts separated and extracted with ether. The combined organic phases `~ are washed twice with brine, dried (MgS04) and concentrated to give a crude residue. The residue is ~ractionated by distillation through a 6 in. Vigreux column. The title compound distilis at ! 106 - 108/0.4 mm, nmr (CDC13) ~ 1.08 (s, 3H), 105 - 2.6 (m, 12 H), 3.66 (s, 3H).
In the same manner but replacing 2-methylcyclohexanone - with an equivalent amount of 2-ethylcyclohexanone or 2-propylcyclo-, hexanone, I-ethyl-2-oxocyclohexanepropionic acid methyl ester, :; ~
bp 117 - 120 C/0.4mm, and 1-propyl-2-oxocyclohexanepropi~onic methyl ester, ~CHC13 1735, 1700cml,are obtained, respectively.
.. i ' ~ . . :~
,. - . .' ~ -31-.`.,' ~
',. . 1:
,, .
, . .
.
, ~ AHP-6154-1-CI
f EXAMPLE 7 6-Methyl-1 4-dioxospiror4.51decane-6-ProPionic acid methyl ester (IO, RI and R = CH3, R2 = H and n = 3) ~ I ~
A solution of l-methyl-2-oxocyclohexanepropionic acid methyl ester (96.1 9, 0.48 mole), described in Example 6, ethylene-glycol (100 ml) and D-toluenesulfonic acid (2.0 9) in dry benzene (1600 ml) is heated at reflux for 6 hr using a water separator. The benzene solution is cooled, washed with ' saturated aqueous sodium bicarbonate solution (2 x 100 ml) then brine (2 x 100 ml), dried (MgS04) and concentrated to yield the title compound as an oil, VmaHX13 1725, IOB5 cml.
i ~In the same manner but replacing l-methyl-2-oxocyclohexane-propionic acid methyl ester with an equivalent amount of l-ethyl- ~ -2-oxocyclohexanepropionic acid methyl ester or 1-propyl-2-oxocyclo-hexanepropionic acid methyl ester, described in Example 6, ¦
6-ethyl-1,4-dioxospiro[4.5]decane-6-propionic acid methyi ester, v CHxl3 1730 cml and 6-propyl-1,4-dioxospiro[4.5]decane-6-propionic ~ i acid methy! ester, v maxl3 1735 cml, are obtained, respectively.
.~:
3 ~~-.
~ : "
:~ . ': , .~ ~ .
.~ .
`; !
~` ~
.: :
-32- ~
! ~ ~
~ ~
, .'. , .
I-Methyl-2-oxocyclohexaneacetic Acid (_, R -CH3JR2 and R5=H, and n = 3 A solution of 6-methyl-1,4-dioxospiro[4.5]decane-6-propionic acid methyl esl-er (52.5 g, 0.21 mole), described in Example 7, in anhydrous ether (500 ml) and dry benzene (100 ml) is added dropwise under nitrogen to a cooled(O - 5C) stirred solution of phenylmagnesium bromide in ether prepared from magnesium turnings (15.9 9, 0.65 mole), bromobenzene lQ
~75 ml, 0.72 mole) and anhydrous ether (500 ml). (Note: Only about 75 ml of ether is used to start the reaction with 15 drops methyl iodide and 2 - 3 ml bromobenzene). The mixture is stirred overnight at room temperature. Following the caretul addition of saturated ammonium chloride solution (114 ml) , 15 with cooling, fhe resulting yellow ether layer is decanted and the precipitated magnesium salts are rinsed thoroughly with ether. The combined ether layers are steam distilled and methanol (100 ml) and 25~ aqueous sodium hydroxide (150 ml) ~-is added to the residue. The mixture is iieated at reflux for ~ ;
2 hr to saponify any unreacted ester. The methanol is e~Japorated and the residue is extracted with ether (4x).
The ether extracts are dried (MgS04) and concentrated to give 6-methyl~a,C~-diphenyl-1,4-dioxaspiro[4.5]decane-6-propanol, mp 115 - 117C after recrystallization from chloroform-hexane, v I x13 3620, 3500, 1092 cml.
The latter compound (35.4 9, 0.07 mole) in acetic acid (500 ml) and water (10 rnl) is heated at reflux tor 4 hr.
, .
., . ~ .
.,. ~j .
j ~ -3~-: . .
.~. ': , ~ .
t AHP-6154-1-CI
,. . .
Evaporation of the solvents under reduced pressure and repeated evaporation with benzene gives 2-methyl-2-(3,3-diphenylallyl)cyc!ohexanone as an oil, v maHxc13 1740 cm .
The latter compound (2.40 9, 7.5 mmole) in acetone is oxidized with ruthenium tetroxide-sodium metaperiodata according to the procedure described in Example 5 to give the title compound, mp 87 - 90C
;~ after recrystallization from acetone hexane.
In the same manner but replacing 6-methyl-1,4-dioxosprio~4.5]decane-6-propionic acid methyl ester with an equivalent amount of 6-ethyl-1,4-dioxospiro~4.5]decane-6 propionic acid methyl ester, described in Example 7, I-ethyl-2-oxocyclohexaneacetic acid, identical to the :~
product of the same name in Example 5, is obtained via the respective intermediates, 6-ethyi-a ~-diphenyl-1,4-dloxaspiro[4.5]decane-6-propanol, VmaHXC13 3450 cm, nmr (CDC13) ~ 0.75 tt, J = 7, 3H), 3.85 (s, 4H), 7.2 - 7.6 (m, IOH) and 2-ethyl-2-(3,3-diphenylallyl)-~ cyclohexanone, v max13 1740 cml.
- 20 Again in the sama manner but replacing 6-methyl-1,4-dioxosprio~4.5]decane-6-propionic acid methyl ester with an e;quivalen~ amount of 6-propyl-1,4-dioxospiro[4.5]decane-6-propionic acid methyl ester, described in Example 7, 2-oxo-1-propylcyclohexaneacatic acid, v mHG13 1775, 1710 cml, is obtained via the respective intermediates, a ~-diphenyl-6-'propy!-1,6-dioxaspiro[4.5]decane-6-propanol, VmHX13 3620, 34~0, 1175, 1130, 1110, 1062 cml, and 2-(3,3-diphenylallyl)-2-propyIcyclohexanone, nmr (CDC13) ~ 0.85 tm, 3H), 6.0 (t~ IH), ;
7.3 (m, IOH).
~, 30 _3~_ ,~, ': ' : ' : ; ;'.' ., ~ :
~ AHP-6154 -I-CI
,,, S~9 ' .
I-Ethyl-2-oxocyclohexaneacetic Acid Methyl Ester (3, Rl = C2H5, : , .
R = H, R5 - CH and n = 3) 3 _ To a stirred solution of freshly prepared l-ethyl-2-i oxocyclohexaneacetic acid (68Q mg, 3.7 mmoles), described in Examples 5 and 8, under nitrogen at room temperature, anhydrous K2C03 (773 mg, 5.6 mmoles) and methyl iodide (3.5 ml, 7.98 9, ~ 56 mmoles)are added. The mixture is heated at reflux of 4.5 hr x10 during which time an additional 3 ml of methyl iodide is added every 1.5 hr. Thereafter the solvent is removed at reduced ~
. :$ . ` :~:
pressure, the residue is partitioned between ether and cold water. The organic layer is separated, washed wTth cold water untTI neutral, then once with brine and dried (MgS04)- Removal ~15 of the solvent at reduced pressure affords the title compound, vmax 3 1735, 1705 cm , nmr (CDC13) 6 0.8 (t, J=7, 3H), 1 3.62 (s, 3H).
;~ ~ In the same manner but replacing methyl iodide with i!~
an equivalent amou~t of ethyl iodide or propyl iodide, `20 i-ethyl-2-oxocyclohexanceacetic acid ethyl ester and 1-ethyl-2-oKocyclohexaneacetic acid propyl ester are obtained, respectively. ¦l In the same manner but replacing l-ethyl-2- 1' oxocyclohexaneacetic acid with an equivalent amount of l-methyl-2-oxocyclohexaneacetic acid, described in Example 8, 1-methyl-2- 11¦
Si~5 oxocyclohexaneacetic acid methyl ester, vCHXcl3 1735, 1705 cm, nmr (CDC13) ~ 1.23 (s,3H), 1.8 (m,6H), 2.1 (s, 2H), 2.6 (m,2H), 3.ff5 (s,3H;, is obtained.
~3 ;~ .
,,, ' .
~ -35-l , , ,., , i ' : ~ , . . .
" ~ ~ .
:., . . :
A~IP-6154-1-CI
.
In the same manner but replacing l-ethyl-2-oxocyclohexane-acetic acid with an equivalent amount of 2-oxo-1-propylchclohexane-acetlc acid, described in Example 8, and replacing mefhyl iodide ~' with an equivalent amount of ethyl iodide, 2-oxo-1-propylcyclohexane-~ acetic acid ethyl ester, ~mHxcl3 1725, 1705 cm, nmr (CDC13) s ~ 0.90 ~m,3H~, 1.25 ~t, J = 7, 3H), 2.52 (d, J = 4, 2H),
.: .
: ~ . :
: . .
~ AHP-6154-1-CI :
,-''' " .
Summary_of the Invent ion The compounds of this invention are represented by formula 1~ R2 ` , R3 ~ ~ )n CH2COOH . ;~
in~ Which Rl iS lower alkyl, lower alkenyl or lower cycloalkyl, R- is hydrogen or lower alky.l, . . :~
lU .K3 is hydrogen, lower alkyl, halo, hydroxy, lower alkoxy, ~
lower alkanoyloxy or trihalomethyl, R4 is hydrogen or lower alkyl :- :
and n Ts an integer from two to four, With the~proviso that Rl is I
othar than methyl when R2 and R3 are both hydrogen. : ..... . ~:
.. . . . . , , .. .. .. - . : , ..
The compounds Of this invention are prepared by a .
process in Which the hydrazine Of tormula 2, ~ ` ~ NR ~H2 in Which R3 and R 3re as defined herein iS condeosed ' .: ~ .
wi~h a compound Of formula 3, ' ~ ~ .
2 ~ I ` .
~ (CH2)n 3 Rl CH2CoOR
in whiCh R , R and n are as de~ined herein and R iS hydrrgen or lower '.
. '" ' 1~ ~. . .
--~
' ~ -alkyl to give the corresponding hydrazone of formula 4, `~
R3 ~ CH2 ~ ` ;:
l (CH21n in which R , R , R3, R , R5~ and n are as defined herein, The hydrazone is then cyclized by treatment with a ~ ~
cyclizing agent to give the corresponding tricyclic compound ; . . .
..
of formula 5~ R2 . -R3 - ~ (CH2)n 5 . R ~ CH COOR
. 2 .
ln which Rl, R2, R3, R , R5 and n are as defined herein;
. followed,when said compound of formula 5 îs other than s~d compound of formula 1, by subjecttng the compound of formuia 5 to hydrolysis conditions to give the desired corresponding ~ ~ 20 compound of formula 1. -- In other words, when R of said compound of formula 5 is hydrogen, the compound is the desired compound of formula I and when R of said compound of formula 5 is ~:
~ ~.
Iower alkyl, the compounds of formula 5 is treated with a ' bydrolyz7ng agent to give the desired correspond7ng compound ;~
of formula 1.
. .
1 :-,.~. : -: :, , :
:;: , . - : . ' A~IP-6154-l-CI
~0~ 19 Detalled Descriptlon of the Invention The term "lower alkyl" as used herein contemplates straight chain alkyl radicals containing from one to six carbon atoms and branched chain alkyl radical containing from three to four carbon atoms and includes methyl, efhyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl and the :
like.
.. . , . .
The term "lower alkenyl" as used herein contemplates straight chain alkenyl radicals containing from two to six 0 carbon atoms and branched chain alkenyl radicals containing . I -~
from three to four carbon atoms and includes vinyl, allyl, I-propenyl, isopropenyl, 2-methyipropenyl and the like.
- The tsrm "lower cycloalkyl" as used herein contemplates saturated cyclic hydrocarbon radicals containing from three ~ i to six carbon atoms and includes cyclopropyl, cyclobutyl, ~;
cyclopenty! and cyclohexyl.
The term "lower alkoxy" as used herein contemplates both straight and branched chain alkoxy radicals containing from one to four carbon atoms and includes methoxy, ethoxy, isopropoxy, t-butoxy and the like.
.~ , .
The term "lower alkanoyloxy" as used herein - ;~
contemplates both straight and branched chain alkanoyloxy ~;
radicals containing from two to six carbon atoms and includes acetoxy, propionyloxy, pivaloyloxy, hexanoyloxy and the li~e.
The term "halo" as used herein contemplates halogens and includes fluorine, chlorine, bromine and iodine.
The term "trihalomethyl" as used herein contemplates trifluoromethyl, trichloromethyl and tribromomethyl. ¦, ,1 ::
` AHP-615~ -I-CI
L9 :
:' ;, The compounds of formula I form salts with suitable pharmaceutically acceptable inorganic and organic bases. These derived salts possess the same activity as the ;
parent acid and are included within the scope of thls invention. The acid is transformed in excellent yield into the corresponding pharmaceutically acceptable salts by neutralization of said acid with the appropriate inorganic ;~
or organic base. The salts are administered in the same manner as the parent acid compounds. Suitable inorganic bases to form these salts include, for example, the ;~
hydroxides, carbonates, bicarbonates or alkoxides of the alkali metals or alkaline earth metals, for example, sodium, - potassium, magnesium, calcium and the like. Suitable organic bases include the following amines; lower mono-, dt- and trialkylamines, the alkyl radicals of which contain up to three carbon atoms, such as methylamine, dimethylamine, ~ ~
trimethylamine, ethylamine, di- and triethylamine, methylethylamine, ~ ~ ;
and the like; mono-; di and trialkanolamines, the alkanol ~:, radicals of which contain up to three carbon atoms, such as mono-, di- and triethanolamine;~alkylene-diamines which contain up to six carbon atoms, such as hexamethylenediamine;
: . ~
cyclic saturated or unsaturated bases containing up to six . ~ ~ - I
carbon atoms, such as pyrrolidine, piperidine, morpholine, piperazine and their N-alkyl and N-hydroxyalkyl derivatives, ¦ ~-such as N-methyl-morpholine and N-(2-hydroxyethyl~piperidine, as wèll as pyridine. Furthermore, there may be mentioned ~;
-. .
": ~' . . ` ' "
.
. . ~ , , ~ A~1P-~154-1-CI
;S~g the corresponding quaternary salts, such as the tetraalkyl (for example tetramethyl), alkyl-alkanol (for example methyl-trimethanol and trimeihyl-monoethanol) and cyclic ammonium sal-ts, for example the N-methyl-pyridinium, N-me-thyl-N~
(2-hydroxyethyl)-morpholinium, N,N-dimethyl-morpholir,ium, N-methyl-N~2-hydroxyethyl)-morpholinium, N,N-dimethyl-piperidinium salts, which are characterized by a good water-solubility. In principle, hcwever, there can be used all the ammonium salts which are physiologically compatible.
The transformations to the salts can be carried out by a variety of methods known in the art. For example, in the case of the inorganic salts, it is preferred to dissolve the selected acid in wa;er containing at least one equivalent amount of a hydroxide, carbonate, or bicarbonate corresponding to the inorganic salt desired. Advantageously, -the reaction is performed in a water-miscible, inert organic solvent, for example~ methanol, ethanol, dioxane, and the like in the presence of water. For example, such use of sodium hydroxide, sodium carbonate or sodium bicarbonate gives a solution of the sodium salt. Evaporation of the solution or addition of a water-miscible solvent of a more moderate polarity, for example, a lower alkanol, for instance, butanol, or a lower alkanone, for instance, ethyl methyl ketone, gives the solid inorganic salt if that form is desir~d. ~
: ``:
, .. . .
.. ,,.~, .
., .
, ~ , , , ~
,,j To produce an amine salt, the selected acid is dissolved in a suitable solvent of either moderate or low ~-polarity, for example, ethanol, acetone, ethyl acetate, ~ ;
d7ethyl ether and benzene. At least an equivalent amount ` - ' of the amine corresponding to the'desired cation is then '~ '~
added to that solution. If the resulting sait does not precipitate, it can usually be obtained in solid form by addition of a miscible diluent of low polarity, for example, benzene or petroleum ether, -or by evaporation. If the amine is relatively volatile, any : .
excess can easily be removed by evaporation. It is preferred to use substantially equivalent amounts of the less volatile amines.
Saits wherein the cation is quaternary ammonium are produced by mixing the selected acid with an equivalent amount of the corresponding quaternary ammonium hydroxide in water solution, followed by evaporation of the water. ;
~ ~ Also included within the scope of this inveniion ;~ are the isomers of the compounds of formula I resulting from - the asymmetric centers contained therein. ; -AntiinflammatorY Activit~Y ' - , ~
- The useful antiinflammatory activities of the tricYclic acetic acid derivatives are demonstrated in standard pharmacologic tests, for example, the tests described by R.A. Turner in i ~ "Screening Methods in Pharmacology", Academic Press, New York and'London, 1965, pp. 152 - 163.
. More particularly exemplIfied the antiinflammatory , ¦
, ~ "
. . 9~
' :'' . :', ' '~ ' ' ' ' ,' .
AHP-6154-1-CI ~-., , ~
. .
effect for the compounds of this invention is demonstrated readily in a modification of the established arthritis test in rats described by B.B. Newbould, Br. J. Pharmac., 35, 487 (1969). In this test rats are made arthritic by treating them with an injection of Freund's adjuvant into the left hind pa~. After 14 days (day 0 of test) a chronic arthritis is established. At this point the rats are treated with a uniform daily dose of the test compound ;
from day 0 to day 8 of the test. Results are expressed as the change in volume of the injected paw from day 0. Untreated arthritic rats show an increased ..
paw size whereas active compounds cause a reduction in ~
. .
the volume of the injected paw. ~;
Typical results obtained for the compounds of -~
the present invention in the aforementioned test are as ~ ~ .
~ ~ follows: ~ --- , :~
Compound Daily Dose Reduction of ~ (mg/kg/p.o.) Paw Size (ml) I-ethyl-1,2,3,4-tetra- 10 0.88 hydrocarbazole-l-aceti~c acid (Example 51) ~;
I-ethyl-8-isopropyl- 10 1.53 ~ i~
1,2,3,4-tetrahydro- ;
carb zole-l-acetic acid (Example 58) -1,8-diethyl-1,2,3,4tetra- 10 1.19 ~1 hydrocarbazole~l-acetic acid (Example 56) In contrast the compo~nd of the prtor art, 1,2,3,4 1-tetrahydrocarbæ ole-l-acetic acid, showed no reduction of paw size at a daily dose of 10 or even 100 mg/kg/pOo. under the conditions of this test. ¦ ~`~
' ' ' - 1 0-!
:',.'. ' : , ; ~.. ' ,, ,' :' o 4 ~ 5 ~, 9 ¦ ¦ -- :: ~
The lack of side effects for the compounds of this invention i ara demonstrated by standard acute toxicity tests (see Turner cTted i ~`
l above) and by prolonged administra-iion of the compound to warm-blooded anlmals.
~,5 When the compounds of this invention are employed as antiinflammatory agents in-- _ I' I .
warm-blooded animals, e.g., rats, they are administered orally, alone or in dosage forms, i.e., capsules or tablets, combined with pharmacologically acceptable excipients, or they are .
administered orally in the form of soiutions in suitab~e ; vehicles such as vegetable oils or water.
The dosage of the indole derivatives of this inventlon will vary with the particular compound chosen and form -~ ~ of administration. Furthermore~ it will vary with the `~ !`
i~l5 parficular host under treatment. Generally, the compounds ;``~
of this invention are administered at a concentration ievel that affords protective effects without any deleterious side ~ `
effects. These antiinflammatorily effective ~
concentration levels are usually obtalned within a therapeutic ~ ;~ ; ;
20~1 range of l.O mg to SOO mg/kg per day, with a preferred ; -~ range of IO to IOO mg/kg per day.
The compounds of thTs invention also possess analgesTc and antipyretic act7vities.
~ The requisite starting materials of formula 2 ,~ 25 phenyihydrazine or subsiituted phenylhydrazines are known or are prepared according to known methods~ A convenient method for preparing the substituted phenylhydrazines involves the diazotizat~on of the appropiately substituted anil?ne to give the corresponding diazo derivative. The ~O la1ter compound is then reduced with stannous chloride or sodium sulfite to give the corresponding phenylhydrazine, -~
see L.F. Fieser and M Fieser, Advanced Organic Chemistry , ,~
: ~, - . , - . , , ~ .
.,,~
~S'~5~ :
' Reinhold Publishins Corporation, New York, 1961, p. 734. 1 The requisite starting mater7als of formula 3 .
are prepared by several methods. Three of these methods l .~ are illustrated in the following flow diagram in ~hlch ~.
Rl, R2, and R5 and n are as deftned herein, R6 ts ~
. hydroxy or butylthio and R7 is lower alkyl: ~;;
' '' ; ,;".
,~ ' : `~
"~ , ' ' ':~' '`'' "' :~
'''i ' - ; ~ ~
' ' ~
-12- 1, ~
.'; . . . ~. . .. .
, AHP-6154-l-CI
,~ ~
~Z~ il9 6~ R CH~ ~ ~
J ~ ~ 1~' R I R 1 CH2CH=CH2 I
6 ~ ~/ 6 ~ ~
~CH2 ) n - ~ :
. ' ~ ' ' ',' . ~ ~ .
R I ~H2COOR5 .,Z . .- . . ~: .
1~ 3 S . .
Y R2 R l~<CCH2)n ~CH2 ) n IX~/CH2 ) n J3 7 CH2COOR :
- 1~\ 7 Rl (CH2)2c R (CH2 )2COOR
.~ , . I
~, 9 10 'I ~ ~ ' ~j - ' . Z
. ~
,. .
.', , .
: - I 3 ,1 ' .~ ,, .
~,' :
9~9 : `
With reference to the first process for preparing the starting material, the substituted cycloalkanone of formula 6 is transformed into its corresponding hydroxymethylene derivative of formula 7 in which Rl, ~i R2 and n are as defined in the first instance and R
is hydroxy by treatment with ethyl formate in the presence i of sodium hydride. In turn the hydroxymethylene derivative s reacts readily with butanethiol to afford the corresponding i butylthiomethylene derivative of formula 7 in which Rl, R2 and n are as defined in the first instance and R
is butylthio. The latter compound is then subjected to .
alkylation with allyl bromide or allyl chloride in the ~-presence of a proton acceptor, preferably sodium tert- ;~
;~ amylate or potassium tert-butoxide, to give the ~_ corresponding butylthiomethylene derivative of the ketone ~ -~
of formula 8. Subsequent removal of the butylthiomethylene ~ -blocking group by heating the latter derivative in aqueous diethyleneglycol with sodium or potassium hydroxide ~
,~ . , . -see R.E. Ireland and J~A. Marshall, J. Amer. Chem. Soc., 81, l I
6336 (1959)] ~ields the corresponding ketone of formula 8.
The ketone of formula 8 is obtained alternatively by reacti;ng the appropriate substituted cycloalkanone o~
~; formula 6 directly with allyl bromide or chloride in the F~!' presence of a strong proton acceptor, for example, sodium terf t~ amylate, potassium tert-butoxide, sodamide, sodium hydride ahd the like, according to the method of J.M. Conia and F. Leyendecker, Bull. Soc. Chem. Fr., 830 (1967~.
~ ~ .
~ !
,~
~,,,~ , ': ' AHP-6154 -I-CI ~ ~
5~9 I I
., . . '' I' Oxidation of the ketone of formula 8 with ruthenium tetroxide-sodium metaperiodate according to the method of S.C. Welch and R.Y. Wong, Tetrahodron Letters, 1853 (1972) gives the desired starting material of formula 3 in which R5 is hydrogen. Thereafter, if desired, the latter compound, a cycloalkanoneacetic acid ;
derivative, is converted to its corresponding lower alkyl ester derivative of formula 3 by standard esterification methods; for example, by treatment with a lower alkanol in the presence of an acid, for instance, methanol and hydrogen chloride, or by treatment w;th an alkyl halide in the presence of a proton acceptor, for ,~ , , .
instance, methyl iodide and potassium carbonate.
`.~f. Alternatively the desired starting material is ., .
obtained by condensing the aforementioned substituted cycloalkanone of formula 6 with methyl acrylate in the presence of potassium tert-butoxide according to the method of H. House and M. Schellenbaum, J. Org. Chem , ;
~, 28, 34 (1963) to obtain the cycloalkanonepropionic acid , ~20 - lower alkyl ester of formula 9 in which Rl, R2, and n are as defined hereinbefore and R is lower alkyl. After , cdnversion of the latter compound to its corresponding ¦
ethylene ketal derivative of formula 10 with ethylene I
glycol and an acid catalyst, preferably p-toluenesulfonic t ~25 - acld, the ketal derivative is subjected to a Barbier-Wieland degredation according to the method of G. Stork, et 1., ~15~
. ,, "' .
;~ :, .. .
~ AHP-6154 -I-CI
~ t~
i7 J. Amer. Chem. Soc.,85, 3419 (1953). Mors specifically, the ketal 10 is first treated with an excess of phenyl magnesium bromide or chloride to give the corresponding diphenyl tertiary alcohol which on simultaneous deketalization and dehydration with aqueous acetic acid, and subsequent ;, oxidation of the resulting keto olefin with ruthenium tetroxide-sodium metaperiodate in the same manner as ' described above gives the corresponding desired starting material of formuia 3 in which R5 is hydrogen. If desired ~10 the latter compound is converted to its ccrresponding ~
Iower alkyl ester by esterification in the manner ~ ;
described previously to give the desired starting material , ~ of formula 3 in which R5 is lower alkyl.
3 Again alternatively a third method for preparing the starting material comprises the direct alkylation of the corresponding cycloalkanoneacetic acid lower alkyl ester of formula 11 in which R2 and n are as defined above and R is lower alkyl with the appropriate lower alkyl, ..
i lower alkenyl or lower cycloalkyl bromide, chloride or iodide Tn the prese~nce of a suitable proton acceptor preferably sodium tert-amylate or potassium tert-butoxide, according to the ¦~
method of Conia and Leyendecker, cited above, followed again by optional esterification as described above.
- The subsititued cycloalkanone utilized for ,~5 the first two processess for preparing the starting material ~are either known, for example, 2-methylcyclohexanone and , I .
,1, ' 'i ,, , , , ~ .. . . ............................. .. . . .
' ' ' ~ .'." , , AHP-6154-1-CI
~046~9 .,~ ' , , . .~' . 2-ethylcyclohexanone or are prepared by known methods, :~
. for example, see "Rodd's Chemistry of Carbon Compounds", . .
` 2nd Ed., S. Coffey, Ed., Elsevier Publishing.Company, .~ Amsterdam, Vol. 2A, 1967, pp. 64 - 168 and Vol. 2B, 1968, pp.92 - 113.
, ~ Likewise the cycloalkanoneacetic acid lower alkyl esters of formula 11, required for tbe aforementioned ~ .
methods are also known, for example, 1,4-dimethyl-2-cyclohexanone-l-acetic acid ethyl ester, see Welch and l : I
` 10 Wong, cited above, or they are prepared by known method, :
for example, see "Chemistry of Carbon Compounds", E.Ho .~ Rodd, Ed.. , Elsevier Publishing Co~, Amsterdam, Vol. 2A, ;
``~ 1953, pp. 220 - 248.
. Still another preparation of the compound of formula 3 is realized by subjecting an appropriately substituted 2-keto- .:
cycloa kaneacetoDitri i f formula 12 - ~C ~ H2) . 2 :
tn which R and n are as defined in the first instance to alkylation :~ ~ with the appropriate lower àlkyl, lower alkenyl or lower I cyclaalkyl bromide,chloride or iodide in the presence of a suitable proton acceptor, preferably sodium tert-amylate or potassium tert-butoxide, according to Ihe method of Conia ,.. ~ . . . ~1:;
. ~ I
,; .. 1~
~ -17- :~
;,~ ~1 AHP-6154 -i-CI
3~ ~ ~
and Leyendecher, cited above, to g7ve the corresponding compound of formula 13 R
~ l3 ~H2 ~ n Rl ~ H2CN
~, :
, , ,i in which R , R2 and n are as defined in the ftrst instance. Thereafter i the latter compound is subject to basic hydrolysis, prsferably - using sodium or potassium hydroxide as the base to give the ? 10 corresponding starting material of formula 3. -Tha requisite 2-ketocycloalkaneacetonitriles are elther known or are prepared by the method of G. Stork, et al., . Amer. Chem. Soc., 85, 207 (1963).
~: .
The above starting materials of formula 2 and , 15 formula _ are used to prepare the compounds of this ;
.~ .
-invention in the following manner: ~
; The starting material of formula 2 is condensed ;
with substantially one molar equivalent of the starting material of formula 3 to give the corresponding hydrazone of formula 4 in which R to R inclusive and n are as , ~ ~
si ~ defined in this first instance.
Generally speaking,the condensation is performed preferably in an inert atmosphere, for example, nitrogen ;
~t 25 or argon. Although not essential it is convenient to ~
effect the condensation in an inert solvent. Suitable ;
solvents include the lower alkanols such as methano, and ~
,, ' ~ ' ' ,; - 18 -., , - ~ ' : , - ,,~ ' .; . ; ; : ::
i :. , `,,:
'~ ethanol, aromatics such as benzene and toluene; the ethers, such as tetrahydrofuran, diethyl etner, dioxane, bis(2-methoxyethyl)-ether and 1he like; and the halogenated hydrocarbons, methylene chloride, chloroform and the like. Methanol and ethanol are especially convenient and practical solvents. Times and temperatures for the condensation generally range from 5 minutes to two ` or three days at 0 to 100C~ Convenient time and temperature ranges include 20C to the boiling point of the mixture and i~ 15 minutes to 24 hours.
The resulting hydrazone 4 is then cyclized to the tricyclic ester of formula 5 by the action of a suitable cyclization agent according to the conditions of the "Fischer Indole Synthesis", for example, see B. Robinson, Chem. Rev. 63, 373 tl963~.
A variety of cyclization agents are effective for this cyclylization; some of the agents suitable for this cyclization include ~-toluenesulfonic acid, hydrogen chloride, : ., -hydrogen bromide, phosphoric acid, sulturic acid, aluminum chloride, zinc chloride, hydrogen bromide in acetic acid, boron trifluoride-etherate, trifluoroacetic acid, cationic ion exchange resins such as Amberlite*lR-120, phenyl or ~¦ ethyl magnesium bromide and aniline salts. In other words ~ the usual catalysts employed for the "Fischer l-dole Synthesis"
`~ are efficacious; however, the preferred cyclization agents are aqueous solutions of strong acids, for example, 10 to 20 ~1 aqùeous sulfuric acid, concentrated hydrochloric acid or ...
~ *Trade Mark . .
~ J
~3 ,~
I g à
` :~ AHP-6154-1-CI
' ' .
L9 `
,~ .
., , , .
10% phosphoric acid.
In practice the isolation of the hydrazone 4 from the condensatlon reaction mixture is optional. Accordingly, the cyclization agent is added either to the above condensation reaction mixture containing the hydrazone, or to the isolated ;~
hydrazone optionally dissolved in one of the above inert i~
solvents, whereby the hydrazone then cyclizes to give the corresponding tricyclic ester of formula 5 in which R to R5 inclusive and n are as defined hereinbefore The cyclization usually proceeds smoothly and rapidly.
Convenient reaction times for the cyclization include five mTnutes to two hours, preferably five to 30 minutes. Convenient temperatures include 20 to 200C, preferably 120 to 180C.
`~ In practice a most convenient and practical procedure for effscting the above cyclization comprises evaporating solvent from the condensation reaction mixture containing the hydrazone, andthen heating the hydrazone at 120 to 200C
in one of the aforementioned solutions of strong acids; the ' use of an inert solvent during the cyclization being , omitted. Incidentally, by follo~wing this latter procedure the formation of a by-product of formula 14 ~: ,, , :
,` .~ ,. .
,:
: ' ' .
' , , ,' ~` '" ' ,, . . ,: . . .
; ~ AHP-6154 -I-CI
,., .
in which Rl, R2, R3 and n are as defined in the first instance, occurring when R of the hydrazone involved represents h~drogen, is substantially reduced by the use of the higher reaction temperatures and strong acid solutions.
As noted previously the starting material of formula 3 m3y be either a cycloalkanoneacetic acid derivative (R = hydrogen) or its corresponding lower alkyl ester (R5 = lower alkyl). Accordingly, when R of the starting material is hydrogen the above process yields the tricyclic compound of formula 5 in which R5 is hydrogen, this compound being identical to the desired compound of formula l;and when R5 of the starting material is lower alkyl the above process yields the tricyclic compound of formula 5 in which R5 is lower alkyl.
The subsequent conversion of the tricyclic compound of formula 5 in which R is lower alkyl to the corresponding compound of formula I is effected readily by subjecting the tricyclic compc,und to hydrolysis. Generally speaking, this conversion is most convsniently performed by employing a base as the hydroly2ing agentO The hydrolysis is performed in the presence of sufficient water, followed by acidification of the reaction mixture to yield the desired compound of formula 1. However, the manner of hydrolysis is not intended to be limited to basic hydrolysis since hydrolysis under acidic conditions and other variations, for example, treatment with lithium iodide in collidine (S~e L.F. Fieser and M. Fieser, "Reagents for Organic Synthesis", John '~iley and Sons, Inc., New York, 1967, pp. 615 - 617) zre also applicable.
For basic hydrolysis a preferred embodiment involves subjecting the tricyclic ester to the action of a base, for example, ,;,. , ~ .
:, . .
.:i :
, ':~., ~ . : ,, .Y
. . . . .
~ ~ AHP-615~ -I-CI
,~i 5~ .
:,. ' ;:
?; sodium or po-~assium carbonate, in the presence of sufficient water to effect hydrolysis of the ester. The hydrolysis is performed using a suitable 50 Ivent, for example, methanol or ethanol.
The reaction mixture is maintained at a temperature ~ of from 25C to the reflux temperature until hydrolysis ? occurs. Usually from lO minutes to 48 hours is sufficient for this hydrolysis. The reaction mixture is then rendered acidic with an acid, for example, acetic acid, hydrochloric acid, sulfuric acid and the like, to release the free acid ~ as a solid.
e Alternatively, the tricyclic ester is hydrolyzed by subjecting the ester to the action of a hydrolyzing agent - which is a strong organic or inorganic acid, for example, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric -~
acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid and the like in a suitable inert solvent at a temperature of at least 60C and preferably from 90C to the boiling point of the mixture until the hydrolysis occurs.
~ 20 Usually from 5 to 24 hours àre required for this hydrolysis.
.~ Suitable solvents include water, acetic acid, aqueous ~
~ alcohols and the like. If acid hydrolysis is used, the free ~ ?
?, . acid is formed directly. If necessary, the reaction mixture ~ can be diluted with water to precipitate the product. ~i ;~ 25 -Finally, it is the intention to cover all changes ~j and modifications of the embodiment of the invention chosen h~rein for the purpose of disclosure which are within the : 3 - ~ ~
, ` ~ ~; , .
:`' . ~ :
:~ :
-22- ~
:! ` . . . .: . .
:.~ ', - . '' ,,, . "' , ~, ' ' " ' , ' ' A~IP-6154-1-CI
seope and spiri~ cl this iUVol~iO~ r ~x~n~ , it wlll be obvious to those skilled in ~he art thal il is not critical to start with a compound of forrnula 2 in which R is lower alkyl in order to prepare a cornpound of forrnula I
in which R is lower alkyl. More specifically exemplified, the preceding process readily lends itseIf to an efficacious modification in which the tricyclic compound of formula 5 in which R is hydrogen is subjected to N-alkylâtion with the appropriate alkyl halide in the presence of one of the aforementioned proton acceptors, preferably sodium hydride, followed by hydrolysis, as described above, of the resulting ' N-alkylated tricyclic compound of formula 5 to give the corresponding compound of formula I in which R is lower alkyl. Likewise the preparation of the same compound 1~ of formula I (R = lower alkyl) by a similar N-alkylation ¦ of the corresponding compound of formula i in which R
is hydrogen is also intended to be included within the scope and spirit of this invention.
In a related aspect of this invention the tricyclic acetic `'~ acid compounds of tormula I as defined in the first instance as well ~ as the compounds of formula I in which Rl is methyl and R2 and R3 -1' are both hydrogen can be converted to corresponding amine derivatives of formula I in which the acetic acid residue is replaced by a ~onoalkylamino or dialkylamino residue and R4 is methyl, ethyl or i;
`3 propyl, This conversion can be effected by the methods described in U.S.Patent No. 3,852,285 of Demerson, et al., issued Dec. 3,1974, and its corresponding Canadian Patent Application, Serial No.
s 161,128 filed Jan.12, 1973, now Canadlan Patent No. 978,526, . _ .
issued November 25, 1975. For example, the tricyclic acetic acid ~ -compound of formula I can be reacted with methyl or ethyl chloroformate ~; in the presence of triethylamine to afford the corresponding mixed anhydrirJe which in turn is transforrned into the corresponding amide ', i,~,,) ,-.
.~ , .
... .
~ AHP-~154-1-CI
.,^ .
., , by treatment wlth the appropriate primary or secondary amine;
thereafter, the amide is reduced to the corresponding indolic amine with a complex metal hydride such as lithium aluminum hydride and said indolic amine is alkylated on the indolic nitrogen by standard methods to yield said corresponding amine. Such corresponding amines include:
1-[2-tdimethylamino)ethyl~-1,2,3,4-tetrahydro-1,9-dimethyl-carbazo1e, nmr (CDC13) ~ 1.4 (s, 3H), 2.19 (s, 6H), 3.8 (s, 3H), corresponding hydrochloride salt has m.p. 223 - 226C (dec), 1-~2-(dimethylamino)ethyl~-9-ethyl-1,2,3,4-tetrahydro-1-methyl- ` ~ ?
carbazole, nmr (CDC13) ~ 1.4 (t, J = 7, 3H), 1.4 (s, 3H), 2.2 ~s, 6H), corresponding hydrochloride salt has m.p. 206 - 209C, 9-ethyl-1,2,3,4-tetrahydro-1-methyl-1-[2-(methylamino)ethyl]- ! .
carbazole, nmr (CDC13) ~ 1.39 (t, J = 7, 3H), 1.41 ts, 3H), ~ -2.37 (s, 3H), corresponding hydrochloride salt has m.p. 213 - 216C, l-r2-(dimethylamino)ethyl]-lJ2~3~4-tetrahydro-l-methyl-9-pr carbazole, nmr (CDC13) ~ 1.0 (t, J = 7, 3H), 1.4 (s, 3H), ~
2.2 (s, 6H), corresponding hydrochloride sait has m.p. 230 - 233C, ~ ;
1-~2-(dimethylamino)ethyl~-8,9-diethyl-1,2,3,4-tetrahydro-1-methyl-carbazole, nmr (CDC13) ~ 1.18 (t, J = 7, 3H), 1.3 (t, J = 7, 3H), 1.47 (s, 3H), corresponding maleate has m.p. 80 - 90C, and 1-~2~dimethylamino)ethyl]-1,9-diethyl-1,2,3,4-tetrahydrocarbazole nmr (CDC13) ~ 0.85 (t, 3H), 1.45 (t, 3H), 2.2 (s, 6H), corresponding hydrobromide has m.p. 207 - 210C (dec).
The said corresponding amines are antidepressant agents and are used for this therapeutic purpose in the same manner as described for the amine antidepressants in said co-pending appl1cation S.N.217,627.
Preferred said amines are those corresponding to thecompound of formula I
in which Rl is methyl and R is methyl, ethyl or propyl.
The following examples illustrate further this invention.
.,, ' ,.
- 23a -:
AHP-615~ -I-CI
' ~0~51~
EXAMP~E I -2-lsopropYlPhenYlhYdrazine (2, R3 = 2-CH(C~13)2 and R = H) A mixture of the substituted aniline, 2-isopropylaniline (279, 0.2 mole), concentrated hydrochloric acid (150 ml) and water ~160 ml) is stirred mechanically for 30 minutes at !~ room temperature. After cooling to 0C, the mixture is diazotized by adding dropwise a solution of sodium nitrife ,~ (14 9, 0.203 mole) in water (140 ml) over a period of 20 minutes.
Stirring is continued for an additional one hour at 0C.
The diazo solution is reduced by adding dropwise a solution of stannous chloride dihydrate (112 9, 0.497 mole) in concentrated h~drochloric acid (90 ml) over a period of 30 minutes at -10C
to -15C. The reaction rnixture is stirred for an additional 1.5 hour at -10C to -15C. The precipitate is collected by filtration to give the hydrochloric acid addition salt of the title compound. The salt is purified further by dissolving ;it in ethanol, concentrating the solution and adding a saturated solution of hydrochloric acid in ether to give the hydrochloride salt with mp 206 - 210C.
~! By following the procedure of this example and USillg the appropriate substituted an~iline then other substituted hydrazines of formula 2, for example those described as starting i material`s in Examples 12 - 50, are obtained. More specifically - exemplified, the replacement of 2-isopropylaniline with anequivalent amount of 2-propylaniline gives 2-propylphenyl- ¦
hydrazine hydrochloride, mp 182 - 184C. Sirnilarily, replacement with 2-ethylaniline gives 2-ethylphenylhydrazine hydrochloride, mp j 181- 183C. ``
fl ~1 -24~
,s, , ` .
,_ . , : , , ,. . .
~ AHp-6l54-l-cl 5~L9 , .' 1:
EXA~PLE 2 2-Ethyl-6-(hydroxymethylene)cyclohexanone~7, Rl - C2H5, R2 = H, ;
R6 = OH and n = 3) To a stirred suspension of sodium hydride (18.2 9 of 53% ~
oil d7spersion, 0.4 mole) in dry ether cooled to 5 under nitrogen, I
absolute ethanol (2 ml) is added dropwise to initiate the reaction.
A solution of the substituted cycloalkanone, 2-ethylcyclohexanone t50.48 9, 0.4 mole), and ethyl formate (48.0 9, 0.6 mole) is ~hen added dropwise over a period of one hr. The mixture is stirred overnight at room temperature. To the stirred yellow suspension absolute ethanol (8 ml) in dry ether (80 ml) is added dropwise. Stirring is continued for one hr, then water ! ~ ' ~' . ~ ~ ' j (80 ml) is added. The mixture is transferred to separatory ~ -funnel, shaken well and the organic layer separated. The organic layer is washed once with waterO The aqueous layers are combined, washed once with ether and rendered acidic by the -~
careful addition of 6N HCI.
The acidic solution is extracted with ether (3 x).
- The ether extracts are washed once with brine, dried (MgS04) and concentrated.~The residue (57.2 9) is distilled to give the title compound, bp 82 - 84Cj8mm, nmr (CDC13) a 8.65 (59 IH), ~ ;
14.70 (broad s, IH). ~ I
,~ ' .
.1 . ' .;, . ' , . '~
. . ~ .
.;j '- . ::
, ~, .:
'i "' ' ' ' ' ' , :~ AHP-6154-1-CI
9 ' '~ i .~ I
`s EXAMPLE 3 ¦
2-[(gutylthio)methylene]-6-ethylcyclohexanone (7, ~ = C2H5, R2 = H, R = n-C4HgS and n - 3) A solution of 2-elhyl-6-(hydroxymethylene)cyclo-hexanone (43.0 9, 0.277 mole), described in Example 2, butylmercaptan (28.6 9, 0.318 mole) and ~-toluenesulfonic acid (50 mg) in dry benzene (200 ml) is heated at reflux under nitrogen for 4 hr using a Dean-Stark water separator.
The reaction mixture is cooled and washed with saturated aqueous ' ~i sodium bicarbonate (50 ml), water and brine, then dried ~MgS043. After removal of the solvent at reduced pressure the ~ residue is distilled to give the title compound, ;~
:~ bp 110 - 115C/1.5 mm, nmr (CDC13) ~ 0.92 (6H), 7.5 (m,lH). ~
.~ , . '' ~:
,~, , ~
,' ' . ~ :, - ' , ' ~ :
.
-'s ~ '; ' ', ~
,1 ~ ' , , . .
' ~, ." ' .
; - 26 -::
~ A~IP-6154-1-CI
;'' . -, ~65~
,` . .
~-~llyl-2-ethylcyclohexanone (8, Rl - C2H5, R2 = H and n = 3) Procedure A: .
To a well stirred solution of potassium ~ -butoxide (17.95 9, 0.16 mole) in dry redistilled tert-butanol (160 ml) under nitrogen, 2-[~butylthio)methylene]-6-ethylcylcohexanone (9.05 9, 0.04 mole), described in 1 Example 3, is added slowly. The mixture is stirred at '~ room temperature for 5 minutes and then chilled in an ice bath. AlIyl bromide (21.8 9, 0.18 mole) is added :
I rapidly to the chilled mixture. The mixture is then stirred at room temperature for 48 hr. Most OT the solvent is then ~;
~ ~ removed under reduced pressure and water (about 150 ml) is -i Hd ' added. The aqueous solution is extracted with ether (3 x).
, 15 The combined ether extracts are washed with brine, dried `~ (MgSO~) and concentrated to yield oil. The oil is subJected to chromotography on silica gel (320 9) using 4%
` ether in hexane as eluant. Concentration of the eluate gives 2-allyl-6-[(butylthio)methylene]-2-ethylcyclohexanone, nmr~CDC13) ~ 0,.85 (t, J=7, 3H), 2.85 (t, J=7, 2H), 4.80 - 6.0 (m, 3H), 7.5 (t, J=2, IH).
,j ; A solution of the latter compound (5.23 9, 0.0196 1 mole) in 25% NaOH (15 ml) and diethylene glycol (15 ml) 1~
, is heated at reflux overnight under nitrogen. The camphor ~ -~! 25 smelling mixture is steam distilled and about 250 ml of distillate is collected. The distillate is saturated with ~;
~?
~ ,i ~., -27~
.:, , ,. ~
,. .~ , .
, ~ . , .
, ~ .
. .
AHP-6154-1-CI ~
., ' .
,~ .
NaCI and ex-iracted with ether (4 x 60 ml). The combined ether extracts are washed with 25% aqueous KOH (2 x 10 m!), :1 then brine (2 x 40 ml) and dried (MgS04). Concentration of the extract affords the title compound as an oil, nmr (CDC13) ~ 0.78 (t, J~7, 3H), 2.15 - ~.4 trn, 4H), 4.8 - 6.1 (m, 3H).
Procedure B:
,ï To a suspension of sodium hydride (55% oil dispersion, 1.74 9, 0.04 mole) in dry dimethoxyethane(75 ml) cooled to ,.
5C, 2-ethylcyclohexanone (5.04 9, 0.04 mole) is added dropwise over a period of 10 minutes. The reaction mixture is allowed to reach room temperature and then heated to 80C for 1/2 hr. The mixture is cooled again at 5C and ;~
allyl bromide (3.45 ml, 4.489, 0.04 mole) is added dropwise.
The mixture is stirred at room temperature for I 1/2 hr. ~ -Water (10 ml) is added dropwise and the mixture transferred to a separatory funnel. It is extracted with ether twice. The ~ -`~ ether extracts are dried (MgS04) and concentrated to give `~ a yellow oil. The oil is subjected to chromatography on ~ -i~ si~ica gel (150 9) using 3~ ether in pentane as eluant.
The second main product to be eluted is the desired title compound identical to the product obtained by Procedure A.
In a manner similar to that described above under "B", , I~
2-methylcyclopentanone (6.6 9, 0.067 mole) and alIyl bromide (9.24 9, 0.07 mole) treated in anhydrous ether under nitrogen with sodium tert.-amylate (0.07 mole),worked up as above and purified by~ distillation, yield 2-alIyl-2-methylcyclopentanone as a colourless oil, b.p. 69-72C/12 mm ~1CmHacl3 1733, 925 cm 1, nmr (CDC13) ~ 1.05 (s), 4.85-6.15 (m).
.~
. , .:
s ~ AHP-6154-1-CI
.''' .
~ 4~ 9 , ~ EXAMPLE 5 -; I-Ethyl-2-oxocyclohexaneacetic Acid ~3, Rl = C2H5, R2 and R5 = H- _ ., and n = 3) A solution of 2-allyl-2-ethylcyclohexanone ~61 9, 0.37 mole), described in Example 4, in reagent acetone ~ is added dropwise under nitrogen to a solutTon of ruthenium J tetroxide (yellow) in carbon tetrachloride prepared as follows:
To ruthenium dioxide (4.7 9) in carbon tetrachloride (600 ml) stirred and cooled (ice bath) under nitrogen, add rapidly sodium metaperiodate (35 9) in water 250 ml. The yellow carbon tetrachloride layer is separated and used as such.
! I
' As the addition proceeds, the reaction mixture turns ¦ brown, then black as ruthenium dioxide precipitates. Reoxidation3, to yellow tetroxide is achieved by intermittent addition of sodium metaperiodate in aqueous solution or neat. Total ~ ;
~ weight of NalO4 used up: 375 9 in about 2 litres of water.
; Some acetone is added to keep the mixture homogeneous. The ;` temperature rises to 45C and some cooling is necessary to ' këep it around 30C.
The reaction is over after about 4.5 hours. Some isopropanol (50 ml) is added to destroy excess tetroxide.
` - The mixture is fiItered through a layer of diatomaceous ¦ -earth (Celite). The fiIter cake is thoroughly washed with 1 ~``i acetone. The organic layer of the fiItrate (CC14)is concentratedunder reduced pressure; the aqueous layer is saturated with sodium chloride and extracted with ether (4x)~ The combined organic fractions are washed with saturated aqueous sodium ~ ! :
.. ~ -... .
~:.$ : ~:
i'':~ ' ' ' ,, ~ , .
AHP~6154-1-CI
J~
s Z ' bicarbonate (7x~. The basic solution is rendered acidic by the careful addition of conc. HCI saturated wTth sodium chloride and then extracted with ether (4x).
The ether extracts are washed once with brine, drted (MgS04) and concentrated to afford the title compound, 3 3400, 1770, 1715 cm;l.
. In the same manner, but replacing 2-allyl-2-qthylcyclo-hexanone by 2-allyl-2-methylcyclopentanone described in Example 4 (6.01 9, 0.045 mole), treating the latter compound with ruthenium ~, 10 tetroxide prepared from 2.6 9 ruthenium dioxide and working up asdescribed above, there is obtained l-methyl-2-oxocyclopentane-acetic acid, m.p. 70-72C after recrystallization from ether-i - - hexane.
The corresponding ethyl ester is obtained by treating the above acid with ethy! bromide and anhydrous potassium carbonate in acetone solution under nitrogen and purifying by distiliafion.
~, - I-Methyl-2-oxocyclopentaneacetlc acid ethyl ester is obtained as ~`
a co!ourless oil, b.p. 63-64C/0.5 mm, vCHxC13 1730 cm ~, nmr - (CDC13) ~ 1.05 (5), 1.22 (t, J=7), 2.36 (d, J=17.5), 2.72 i- . - . : - ~
(d, J=17.5), 4.1 (q, J-7), identical with the compound described 5~ by L.E. King and R. Robinson in J. Chem. Soc. (1941), 465-470. -'ir' ;~ r ,, ;, ' . ' .
t~
, ~ :
.;., .: , .
~ ~IP-~154-1-CI
.
, ! -MathYI-2-ox~cYclohexanepropionic Acid Methyl Este _(9! Rl and R = CH3, R = H and n = 3) The substituted cycloalkanone, 2-methylcyclohexanone-(160 9. 1.27 mole), is added dropwise to a stirred solution of potassium tert-butoxide (7.0 9, 0.062 mole) in redistilled tert-butanol (325 ml) under nitrogen, followed by the addition ~ -of methyl acrylate (102.4 9, 1.20 mole). The temperature is kept below 30C by intermittent use of a cooling bath. Thereafter ~ -the mixture is stirred at room temperature for 2 hr. Dilute sulfuric acid (200 ml) is then added slowly. The aqueous phase ~ Ts separated and extracted with ether. The combined organic phases `~ are washed twice with brine, dried (MgS04) and concentrated to give a crude residue. The residue is ~ractionated by distillation through a 6 in. Vigreux column. The title compound distilis at ! 106 - 108/0.4 mm, nmr (CDC13) ~ 1.08 (s, 3H), 105 - 2.6 (m, 12 H), 3.66 (s, 3H).
In the same manner but replacing 2-methylcyclohexanone - with an equivalent amount of 2-ethylcyclohexanone or 2-propylcyclo-, hexanone, I-ethyl-2-oxocyclohexanepropionic acid methyl ester, :; ~
bp 117 - 120 C/0.4mm, and 1-propyl-2-oxocyclohexanepropi~onic methyl ester, ~CHC13 1735, 1700cml,are obtained, respectively.
.. i ' ~ . . :~
,. - . .' ~ -31-.`.,' ~
',. . 1:
,, .
, . .
.
, ~ AHP-6154-1-CI
f EXAMPLE 7 6-Methyl-1 4-dioxospiror4.51decane-6-ProPionic acid methyl ester (IO, RI and R = CH3, R2 = H and n = 3) ~ I ~
A solution of l-methyl-2-oxocyclohexanepropionic acid methyl ester (96.1 9, 0.48 mole), described in Example 6, ethylene-glycol (100 ml) and D-toluenesulfonic acid (2.0 9) in dry benzene (1600 ml) is heated at reflux for 6 hr using a water separator. The benzene solution is cooled, washed with ' saturated aqueous sodium bicarbonate solution (2 x 100 ml) then brine (2 x 100 ml), dried (MgS04) and concentrated to yield the title compound as an oil, VmaHX13 1725, IOB5 cml.
i ~In the same manner but replacing l-methyl-2-oxocyclohexane-propionic acid methyl ester with an equivalent amount of l-ethyl- ~ -2-oxocyclohexanepropionic acid methyl ester or 1-propyl-2-oxocyclo-hexanepropionic acid methyl ester, described in Example 6, ¦
6-ethyl-1,4-dioxospiro[4.5]decane-6-propionic acid methyi ester, v CHxl3 1730 cml and 6-propyl-1,4-dioxospiro[4.5]decane-6-propionic ~ i acid methy! ester, v maxl3 1735 cml, are obtained, respectively.
.~:
3 ~~-.
~ : "
:~ . ': , .~ ~ .
.~ .
`; !
~` ~
.: :
-32- ~
! ~ ~
~ ~
, .'. , .
I-Methyl-2-oxocyclohexaneacetic Acid (_, R -CH3JR2 and R5=H, and n = 3 A solution of 6-methyl-1,4-dioxospiro[4.5]decane-6-propionic acid methyl esl-er (52.5 g, 0.21 mole), described in Example 7, in anhydrous ether (500 ml) and dry benzene (100 ml) is added dropwise under nitrogen to a cooled(O - 5C) stirred solution of phenylmagnesium bromide in ether prepared from magnesium turnings (15.9 9, 0.65 mole), bromobenzene lQ
~75 ml, 0.72 mole) and anhydrous ether (500 ml). (Note: Only about 75 ml of ether is used to start the reaction with 15 drops methyl iodide and 2 - 3 ml bromobenzene). The mixture is stirred overnight at room temperature. Following the caretul addition of saturated ammonium chloride solution (114 ml) , 15 with cooling, fhe resulting yellow ether layer is decanted and the precipitated magnesium salts are rinsed thoroughly with ether. The combined ether layers are steam distilled and methanol (100 ml) and 25~ aqueous sodium hydroxide (150 ml) ~-is added to the residue. The mixture is iieated at reflux for ~ ;
2 hr to saponify any unreacted ester. The methanol is e~Japorated and the residue is extracted with ether (4x).
The ether extracts are dried (MgS04) and concentrated to give 6-methyl~a,C~-diphenyl-1,4-dioxaspiro[4.5]decane-6-propanol, mp 115 - 117C after recrystallization from chloroform-hexane, v I x13 3620, 3500, 1092 cml.
The latter compound (35.4 9, 0.07 mole) in acetic acid (500 ml) and water (10 rnl) is heated at reflux tor 4 hr.
, .
., . ~ .
.,. ~j .
j ~ -3~-: . .
.~. ': , ~ .
t AHP-6154-1-CI
,. . .
Evaporation of the solvents under reduced pressure and repeated evaporation with benzene gives 2-methyl-2-(3,3-diphenylallyl)cyc!ohexanone as an oil, v maHxc13 1740 cm .
The latter compound (2.40 9, 7.5 mmole) in acetone is oxidized with ruthenium tetroxide-sodium metaperiodata according to the procedure described in Example 5 to give the title compound, mp 87 - 90C
;~ after recrystallization from acetone hexane.
In the same manner but replacing 6-methyl-1,4-dioxosprio~4.5]decane-6-propionic acid methyl ester with an equivalent amount of 6-ethyl-1,4-dioxospiro~4.5]decane-6 propionic acid methyl ester, described in Example 7, I-ethyl-2-oxocyclohexaneacetic acid, identical to the :~
product of the same name in Example 5, is obtained via the respective intermediates, 6-ethyi-a ~-diphenyl-1,4-dloxaspiro[4.5]decane-6-propanol, VmaHXC13 3450 cm, nmr (CDC13) ~ 0.75 tt, J = 7, 3H), 3.85 (s, 4H), 7.2 - 7.6 (m, IOH) and 2-ethyl-2-(3,3-diphenylallyl)-~ cyclohexanone, v max13 1740 cml.
- 20 Again in the sama manner but replacing 6-methyl-1,4-dioxosprio~4.5]decane-6-propionic acid methyl ester with an e;quivalen~ amount of 6-propyl-1,4-dioxospiro[4.5]decane-6-propionic acid methyl ester, described in Example 7, 2-oxo-1-propylcyclohexaneacatic acid, v mHG13 1775, 1710 cml, is obtained via the respective intermediates, a ~-diphenyl-6-'propy!-1,6-dioxaspiro[4.5]decane-6-propanol, VmHX13 3620, 34~0, 1175, 1130, 1110, 1062 cml, and 2-(3,3-diphenylallyl)-2-propyIcyclohexanone, nmr (CDC13) ~ 0.85 tm, 3H), 6.0 (t~ IH), ;
7.3 (m, IOH).
~, 30 _3~_ ,~, ': ' : ' : ; ;'.' ., ~ :
~ AHP-6154 -I-CI
,,, S~9 ' .
I-Ethyl-2-oxocyclohexaneacetic Acid Methyl Ester (3, Rl = C2H5, : , .
R = H, R5 - CH and n = 3) 3 _ To a stirred solution of freshly prepared l-ethyl-2-i oxocyclohexaneacetic acid (68Q mg, 3.7 mmoles), described in Examples 5 and 8, under nitrogen at room temperature, anhydrous K2C03 (773 mg, 5.6 mmoles) and methyl iodide (3.5 ml, 7.98 9, ~ 56 mmoles)are added. The mixture is heated at reflux of 4.5 hr x10 during which time an additional 3 ml of methyl iodide is added every 1.5 hr. Thereafter the solvent is removed at reduced ~
. :$ . ` :~:
pressure, the residue is partitioned between ether and cold water. The organic layer is separated, washed wTth cold water untTI neutral, then once with brine and dried (MgS04)- Removal ~15 of the solvent at reduced pressure affords the title compound, vmax 3 1735, 1705 cm , nmr (CDC13) 6 0.8 (t, J=7, 3H), 1 3.62 (s, 3H).
;~ ~ In the same manner but replacing methyl iodide with i!~
an equivalent amou~t of ethyl iodide or propyl iodide, `20 i-ethyl-2-oxocyclohexanceacetic acid ethyl ester and 1-ethyl-2-oKocyclohexaneacetic acid propyl ester are obtained, respectively. ¦l In the same manner but replacing l-ethyl-2- 1' oxocyclohexaneacetic acid with an equivalent amount of l-methyl-2-oxocyclohexaneacetic acid, described in Example 8, 1-methyl-2- 11¦
Si~5 oxocyclohexaneacetic acid methyl ester, vCHXcl3 1735, 1705 cm, nmr (CDC13) ~ 1.23 (s,3H), 1.8 (m,6H), 2.1 (s, 2H), 2.6 (m,2H), 3.ff5 (s,3H;, is obtained.
~3 ;~ .
,,, ' .
~ -35-l , , ,., , i ' : ~ , . . .
" ~ ~ .
:., . . :
A~IP-6154-1-CI
.
In the same manner but replacing l-ethyl-2-oxocyclohexane-acetic acid with an equivalent amount of 2-oxo-1-propylchclohexane-acetlc acid, described in Example 8, and replacing mefhyl iodide ~' with an equivalent amount of ethyl iodide, 2-oxo-1-propylcyclohexane-~ acetic acid ethyl ester, ~mHxcl3 1725, 1705 cm, nmr (CDC13) s ~ 0.90 ~m,3H~, 1.25 ~t, J = 7, 3H), 2.52 (d, J = 4, 2H),
4.15 (q, J = 7, 2H), is obtained.
' By following serially the procedures of Examples 2,3,4,5 ;~ and optionally the procedure of Example 9 and using the appropriate 1~ substituted cycloalkanone then other starting materials of formula 3, for example those described as starting materials in Examples 12 - 50 are obtained.
:~ ' - , ,:
,3 `''; ~ ~ ,' .
; . 1 ~ -36- 1 : s ~ ~1 Al-IP-615~1-CI
.' . '', ,'' .
EXAMPLE IO
1.2~3,4-Tetrahvdro-l-methyl_arbazole-l-acetic Acid Methyl Ester (5, Rl and R = ÇH3, R2, R3 and R = ~1 and n = 3) ; A solution of the starting material of formula 3,,! 5 1-methyl-2-oxocyclohexaneacetic acid methyl ester (18.0 g, 0.097 mole~, described in Example 9, and phenylhydrazine (10.6 9, 0.097 mole) in anhydrous ethanol (300 ml) is heated at reflux under nitrogen for 4 hr. Concentration of the reaction mixture affords the corresponding phenylhydrazone of the starting material of formula 3 as a solid , mp 84.5 - 86.5C.
The phenylhydrazone is heated at reflux (bath temp = 150C) with an excess of 10% aqueous sulfuric acid for 15 minutes. The solution is cooled rapidly,~ -saturated with sodium chloride and extracted with ether (4x).
The ether extracts are combined and washed with 5% aqueous NaOH dried (MgS04) and concentrated. The residue is subjected to chromatography on silica gel using 2.5% acetone in benzene as eluant. Concentration of the eluate gives the . ~ .
title compound, nmr (CDC13~ ~ 1.45 (s, 3H), 1.75 - 2.0 (m, 4H), 2.65 (s, 2H), 2.75(m, 2H), 3.68 (s, 3H), 6.9 - 7.6 (m, 4H), 9.2 (s, IH). `~
Further elution with the same eluent afforded a small amount of the by-product, 4a-methyl-2-phenyl-4,4a,5,6,7,8-hexahydro-3(2H)-cinnolinone, (14, Rl - CH3, R2 and R3 = H and ~ n = 3), mp 82 - 83C after recrystallization from hexane.
The procedure of Example 10 is followed to prepare ; ~
."
:
: .
'i : , ' AHP-6154-1-CI
other compounds of formula 5 in which Rl, R2, R3, R , R5 and n are as defined in the first instance. For example, by using and equivalent amoun-t of l-ethyl-2-oxocyclohexane . acetic acid me-thyl ester, described in Example 9, instead .~ 5 of 1-methyl-2-oxocyclohexane acetic acid in the procedure of.Example 10, 1-ethyl-1,2,3,4tetrahydrocarbazole-1-acetic acid methyl ester, (5, R = C2H5, R2, R3 and R4 = H, R = CH3 . and n = 3), mp 67 - 71C af-ter crystallization from benzene, ~ is obtained via the intermediate hydrazone, I-ethyl-2-`f 10 oxocyclohexaneacetic acid methyl ester phenyl hydrazone ~:
(4, Rl = C2H5, R2, R3 and R4 = H, R5 = CH3 and n = 3), ~ :
mp 98 - 99.5C after recrystallization from ethanol.
, Further examples of such compounds of formula 5 whlch can be prepared by the procedure of Example 10 are llsted in Tables I, II and III . In each of these examples .~
an equivalent amoun-t of the hydrazine of formula 2 and the :~ starting material of formula 3, listed therein, is used in : place of the phenylhydrazine and the starting material of ,, , ~ formula 3 noted in Example 10. 1 1 . I ;~
, ~ . .
,, . ! ' ~
' ~:
.. -~ 38 ~ :
,,',. -. : ' : . ' ' TABLE I
. .
Product: (Pre~ix listed below~- 1,2,3,4-Hydrazine of Starting Material tetrahydrocarbazole-l-ace,i~
Ex Formula 2 of Formula _ acid (suf~Tx listed ~elo~l) !
` = R3 R Rl R2 R5 n PREFIX//SUFFIX
11 H H n-C H7 HC2H5 3 I-propyl//ethyl ester~ mp 64-S6C ¦
3 vmaHC13 3400, 1715 cm .
lla H H n~C3H7 H CH3 3 I-propyl//methyl ester, mp 88-90 12 2-CH3 H CH3 HCH3 3 1,8-dimethyl/~methyl ester ; 13 3-C H CH CH H CH 3 5-(and 7-)methyl-1,9-dimethyl//
2 5 3 3 3 methyl ester 14 4-(i-C3H7) H CH3 HC2H5 3 6-isopropyl-1-methyl/~ethyl ester H C2~5 CH3 H H 3 9-ethyl-1-methylj~(no suffix) nmr (CDCI ) ~ 1.35 (t, J = 7, 3H) 1.4 (s, 3~), 4.3 (q, 2H) 16 2-C2H5 H C2H5 H CH3 3 mp 91 _ gY3oc/ Y
~:~ 17 2-(n-C H7) H C2H5 H CH3 3 mp ggY 100CPY I ;
~ 18 2-(i-C H ) H C H H CH3 3 1-ethyl-8-isopropyl//methyl ester 1~ 3 7 2 5 nmr (CDCI ) ~ 0.85 (t, J = 7, 3H), 1.41 (d, J3 = 7, 6~), 1.8 (m, 6), 2.7 (m, 4), 3.25 (m, IH), 3.70 1 (s, 3H), 7.2 (m, 3H), 9.6 (b, IH) -1 19 2-CI` H C2H5 H CH3 3 8-chloro~l-ethyl//methyl ester 4-F n-C H C H 4- H 3 1-ethyl-6-fluoro-4-methyl-9-propyl ;~ 3 2 5 CH3 ~ // (no suffix) ~-~ 21 4-OCH3 H; C2H5 H CH3 3 mp 75 - 78C I
-~;- 22 3-OC H H C2H5 _ C2H5 3 1,3-diethy1-5-(and 7-)ethoxy/i 2 5 2H5 ethyl ester 23 2-OCOCH3 H C2H5 , H CH3 3 8-acetoxy-1-ethyl//methyl est:r 24 4-OCOC2H5 H C2H5 H CH3 3 1-ethy1-6-propionoxy//methyl este . 25 2-CF3 C2H5 C2H5 H C2H5 3 1,9-diethyl-8-trifluoromet y //
. . _ , : ` ' '.~ . .
.~ - , ~ ' 1 _ 39 ,;, .
~ ` AHP-6154-1-CI
, TABLE I
,.; _ .; Product: (Pre'ix listed !
' '~elow)- 1,2,3,4-: Hydrazine of Starting Material tetrahydrocarbazole-l-acetic Ex Formula 2 of Formula ~ acid (suffix. ITsted belo~
= R3 R4 R R2 R5 n PREFIX//SUFFIX
264-CF3 H C2H5 H CH3 3 1-ethy1-6-trifluoromethyl//
. methyl ester , .
., 27 H H n~C3H7 H H 3I-propyl//(no suffix), vCaHx13 ..
. 3490 - 3430, 1705 cml.
., 282-OH H n~C3H7 5_ C2H5 3 8-hydroxy-3-methyl-1-propyl//
", 10 CH3 ethyl ester ;~ 29 2-CH CH3 n~C3H7 4~ CH3 34,8,9-trimefhyl-1-propyl// ~~ 3 . CH~ methyl ester ' . , ;
.~:. 30 H H n-C4Hg H CH3 3 I-but'yl//methyl es,ter ., . 31 2 5 H n-C4~Jg H CH3 3 1-butyl-8-et'nyl//methyl ester , 1 ¦ 32 ~n~C ~9 11-C4Hg ¦ H ~:H3 ¦ 3 ~ 1,8- i~utyl//mrthvl 5ter i ~ ~ l ~ ¦
i~,.,', . ~ '.' I .
~J, . . _ _ . .
.. _ __ ~ .... . ~., .`, ' ' .
-40- . I
,, .
t AHP-6154-1-CI
~O~
TA@LE II
:. _ _ . Product: ~Prefix llsted below)- ' . 1,2,3,4-tetrahydrocyclopent~b]-Hydrazine of Starting Material indole-3-acetic acid (suffix Ex Formula 2 of Formula_ listed below) = R4 R R2 R5 n PREFIX//SUFFIX _
' By following serially the procedures of Examples 2,3,4,5 ;~ and optionally the procedure of Example 9 and using the appropriate 1~ substituted cycloalkanone then other starting materials of formula 3, for example those described as starting materials in Examples 12 - 50 are obtained.
:~ ' - , ,:
,3 `''; ~ ~ ,' .
; . 1 ~ -36- 1 : s ~ ~1 Al-IP-615~1-CI
.' . '', ,'' .
EXAMPLE IO
1.2~3,4-Tetrahvdro-l-methyl_arbazole-l-acetic Acid Methyl Ester (5, Rl and R = ÇH3, R2, R3 and R = ~1 and n = 3) ; A solution of the starting material of formula 3,,! 5 1-methyl-2-oxocyclohexaneacetic acid methyl ester (18.0 g, 0.097 mole~, described in Example 9, and phenylhydrazine (10.6 9, 0.097 mole) in anhydrous ethanol (300 ml) is heated at reflux under nitrogen for 4 hr. Concentration of the reaction mixture affords the corresponding phenylhydrazone of the starting material of formula 3 as a solid , mp 84.5 - 86.5C.
The phenylhydrazone is heated at reflux (bath temp = 150C) with an excess of 10% aqueous sulfuric acid for 15 minutes. The solution is cooled rapidly,~ -saturated with sodium chloride and extracted with ether (4x).
The ether extracts are combined and washed with 5% aqueous NaOH dried (MgS04) and concentrated. The residue is subjected to chromatography on silica gel using 2.5% acetone in benzene as eluant. Concentration of the eluate gives the . ~ .
title compound, nmr (CDC13~ ~ 1.45 (s, 3H), 1.75 - 2.0 (m, 4H), 2.65 (s, 2H), 2.75(m, 2H), 3.68 (s, 3H), 6.9 - 7.6 (m, 4H), 9.2 (s, IH). `~
Further elution with the same eluent afforded a small amount of the by-product, 4a-methyl-2-phenyl-4,4a,5,6,7,8-hexahydro-3(2H)-cinnolinone, (14, Rl - CH3, R2 and R3 = H and ~ n = 3), mp 82 - 83C after recrystallization from hexane.
The procedure of Example 10 is followed to prepare ; ~
."
:
: .
'i : , ' AHP-6154-1-CI
other compounds of formula 5 in which Rl, R2, R3, R , R5 and n are as defined in the first instance. For example, by using and equivalent amoun-t of l-ethyl-2-oxocyclohexane . acetic acid me-thyl ester, described in Example 9, instead .~ 5 of 1-methyl-2-oxocyclohexane acetic acid in the procedure of.Example 10, 1-ethyl-1,2,3,4tetrahydrocarbazole-1-acetic acid methyl ester, (5, R = C2H5, R2, R3 and R4 = H, R = CH3 . and n = 3), mp 67 - 71C af-ter crystallization from benzene, ~ is obtained via the intermediate hydrazone, I-ethyl-2-`f 10 oxocyclohexaneacetic acid methyl ester phenyl hydrazone ~:
(4, Rl = C2H5, R2, R3 and R4 = H, R5 = CH3 and n = 3), ~ :
mp 98 - 99.5C after recrystallization from ethanol.
, Further examples of such compounds of formula 5 whlch can be prepared by the procedure of Example 10 are llsted in Tables I, II and III . In each of these examples .~
an equivalent amoun-t of the hydrazine of formula 2 and the :~ starting material of formula 3, listed therein, is used in : place of the phenylhydrazine and the starting material of ,, , ~ formula 3 noted in Example 10. 1 1 . I ;~
, ~ . .
,, . ! ' ~
' ~:
.. -~ 38 ~ :
,,',. -. : ' : . ' ' TABLE I
. .
Product: (Pre~ix listed below~- 1,2,3,4-Hydrazine of Starting Material tetrahydrocarbazole-l-ace,i~
Ex Formula 2 of Formula _ acid (suf~Tx listed ~elo~l) !
` = R3 R Rl R2 R5 n PREFIX//SUFFIX
11 H H n-C H7 HC2H5 3 I-propyl//ethyl ester~ mp 64-S6C ¦
3 vmaHC13 3400, 1715 cm .
lla H H n~C3H7 H CH3 3 I-propyl//methyl ester, mp 88-90 12 2-CH3 H CH3 HCH3 3 1,8-dimethyl/~methyl ester ; 13 3-C H CH CH H CH 3 5-(and 7-)methyl-1,9-dimethyl//
2 5 3 3 3 methyl ester 14 4-(i-C3H7) H CH3 HC2H5 3 6-isopropyl-1-methyl/~ethyl ester H C2~5 CH3 H H 3 9-ethyl-1-methylj~(no suffix) nmr (CDCI ) ~ 1.35 (t, J = 7, 3H) 1.4 (s, 3~), 4.3 (q, 2H) 16 2-C2H5 H C2H5 H CH3 3 mp 91 _ gY3oc/ Y
~:~ 17 2-(n-C H7) H C2H5 H CH3 3 mp ggY 100CPY I ;
~ 18 2-(i-C H ) H C H H CH3 3 1-ethyl-8-isopropyl//methyl ester 1~ 3 7 2 5 nmr (CDCI ) ~ 0.85 (t, J = 7, 3H), 1.41 (d, J3 = 7, 6~), 1.8 (m, 6), 2.7 (m, 4), 3.25 (m, IH), 3.70 1 (s, 3H), 7.2 (m, 3H), 9.6 (b, IH) -1 19 2-CI` H C2H5 H CH3 3 8-chloro~l-ethyl//methyl ester 4-F n-C H C H 4- H 3 1-ethyl-6-fluoro-4-methyl-9-propyl ;~ 3 2 5 CH3 ~ // (no suffix) ~-~ 21 4-OCH3 H; C2H5 H CH3 3 mp 75 - 78C I
-~;- 22 3-OC H H C2H5 _ C2H5 3 1,3-diethy1-5-(and 7-)ethoxy/i 2 5 2H5 ethyl ester 23 2-OCOCH3 H C2H5 , H CH3 3 8-acetoxy-1-ethyl//methyl est:r 24 4-OCOC2H5 H C2H5 H CH3 3 1-ethy1-6-propionoxy//methyl este . 25 2-CF3 C2H5 C2H5 H C2H5 3 1,9-diethyl-8-trifluoromet y //
. . _ , : ` ' '.~ . .
.~ - , ~ ' 1 _ 39 ,;, .
~ ` AHP-6154-1-CI
, TABLE I
,.; _ .; Product: (Pre'ix listed !
' '~elow)- 1,2,3,4-: Hydrazine of Starting Material tetrahydrocarbazole-l-acetic Ex Formula 2 of Formula ~ acid (suffix. ITsted belo~
= R3 R4 R R2 R5 n PREFIX//SUFFIX
264-CF3 H C2H5 H CH3 3 1-ethy1-6-trifluoromethyl//
. methyl ester , .
., 27 H H n~C3H7 H H 3I-propyl//(no suffix), vCaHx13 ..
. 3490 - 3430, 1705 cml.
., 282-OH H n~C3H7 5_ C2H5 3 8-hydroxy-3-methyl-1-propyl//
", 10 CH3 ethyl ester ;~ 29 2-CH CH3 n~C3H7 4~ CH3 34,8,9-trimefhyl-1-propyl// ~~ 3 . CH~ methyl ester ' . , ;
.~:. 30 H H n-C4Hg H CH3 3 I-but'yl//methyl es,ter ., . 31 2 5 H n-C4~Jg H CH3 3 1-butyl-8-et'nyl//methyl ester , 1 ¦ 32 ~n~C ~9 11-C4Hg ¦ H ~:H3 ¦ 3 ~ 1,8- i~utyl//mrthvl 5ter i ~ ~ l ~ ¦
i~,.,', . ~ '.' I .
~J, . . _ _ . .
.. _ __ ~ .... . ~., .`, ' ' .
-40- . I
,, .
t AHP-6154-1-CI
~O~
TA@LE II
:. _ _ . Product: ~Prefix llsted below)- ' . 1,2,3,4-tetrahydrocyclopent~b]-Hydrazine of Starting Material indole-3-acetic acid (suffix Ex Formula 2 of Formula_ listed below) = R4 R R2 R5 n PREFIX//SUFFIX _
5 33 H H CH3 H C2H5 2 3-methyl//ethyl ester J ~Jmaxl3 3440 34 H H C2H5 H CH3 2 ~730hcl/~methyl ester, ~CHC13 344 2-CH3 H C2H5 H CH3 2 3-ethyl-5-methyl//methyl ester : 36 2-C2H5 H C2H.5 H CH 2 3,5-diethyl//methyl ester, vCHC13 3 3440, 1722 cm~l - max 10 37 2-(n-C H H C2H5 H CH3 2 3-ethyl-5-propyl//methyl ester38 4-Br CH3 C2H5 H CH3 2 7-bromo-3-ethyl-4-methyl//met 39 H H n~C3H7 H CH3 2 3-propyl//methyl ester . 40 4-OH H i-C3H7 H CH3 2 7-hydroxy-3-isopropyl//methyl ~ I ¦ H ~ ¦ n C4Hg I H ¦ C13 2 ~ 3-but 1/ ~methvl ester .~ ~
'~ . ........... ... , ' " '' . , .
'~ . ' .' .
___ L__ _ `13 ., ,, .
,~
~)4t;519 TABLE ~ !
.~ Product: (Prefix listed below) Hydrazine of Starting Material 5,6,7 8jgJlo heta~cYac~d (suffiX
Ex Formula 2 of Formula _ listed below) = __________ R R ~2 R5 n ~ PREFlX//SlJFFlX
42 H H CH3 H C2H5 4 6-me-thyl//ethyl ester ~ 43 2-CH3 H CH3 H C2H5 4 4J6-dimethyl//ethyl ester si 44 H . H C2H5 H C2H5 4 6-ethyl//ethyl ester .
45 2-C2H5 H C2H5 H CH3 4 4~6-dlethyl//methyl ester : :
46 4-OCOC2H5 H C2H5 H C2H5 4 6-ethyl-2-prop.~noxy//2thyl ester :~ 47 H H C2H5 C-H3 C2H5 4 6-ethyl-10-methyl//ethyl ester :
48 4-CI H C3H7 H C2H5 4 2-chloro-6-propyl//ethyl ester 1~ 49 2-~n-C3H7) H n~C3H7 H C2H5 4 4,6-dipropyl//ethyl ester .
~50 ~ 3 ¦C 3 n-c3H7 ~H ~C2H ~ ~2~5-d me~hyl-6 prop~ thyl st-rj I I I
~' . ' . . .~' ., L~L ~ ,~. ~:
: ~, 1 '''' . ' .~ ~ . , .
.., ,.,.;
,~, ' .
.
, EXAMPLE 51 ', 1,2,3,4-Tetrahydro-l-methylcarbazole-l-acetic Acid (I, RI = CH3, R2 R3, R4 = H aQd n = 3) A mixture of the tricyclic compound of forMula 5 ' havTng R = lower alkyl, 1,2,3,4-tetrahydro-1-methylcarbazole-1-acetTc acid methyl ester (5.6 9, 21.8 mmole), described in Example 10, anhydrous potassium carbonate (1.52 9, 11.0 mmole), methanol (65 ml) and water (6.5 ml) is stirred and heated at ' reflux under nitrogen for 20 hr. Evaporation to dryness of ~ the mixture affords the potassium salt of the title compound.
;~ The salt is taken up in water and the solution extracted with etner. The aqueous phase is then rendered acidic with 6N
HCI and extracted with ether. This latter extraCt is washed ;~ with brine, dried (MgS04) and concentrated. The residue crystallized on trituration with a benzene-hexane (4 mixture to afford the title compound, mp 188 - 189C, vmaX13 3410, 1718 cml.
By following the procedure of Example 51 but ,~ :
-~ ` using an equivalent amount of the appropriate tricyclic ~compound of formula 5 having R5 - lower alkyl, for example those described in Examples 10 - 50 instead of 1,2,3,4-tetrahydro-l methylcarbazole-l-acetic acid methyl ester, ¦~
then the corresponding compounds of formula I are obtained.
For example by following the procedure of Example 51 but replacing 1,2,3,4-tetrahydro-1-methylcarbazole-1-acetic , a~cid methyl ester with an equivalent amount of l-ethyl-1,2,3,4- ~ ;
; tetrahydrocarbazole-l-acetic acid methyl ester, described in . ,~ , ~ .
: :
,3 _ 43 _ ~; . - ., ~,~
,~ .
;,. :: ' :i ' AHP-615~ CI
,.
Example 10, 1-ethyl-1,2,3~4-tetrahydrocarbazole-1-acetic acid, mp 148 - 150C after recrystallization from benzene, is obtained.
Examples of other such compounds of formula I are listed in Tables IV, V and Vl together with the requisite tricyclic compound starting material. In each case the tricyclic compound isnoted by the example in which it ~s prepared.
, ,~.i , . . : ~
, ' - ' . ~ ", , ~ ~
'( '" ' ' ~.
-, . . .
." :
., .
. -4~-,, .
'~ ~'' '.
., .
TABLE IV
.
. No. of the Example in which Product: (Prefix Itsted below)-the Tricyclic Compound of 1,2,3,4 tetrahydrocarbazole-l-Example Formula 5 is Prepared acetic acid ; 5 CHCI
52 11 ~ I-propyl, ~m~x 3 3490 - 3430, 1740, 1705 cml, nmr ~CDC13) o.85 (t, j = 7, 3H), 2.7 - 2.7c (s, 4H), 6.9 - 7.6 (m, 4H) 53 12 1,8-dimethyl 54 13 5- (and 7-)ethyl-1,9-dimethyl 14 5-isopropyl-1-methyl - 56 16 1,8-diethyl, mp 119 - 121C
57 17 1-ethyl-8-propyl, mp 127-128C
58 18 1-ethyl-8-isopropyl, mp 181-184C
nmr (CDC13) ~ 0.9 (t, J=7, 3H) 1.35 (d, J=7, 6H), 1.85 (m, 6H) 2.7 (m, 2H), 2.8 (s, 2H), 3~2 (m, IH), 7.2 (m, 3H), 9.2 (s, IH), 11.4 (s, IH) 59 19 8-chloro-1-ethyl 21 1-ethyl-6-methoxy, mp 95-97C
61 22 ~_ 1,3-diethyl-5-(and 7-)ethoxy 62 23 ; 8-acetoxy-1-ethyl ~ 63 24 1-ethyl-6-propionoxy ~ ;
; 64--- - ~ 25 1,9-diethyl-8-trifluoromethyl 26 1-ethy1-6-tri f luoromethyl 66 28 8-hydroxy-3-methyl-1-propyl 67 29 4,8,9 trimethyl-l-propyl ~ ~
~ ~.` . ~ ~ ;
~,, .
'' '' , :
,` ` ~.
~5 .:' ' , ' .
-~ :
~ AHP-6154 -I-CI
,, .
S~9 TABLE IV
,~ , , , . . . j ~ .
No, of the Example in which the Product: (Prefix listed below)-. Tricyclic Compound of Formula 5 1,2,3,4-tetrahydrocarbazole-Example is Prepared I-acetic acid ~ . ~_ 68 30 1-buty1-8-ethyl 69 31 I-butyl ~ ~L~
s~
.. . . .
.. . .
-~6-:. ' :' "' ' ' '.' ~' . ' '', ' ' ' ,'. ' '" , " ' ~ , . , ~
,' ',, ' ' ' . '' ' ~ :
'. , ' ". " , ' . . . ' ~-IP-6154-1-CI
--~ .
.,' . ., TABLE V
_ . No. of the Example in which Product: (PrefTx listed belo~
~:: the Tricyclic Compound of 1,2,3,4-tetrahydrocyclopent[b]-Example Formula 5 is Prepared indole-3-acetic acid . 71 33 3-methyl, m.p. 146-150C
.~ 72 34 3-ethyl, m.p. 138-139C
.; 73 35 3-ethy1-5-methyl 74 36 3,5-diethyl, VCHmacl3 3460, 1705 cm I
;. 75 37 3-ethy1-5-propyl . 76 38 7-bromo-3-ethyl-4 methyl 77 39 3-propyl ~J 78 40 7-hydroxy-3-isopropy r 3 79 ¦ 41 3-butyl --- -' ., -I
1 . ' .~
`~
.'J _ . _ ' ' ~ `
t , : .
.. . .
. AHP-6154 -I-CI
? .
. ' .
~.~3~
, TABLE Vl ~ :
. __ _ . No. of the Example in which Product: (Pref7x listed below)-the Tricyclic Compound of 5,6,7J8,9J10-hexahydrocyclohept-Example Formula 5 is Prepared [b3indole-6-acetic acid ~?
_ . ... . .
' 80 42 6-methylJ m.p. 119-122C
:i. 81 . 43 4,6-dimethyl. :
82 44 6-ethyl 83 45 4,6-diethyiJ m.p. 103-107C ~ ~1 ?
~; 10 84 46 6-ethyl-2-propionoxy ;
47 6-ethyl-10-methyl 86 48 2-chloro-6-propyl 87 49 4,6-dipropyl . ~;
~, 15 88 50 2,5-dir~thyl-'-pro~yl : ~
,,', '' ~
' ' ~
, ., ~n , :
-~8-." ~ ~
. . .
~' ,' . '',' '.'' - " " ' ' ' ' .
~ ~P-6154-1-CI
!
5~
. ~ .
E~AMPLE a9 I-Ethy1-1 2 3 4-~etrahydro-9-metllylcar~a~ole-1-ac~1ic ~ci (1, R = C2~15, R and R = ~1, R = CH3 and n = 3) . .
A solution of the compound of formula 1, I-ethyl 1,2,3,4-~etrahydrocarbazole-1-acetic acid (2~0 9, 7.4 mmole), described in Example 51, in dry tetrahydrofuran (THF, 50 ml) is 3 added dropwise under nitrogen to a stirred suspension of sodium hydride (I g, 50~ dispersion, 0.02 mole) in dry THF
(25 ml). The reaction mixture is stirred for 15 minutes after the end of the addition. The lower alkyl halide, methyl-iodide ~ tl.5 ml), is added dropwise. The reaction mixture is heated ;~ inititally to 40C then stirred for one hour at room 3 temperature. A small amount of water is added cautiously to ' destroy excess sodium hydride followed by the addition o~ more water (50 ml). The mixture is washed with ether then rendered acidic and extracted with ether. The ether extract is dried (MgS04), treated with charcoal and fiItered through diatomaceous earth, Evaporation of the ether gives an oil which ~j 20 on recrystallization from benzene affords the title compound, mp 140 - 143C, nmr (CDC13) ~ 0.72 (t, J = 7, 3H), 1.9 (m, 6 i 2.75(m,AH~ , 3.76 (s, 3H), 7.2 (m, 4H).
By following the procedure of Example 89 and using , the appropriate compound of formula I in which R is hydrogen, ¦ 25 for instance those described in Examples 52 - 88, together with the appropriate lower alkyl halide, other compounds of formula I in which R is lower alkyl are cbtained. For example, ... .
}
. ~
'1 p`, 9~ ` ~'~
~ ;' ',, ' , ' AHP-615~ -I-CI
,, , .
,, .
.
t the llse of the compound of formula !~ I,2,3,4-tetrahydro-t-methylcarbazole-l-acetic acid, described in Example 51, :~
wTth the lower alkyl halide, ethyl bromide,gives 9-ethyl-1-; methyl-1,2,3,4-tetrahydrocarbazole-1-acetic acid, identical .; 5 . to the product of Example 15. .
` By following the procedure of Example 81 but replacing the compound of formula I with an equivalent amount ¦
of a compound of formula 5 in which R4 is hydrogen and R5 , ~ is lower alkyl and using the appropriate lower alkyl halide, :, 10 the corresponding compounds of formula 5 in which R is lower alkyl and R is lower alkyl are obtained. More specifically i exempJified, by replacing l-ethyl-1,2,3,4-tetrahydrocarbazole- !;:~
I-acetic acid with an equivalent amount of l-ethyl-1,2,3,4 tetrahydrocarbazc;le-l-acetic acid methyl ester, in the procedure of Example 89, 1-ethy~ 2~3~4-tetrahydro-9-meth carbazole-l-acetic acid methyl ester, is obtained.
.~, , .
"~
~ ~ I
: ' ' 1 ' .;~, - . 1 3~
, ~
.::
:',, , ~ ,.' ' `!
,.,~ . ' . ' i:l :
', , :
-.
S~L9 EXA_LE 90 5-Ethyl-1,2 3,4-tetrahydro-3-methylcyclopentrblindole-3-acetic acid (I, Rl = CH3, R2 = H, R = 5-C ~1, R4 = H, n = 2) A solution of sodium tert.amylate in toluene i~ (70 ml, 0.1 mole) is added dropwise with stirring under an atmos-phere of nitrogen to a solution of 2-methylcyclopentanone (9.8 9, 0.1 mole) and ethyl bromoacetate (16.7 9, 0.1 mole) in dry benzene (100 ml). The reaction is exothermic, a precipitate is formed, and the mixture turns yellow-orange. Stirring is continued for 3 hrs.
;1 at room temperature, the solution is washed with lg HCI, cold water, and brine, dried over anhydrous magnesium sulfate and the solvent evaporated to yield l-methyl-2-oxocyclopentane acetic acid ethyl ester as a pale yellow oil which is used wi!thout further puriflcation in the subsequent step and which is identical with the same compound described in Example 5.
The above ester (27.78 9, 0.15 mole) and 2-ethylphenylhydrazine hydrochloride (25.89 9, 0.15 mole, prepared as described in Example I
-~ in dry ethanol (400 ml~ is stirred and heated to reflux overnight under nitrogen. The solvent is evaporated, the residue taken up in , hot 20% aqueous sulfuric acid (225 ml) and the mixture is stirred at :~ O
150 C for one hr., cooled, saturated with sodium chloride, and extracted with ether. After separation of some tarry by-produc-rs the -~ ether extracts are washed with water, 5g aqueous sodium hydroxide, water, and brine, dried over anhydrous magnesium sulfate and evaporated. The residue is purified by chromatography on silica gel using benzene-hexane as ~he solvent, and evaporation of the eluates yields the ethyl ester of the title compound, nmr ~CDC13) 8 1.25 (t, J=7), 1.50 (t, J=7), 1.50 (s), 4.23 (t, J=71, 6.95 -7.4 (m), 8.8 (broad).
~;., i~ , .' :
., .
- .
., .
~O~ 9 :
A mixtul-e of the above ethyl ester ~2.55 9, 0.0095 mole) potassium carbonate (1.5 9, 0.011 m) methanol (60 ml), and water (10 ml) is stirred under nitrogen and heated to reflux for 19 hrs. Evaporating the solvent, dissolving the resldue in water (50 ml), extraction witn ether, acidify-Tng the aqueous phase with dilute hydroch10ride acid, saturating withsodium chloride, extracting with ether containi~ng a small amauRt (50 mg~
of 2,6-di-tert-butyl-p-cresol ("Ionol" as anti-oxident, drying over anhydrous magnesium sulfate and evaporating yields the title compound with m.p. 124-129C after crystallization from hexane, nmr ~CDC13) 1.35 (t, J=7), 1.4 (s), 2.2 - 3.0 (m), 6.9 - 7.45 (m), 8.5 (s), 10.4 ~broad).
. - ~
:~ .~
.~ . ; ~ .
.', .
. ~ . ~ ' ,~ , . ` ~
i . . : ~
`:~ :
~ . ~ , ,~. . ', .'' . '~.
:, .
:, ~ - 52 -., .
~ ~ AHP-6154-1-CI
lL9 j 8-~utyl-_l-ethy~ 3~4-tetrahydrocarbazole-l-acetic acid (1, Rl = C2~15, R2 = H, R3 = 8-n-C4Hg, R4 = H, n = 3) ;, . __ A mixture of 2-butylphenylhydrazine (prepared from !. g of the hydrochloride salt, 0.05 mole;obtained from 2-bufylanll1ne and sodium nitrite in a simiiar maaner to that described in Example 1) and l-ethyl-2-oxocyclohexaneacetic acid methyl ester (10.0 9, 0.05 mole, prepared as described in Example 9) in ethanol (50 ml) is heated to reflux under an atmosphere of nitrogen for Z4 hrs. The mixture is cooled, the solvent evaporated, and the residue is heated to reflux (bath temperaturs 160C) with 20~ aqueous sulfuric acid (100 ml) under nitrogen for 30 minutes. The mixture is poured on crushed ice, extracfed with ether, the ether extracts washed with 5% sodium hydroxide solution and evaporated. The residue is purified by ;
chromatography on silica gel using benzene-hexane (1:1) as the eluant and evaporation of the eluates yields the methyl ester of the title compound as an oil.
The above methyl ester (3.8 9, 0.011 mole), potassium carbonate (2.0 9, 0.014 mole) in methanol (100 ml) and water -(10 ml) is stirred under nitrogen ànd heated to reflux for 20 hrs, ~ `;
i Evaporation of the solvent, addition of water (50 ml), acidification _with 6N hvdrochloric acid (1~ ml! and extrac+i~n ^w +h sther, drying - the ether extrac-~sover magnesium sulfate, filtering through activated carbon and evaporating yields the title compound, m.p. 131-134C `
after recrystallization from hexane, nmr (CDC13) ~ 0.9 (m~, 7.2 (m), 8.8 (sj, IG.6 (broad).
.~'. ~ .
,) .......... . .
.
.
. AHP-6154-1-CI
' EXAMPLE 92 ,, 4-Ethyl-5.6,7.8.9.10-hexahydro-6-methylcycloheptrblindole-6-acetic- ~ :' acid (1, Rl = CH3, R2 = H, R3 = 4-C2H5, R4 = H, n = 4) A mlxture of cycloheptanone pyrrolidine enamine (151.0 9, 0.92 mole) and chloroacetonitrile (151.0 9, 2 moles) in dry, per-~' oxide-frée dioxane is heated to reflux under nitroyen for 3 hrs.
The reaction mixture is cooled, poured onto ice, extracted wilh ether, the combined ether extracts washed with IN hydrochloric ' acid, water and saturated sodium chloride solution, and dried over i magnesium sulfate. Evaporation of the solvent and distillation of 1 the residue yields 2-cyanomethylcycloheptanone, bp 162-165C/16 mm, .. .
vmax 3 2240, 1700 cm 1, nmr (CDC13) ~ 1.8 (m), 2.4 - 3.1 (m).
A solution of sodium tert.-amylate in toluene (340 ml, 0.297 mole) ' is added dropwise with stirring under nitrogen to a solution of 2-cyanomethylcycloheptanone (44.6 9, 0.297 mole~ obtained as described above) and methyl iodide (42.6 9, 0.3 mole) in dry benzene (200 ml), and the mixture is stirred at 65C for 4 hrs. and allowed -to stand overnigh-t at room temperature. The reaction mixture is washed with 1~' aqueous hydrochloric acid, water, saturated sodium chloride solution, dried over magnesium sulfate, and the solven-t is evaporated. Distillation of the residue under reduced pressure J yields 2-cyanomethyl-2-methylcycloheptanone, bp. 152-158C/14 mm, nmr (CDC13) 6 1.27 (s, 3H).
'? A solution of 2-methyl-2-cyanomethylcycloheptanone described above (34.3 9, 0.208 mole) in 10% aqueous sodium hydroxide (500 ml) is heated to reflux for 3 hrs, cooled, washed with ether, acidified with.6N hydrochloric acid, saturated with sodium chlor;de and extracted with ether. The ether phase is separated, washed with ~:~
,-, :
~i',i, , ' !
.~, . ' .
, i ~, : :. . ~ : . .. :;, , ~~ AHP-6154-1-CI
S~
, . .
saturated sodium chloride solution, dried over magnesium su!fate and evaporated to yield l-methyl-2-oxocycloheptanèacetic acid, m.p. 43-45C aftsr crystallization from ether-haxano, max3 2900, 1705 cm 1, nmr (CDC13) ~ 1.25 ts), 1.65 tm), 2.58 tm), 10.1 ts).
A mixture of l-methyl-2-oxocycloheptaneacettc acid (3.0 9, 0.0163 mole, obtained as described above), anhydrous potassium carbonate (2.76 9, 0.020 mole) and methyl iodide (8 ml) in acetone (50 ml) is stirred and heated to reflux for 2 hrs. Methyl iodide (3 ml) is added and heating to reflux is continued for another 3 hrs. The solvent is evaporated, the residue taken up in water t50 ml),-saturated with sodium chloride, and extracted with ether. ~ `
~ccmbined ether extracts are washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated to yield -I-methyl-2-oxocycloheptaneàcetic acid methyl ester as an oil, vmax 3 1730, 1700 cm 1, nmr tCDC13) ~ 1.2 ts), 3.67 ts).
A mixture of l-methyl~2-oxocycloheptaneacetic acid methyl ester t5.0 9, 0.025 mole), 2-ethylphenylhydrazine tprepared from 4.4 9 of the hydrochloride salt, 0.025 mole) and 2-ethylphenyl-hydrazine hydrochloride t3.0 9,` 0.017 mole, prepared as described in Example 1) in anhydrous ethanol t35 ml) is stirred and heated ~
to reflux under nitrogen for 18 hrs. The reaction mixture is ;
cooled, the solvent evaporated, and the residue is heated to reflux tbath temperature 160-180C) under nitrogen with 20% aqueous su~lfuric acid (50 ml) for 45 minutes. The reaction mixture is poured on tce, extracted with ether, the ether extracts washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, evaporated to dryness, and the residue is passed through : , ,.
... . .
'~ ~, ': '~ '.
~ -- AHP-6154-1-CI
9 ~ ~
... .
a column of silica gel. Elution wtth benzene followed by benzene containing 2~ acetone and evaporation of the eluates yields the methyl ester of the title compound as an oil, nmr tCDC13) 6 1.25 (m), 1.50 ts), 1.90 tm), 2.85 tm), 3.65 ts), 7.0 - 7.5 tm). ;
x The methyl ester of the title compound obtained as described above (1.0 9), potassium carbonate tO.6 9), methanol t30 ml), and water t5 ml~ is stirred and heated to reflux under nitrogen for 20 hrs. The reaction mixture is concentrated to 1~2 volume, . ~ -water is added, and the mixture is washed with ether. The aqueous 1~ ~
; . .. -; layer is acTdified with 6N hydrochloric acid and extracted with ether, the ether extracts dried, filtered through ac-,ivated carbon, and evaporated to yield the title compound, m.p. 148-151C after ~¦ recrystallization from ether-hexane, nmr (CDC13) 6 i.35 (t, J=7), ;~
1.55 (s), 1.9 tm), 2.8 tm), 7.0 - 7.5 tm), 8.5 ts), 11.3 ts).
I
.~ ~ I ,. .
4 1 :
~''',~ ',1 ~
~ ' . ~ ~"
~ '.
,;'~ ' ' ~ '' ~'~
:r'',' ,, ' ' , ' ~ ' .~ . "
, ............... .
'~ . ........... ... , ' " '' . , .
'~ . ' .' .
___ L__ _ `13 ., ,, .
,~
~)4t;519 TABLE ~ !
.~ Product: (Prefix listed below) Hydrazine of Starting Material 5,6,7 8jgJlo heta~cYac~d (suffiX
Ex Formula 2 of Formula _ listed below) = __________ R R ~2 R5 n ~ PREFlX//SlJFFlX
42 H H CH3 H C2H5 4 6-me-thyl//ethyl ester ~ 43 2-CH3 H CH3 H C2H5 4 4J6-dimethyl//ethyl ester si 44 H . H C2H5 H C2H5 4 6-ethyl//ethyl ester .
45 2-C2H5 H C2H5 H CH3 4 4~6-dlethyl//methyl ester : :
46 4-OCOC2H5 H C2H5 H C2H5 4 6-ethyl-2-prop.~noxy//2thyl ester :~ 47 H H C2H5 C-H3 C2H5 4 6-ethyl-10-methyl//ethyl ester :
48 4-CI H C3H7 H C2H5 4 2-chloro-6-propyl//ethyl ester 1~ 49 2-~n-C3H7) H n~C3H7 H C2H5 4 4,6-dipropyl//ethyl ester .
~50 ~ 3 ¦C 3 n-c3H7 ~H ~C2H ~ ~2~5-d me~hyl-6 prop~ thyl st-rj I I I
~' . ' . . .~' ., L~L ~ ,~. ~:
: ~, 1 '''' . ' .~ ~ . , .
.., ,.,.;
,~, ' .
.
, EXAMPLE 51 ', 1,2,3,4-Tetrahydro-l-methylcarbazole-l-acetic Acid (I, RI = CH3, R2 R3, R4 = H aQd n = 3) A mixture of the tricyclic compound of forMula 5 ' havTng R = lower alkyl, 1,2,3,4-tetrahydro-1-methylcarbazole-1-acetTc acid methyl ester (5.6 9, 21.8 mmole), described in Example 10, anhydrous potassium carbonate (1.52 9, 11.0 mmole), methanol (65 ml) and water (6.5 ml) is stirred and heated at ' reflux under nitrogen for 20 hr. Evaporation to dryness of ~ the mixture affords the potassium salt of the title compound.
;~ The salt is taken up in water and the solution extracted with etner. The aqueous phase is then rendered acidic with 6N
HCI and extracted with ether. This latter extraCt is washed ;~ with brine, dried (MgS04) and concentrated. The residue crystallized on trituration with a benzene-hexane (4 mixture to afford the title compound, mp 188 - 189C, vmaX13 3410, 1718 cml.
By following the procedure of Example 51 but ,~ :
-~ ` using an equivalent amount of the appropriate tricyclic ~compound of formula 5 having R5 - lower alkyl, for example those described in Examples 10 - 50 instead of 1,2,3,4-tetrahydro-l methylcarbazole-l-acetic acid methyl ester, ¦~
then the corresponding compounds of formula I are obtained.
For example by following the procedure of Example 51 but replacing 1,2,3,4-tetrahydro-1-methylcarbazole-1-acetic , a~cid methyl ester with an equivalent amount of l-ethyl-1,2,3,4- ~ ;
; tetrahydrocarbazole-l-acetic acid methyl ester, described in . ,~ , ~ .
: :
,3 _ 43 _ ~; . - ., ~,~
,~ .
;,. :: ' :i ' AHP-615~ CI
,.
Example 10, 1-ethyl-1,2,3~4-tetrahydrocarbazole-1-acetic acid, mp 148 - 150C after recrystallization from benzene, is obtained.
Examples of other such compounds of formula I are listed in Tables IV, V and Vl together with the requisite tricyclic compound starting material. In each case the tricyclic compound isnoted by the example in which it ~s prepared.
, ,~.i , . . : ~
, ' - ' . ~ ", , ~ ~
'( '" ' ' ~.
-, . . .
." :
., .
. -4~-,, .
'~ ~'' '.
., .
TABLE IV
.
. No. of the Example in which Product: (Prefix Itsted below)-the Tricyclic Compound of 1,2,3,4 tetrahydrocarbazole-l-Example Formula 5 is Prepared acetic acid ; 5 CHCI
52 11 ~ I-propyl, ~m~x 3 3490 - 3430, 1740, 1705 cml, nmr ~CDC13) o.85 (t, j = 7, 3H), 2.7 - 2.7c (s, 4H), 6.9 - 7.6 (m, 4H) 53 12 1,8-dimethyl 54 13 5- (and 7-)ethyl-1,9-dimethyl 14 5-isopropyl-1-methyl - 56 16 1,8-diethyl, mp 119 - 121C
57 17 1-ethyl-8-propyl, mp 127-128C
58 18 1-ethyl-8-isopropyl, mp 181-184C
nmr (CDC13) ~ 0.9 (t, J=7, 3H) 1.35 (d, J=7, 6H), 1.85 (m, 6H) 2.7 (m, 2H), 2.8 (s, 2H), 3~2 (m, IH), 7.2 (m, 3H), 9.2 (s, IH), 11.4 (s, IH) 59 19 8-chloro-1-ethyl 21 1-ethyl-6-methoxy, mp 95-97C
61 22 ~_ 1,3-diethyl-5-(and 7-)ethoxy 62 23 ; 8-acetoxy-1-ethyl ~ 63 24 1-ethyl-6-propionoxy ~ ;
; 64--- - ~ 25 1,9-diethyl-8-trifluoromethyl 26 1-ethy1-6-tri f luoromethyl 66 28 8-hydroxy-3-methyl-1-propyl 67 29 4,8,9 trimethyl-l-propyl ~ ~
~ ~.` . ~ ~ ;
~,, .
'' '' , :
,` ` ~.
~5 .:' ' , ' .
-~ :
~ AHP-6154 -I-CI
,, .
S~9 TABLE IV
,~ , , , . . . j ~ .
No, of the Example in which the Product: (Prefix listed below)-. Tricyclic Compound of Formula 5 1,2,3,4-tetrahydrocarbazole-Example is Prepared I-acetic acid ~ . ~_ 68 30 1-buty1-8-ethyl 69 31 I-butyl ~ ~L~
s~
.. . . .
.. . .
-~6-:. ' :' "' ' ' '.' ~' . ' '', ' ' ' ,'. ' '" , " ' ~ , . , ~
,' ',, ' ' ' . '' ' ~ :
'. , ' ". " , ' . . . ' ~-IP-6154-1-CI
--~ .
.,' . ., TABLE V
_ . No. of the Example in which Product: (PrefTx listed belo~
~:: the Tricyclic Compound of 1,2,3,4-tetrahydrocyclopent[b]-Example Formula 5 is Prepared indole-3-acetic acid . 71 33 3-methyl, m.p. 146-150C
.~ 72 34 3-ethyl, m.p. 138-139C
.; 73 35 3-ethy1-5-methyl 74 36 3,5-diethyl, VCHmacl3 3460, 1705 cm I
;. 75 37 3-ethy1-5-propyl . 76 38 7-bromo-3-ethyl-4 methyl 77 39 3-propyl ~J 78 40 7-hydroxy-3-isopropy r 3 79 ¦ 41 3-butyl --- -' ., -I
1 . ' .~
`~
.'J _ . _ ' ' ~ `
t , : .
.. . .
. AHP-6154 -I-CI
? .
. ' .
~.~3~
, TABLE Vl ~ :
. __ _ . No. of the Example in which Product: (Pref7x listed below)-the Tricyclic Compound of 5,6,7J8,9J10-hexahydrocyclohept-Example Formula 5 is Prepared [b3indole-6-acetic acid ~?
_ . ... . .
' 80 42 6-methylJ m.p. 119-122C
:i. 81 . 43 4,6-dimethyl. :
82 44 6-ethyl 83 45 4,6-diethyiJ m.p. 103-107C ~ ~1 ?
~; 10 84 46 6-ethyl-2-propionoxy ;
47 6-ethyl-10-methyl 86 48 2-chloro-6-propyl 87 49 4,6-dipropyl . ~;
~, 15 88 50 2,5-dir~thyl-'-pro~yl : ~
,,', '' ~
' ' ~
, ., ~n , :
-~8-." ~ ~
. . .
~' ,' . '',' '.'' - " " ' ' ' ' .
~ ~P-6154-1-CI
!
5~
. ~ .
E~AMPLE a9 I-Ethy1-1 2 3 4-~etrahydro-9-metllylcar~a~ole-1-ac~1ic ~ci (1, R = C2~15, R and R = ~1, R = CH3 and n = 3) . .
A solution of the compound of formula 1, I-ethyl 1,2,3,4-~etrahydrocarbazole-1-acetic acid (2~0 9, 7.4 mmole), described in Example 51, in dry tetrahydrofuran (THF, 50 ml) is 3 added dropwise under nitrogen to a stirred suspension of sodium hydride (I g, 50~ dispersion, 0.02 mole) in dry THF
(25 ml). The reaction mixture is stirred for 15 minutes after the end of the addition. The lower alkyl halide, methyl-iodide ~ tl.5 ml), is added dropwise. The reaction mixture is heated ;~ inititally to 40C then stirred for one hour at room 3 temperature. A small amount of water is added cautiously to ' destroy excess sodium hydride followed by the addition o~ more water (50 ml). The mixture is washed with ether then rendered acidic and extracted with ether. The ether extract is dried (MgS04), treated with charcoal and fiItered through diatomaceous earth, Evaporation of the ether gives an oil which ~j 20 on recrystallization from benzene affords the title compound, mp 140 - 143C, nmr (CDC13) ~ 0.72 (t, J = 7, 3H), 1.9 (m, 6 i 2.75(m,AH~ , 3.76 (s, 3H), 7.2 (m, 4H).
By following the procedure of Example 89 and using , the appropriate compound of formula I in which R is hydrogen, ¦ 25 for instance those described in Examples 52 - 88, together with the appropriate lower alkyl halide, other compounds of formula I in which R is lower alkyl are cbtained. For example, ... .
}
. ~
'1 p`, 9~ ` ~'~
~ ;' ',, ' , ' AHP-615~ -I-CI
,, , .
,, .
.
t the llse of the compound of formula !~ I,2,3,4-tetrahydro-t-methylcarbazole-l-acetic acid, described in Example 51, :~
wTth the lower alkyl halide, ethyl bromide,gives 9-ethyl-1-; methyl-1,2,3,4-tetrahydrocarbazole-1-acetic acid, identical .; 5 . to the product of Example 15. .
` By following the procedure of Example 81 but replacing the compound of formula I with an equivalent amount ¦
of a compound of formula 5 in which R4 is hydrogen and R5 , ~ is lower alkyl and using the appropriate lower alkyl halide, :, 10 the corresponding compounds of formula 5 in which R is lower alkyl and R is lower alkyl are obtained. More specifically i exempJified, by replacing l-ethyl-1,2,3,4-tetrahydrocarbazole- !;:~
I-acetic acid with an equivalent amount of l-ethyl-1,2,3,4 tetrahydrocarbazc;le-l-acetic acid methyl ester, in the procedure of Example 89, 1-ethy~ 2~3~4-tetrahydro-9-meth carbazole-l-acetic acid methyl ester, is obtained.
.~, , .
"~
~ ~ I
: ' ' 1 ' .;~, - . 1 3~
, ~
.::
:',, , ~ ,.' ' `!
,.,~ . ' . ' i:l :
', , :
-.
S~L9 EXA_LE 90 5-Ethyl-1,2 3,4-tetrahydro-3-methylcyclopentrblindole-3-acetic acid (I, Rl = CH3, R2 = H, R = 5-C ~1, R4 = H, n = 2) A solution of sodium tert.amylate in toluene i~ (70 ml, 0.1 mole) is added dropwise with stirring under an atmos-phere of nitrogen to a solution of 2-methylcyclopentanone (9.8 9, 0.1 mole) and ethyl bromoacetate (16.7 9, 0.1 mole) in dry benzene (100 ml). The reaction is exothermic, a precipitate is formed, and the mixture turns yellow-orange. Stirring is continued for 3 hrs.
;1 at room temperature, the solution is washed with lg HCI, cold water, and brine, dried over anhydrous magnesium sulfate and the solvent evaporated to yield l-methyl-2-oxocyclopentane acetic acid ethyl ester as a pale yellow oil which is used wi!thout further puriflcation in the subsequent step and which is identical with the same compound described in Example 5.
The above ester (27.78 9, 0.15 mole) and 2-ethylphenylhydrazine hydrochloride (25.89 9, 0.15 mole, prepared as described in Example I
-~ in dry ethanol (400 ml~ is stirred and heated to reflux overnight under nitrogen. The solvent is evaporated, the residue taken up in , hot 20% aqueous sulfuric acid (225 ml) and the mixture is stirred at :~ O
150 C for one hr., cooled, saturated with sodium chloride, and extracted with ether. After separation of some tarry by-produc-rs the -~ ether extracts are washed with water, 5g aqueous sodium hydroxide, water, and brine, dried over anhydrous magnesium sulfate and evaporated. The residue is purified by chromatography on silica gel using benzene-hexane as ~he solvent, and evaporation of the eluates yields the ethyl ester of the title compound, nmr ~CDC13) 8 1.25 (t, J=7), 1.50 (t, J=7), 1.50 (s), 4.23 (t, J=71, 6.95 -7.4 (m), 8.8 (broad).
~;., i~ , .' :
., .
- .
., .
~O~ 9 :
A mixtul-e of the above ethyl ester ~2.55 9, 0.0095 mole) potassium carbonate (1.5 9, 0.011 m) methanol (60 ml), and water (10 ml) is stirred under nitrogen and heated to reflux for 19 hrs. Evaporating the solvent, dissolving the resldue in water (50 ml), extraction witn ether, acidify-Tng the aqueous phase with dilute hydroch10ride acid, saturating withsodium chloride, extracting with ether containi~ng a small amauRt (50 mg~
of 2,6-di-tert-butyl-p-cresol ("Ionol" as anti-oxident, drying over anhydrous magnesium sulfate and evaporating yields the title compound with m.p. 124-129C after crystallization from hexane, nmr ~CDC13) 1.35 (t, J=7), 1.4 (s), 2.2 - 3.0 (m), 6.9 - 7.45 (m), 8.5 (s), 10.4 ~broad).
. - ~
:~ .~
.~ . ; ~ .
.', .
. ~ . ~ ' ,~ , . ` ~
i . . : ~
`:~ :
~ . ~ , ,~. . ', .'' . '~.
:, .
:, ~ - 52 -., .
~ ~ AHP-6154-1-CI
lL9 j 8-~utyl-_l-ethy~ 3~4-tetrahydrocarbazole-l-acetic acid (1, Rl = C2~15, R2 = H, R3 = 8-n-C4Hg, R4 = H, n = 3) ;, . __ A mixture of 2-butylphenylhydrazine (prepared from !. g of the hydrochloride salt, 0.05 mole;obtained from 2-bufylanll1ne and sodium nitrite in a simiiar maaner to that described in Example 1) and l-ethyl-2-oxocyclohexaneacetic acid methyl ester (10.0 9, 0.05 mole, prepared as described in Example 9) in ethanol (50 ml) is heated to reflux under an atmosphere of nitrogen for Z4 hrs. The mixture is cooled, the solvent evaporated, and the residue is heated to reflux (bath temperaturs 160C) with 20~ aqueous sulfuric acid (100 ml) under nitrogen for 30 minutes. The mixture is poured on crushed ice, extracfed with ether, the ether extracts washed with 5% sodium hydroxide solution and evaporated. The residue is purified by ;
chromatography on silica gel using benzene-hexane (1:1) as the eluant and evaporation of the eluates yields the methyl ester of the title compound as an oil.
The above methyl ester (3.8 9, 0.011 mole), potassium carbonate (2.0 9, 0.014 mole) in methanol (100 ml) and water -(10 ml) is stirred under nitrogen ànd heated to reflux for 20 hrs, ~ `;
i Evaporation of the solvent, addition of water (50 ml), acidification _with 6N hvdrochloric acid (1~ ml! and extrac+i~n ^w +h sther, drying - the ether extrac-~sover magnesium sulfate, filtering through activated carbon and evaporating yields the title compound, m.p. 131-134C `
after recrystallization from hexane, nmr (CDC13) ~ 0.9 (m~, 7.2 (m), 8.8 (sj, IG.6 (broad).
.~'. ~ .
,) .......... . .
.
.
. AHP-6154-1-CI
' EXAMPLE 92 ,, 4-Ethyl-5.6,7.8.9.10-hexahydro-6-methylcycloheptrblindole-6-acetic- ~ :' acid (1, Rl = CH3, R2 = H, R3 = 4-C2H5, R4 = H, n = 4) A mlxture of cycloheptanone pyrrolidine enamine (151.0 9, 0.92 mole) and chloroacetonitrile (151.0 9, 2 moles) in dry, per-~' oxide-frée dioxane is heated to reflux under nitroyen for 3 hrs.
The reaction mixture is cooled, poured onto ice, extracted wilh ether, the combined ether extracts washed with IN hydrochloric ' acid, water and saturated sodium chloride solution, and dried over i magnesium sulfate. Evaporation of the solvent and distillation of 1 the residue yields 2-cyanomethylcycloheptanone, bp 162-165C/16 mm, .. .
vmax 3 2240, 1700 cm 1, nmr (CDC13) ~ 1.8 (m), 2.4 - 3.1 (m).
A solution of sodium tert.-amylate in toluene (340 ml, 0.297 mole) ' is added dropwise with stirring under nitrogen to a solution of 2-cyanomethylcycloheptanone (44.6 9, 0.297 mole~ obtained as described above) and methyl iodide (42.6 9, 0.3 mole) in dry benzene (200 ml), and the mixture is stirred at 65C for 4 hrs. and allowed -to stand overnigh-t at room temperature. The reaction mixture is washed with 1~' aqueous hydrochloric acid, water, saturated sodium chloride solution, dried over magnesium sulfate, and the solven-t is evaporated. Distillation of the residue under reduced pressure J yields 2-cyanomethyl-2-methylcycloheptanone, bp. 152-158C/14 mm, nmr (CDC13) 6 1.27 (s, 3H).
'? A solution of 2-methyl-2-cyanomethylcycloheptanone described above (34.3 9, 0.208 mole) in 10% aqueous sodium hydroxide (500 ml) is heated to reflux for 3 hrs, cooled, washed with ether, acidified with.6N hydrochloric acid, saturated with sodium chlor;de and extracted with ether. The ether phase is separated, washed with ~:~
,-, :
~i',i, , ' !
.~, . ' .
, i ~, : :. . ~ : . .. :;, , ~~ AHP-6154-1-CI
S~
, . .
saturated sodium chloride solution, dried over magnesium su!fate and evaporated to yield l-methyl-2-oxocycloheptanèacetic acid, m.p. 43-45C aftsr crystallization from ether-haxano, max3 2900, 1705 cm 1, nmr (CDC13) ~ 1.25 ts), 1.65 tm), 2.58 tm), 10.1 ts).
A mixture of l-methyl-2-oxocycloheptaneacettc acid (3.0 9, 0.0163 mole, obtained as described above), anhydrous potassium carbonate (2.76 9, 0.020 mole) and methyl iodide (8 ml) in acetone (50 ml) is stirred and heated to reflux for 2 hrs. Methyl iodide (3 ml) is added and heating to reflux is continued for another 3 hrs. The solvent is evaporated, the residue taken up in water t50 ml),-saturated with sodium chloride, and extracted with ether. ~ `
~ccmbined ether extracts are washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated to yield -I-methyl-2-oxocycloheptaneàcetic acid methyl ester as an oil, vmax 3 1730, 1700 cm 1, nmr tCDC13) ~ 1.2 ts), 3.67 ts).
A mixture of l-methyl~2-oxocycloheptaneacetic acid methyl ester t5.0 9, 0.025 mole), 2-ethylphenylhydrazine tprepared from 4.4 9 of the hydrochloride salt, 0.025 mole) and 2-ethylphenyl-hydrazine hydrochloride t3.0 9,` 0.017 mole, prepared as described in Example 1) in anhydrous ethanol t35 ml) is stirred and heated ~
to reflux under nitrogen for 18 hrs. The reaction mixture is ;
cooled, the solvent evaporated, and the residue is heated to reflux tbath temperature 160-180C) under nitrogen with 20% aqueous su~lfuric acid (50 ml) for 45 minutes. The reaction mixture is poured on tce, extracted with ether, the ether extracts washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, evaporated to dryness, and the residue is passed through : , ,.
... . .
'~ ~, ': '~ '.
~ -- AHP-6154-1-CI
9 ~ ~
... .
a column of silica gel. Elution wtth benzene followed by benzene containing 2~ acetone and evaporation of the eluates yields the methyl ester of the title compound as an oil, nmr tCDC13) 6 1.25 (m), 1.50 ts), 1.90 tm), 2.85 tm), 3.65 ts), 7.0 - 7.5 tm). ;
x The methyl ester of the title compound obtained as described above (1.0 9), potassium carbonate tO.6 9), methanol t30 ml), and water t5 ml~ is stirred and heated to reflux under nitrogen for 20 hrs. The reaction mixture is concentrated to 1~2 volume, . ~ -water is added, and the mixture is washed with ether. The aqueous 1~ ~
; . .. -; layer is acTdified with 6N hydrochloric acid and extracted with ether, the ether extracts dried, filtered through ac-,ivated carbon, and evaporated to yield the title compound, m.p. 148-151C after ~¦ recrystallization from ether-hexane, nmr (CDC13) 6 i.35 (t, J=7), ;~
1.55 (s), 1.9 tm), 2.8 tm), 7.0 - 7.5 tm), 8.5 ts), 11.3 ts).
I
.~ ~ I ,. .
4 1 :
~''',~ ',1 ~
~ ' . ~ ~"
~ '.
,;'~ ' ' ~ '' ~'~
:r'',' ,, ' ' , ' ~ ' .~ . "
, ............... .
Claims (36)
1. A process for preparing a compound of formula I
1 in which R1 is lower alkyl, lower alkenyl or lower cycloalkyl, R2 is hydrogen or lower alkyl, R3 is hydrogen, lower alkyl, halo, hydroxy, lower alkoxy, lower alkanoloxy, or trihalomethyl, R4 is hydrogen or lower alkyl and n is an integer from two to four which comprises:
a) condensing a formula of formula 2 2 in which R3 and R4 are as defined herein with a compound of formula 3 3 in which R1, R2 and n are as defined herein and R5 is hydrogen or lower alkyl to obtain a corresponding hydrazone of formula 4 in which R1, R2, R3, R4, R5 and n are as defined herein;
b) cyclizing the hydrazone is the presence of a cyclizing agent to obtain the corresponding compound of formula 5 in which R1, R2, R3, R4,R5 and n are as defined herein, which is the desired corresponding compound of formula 1 when R5 is hydrogen; and c) when R5 of said compound of formula 5 is lower alkyl subjecting the compound of formula 5 to hydrolysis conditions to give the desired corresponding compound of formula 1; or d) when a compound of formula 1 in which R4 is lower alkyl is required, subjecting the last said compound of formula 5 in which R4 is hydrogen and R5 is hydrogen or lower alkyl to N-alkylation with an appropriate alkyl halide in the presence of a proton acceptor to obtain the corresponding compound of formula 5 in which R4 is lower alkyl and R5 is hydrogen or lower alkyl,which is the desired corresponding compound of formula 1 which R5 is hydrogen; and when R5 of the last said compound of formula 5 is lower alkyl subjecting the last named compound of formula 5 to hydrolysis conditions to give the desired corresponding compound of formula 1.
1 in which R1 is lower alkyl, lower alkenyl or lower cycloalkyl, R2 is hydrogen or lower alkyl, R3 is hydrogen, lower alkyl, halo, hydroxy, lower alkoxy, lower alkanoloxy, or trihalomethyl, R4 is hydrogen or lower alkyl and n is an integer from two to four which comprises:
a) condensing a formula of formula 2 2 in which R3 and R4 are as defined herein with a compound of formula 3 3 in which R1, R2 and n are as defined herein and R5 is hydrogen or lower alkyl to obtain a corresponding hydrazone of formula 4 in which R1, R2, R3, R4, R5 and n are as defined herein;
b) cyclizing the hydrazone is the presence of a cyclizing agent to obtain the corresponding compound of formula 5 in which R1, R2, R3, R4,R5 and n are as defined herein, which is the desired corresponding compound of formula 1 when R5 is hydrogen; and c) when R5 of said compound of formula 5 is lower alkyl subjecting the compound of formula 5 to hydrolysis conditions to give the desired corresponding compound of formula 1; or d) when a compound of formula 1 in which R4 is lower alkyl is required, subjecting the last said compound of formula 5 in which R4 is hydrogen and R5 is hydrogen or lower alkyl to N-alkylation with an appropriate alkyl halide in the presence of a proton acceptor to obtain the corresponding compound of formula 5 in which R4 is lower alkyl and R5 is hydrogen or lower alkyl,which is the desired corresponding compound of formula 1 which R5 is hydrogen; and when R5 of the last said compound of formula 5 is lower alkyl subjecting the last named compound of formula 5 to hydrolysis conditions to give the desired corresponding compound of formula 1.
2. A compound of formula 1, as defined in Claim 1, when prepared by the process of Claim 1, or an obvious chemical equivalent thereof.
3. The process of Claim 1 in which R1 is lower alkyl containing from two to six carbon atoms, R2 is hydrogen and R3, R4 and n are as defined therein.
4. A compound of formula 1 of Claim 3 in which R1 is lower alkyl containing from two to six carbon atoms, R2 is hydrogen and R3, R4 and n are as defined therein, when prepared by the process of Claim 3, or an obvious chemical equivalent thereof.
5. The process of Claim 1 in which the compound of formula 1 is transformed into the corresponding pharmaceutically acceptable salt.
6. A pharmaceutically acceptable salt of the compound of formula 1 of Claim 5, when prepared by the process of Claim 5, or an obvious chemical equivalent thereof.
7. The process of Claim 1 in which R1 is ethyl, R2, R3 and R4 each is hydrogen, R5 is methyl and n is 3.
8. 1-Ethyl-1,2,3,4-tetrahydrocarbozote-1-acetic acid, when prepared by the process of Claim 7, or an obvious chemical equivalent thereof.
9. The process of Claim 1 in which R1 is propyl, R2, R3 and R4 each is hydrogen, R5 is ethyl and n is 3.
10. 1-Propyl-1,2,3,4-tetrahydrocarbozole-1-acetic acid, when prepared by the process of Claim 9, or an obvious chemical equivalent thereof.
11. The process of Claim 1 in which R1 is ethyl; R2 is hydrogen;
R3 and R4 of the compound of formula 2 are 2-methyl and hydrogen, respect-ively, and R3 and R4 of the compound of formula 1 are 8-methyl and hydrogen, respectively; R5 is methyl and n is 3.
R3 and R4 of the compound of formula 2 are 2-methyl and hydrogen, respect-ively, and R3 and R4 of the compound of formula 1 are 8-methyl and hydrogen, respectively; R5 is methyl and n is 3.
12. 1,8-Diethyl-1,2,3,4-tetrahydrocarbazole-1-acetic acid, when prepared by the process or Claim 11 or an obvious chemical equivalent thereof.
13. The process of Claim 1 in which R1 is ethyl; R2 is hydrogen;
R3 and R4 of the compound of formula 2 are 2-propyl and hydrogen, respect-ively, and R3 and R4 of the compound of formula 1 are 8-propyl and hydrogen, respectively; R5 is methyl and n is 3.
R3 and R4 of the compound of formula 2 are 2-propyl and hydrogen, respect-ively, and R3 and R4 of the compound of formula 1 are 8-propyl and hydrogen, respectively; R5 is methyl and n is 3.
14. 1-Ethyl-8-propyl-1,2,3,4-tetrahydrocarbazole-1-acetic acid, when prepared by the process or Claim 13, or an obvious chemical equiva-lent thereof.
15. The process of Claim 1 in which R1 is ethyl; R2 is hydrogen;
R3 and R4 of the compound of formula 2 are 2-isopropyl and hydrogen, respectively, and R3 and R4 of the compound of formula 1 are 8-isopropyl and hydrogen, respectively; R5 is methyl and n is 3.
R3 and R4 of the compound of formula 2 are 2-isopropyl and hydrogen, respectively, and R3 and R4 of the compound of formula 1 are 8-isopropyl and hydrogen, respectively; R5 is methyl and n is 3.
16. 1-Ethyl-8-isopropyl-1,2,3,4-tetrahydrocarbazole-1-acetic acid, when prepared by the process or Claim 15, or an obvious chemical equivalent thereof.
17. The process of Claim 1 in which R1 is ethyl; R2 is hydrogen;
R3 and R4 of the compound of formula 2 are 4-methoxy and hydrogen, respect-ively, and R3 and R4 of the compound of formula 1 are 6-methoxy and hydro-gen, respectively; R5 is methyl and n is 3.
R3 and R4 of the compound of formula 2 are 4-methoxy and hydrogen, respect-ively, and R3 and R4 of the compound of formula 1 are 6-methoxy and hydro-gen, respectively; R5 is methyl and n is 3.
18. 1-Ethyl-6-methoxy-1,2,3,4-tetrahydrocarbazole-l-acetic acid, when prepared by the process or Claim 17, or an obvious chemical equivalent thereof.
19. The process of Claim 1 in which R1 is ethyl; R2 is hydrogen;
R3 and R4 of the compound of formula 2 each is hydrogen; and R3 and R4 of the compound of formula I are hydrogen and methyl, respectively; R5 is hydrogen and n is 3.
R3 and R4 of the compound of formula 2 each is hydrogen; and R3 and R4 of the compound of formula I are hydrogen and methyl, respectively; R5 is hydrogen and n is 3.
20. 1-Ethyl-1,2,3,4-tetrahydro-9-methylcarbazole-1-acetic acid, when prepared by the process or Claim 19, or an obvious chemical equivalent thereof.
21. The process of Claim 1 in which R1 is methyl; R2 is hydro-gen; R3 and R4 of the compound of formula 2 are hydrogen and ethyl, respectively, and R3 and R4 of the compound of formula 1 are hydrogen and ethyl, respectively; R5 is hydrogen and n is 3.
22. 9-Ethyl-l-methyl-1,2,3,4-tetrahydrocarbazole-1-acetic acid, when prepared by the process or Claim 21, or an obvious chemical equiva-lent thereof.
23. The process of Claim I in which R1 is methyl; R2, R3 and R4 each is hydrogen; R5 is ethyl and n is 2.
24. 3-Methyl-1,2,3,4-tetrahydrocyclopent[b]indole-3-acetic acid, when prepared by the process or Claim 23, or an obvious chemical equiva-lent thereof.
25. The process of Claim 1 in which R1 is ethyl; R2, R3 and R4 each is hydrogen; R5 is methyl and n is 2.
26. 3-Ethyl-1,2,3,4-tetrahydrocyclopent[b]indole-3-acetic acid, when prepared by the process or Claim 25, or an obvious chemical equiva-lent thereof.
27. The process of Claim 1 in which R1 is methyl; R2 is hydrogen;
R3 and R4 of the compound of formula 2 are ethyl and hydrogen respectively, and R3 and R4 of the compound of formula 1 are ethyl and hydrogen respectively; R5 is ethyl and n is 2.
R3 and R4 of the compound of formula 2 are ethyl and hydrogen respectively, and R3 and R4 of the compound of formula 1 are ethyl and hydrogen respectively; R5 is ethyl and n is 2.
28. 5-Ethyl-1,2,3,4-tetrahydro-3-methylcyclopent[b]indole-3-acetic acid when prepared by the process or Claim 27, or an obvious chemical equivalent thereof.
29. The process of Claim 1 in which R1 is ethyl; R2 is hydrogen;
R3 and R4 of the compound of formula 2 are 2-butyl and hydrogen, respectively, and R3 and R4 of the compound of formula 1 are 8-butyl and hydrogen, res-pectively; R5 is methyl and n is 3.
R3 and R4 of the compound of formula 2 are 2-butyl and hydrogen, respectively, and R3 and R4 of the compound of formula 1 are 8-butyl and hydrogen, res-pectively; R5 is methyl and n is 3.
30. 8-Butyl-1-ethyl-1,2,3,4-tetrahydrocarbazole-1-acetic acid, when prepared by the process or Claim 29 or an obvious chemical equiva-lent thereof.
31. The process of Claim 1 in which R1 is methyl; R2, R3 ana R4 each is hydrogen respectively; R5 is ethyl and n is 4.
32. 6-Methyl-5,6,7,8,9,10-hexahydrocyclohept[b]indole-6-acetic acid, when prepared by the process or Claim 31, or an obvious chemical equivalent thereof.
33. The process of Claim 1 in which R1 is ethyl; R2 is hydrogen;
R3 and R4 of the compound of formula 2 are 2-ethyl and hydrogen, respectively;
and R3 and R4 of the compound of formula 1 are 4-ethyl and hydrogen, respectively; R is methyl and n is 4.
R3 and R4 of the compound of formula 2 are 2-ethyl and hydrogen, respectively;
and R3 and R4 of the compound of formula 1 are 4-ethyl and hydrogen, respectively; R is methyl and n is 4.
34. 4,6-Diethyl-5,6,7,8,9,10-hexahydrocyclohept[b]indole-6-acetic acid, as claimed in Claim 1 when prepared by the process or Claim 33, or an obvious chemical equivalent thereof.
35. The process of Claim 1 in which R1 is methyl; R2 is hydrogen;
R3 and R4 of the compound of formula 2 are 2-ethyl and hydrogen, respectively, and R3 and R4 of the compound of formula 1 are 4-ethyl and hydrogen, respectively; R5 is methyl and n is 4.
R3 and R4 of the compound of formula 2 are 2-ethyl and hydrogen, respectively, and R3 and R4 of the compound of formula 1 are 4-ethyl and hydrogen, respectively; R5 is methyl and n is 4.
36. 4-Ethy1-5,6,7,8,9,10-hexahydro-6-methylcyclohept[b]-indole-6-acetic acid, when prepared by the process or Claim 35, or an obvious chemical equivalent thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA234,428A CA1046519A (en) | 1975-08-28 | 1975-08-28 | Trycyclic acetic acid derivatives |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA234,428A CA1046519A (en) | 1975-08-28 | 1975-08-28 | Trycyclic acetic acid derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1046519A true CA1046519A (en) | 1979-01-16 |
Family
ID=4103931
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA234,428A Expired CA1046519A (en) | 1975-08-28 | 1975-08-28 | Trycyclic acetic acid derivatives |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1046519A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5238953A (en) * | 1991-01-22 | 1993-08-24 | Farmitalia Carlo Erba S.R.L. | N-imidazolyl derivatives of substituted tetrahydrocarbazole and cyclohept (b) indole |
-
1975
- 1975-08-28 CA CA234,428A patent/CA1046519A/en not_active Expired
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5238953A (en) * | 1991-01-22 | 1993-08-24 | Farmitalia Carlo Erba S.R.L. | N-imidazolyl derivatives of substituted tetrahydrocarbazole and cyclohept (b) indole |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US4057559A (en) | Carbazole acetic acid derivatives | |
| US3293263A (en) | Diphenylbenzocycloalkenes | |
| Martin et al. | New methods for alkaloid synthesis. Facile total syntheses of (.+-.)-O-methyljoubertiamine and (.+-.)-mesembrine | |
| CA2184174A1 (en) | Novel thiazolidin-4-one derivatives | |
| US4238486A (en) | Indolobenzoxazines | |
| US4478750A (en) | 1-Phenyl-azepinoindoles | |
| CA1046519A (en) | Trycyclic acetic acid derivatives | |
| Hino et al. | Agents Acting on the Central Nervous System.: Synthesis of 3-Phenyl-2-piperazinyl-1-benzazocines, 3-Substituted-2-piperazinyl-1-benzazepines and Related Compounds | |
| CA1047039A (en) | Tricyclic alkylamine derivatives and preparation thereof | |
| US3954794A (en) | Heterocyclic compounds | |
| Asselin et al. | Cycloalkanoindoles. 2. 1-Alkyl-1, 2, 3, 4-tetrahydrocarbazole-1-ethanamines and related compounds. Potential antidepressants | |
| US4008277A (en) | Benzo-bicyclononene derivatives | |
| CA1132553A (en) | Isoquinoline derivatives | |
| GB1594450A (en) | 1,3-oxathiolane sulphoxides and their use in the preparation of 5,6-dihydro-2-methyl-1,4-oxathiin derivatives | |
| US3960894A (en) | 9-Bromo-or chloro-9,10-dihydro-10-dihydro-10-alkoxy-4H-benzo[4,5]cyclo-hepta[1,2-b]thiophen-4-ones | |
| EP0240176B1 (en) | Substituted pyrimidoindoles | |
| US3965106A (en) | 3-Phenoxypropylamine derivatives | |
| US3244705A (en) | Triphenylhaloethylene derivatives | |
| US3952017A (en) | Tricyclic compounds | |
| US3795709A (en) | Benzobenzazulenes | |
| US3442903A (en) | Certain aminopropylidenebenzo(5,6)cyclohepta(1,2-d)thiazoles | |
| US3509132A (en) | Decahydro-1,6-diazecines | |
| US3459806A (en) | Benzobenzazulenes | |
| US3956391A (en) | Amino substituted tetrahydropleiadenes | |
| US3306934A (en) | 5-(aminopropylidene)-and 5-hydroxy-5-(aminopropyl)-3-dialkylsulfamoyl-5h-dibenzo[a,d] cycloheptenes |