IE48649B1 - Tetrahydro-2h-benzo(c)pyrroles - Google Patents

Description

The invention of our Patent Specification No. provides substituted 4,5,6,7-tetrahydro-2H-benzo[c]pyrroles of the general formula .Am Λ <·' Ε1-»210 wherein R^ is H or R2; Am is NCR2),; and 2 Z each R is independently allyl, methyl, ethyl, or n-propyl; and the pharmaceutically-acceptable acid addition salts thereof.

Preferably the two R groups in Am are identical. The compounds of formula I are prepared by reacting a 5-amino-4,5,6,7-tetrahydro-2H-benzo [clpyrrole compound of the formula /’χ — NH2 ι '1 IN-♦ with an aldehyde and then reducing with a metal hydride; or with an alkyl halide, then an acyl halide followed by reducing with a metal hydride; to provide the compounds of 2 formula I wherein R is H, and Am is N(R optionally followed by reacting with an alkyl halide and base to provide the compounds of formula I wherein R1 is R2, and Am is N(R2)2> The compounds of formula I are useful as 5 dopamine agonists including their use in treating Parkinson's Syndrome and as prolactin inhibitors.

This invention relates to ampounds which are useful as intermediates in the formation of the compounds of formula X of Patent Specification No. , and which have the general formula Am /v’ IA wherein 0 3 κ is H or R -C; Am is NH, or NH-C-R3; R is methyl, ethyl or n-propyl; 7 » except that R is not R~-C when Am is NH2; and the acid addition salts thereof when Am is NH^.

As examples of acid addition salts of the compounds of formula IA which are pharmaceutically-acceptable are those salts derived from non-toxic inorganic acids such as, for example, hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydriodic acid, nitrous acid and phosphorous acid, as well as salts derived from non-toxic organic acids such as, for example, 48642 aliphatic mono and dicarboxylic acids, phenylsubstituted alkanoic acids, hydroxy alkanoic and alkandioic acids, aromatic acids and aliphatic and aranatic sulfonic acids. Such pharmaceutically-acceptable salts thus include, for example, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, butyne1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxy15 benzoate, methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, βhydroxybutyrate, glycollate, malate, tartrate, methane20 sulfonate, propanesulfonate, naphthalene-l-sulfonate and naphthalene-2-sulfonate.

Acid addition salts of compounds of formula IA are not restricted to those formed with non-toxic anions since the chief use of such salts is for isolation and purification of the intermediates involved.

While the compounds have been named as 4,5,6,7tetrahydro-2H-benzo [c]-pyrroles, an alternative name can be used; i.e., the compounds can be named as 4,5,6,7-tetrahydro isoindoles.

The presence of a substituent at C-5 in the benzo [c]pyrrole or isoindole ring introduces a center of asymmetry into those molecules. Thus, the compounds include two optical isomers occurring as a dl pair or racanate. Resolution of a dl pair into its optical antipodes can be accomplished by procedures known to those skilled in the art.

A process for preparing the compounds of the invention of the general formula IA r’-Λ· wherein . 3 H ΚΑ is H or R ~C; Am is NK, or NK-^-R0; z R is methyl, ethyl, or n-propyl; except that R3 is not R3-C when Am is NH^; and the acid addition salts thereof when Am is NH2> which comprises reacting either (A) a compound of formula III I / ^Ι=εΗ-Ν(θί3)β I J HI \z Zh-CO-Rs - 48649 wherein R3 is defined as above, with sodium glycinate followed by a ring closure reaction in the presence of acetic anhydride to provide the compounds of formula IA where Am is 0 0 NH-C-R3 and R1 is R3-C; optionally followed by reacting the product with base to provide the compounds of formula IA where Am is NH^ and R is H; or (B) a compound of formula XI z\ , I r’ • \ / NH-CO-R Hooc-r « HR-»-COOH XI wherein R3 is defined as above, with copper powder in the presence of quinoline to provide the compounds of formula IA 0 where Am is NH-5-R3 and R3 is H; optionally followed by basic hydrolysis to provide the compounds of formula IA where Am is NHj and R3 is H.

The above reactions for production of compounds of formula IA as well as the steps involved in producing compounds of formula I therefrom are set out in the following Reaction Sequences. Thus, process (A) and preceding and subsequent steps are illustrated in Reaction Sequence I below: Reaction Sequence I t ό Lu (CH3)eN-CH(OCHa)2 Z '''yCH-NCCHajE \Z CO-R II III I sodium I glycinate (CHsCO)eO z\ i r Z\Z I ΰv HN-ΝΗϊ < NaOH base 3 I I \ / » IV NaCNBHj HCHO or CHsCHO or CH3CH2CHO or CHz=CH-OC CO-CH, Z\ 2 • »-N(R2)2 Z \Z X-J V, base 4-8 649 According to Reaction Scheme 1, 4-acetamidocyclohexanone, prepared by the procedure of Fraser and Swingle, Can. J. Chem., 48, 2065 (1970) is reacted with the dimethylacetal of dimethylformamide to yield 2-dimethylaminomethylene-4-acetamidocyclohexanone (III) . Reacting this compound with sodium glycinate followed by a ring closure reaction in the presence of acetic anhydride yields, when R3 is methyl, dl-2acetyh-5-acetamid©-4, 5, 6., 7-tetrahydxo-2H-benzo [c] 10 pyrrole (IV), which is a compound of the invention.

Treatment of this latter compound with base gives a further compound of the invention, dl-5-emino-4,5,6,7-tetrahydro-2H-benzo[c]pyrrole (V). This latter compound can be preferentially alkylated on the amino group at C-5 using a reductive alkylation procedure; i.e., reaction with an aldehyde (formaldehyde, acetaldehyde, acrolein, or propion aldehyde) in the presence of a metal hydride reducing agent, such as sodium cyanoborohydride to yield a compound VI, i.e., a compound of formula I wherein R1 is H. The dialkylated compound, for instance, dl-5-di(npropyl) amino-4,5,6,7-tetrahydro-2H-benzo[c]pyrrole (VI) can also be alkylated on the pyrrole ring nitrogen 2 under basic conditions using an alkyl halide R X (methyl iodide, allyl chloride, ethyl bromide, or the like) to yield a dl-2-(C^-C^ alkyl or allyl)-5-disubstitutedamino-4,5, 6,7-tetrahydro-2H-benzo[c]-pyrrole of formula VII, i.e., a canpound of 1 2 formula I wherein R is R .

Other methods of alkylation of the amine groups at C-5 can be employed in addition to the reductive alkylation procedure illustrated above for converting V to VI. For example, direct alkylation with an alkyl halide, particularly an iodide, followed 8 64-9 by a reaction of the thus-formed secondary amine with a suitable acyl halide; i.e., acetyl chloride or crotyl chloride followed by reduction again with a metal hydride reducing agent, such as lithium aluminum hydride or diborane, yields a 5-dialkylamino compound. This latter procedure particularly lends itself to the preparation of unsymmetrically substituted amine groups at C-5.

Process (B) and preceding and subsequent steps are illustrated in Reaction Sequence XX below: Reaction Sequence II z\ 1 \/ ί NH-CO-R II CH(0CzHs)3 acid catalyst Z\ 3 | j—NH—CO“R ,® e Z\Z / Zn CH3OOC-Z » <ζHN-e-COOCHs X HOAc HOOC\Z base / Y-NH-CO-R3 I I ./Y HtJ-»-COOH XI Cu powder quinoline OCeHb z\ kJ I H-CO-R VIII ^OOCHs CH3 z\ 3 • |-NH-CO-R3 CH3OOC y\/ ( I ΥΖ roocHc IX > Z*\ 3 NH-CO-R3 I r zy \z XII base / Y-NHs V η v Hl According to Reaction Sequence II, the same starting material 4-acylamidocyclohexanone, is employed as in Reaction Sequence I. The reaction of this starting material with ethyl orthoformate in the presence of an acid catalyst such as p-toluene sulfonic acid produces an enol ether; i.e., 4-acetamido1-ethoxycyclohexene (VIII). Reaction of this derivative with 1,2,4,5-tetrazine dicarboxylic acid, dimethyl ester [prepared by the procedure of Sauer, et al. Chem. Ber., 98, 1435 (1965)] yields a pyridazine diester (IX). Reduction of this diester with zinc in acetic acid or other suitable metal-acid reducing system causes a ring contraction to yield dl-1,3dicarbomethoxy-5-acetamido-4,5,6,7-tetrahydro-2Hben2O[clpyrrole (X). Selective hydrolysis of the diester with base yields the corresponding dicarboxylic acid (XI) which, on decarboxylation with copper powder in the presence of quinoline, gives dl-5-acetamido-4.5.6,7-tetrahydro-2H-benzo[c]pyrrole (XII), which is a compound of the invention. Hydrolysis under basic conditions of the acyl group then yields the free amine, dl-5-amino-4,5,6,7-tetrahydro-2H-benzo[c] pyrrole (identical to compound V from Reaction Sequence I) and which is a compound of formula I in which Am is NH^ and R1 is H. Other acyl protecting groups can be used in the 4-acylamido cyclohexanone starting material besides acetyl including, for example, propionyl, butyryl and isobutyryl as well as benzoyl, dinitrobenzoyl and phenylacetyl.

This invention is further illustrated by the following preparative examples: Example 1 PREPARATION OP dl-2-ACETYL-5-ACETAMIDO-4,5,6,7-TETRAHYDRO 2H-BENZO [c]-PYRROLE A reaction mixture was prepared from 15.5 g. of 4-acetamidocyclohexanone [prepared by the procedure of Fraser and Swingle, Can. J. Chem., 48, 2065 (1970)], 80 g. of the dimethylacetal of dimethylformamide, 1.5 ml. of triethyiamine and 500 ml. of benzene. The benzene was distilled therefrom over a 1.5 hour period until the volume was reduced to about 1/2 of the original volume. An additional 250 ml. of benzene were added. The reaction mixture was heated just below the boiling point of benzene for about 2 hours and was then distilled again until the volume was about one-half of that originally present (250 ml.) The above process was repeated once more except that the volume was reduced to one-third of the original volume (167 ml.). The reaction mixture was then cooled and filtered. The filter cake consisted of dl-4-acetamido-2-dimethylaminomethylenecyclohexanone formed in the above reaction; weight = 6.45 g. Evaporation of the filtrate to dryness yielded a residue, chromatography of a chloroform solution of which ever 200 g. of Florisil (Trade Mark) using chloroform containing increasing amounts of methanol (0-5%) as an eluant, yielded more dl-4-acetamido-2-dimethylaminomethylenecyclohexanone; M.P. = 132-133“C. (from benzene); yield = 5.55 g.; total yield = 12 g.

Analysis Calc.: C, 62.83; H, 8.63; N, 13.32 Found: C, 63.07; H, 8.38; N, 13.12 6 49 Potassium glycinate was prepared by reacting 9 g. of glycine and 6,7 g. of potassium hydroxide in 400 ml. of anhydrous ethanol. 22.6 g. of dl-4acetamido-2-dimethylaminomethylenecyclohexanone were added thereto and the resulting mixture heated to refluxing temperature under a nitrogen atmosphere for 1.75 hours. The reaction mixture was cooled, diluted with ether, and filtered. The filter cake, which weighed 28.7 g., was added to 400 ml. of acetic anhydride and the resulting mixture heated to reflux temperature under a nitrogen atmosphere for one hour.

The reaction mixture was cooled and the volatile constituents removed by evaporation in vacuo. The resulting residue was suspended in chloroform and filtered. The filtrate was chromatographed over 350 g. of Florisil, using chloroform containing increasing amounts (0-2%) of methanol as the eluant. Fractions shown by TLC to contain dl-2-acetyl-5-acetamido-4,5,6,7tetrahydro-2H-benzo(c]pyrrole formed in the above reaction were combined and the solvent evaporated therefrom. Crystallization of the residue from ether yielded purified dl-2-acetyl-5-acetanido-4,5,6,7tetrahydro-2H-benzo[c]pyrrole melting at 151-153°C.; yield = 17.7 g.

Analysis Calc.; C, 65.43; H, 7.32; N, 12.72; Found; C, 65.72; H, 7.34; N, 12.45.

EXAMPLE 2 PREPARATION OF (11-5-AMINO-4,5,6,7-TETRAHYDRO-2HBENZO [c]-PYRROLE A hydrolysis mixture was prepared from .1 g. of dl-2-acetyl-5-acetamido-4,5,6,7-tetxahydro2H-benzo[c J pyrrole, 50 g. of sodium hydroxide, 50 ml. of water, and 200 ml. of ethanol. The mixture was heated to refluxing temperature under a nitrogen atmosphere for about 16 hours and was then cooled.

The cooled mixture was diluted with water. The alkaline aqueous mixture was extracted several times with methylene dichloride, the methylene dichloride extracts were combined and the combined extracts washed with saturated aqueous sodium chloride and dried. Evaporation of. the solvent therefrom yielded a residue comprising dl-5-amino-4,5,6,7-tetrahydro-2Hbenzo[c]pyrrole fonted in the above reaction. A chloroform solution of the residue was filtered through 105 g. of alumina (grade II). Concentration of the resulting filtrate yielded 2.52 g. of a yellow solid comprising dl-5-amino-4,5,6,7-tetrahydro2H-benzo[c]pyrrole.

Example 3 PREPARATION OF dl-5-ACETAMIDO-4,5,6,7-TETRAHYDRO-2E25 BENZO[c]PYRROLE To a solution of 6.7 g. of 4-acetamidocyclohexanone [prepared by the method of Fraser and Swingle, Can. J. Chem,, 48, 2065 (1970)], in 150 ml. of anhydrous ethanol were added 25 ml. of ethyl orthoformate containing a few crystals of p-toluenesulfonic acid monohydrate. The reaction mixture was stirred at ambient temperature for about 16 hours, after which time the volatile constituents were removed by evaporation in vacuo. The residue comprising the diethylketal was dissolved in 200 ml. of toluene and the toluene was removed by distillation under a nitrogen atmosphere, until all of the diethylketal had been converted to the 1-ethoxycyclohexene derivative. The solution was cooled, washed with aqueous sodium bicarbonate and dried. Evaporation of the toluene yielded a residue comprising 4-acetamido1-ethoxycyclohexene melting at 100-102®C. after reorystallization from an ether-hexane solvent mixture; yield = 6.2 g.

A solution of 3 g. of 4-acetamido-l-ethoxycyclohexene in 40 ml. of dioxane was added slowly to a solution of 3.2 g. of 1,2,4,5-tetrazine dicarboxylic ester [prepared by the method of Sauer, et al., Chem. Ber., 98, 1435 (1965)] in 100 ml. of dioxane.

The reaction mixture was stirred at ambient temperature for about 3 days after which time TLC indicated one major spot with several minor spots present. The reaction mixture was evaporated in vacuo, the resulting residue dissolved in chloroform, and the chloroform solution chromatographed over 200 g. of Florisil using chloroform containing increasing amounts (2-54) of methanol as the eluant. Fractions shown to contain a single major spot material by TLC were combined and the solvent removed from the combined fractions in vacuo. The residue was crystallized by triturating with ether; mp = 137-139eC; yield « 3.21 g.

Recrystallization of the residue from the ethermethanol solvent mixture yielded purified dl-648649 acetamido-1,4-di(carbomethoxy)-5,6,7,8-tetrahydrobenzo[djpyridazine melting at 143-144°C.

Analysis Calc.: C, 54.72; H, 5.58; N, 13.67; Found: C, 54.75; H, 5.64; N, 13.49.

A solution was prepared by adding 2.59 g. of dl-6-acetamido-l,4-di(carbomethoxy)-5,6,7,8-tetrahydrobenzo[djpyridazine to 100 ml. of glacial acetic acid. 5 g. of zinc dust were added and the resulting mixture stirred at ambient temperature for about 1 day. An additional 5 g. of zinc dust were added after 6 hours. The reaction mixture was then filtered to remove unreacted zinc dust and the resulting filtrate poured over ice. The filtrate was made basic with 14N aqueous ammonium hydroxide and the alkaline mixture extracted several times with a chloroform-isopropariol solvent combination. The organic extracts were separated and combined, and the combined extracts washed with saturated aqueous sodium chloride and then dried. Evaporation of the solvent therefrom yielded dl-5-acetamido-l,3-di(carbomethoxy)-4,5,6,7-tetrahydro-2H-benzo[c]pyrrole formed in the above reaction; yield = 1.83 g. Recrystallization from methanol yielded crystalline material melting at 231-232°C.

Analysis Calc.: C, 57.14; H, 6.16; N, 9.52 Found: C, 57.05; H, 5.99; N, 9.26 A reaction mixture was prepared containing 1.8 g. of dl-5-acetamido-l,3-di(carbomethoxy)-4,5,6,7tetrahydro-2H-benzo[c]pyrrole, 80 ml. of THF and 20 ml. of 2N aqueous sodium hydroxide. The reaction 4-8 6 49 mixture was heated to refluxing temperature under a nitrogen atmosphere for about 3 hours after which time it was cooled and the volatile constituents evaporated therefrom in vacuo. The residue was dissolved in 25 ml. of water and the aqueous solution made acidic by the addition of IN aqueous hydrochloric acid. The diacid, dl-5-acetamido-l,3-dicarboxy-4,5,6,7-tetrahydro-2H-benzo[c]pyrrole, formed in the above hydrolysis being insoluble in the acidic layer precipitated and was collected by filtration. Recrystallization from a benzene-methanol solvent mixture yielded crystalline diacid melting at 233-235°C. with decomposition.

Analysis Calc.: C, 54.13; H, 5.30; N, 10.52 Found: C, 53.90; H, 5.37; N, 10.45 A reaction mixture, prepared from 850 mg. of dl-5-acetamido-l,3-dicarboxy-4,5,6,7-tetrahydro-2Hbenzo[c]pyrrole, 50 mg. of copper powder and 25 ml. of quinoline, was heated to 200°C. under a nitrogen atmosphere. Gas evolution was noticeable as the temperature approached 150°C. Heating in the range 200-210'C. was carried on for 15 minutes after which time the reaction mixture was poured over ice. The resulting aqueous mixture was extracted with chloroform, and the chloroform extract was separated, washed with 0.1N aqueous hydrochloric acid, 10 percent aqueous sodium hydroxide and finally water. The chloroform was removed therefrom by evaporation in vacuo to yield 0.26 g. of a dark oil as a residue. Chromatography over 15 g. of Florisil using chloroform containing from 0 to 1 percent methanol as the eluant yielded 40 mg. of dl-5-acetamido-4,5,6,7-tetrahydro-2Hbenso [cjpyrrole. The product was identical to the compound prepared by deacetylation of dl-5-acetamido-2-acetyl4,5,6,7-tetrahydro-2H-benzo [c]pyrrole from Example 1.

Claims (6)

1. CLAIMS:1. A compound of the general formula : /\ -Am IA 1 I If R -N-wherein θ 1 3 1 5 R is H or R -C; II 3 Am is NH 2 or NH-C-R ; R 3 is methyl, ethyl, or n-propyl; 1 3 1* except that R is not R -C when Am is NH 2 ; and the acid addition salts thereof when Am is NH 2 · 10

2. dl-2-Acetyl-5-acetamido-4,5,6,7-tetrahydro-2Hbenzo [c] pyrrole.

3. dl-5-Amino-4,5,6,7-tetrahydro-2H-benzo[c]pyrrole.

4. dl-5-Acetamido-4,5,6,7-tetrahydro-2H-benzo [o]pyrrole.

5. A process for preparing compounds of claim 1 which 15 comprises reacting either (A) a compound of formula III \ ’•=CH-N(CH 3 ) 2 NH-CO-R 3 III 4-8 6 4-9 wherein R is defined as above, with sodium glycinate followed by a ring closure reaction in the presence of acetic anhydride to provide a compound of formula IA where Am is 0 0 It 3 i 3 H 5 NH-C-R and R is R -C; optionally followed by reacting the product with base to provide the compounds of formula IA where Am is NH_ and R is H; or (B) a compound of formula XI / \ 3 • * -NH-CO-R HOOC//// XI -COOH 10 wherein R^ is defined as above, with copper powder in the presence of quinoline to provide the compounds of formula IA H 3 p where Am is NH-C-R and R is H; optionally followed by basic hydrolysis to provide a 15 compound of formula IA where Am is NH 2 and R^ is H.

6. A process for preparing a compound of formula IA as defined in claim 1 as hereinbefore described, with reference to any one of the Examples.