NZ215832A - Indolylalkylamino-propanol derivatives - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number £15832 2 1 5832 Under the provisions of RegU^ lation 23 (I) the Specification has been ante-dated; to 19 <£3m [ pr:p- 9 Priority Date(s): .... i«• •' ■ J «• • ?-2 • i» •»•••••• • »•••••••• • • $!l?:. *. •. '.v. •. - ;>. P.EC. iaee.. ;iiftit*1 .9.O.

Patents Form No. 5 NO DRAWIN8S NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION "SUBSTITUTED INDOLYLALKYLAMINO PROPANOLS AND PREPARATION THEREOF" ✓T/'WE, BRISTOL-MYERS COMPANY, a Delaware Corporation of 345 Park Avenue, New York, 10022, U.S.A., hereby declare the invention, for which ^r/we pray that a patent may be granted to jj^/us, and the method by which it is to be performed, to be particularly described in and by the following statement ffoffowed by page I - 1A - 215832 The present invention is concerned with compounds of use as intermediates for producing heterocyclic carbon compounds of the indole series having an amino substituent, and with drug bio-affecting and body-treating processes employing these compounds. These latter compounds are described and claimed in New Zealand Patent Specification No. 205466 from which this specification has been divided.

This invention concerns compounds of the formulae IIB H N-G IIB wherein V/ is a halogen or hydroxyl group; wherein R is hydrogen or from Ci-C^Q alkyl, phenyl, substituted phenyl, or phenylalkyl; 12 ° with R , R , A, and B being independently—chosen from hydrogen or lower alkyl and with C representing a substituent in the benzo ring of indole and being selected from hydrogen, halogen, lower alkyl, lower alkoxy, or hydroxy.

The invention includes compounds having the foregoing structural formula IIB. In structural Formula IIB, the indole moiety itself is preferably coupled to the main side chain through its 3- position. The term "lower" as used with carbon containing radicals throughout the specification and claims means a group having 1 to 4 carbon atoms.

O II C-L , with L being selected 2 t 583 It is also to be understood that the compounds of the present invention include all the optical isomer forms, that is, mixtures of enantiomers, e.g., racemic modifications as well as the individual enantiomers. These individual enantiomers are commonly designated according to the optical rotation they effect, by (+) and (-), (1) and (d), or combinations of these symbols. The symbols (L) and (D) and the symbols (S) and (R), which stand for sinister and rectus respectively, designate an absolute spatial configuration of the enantiomer. Where no isomer designation is given for a compound, the compound is the racemic modification.

The indolylalkylaminopropanols (IIB; R = H), are conveniently prepared by reacting an appropriately substituted indolylalkylamine (III) with 3-chloro-l,2-propanediol in refluxing alcohol containing sodium carbonate. This process is illustrated by reaction equation 3.

Reaction 3 G Base B B (III) (IIB) 1 2 In reaction scheme 3, R , R , A, B, and C are as defined in Formula IIB 215832 The indolylalkylamines (III) are described in Kreighbaum, et_al.New Zealand Patent Specification No. 187763> and Journal of Medicinal Chemistry 23:3, 285-289 (1980), which are hereby incorporated by reference, as well as certain references cited therein. Although these referenced procedures are applicable to the preparation of other indolylalkylamine intermediates not specifically disclosed therein but which are required as intermediates for the present invention, representative syntheses of Formula III compounds are given hereinbelow for further exemplification.

The compounds which constitute this invention and their methods of preparation will appear more fully from a consideration of the following examples and appended claims which are given for the purpose of illustration only and are not to be construed as limiting the invention in sphere or scope. In the following examples, used to illustrate the foregoing synthetic processes, temperatures are expressed in degrees Celsius (°) and melting points are uncorrected. The nuclear magnetic resonance (NMR) spectral characteristics refer to chemical shifts (6 expressed as parts per million (ppm) versus tetramethylsilane (TMS) as reference standard. The relative area reported for the various shifts in the H NMR spectral data corresponds to the number of hydrogen atoms of a particular functional type in the molecule. The nature of the shifts as to multiplicity is reported as broad singlet (bs), singlet (s), multiplet (m), or doublet (d). Abbreviations 2 1583 2 anployed are'DMSO-d, (deuterodiraethylsulfoxide) , CDCl_ , D J (deuterochloroforro) and are otherwise conventional. The infrared (IR) spectral descriptions include only absorption wave numbers (cm ^") having functional group identification value. The IR determinations were employed using potassium bromide (KBr) as diluent. The elemental analyses are reported as percent by weight.

Synthesis of Intermediates A. Intermediates of Formula III EXAMPLE 1 3-(2-Araino-2-roethylpropyl)-6-methoxyindole • (R «= R «= Me, A and B ■= H, C = 6-MeO) To 15.2 mL of a chilled 25% aqueous solution of dimethyl-amine the following were added sequentially with stirring and continued cooling: 16.9 mL of acetic acid, 7.2 mL of 37% formaldehyde, 27 mL of 95% ethanol. The resulting stirred solution was kept at 0° to -5° with a cooling bath while 6-methoxyindole (10.0 g, 0.07 mole) was added in portions. This mixture was stirred and gradually warmed to 30° over a period of one-half hour and then held at 30° with stirring for 3 hrs. The reaction mixture was then chilled to 10-15° and acidified with 170 mL of 2N HC1. This acidic mixture was decolorized (Darco G-60), filtered and the filtrate made basic using 245 mL of 20% NaOH while being cooled and stirred. A resulting brown oily precipitate was ether extracted, and the extracts were water-washed, dried (MgSO^) and concentrated to a brown oily residue (14 g). The residue was recrystallized from isopropylether and hexane to yield 9 g (65%) of 6-methoxygramine as a tart solid, m.p. 88-90°.

A mixture comprised of the 6-methoxygramine (7.7 g, 0.04 mole), 2-nitropropane (26.5 g, 0.3 mole), and NaOH (1.7 g pellets, 0.04 mole) was refluxed under a nitrogen atmosphere for 3-5 hrs. The reaction mixture was cooled to room temperature, acidified with 10% acetic acid and extracted with ether. The ether extracts were water-washed, dried (MgSO^), and concentrated in vacuo to a residue. Recrystallization of the residue from isopropyl alcohol-water gave 7.6 g (80%) of 3-(2-methyi-2-nitropropyl)-6-methoxyindole as a tan solid, m.p. 98-100°.

The nitropropylindole compound and activated Raney nickel (4.2 g) were combined in 80 mL 95% ethanol and heated to reflux. Heating was halted as a solution comprised of 85% hydrazine hydrate (7.8 g) in 8 mL 95% ethanol was added dropwise. The reaction mixture was then heated at reflux for 2 hrs, cooled to room temperature and filtered. The filtrate was concentrated to a residual oil which slowly solidified and was recrystallized from ethyl acetate-isopropyl ether to give 4.2 g of product, m.p. 125-128°.

EXAMPLE 2 2-(2-Amino-2-methylpropyl)indole (R ■= R ■= Me, A, B, and C = H) A solution comprising indole-2-carboxylic acid (10.0 g, 0.06 mole) and thionyl chloride (20.0 g, 0.17 mole) in 130 mL of dry Et20 was stirred for 12-18 hrs at room temperature under a nitrogen atmosphere. The reaction mixture was filtered and the filtrate was concentrated to an oily residue which was taken up in 150 mL of dry EtgO. This ether solution was treated with 80 mL of dimethylamine in 90 mL of Et20. The ethereal reaction mixture was concentrated to dryness and the tesidue crystallized in isopropyl alcohol. The solid 215832 was isolated by filtration to give 4.0 g (34%) of the 2-indolylamide product, m.p. 181-183°.

The amide was dissolved in 100 mL THF and this solution was added dropwise to a stirred suspension comprised of 3 g lithium aluminum hydride in 50 mL of THF under a nitrogen atmosphere. After heat at reflux for 2 hr, the reaction mixture was cooled and decomposed with a small amount of water and dilute NaOH solution. This mixture was filtered and the filtrate concentrated to a residual oil which was taken up in absolute ethanol and treated with a slight excess of dimethyl sulfate. The resulting alcoholic solution was stirred at room temperature for 4 hrs and then concentrated in vacuo to dryness giving as residue the trimethylamine quaternary salt.

The crude quaternary salt product (3.0 g, 0.01 mole) was combined with NaOH (2.0 g pellets, 0.05 mole) and 2-nitropropane (15 mL) and the mixture was heated at reflux under a nitrogen atmosphere for 1 hr. The resultant dark thick mixture was cooled, diluted with water, acidified with acetic acid to a pH of approximately 6 and then extracted with Et^O. These Et^O extracts were combined, washed with water, dried (MgSO^) and concentrated to a dark residue which was chromatographed on a silica column and diluted with methylene chloride. Removal of the methylene chloride and recrystallization of the crude material from isopropyl alcohol-water gave 0.4 g of 2-(2-methyl-2-nitropropyl)indole as a cream colored solid, m.p. 102-103°.

Reduction of this nitro product with Raney nickel and hydrazine according to the procedure used in Example 1 above yields the desired indolalkylamine as a white solid, m.p. 130-133°.

Additional examples of indolealkylamines are displayed in Table 1. 215832 Table 1 Indolealkylamlnes (III).

Example R1 R2 A • B C 3 Me H 3-H Me H 4 Me Me 2-Me H H Me Me 2-H H -Br 6 Me Me 2-H H -OMe 7 H Me 2-H H H 8 H Me 2-Me Me -OPr 9 H Me 3-Me Me -Br Me Me 2-H H 6-0Me 11 Me H 2-Et H 4-C1 12 Me H 2-H H 7-0Me 215832 Products of Formula IIB EXAMPLE 13 3-[[2-(3-Indolyl)-l,1-dimethylethyl] amino]-!,2-propanediol Hydrate (IIB) A mixture of or,or-dimethyl-f3-(3-indolyl)ethanamine (10.0 g, 0.05 mole), Na^CO^ (11.3 g, 0.11 mole), 3-chloro-l,2-propanediol (7.0 g, 0.06 mole) and EtOH (250 mL) was stirred overnight at reflux. After cooling, the mixture was filtered and concentrated in vacuo. The residue was dissolved in EtOAc, decolorized (Darco G-60), and 10 evaporated to a volume of 100 mL. The solution deposited a white solid which was recrystallized from EtOAc to give 7.7 g (55%), m.p. 112-114°C. The material crystallized with one-fifth mole of water. similar procedure readily gives a variety of Formula IIB compounds.

The following abbreviations used herein have the following meanings: Ph stands for a phenyl group, Pr stands for a propyl group, Me stands for methyl group, and Et stands for an ethyl group. chemistry has been used throughout. For alkyl structures, in a shorthand form, joined line sigments substitute for explicit notation of C and H groups. Thus, for example, formula I can also be written: Using other intermediates of Formula III in this or a Additionally, an accepted convention in modern organic Y B 215832

Claims (5)

WHAT WE CLAIM IS:

1. A compound having the formula IIB H N-G OR IIB wherein W is a halogen or hydroxyl group; wherein R is hydrogen or O II C-L , with L being selected from C^-Cjg alkyl, phenyl, substituted phenyl, or phenylalkyl; and wherein G is the radical 1 7 with R , R , A, and B being independently chosen from hydrogen or lower alkyl and with C representing a substituent in the benzo ring of indole and being selected from hydrogen, halogen, lower alkyl, lower alkoxy, or hydroxy.

2. A process for preparing a compound having the formula IIB wherein W is a halogen or hydroxyl group; 0 II C-L , with L being selected wherein R is hydrogen or from C^-C^g alkyl, phenyl, substituted phenyl, or phenylalkyl; and wherein G is the radical - 10 - 215832 12 with R , R , A, and B being independently chosen from hydrogen or lower alkyl and with C representing a substituent in the benzo ring of indole and being selected from hydrogen, halogen, lower alkyl, lower alkoxy, or hydroxy; said process comprising: reacting a compound of formula III wherein A, B, R1, R2, and C are as defined above, with 3-chloro-l,2-propanediol in refluxing alcohol and a base.

3. A process as claimed in claim 2 wherein the base is sodium carbonate.

4. A compound as claimed in claim 1 and as specifically set forth herein.

5. A process for preparing a compound as claimed in claim 1 substantially as herein described with reference to any one of the Examples. BRISTOL-MYERS COMPANY