United States Patent [:91
`Glamkowski et al.
`
`*'
`
`[11]
`
`[45]
`
`4,448,784
`
`May 15, 1984
`
`[54]
`
`1-(AMINOALKYLPHENYL AND
`AMINOALKYLBENZYL)-INDOLES AND
`INDOLINESAND ANALGESIC METHOD OF
`USE THEREOF
`
`[75]
`
`Inventors: Edward J. Glamkowski, Warren,
`N..Y.; James M. Fortunate, North
`Wales, Pa.
`
`‘T(CH2)m
`
`(lower alkylene)—N
`
`R1
`
`R:
`
`[73] Assignee: Hnechst-ReusselPharmaeenticals,
`Inc., Somerville, NJ.
`
`where R1 and R2 are the same or different and are hy~
`drogen, lower alkyl, cycloalkyl and acyl of the formula
`
`0I
`
`I
`R30-
`
`where R3 is lower alkyl,
`phenyl of the formula
`
`lower alkoxy, cycloalkyl,
`
`[21] Appl. No.: 367,707
`
`[22] “Filed:
`
`Apr. 12, 1932
`
`[51]
`[52]
`
`Im. 01.: ................. .. A511; 31/405;C07D 209/03
`11.5.01. .................................. ,. 424/214;s4s/491;
`548/469
`[58] Field of Search ............... .. 548/491, 469; 424/274
`
`-<3"
`
`[56]
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`4,186,199
`
`1/1930 Glamkowski et al.
`
`424/274 X
`
`OTHER PUBLICATIONS
`
`Glarnkowski et al., J. of Heterocyclic Chemistry, 16,
`pp. 865—369, (19.79).
`
`and At lower alkyl of the formula -lower alkylene
`
`X
`
`,Iowerflky]me ;
`
`X is hydrogen, halogen, lower alkoxy, Ar lower alkoxy
`of the formula
`
`Primary Examiner-—Paul M. Coughlan, Jr.
`Assmanr Exam1'r1er—David B. Springer
`Attorney, Agent, or Pi?-m—Jeron1e Rosenstock
`
` Iemralkylene-0-; I
`
`I
`
`[57]
`
`ABSTRACT
`
`The invention relates to 1~(a.minoalkylpheny1 and ami-
`noalkylbenzylflndoles and indolinea of the formula:
`
`m and p are independently integers of 0 and l and the
`pharmaceutically acceptable acid addition salts thereof.
`
`31 Claims, No Drawings
`
`Ioflfi
`
`PENN EX. 2190
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`CFAD V. UPENN
`lPR20l5-01836
`
`

`
`1
`
`4,448,784
`
`2
`sessing at least one carbocyclic ring, of 3 to 7 carbon
`atoms, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cy-
`clohexyl, cycloheptyl, etc., having its free valence bond
`from a carbon of the carbocylic ring; the term “Ar
`lower alkyl” refers to a monovalent substituent which
`consists of an aryl group, e.g., phenyl, p-nitrophenyl,
`o-tolyl, m—methoxy phenyl etc. linked through a lower
`alkylene group having its free valence bond from a
`carbon of the lower alkylcne group, and having a for-
`mula of
`
`1-(AMINOALKYLPHENYL AND
`AMINOALKYLBENZYLJ-INDOLIES AND
`INDOLINES AND ANALGESIC METHOD OF USE
`THEREOF
`
`To the best of our knowledge the compounds of the
`present invention have not heretofore been described or
`suggested.
`_ The compounds of the present invention have the [0
`general formula
`
`(I)
`
`x
`
`(Cflzlm
`
`(lower aIkylene)—N
`
`R1
`
`1'12
`
`where X is as previously defined; the term “alkylene”
`refers to a bivalent radical of the lower branched or
`unbranohed alkyl group it is derived from having va-
`lence bonds from two terminal carbons thereof, e.g.
`ethylene (—CH1CH2-—-), propylene
`(—CH2CH2C-
`H2---) isopropylene
`
`where R1 and R1 are the same or different and are hy-
`drogen, lower alkyl, cycloalkyl and acyl of theformula 25
`
`I
`(CI-I3--CH"-CH2"").
`
`etc.; and the term “halogen" refers to a member of the
`family consisting of fluorine, chlorine, bromine and
`iodine.
`
`The compounds of the present invention are prepared
`in the following manner. The substituents X, R1, R2 and
`R3 and the integers In and p are as defined above unless
`indicated otherwise.
`A. A substituted indoline or indole of the formula
`
`(II)
`
`(-19
`
`NH
`
`x
`
`0I
`
`I
`R3C—,
`
`where R3 is lower alkyl,
`phenyl of the formula
`
`lower alkoxy. cycloalkyl,
`
` x
`
`and Ar lower alkyl of the formula
`
`-lower alkylene
`
`is selected. Compolmd (II) is reacted with a haloben-
`zonitrile or a halo tolunitrile having the formula
`
`X is hydrogen, halogen, lower alkoxy, A: lower alkoxy,
`of the formula
`
`Hal-(CH2)».-
`
`as
`
`,
`
`am
`
`lower alkylene-0-;
`
`where Hal is a halogen selected from F, Cl, Br and I to
`form an intermediate of the invention.
`
`in and p are independently an integer of 0 or 1 and the
`pharmaceutically acceptable acid addition salts thereof.
`In the above definitions the term “lower” means the
`group it is describing contains from 1 to 6 carbon atoms.
`The term “alkyl” refers to a straight or branched chain
`hydrocarbon containing no unsaturation, e.g. methyl,
`ethyl, isopropyl, 2-butyl, neopenty], n-hexyl, etc.; the
`term "alkoxy” refers to a monovalent substituent which
`consists of an alkyl group linked through an ether oxy-
`gen having its free valence bond from the ether oxygen,
`e.g. methoxy, ethoxy, propoxy, butoxy, pentoxy, etc.;
`the term “cycloalkyl” refers to a monovalent substitu-
`ent consisting of a saturated hydrocarbon group pos-
`
`x
`
`(-35!
`
`(IV)
`
`(CH2)m
`
`CN
`
`Compound IV is typically obtained by reacting com-
`pounds II and 111 under nucleophilic substitution reac-
`
`2of16
`
`PENN EX. 2190
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`CFAD V. UPENN
`lPR20l5-01836
`
`

`
`3
`tion conditions. Typically, where p= 1, compound II is
`reacted with compound [II in the presence of a base,
`e.g. NaH, (CH3)3—C—OK, Cal-l5Li, and in a solvent,
`
`4,448,784
`
`4
`
`ax)
`
`CH20SO1R4
`
`_
`
`N
`(‘EH2
`
`e.g., diniethylsulfoxide (DMSO), dimethylformainide 5
`(DMF), xylene, etc. at a temperature oft)“ to 200° C. for
`l
`to 24 hours to form compound IV. Alternatively,
`where p=0, compound II is reacted with compound III
`in the presence of a base, e.g., KzCO3, NaHCO3, or In
`when R4 is lower alkyl_ e_g_ methyl’ or pheny1_ -1-ypi_
`even an excess of the ‘indoline 11 serving as base, etc,
`cauy compound V11 is reacted with compound V1" in
`without or with an inert solvent, e.g., chloroform,
`an inert solvent, e.g. dichloroinethane, ether, etc. at a
`methylene ¢]11°I‘ld'-‘vi
`l30111"-‘$119 919- at 3 temper-W-lf¢ Of
`temperature of 0" to 100° C. for l to 24 hours to form
`— 10° to 100“ C. for l to 24 hours to form compound IV.
`Compound IV in turn is reduced by conventional 15 compound IX. Compound IX is then reacted with an
`means, e.g. with a metal hydride such as LiAlI-I4, BH3
`inorganic cyanide, e.g. NaCN, KCN, in a conventional
`etc. in an inert solvent such as tetrahydrofuran (THF),
`manner in the presence ofa solvent. typically an aprotic
`diet]-lyletj-,3,-, diam“, am at 3 temperature of _ 10° to
`polar solvent such as methanol, ethanol, dimethyl forni-
`100' C. for 1 to 24 hours to reduce the cyano group to
`"mid? (DMFL N'm°thy1'2'P3"’°1id°“°, °' dlmcthld
`form 3 compound of the invention
`2° sulfoxide (DMSO), to form an inten-nedlatc of the in-
`vention having the formula
`
`X
`
`(‘)9
`N
`|
`(CH2
`
`CH NH
`2
`
`2
`
`(V)
`
`25
`
`30
`
`(X)
`
`Cl-I2CN
`
`(_)P
`
`N
`I(CH2
`
`B‘ Comfitmfnd ‘l’ is 1‘Yd'°_1Y_“i“ in 3 cfionventillnal
`manner ut izing either an acidic or alkaline medium
`whereby the cyano group is hydrolyzed to a carboxyl
`group to give an intermediate of the invention having 35
`the formula
`
`The cyano group of compound X is reduced in the
`manner previously described to form a compound of
`the invention having the formula
`
`(X0
`
`X
`
`(__]P
`
`(vi)
`
`"
`
`40
`
`H’
`
`ll“
`
`C-H1C‘H2NI'I2
`
`I(m2
`
`45
`
`C. Compound IV is reacted in a conventional manner
`with a Grignard reagent of the formula R5 MgHal,
`(XII) where Hal is a halogen selected from Cl, Br and I
`Compound V1 is reduced by reaction with a metal l1y-
`9-fld R5 is 8-H fllkyl E1‘°'1P Of 1 to 5 0315011 atoms. 01‘
`dride, e.g. LiAlH4, BI-I3, AIH3, etc., in an inert solvent,
`phenyl to form an intermediate of the invention having
`e_g_ THE ether, dioxan, etc, typically at 3 tempemtme
`of — 10' to 100” c. for l to 24 hours to form an alcohol 50 “'3 f°“1“1la
`intermediate of the invention having the formula
`
`[X110
`
`R5
`I
`CIIN'MgHaJ
`
`x
`
`‘-15
`
`(CH2
`
`(VII)
`
`55
`
`x
`
`(-19
`
`IINT
`
`«eleo
`
`60 Typically, compound IV is reacted with the Grignard
`reagent (XII) in an inert solvent, e.g. tetrahydrofuran
`.
`.
`.
`.
`(THF), ether’ diam“ etc“ at a temperature of 0° to 100.
`Compound VII is, in turn, reacted with a sulfonyl halide
`C. for 1 to 24 hours to form compound XIII. Compound
`°f the f°m“'1“ R“So1“H“l (VH1) when H31 is 5 131°‘
`gen selected from F, Cl, Br and I, and R4is lower alkyl, 65 x11] is men reflucgd by 1-educfign with metal 1-mime,
`e-g- methyl. or aryl such as phenyl or tolyl. to form a
`e.g. LiAlI-I4, as previously described for the reduction
`sulfonate intermediate of the invention having the for—
`of the cyano group. to fonn a compound of the im,-en-
`mula
`tion having the formula
`
`3 of 16
`
`PENN Ex. 2190
`CFAD V. UPENN
`lPR2015-01836
`
`

`
`4,448,784
`
`6
`
`TABLE I-continued
`Dose
`Inhibition
`(sI.1b:rutaneou_s}
`mg/ltg of body Of wriltting
`__.j.
`Weight
`%
`Cornpolmd
`3-(1-i.ndclyl)benaenetneth.enamine
`19.1
`59
`hydrochloride
`3-{5—chJoro-l-i.ndclinylmethyl)-
`b-eimncmcthanaiiiine fumarate
`N—cyciopropylcarbony1-3-(l-
`indoliityl)-benzcnetnethannmine
`N—cycJopropyhnethyl-3-(l-
`indolinynbatzenemethananiinc
`hydrocltloride
`N,N—dimethyl-3-(1-indolinyl)
`beuzeneinethnnamine hydrochloride
`3-(1-indolinyl)-2-benzene
`ct|tanami.ne.§ fumarate
`3-(l-inttolinyl)-a-methylbenzene-
`methanamine hydrochloride
`
`
`3.9'propoxyphene St!
`
`at
`
`59.3
`
`49.3
`
`56.5
`
`57.0
`
`«ind
`
`29.2
`
`19.5
`
`lfihfl
`
`23.6
`
`1&9
`
`10.0
`
`
`
`The analgesic relief of pain is achieved when the
`compounds of the invention are administered to a sub-
`ject requiring such treatment at an effective oral, paren-
`teral or intravenous dose of from 1.0 to 25 mg/kg of
`body weight per day. A preferred effective dose within
`this range is from about 1 to lo mg/kg of body weight
`per day. A particularly preferred effective amount is
`about 5 mg/kg of body weight per day. It is to be under-
`stood, however, that for any particular subject, specific
`dosage regimens should be adjusted according to the
`individual need. It is further to be understood that the
`dosages set forth herein are examples only and that they
`do not. to any extent, limit the scope of practice of the
`invention.
`
`Effective amount of the compounds of the present
`invention may be administered to a subject by one of
`various methods, for example, orally as in capsules or
`tablets, parenterally in the form of sterile solutions or
`suspensions, and in some cases intravenously in the form
`of sterile solutions. The compounds of the invention,
`while effective themselves, may be formulated and ad-
`ministered in the form of their phannaceutically accept-
`able acid addition salts for purposes of stability, conve-
`nience of crystallization,
`increased solubility and the
`like.
`
`Preferred pharmaceutically acceptable acid addition
`salts include those derived from inorganic acids such as
`hydrochloric, hydrobrornic, sulfuric, nitric, phosphoric,
`perchloric acids and the like as well as organic acids
`such as tartaric, citric, acetic, succinic, maleic, fumaric
`acids and the like.
`
`(-ls
`
`(CH2
`
`CH—NH2
`
`(XIV)
`
`5
`
`ID
`
`D. The N-alkyl or N-acyl derivatives of compounds
`V, XI and XIV are prepared in a conventional manner,
`as for example by reaction with a lower alkyl halide or
`a cycloalkyl halide or an acylhalide of the formula
`
`iiP.3C"'I‘!.Bl
`
`where Hal is a halogen selected from F, Cl, Br and I and
`R3 is as previously defined, whereby a mo:1o- or bi-sub-
`stituted compound of the invention, Compound I,
`is
`obtained where at least R1 or R2 is lower alkyl, cycloni-
`lcyl or acyl of the formula
`
`20
`
`0I
`
`I
`R3C—.
`
`Alternatively, compounds V, XI and XIV can be re-
`acted in a conventional manner with an alkylchlorofor-
`mate followed by reduction of the resultant compound,
`as with LiAlH4, NaBH4., to form compound I of the
`invention where at least R1 or R2 is methyl. In another
`alternative embodiment, compounds V, XI and XIV
`can be reacted in a conventional manner with an acid
`anliydride.
`
`30
`
`35
`
`in’
`(lower allryl (2)10.
`
`45
`
`to form compound I of the invention where at least R:
`or R2 is lower alkyl.
`E. Where p is 1 in_ compound IV, it is typically re-
`duced to compound IV where p is 0 by reaction with
`sodium cyanoborohydride. Typically this reaction is
`carried out in a solvent of THF, acetonitrile, or acetic
`acid at a temperature of 0° to l00° C. for l to 24 hours.
`The compounds of the invention are useful as analge-
`sic agents due to their ability to alleviate pain in mam-
`mals. The activity of the compound is demonstrated in
`the 2-phcnyl-1,4-benzoquinone-induced writhing test in
`mice, a standard assay for analgesia [Proc. Soc. Exptl.
`Biol. Med, 95, 729 0975)]. The analgesic activity of
`some of the compounds expressed in terms of percent
`inhibition of writhing is given in Table l.
`
`TABLE I
`Dose
`<==°*=='====;g>
`
`em-wed
`.
`.
`_
`Iil£ll1:'nd:Iii?n3:)hyflr0C;lOfidB
`2-(l-indolinyl)benzene-
`m=I|1=_anm?}in= lwflrflchloride
`:';I';'J'lja‘;i:;1)hh°"z°ydmgiim.de
`3_l5_Ch]Om_]_h.,do]m5,1Jbmzene_
`methertarnine hydrochloride
`
`5a
`53
`56
`
`55
`
`4'2
`14.1
`5 3
`2 '
`43
`
`55
`
`invention may be
`The compounds of the present
`administered orally, for example, with an inert diluent
`or with an edible carrier. They may be enclosed in
`gelatin capsules or compressed into tablets. For the
`purpose of oral therapeutic administration, the com-
`pounds may be incorporated with excipients and used in
`the form of tablets, troches, capsules, elixirs, suspen-
`'
`’
`'
`60 §‘?t'If;f§'ti.'3f.’§’ lfiifiii’ ‘i.3LT..T..g §i’"f2;';'2d$’3,t?i ‘L“r°'.ii’°i?
`«‘“:“:*°““"s‘::’.‘.2.‘;’ :;.£a"*i?.°3‘:‘.=::.:°'::sef.‘::°:“t::
`moineso
`n
`n,
`e
`n,
`may be varied depending upon the particular form and
`may conveniently be between 4% to about 70% of the
`65 weight of the unit. The amount of the compound pres-
`eat in such compositions is such thatla suitable dosage
`will be obtained. Preferred compositions and prepara-
`tions according to the present invention are prepared so
`
`_4 of 16
`
`PENN Ex. 2190
`CFAD V. UPENN
`lPR20l5-01836
`
`

`
`4,448,784
`
`‘T
`that an oral dosage unit form contains between 5.0—300
`milligrams of the 1-(aminoalkylphcnyl and aminoalkyl-
`benzyl)indoles and indolines of the invention.
`The tablets, pills, capsules, troches and the like may
`also contain the following adjuvants: a binder such as
`microcrystalline cellulose, gum tragacanth or gelatin;
`an excipient such as starch or lactose, a disintegrating
`agent such as alginic acid, Primogel, corn starch and the
`like; a lubricant such as magnesium stearate or Sterotex;
`a glidant such as colloidal silicon dioxide; and a sweet-
`ening agent such as sucrose or saccharin may be added
`or a flavoring agent such as peppermint, methyl saticyl-
`ate or orange flavoring. When the dosage unit form is a
`capsule, it may contain, in addition to materials of the
`above type, a liquid carrier such as a fatty oil. Other
`dosage unit forms may contain other various materials
`which modify the physical form of the dosage unit, for
`example, as coatings. Thus,
`tablets or pills may be
`coated with sugar, shellac, or other criteria coating
`agents. A syrup may contain, in addition to the present
`compounds, sucrose as a sweetening agent and certain
`preservatives, dyes and eolorings and flavors. Materials
`used in preparing these various compositions should be
`pharmaceutically pure and non-toxic in the amounts
`used.
`
`10
`
`25
`
`8
`vacuum, thus affording 4.33 g (3.9% overall) of 2-(in-
`do1inyl)benzonitrile M.P. 94.0"—96.5° C.
`ANALYSIS: Calculated for C15H12N2: 8l.79%C,
`5.49%H,
`l2.72%N, Found:
`8l.60%C,
`5.54%]-I,
`l2.65%N.
`‘
`
`2-(1-Indolinyl) benzenemethanamine hydrochloride
`A solution of 17.18 g (0.073 mole) of 2(l-indolinyl)-
`benzonitrile of Example la in 150 ml dry tetrahydrofu-
`ran (THF) was added dropwise to a rapidly stirred ice
`cold solution of BH3 in THF (236 ml of 1 M solution;
`0.236 mole) under nitrogen. At the end of the addition
`the resultant solution was permitted to" warm to room
`temperature and stir for 3 hours and then heated at
`reflux for 50 minutes. The product was then cooled to
`0° C., treated dropwise with 6 N HCl (100 ml), and
`permitted to stand overnight (about 16 hours) at room
`temperature. The reaction mixture was cooled to 0" C.
`and made basic using solid NaOH. The resulting aque-
`ous layer was extracted with ether (200 ml) and the
`combined organic portions were washed twice with
`brine (200 ml portions), dried over K2003, and concen-
`trated to afford 21.1 g of crude free base. The free amine
`was dissolved in dry ether (300 ml), cooled to 0' C., and
`treated with gaseous HCl. The resulting salt was fil-
`tered. washed with dry ether (300 ml), and dried under
`vacuum at 40" C. thus affording 19.25 g (94.4%) of
`crude salt, m.p. 226"—228° C. Recrystallization of 15.59
`g of the crude salt from methanol-ether afforded 10.49 g
`(67.3% recovery) of 2-(1-indolinyl) benzenemethana-
`mine hydrochloride, m.p. 23l°—232° C.
`C15H]5N2.HCl:
`ANALYSIS:
`Calculated
`for
`69.09%C,
`6.5‘!%H,
`l0.74%N, Found:
`68.85%C,
`6.5}'%H, l0.64%N.
`
`EXAMPLE 2
`
`4-(1-Indolinyl)benzonitrile
`
`4.94 g (0.206 mole) 99% NaH was added in one por-
`tion to a solution of 21.6 ml (0.188 mole) indoline in 85
`ml sieve dried dimethylsulfoxide (DMSO) at room tem-
`perature. The resulting slurry was permitted to stir at
`room temperature for 2 hours and then cooled in an ice
`bath. A solution of 25 g (0.206 moles) 2-fluorobenzoni-
`trile in 35 ml DMSO was added dropwise. At the end of
`the addition, the ice bath was removed and the mixture
`was permitted to stir at room temperature overnight
`(about 16 hours). The product was poured onto 300 ml
`of ice and extracted with CHC13 (300 ml). The organic
`phase was thrice washed with water (500 ml portions),
`brine (500 ml), dried (Na2SO4) and concentrated to give
`39.9 g (96.4%) of crude material. Two recrystallizations
`from isopropyl ether afforded 4~(1-indolinyl)benzoni-
`trile, ru.p. 88.5”-89.5“ C.
`ANALYSIS: Calculated for C15H12N2: 8l.79%C,
`5.49%H,
`12.'.~'2%N, Found:
`8l.60%C,
`5.52%H,
`l2.72%N.
`
`For the purpose of parenteral therapeutic administra-
`tion, the compounds of the present invention may be
`incorporated into a solution or suspension. ‘These prepa-
`rations should contain at least 0.1% of the 1-(aminoalk-
`ylphenyl and aminoalkylbenzyl) indoles and indolines 30
`of the invention, but may be varied to be between 0.1
`and about 50% of the weight thereof. The amount of
`the inventive compound present in such compositions is
`such that a suitable dosage will be obtained. Preferred
`compositions and preparations according to the present
`invention are prepared so that a parenteral dosage unit
`contains between 5.0 to 100 milligrams of the 1-
`(aminoalltylphenyl and arninoalkylbenzyl) indoles and
`indolines of the invention.
`The solutions or suspensions may also include the
`following adjuvants: a sterile diluent such as water for
`injection, saline solution, fixed oils, polyethylene gly-
`cols, glycerine, propylene glycol or other synthetic
`solvents; antibacterial agents such as benzyl alcohol or
`methyl paraben; antioxidants such as ascorbic acid or
`sodium bisulfite; ehelating agents such as ethylene
`diaminetetraacetic acid; buffers such as acetates, citrates
`or phosphates and agents for the adjustment of tonicity
`such as sodium chloride or dextrose. The parenteral
`preparation can be enclosed in ampules, disposable sy-
`ringes or multiple dose vials made of glass or plastic.
`The following examples are for illustrative purposes
`and are not to be construed as limiting the invention
`disclosed herein. All temperatures are given in degrees
`centigrade.
`
`35
`
`45
`
`55
`
`EXAMPLE 1
`
`2«(l -Indo1iny1)benzonitrile
`A stirred mixture of 61.63 g (0.509 mole) 2-fluoroben-
`zonitrile and 125.6 ml (1.12 mole) indoline under nitro-
`gen was heated at
`l70°—l30° C. for 22.5 hours. The
`resulting suspension was transferred to a separatory
`funnel with the aid of400 ml of Cl-[gCl2 and this solution
`was washed twice with water (400 ml), four times with
`4 N HCl (450 ml), water (450 ml), brine (400 ml), dried
`(NazS04), and concentrated to give 78.6 g (71 .5%) of a
`liquid. The crystals which formed on standing were
`filtered, washed with ether and dried at 42° C. under
`
`b. 4—(l-Indolinynbenzenemethanamine hydrochloride
`
`A solution of 12.06 g (54.3 mmole) of 4-(1-indo1inyl)-
`benzonitrile of Example 2a in 62 ml tetrahydrofuran
`(THF) was added dropwise to a rapidly stirred ice cold
`solution of BH3 in THF (181 ml of 0.93 M solution, 3.0?
`equiv. 163.4 mmole) under nitrogen. After heating at
`reflux for 1.5 hours, the solution was permitted to cool
`to room temperature and stand overnight. The ice cold
`reaction mixture was then treated dropwise with 6 M
`aq. HCI (100 ml), heated at reflux for 40 minutes, cooled
`
`65
`
`5of16
`
`PENN EX. 2190
`
`CFAD V. UPENN
`lPR20l5-01836
`
`

`
`9
`to 0“ C., and made basic using solid NaOH. The result-
`ing aqueous phase was extracted with ether and the
`combined organic portions (if!) ml total) were washed
`with water (300 ml), twice with brine (300 all portions)
`dried (Na;S04) and concentrated to atlbrd 13.2 g of
`crude free base. A solution of 7.5 g (33.4 mmole) of
`crude free base in 200 ml 1:} ethanol-ether was treated
`with 50 ml of ethanolic HC1. 200 ml dry ether was
`added and the resulting solid was filtered. washed with
`dry ether, and dried thus giving 5.9 g (67.'i'%) of crude
`product. Recrystallization from hot
`ethanol-ether
`(charcoal) afforded 2.98 g of pure 4-(1-indo1inyl}ben-
`zenemethanamine hydrochloride, m.p. 25l.5°—252.5° C.
`ANALYSIS:
`Calculated
`for
`C15H15N2.HCl:
`69.D9%C,
`6.57%H,
`l0.74%N,
`Found:
`69.02%.
`6.60%H, lD.66%N.
`
`5
`
`ID
`
`EXAMPLE 3
`
`3-(1-Indoliny1)benzonitrile
`4.63 g (0.0193 mole, 1.1 equiv.) 99% NaH was added
`in one portion to a stirred solution of 19.8 ml (0.175
`mole) indoline in 90 ml sieve dried DMSO under-nitro-
`gen at room temperature. After 65 minutes. the mixture
`was cooled in an ice bath and treated dropwise with a
`solution of 23.43 g (0.193 mole, 1.1 equiv.) 3-t1uoroben-
`zonitrile i.n 34 ml dry DMSO. The product was permit-
`ted to stir overnight at room temperature, poured onto
`300 ml ice and extracted with CHCI3. The organic layer
`was washed five times with water (800 ml portions),
`dried over MgSO4, and concentrated to give 42.75 1 g 30
`(38.6 g theory) of oil. 2.0 g of the crude product was
`chromatographed on silica gel (104 g) using ether-hex-
`ane thus affording a 0.99 g sample of an oil of pure
`3—(1—indolinyl)benzonitrile.
`ANALYSIS: Calculated for C15H1-2N2: 3l.79%C,
`5.4-9%H,
`l2.T2%l"-i,
`Found:
`8l.76%C,
`5.37%H.
`l2.59%N.
`
`3-(1-Indolinyl)benzenemethanamine hydrochloride
`
`A solution of 7.1 g (32.3 mole) of 3-(l-indoli.nyl)-
`benaonitrile of Example 3a in 44 ml TI-IF was added
`dropwise over 30 minutes to an ice cold solution of 129
`ml (129 mmole, 4 equivalents) of 1 M BI-I3.'I‘I-IF com-
`plex under nitrogen. After heating at reflux for 1 hour,
`the reaction mixture was cooled to 0°-5° C. and treated 45
`dropwise with 50 ml concentrated HC1. The resulting
`suspension was heated at reflux for 1 hour, permitted to
`stand at room temperature overnight (about 16 hours)
`and then made basic using 50% NaOH (60 ml). The
`reaction mixture was partitioned between wate-
`r—CH2Clg (300 ml each) and the organic phase was
`washed with brine (300 ml), dried over MgSQ4 and
`concentrated to give 8.9 g of crude free base. Conver-
`sion as in Example 1 to the HCl salt (ethanol/ethereal
`HCl)
`and recrystallization from hot acetonitrile-
`methanol afforded 2.86 g (34% overall) of 3-0-
`indolinyl)ben2enemethanamine
`hydrochloride, m.p.
`l70.5°—l73.5° C.
`C15H15N2.HCl:
`for
`Calculated
`ANALYSIS:
`69.09%C,
`6.57%H,
`10.74%N, Found: 69.l3%C.
`6.64%H, 10.'l‘8%N.
`
`EXAMPLE 4
`
`4,448,784
`
`10
`ice bath, a solution of 12.11 g (0.1 mole) 3-l1uoroben-
`zonitrile in 15 ml sieve dried DMSO was then added
`dropwise over 15 minutes. At the end "of the addition,
`the ice bath was removed and the reaction mixture was
`permitted to warm to room temperature and stir over-
`night (20 hours). The product was Poured onto ice and
`then extracted twice with CHCI3. The combined or-
`gauic portions (400 ml) were washed four times with
`water (400 ml portions), 4 N HCl (three 300 ml por-
`tions) brine (300 ml), dried over Na2S04, and concen-
`trated to give 28.03 g (25.47 g theory) of a solid. Recrys-
`tallization from hot absolute ethanol containing 5—l0%
`CHCI3 afforded 11.12 g (43.66% overall) of 3-(5-chloro-
`l-indo1inyl)benzonitrile, m.p. 120°—121° C.
`ANALYSIS: Calculated for C151-!11C1N2: 70.73%C,
`4.3S%H.
`13.92%Cl,
`11.00%N, Found:
`70.46%-C.
`4.40%l-I, 14.0'3'%Cl, l0.82%N.
`
`b. 3-(5—Chlcro-1-indolinyl)benzenemetl1anan1ine
`hydrochloride
`
`A solution of 10.66 g (41.85 mole) of 3-(5-chloro-L
`indolinyl)be-nzonitrile of Example 4a in 100 ml dry THF
`was added dropwise to an ice cold rapidly stirred slurry
`of 6.35 g (167.4 mmole, 4 equiv.) LiAlH4 in 100 ml dry
`THF under nitrogen. After heating at reflux for 2 hours,
`the reaction mixture was cooled in an ice bath and
`treated dropwise with 6 ml H20, 6 ml 10% NaOH and
`18 ml H20. The resulting salts were filtered and washed
`with hot CHCI3. The filtrate was concentrated and the
`residue was dissolved in CHCI3 (200 ml), washed with
`brine (400 ml). dried over NazS04, and concentrated to
`give 10.22 g (94.4%) of free base. The resultant base was
`converted to the I-1C1 salt (isopropanol-ethereal HCI) as
`in Example 1, and recrystallized from hot isopropanol-
`methanol to give 9.09 g (78.6% overall) of 3-(5-ch1oro-
`l-indolinyl)benzer1emethana.mine hydrochloride, m.p.
`220°—222° C.
`for C15H15ClNz.HCl:
`ANALYSIS: Calculated
`61.03%, 5.46%H, 9.49%N, Found: 6l.26%C, 5.50%H,
`9.57%N.
`
`EXAMPLE 5
`
`a. :1-(1-Indolinyl)-in-tolunitrile
`
`An ice cold slurry of 10.6 g 06.9 mmole) K;CO3 in
`8.6 ml (76.9 mmole) indoline and 50 ml sieve dried di-
`methylformamide (DMF) "was treated dropwise with a
`solution of 15 g (76.9 mmole) ct-bromo-m-tolunitrile in
`75 ml sieve dried DMF. After stirring for 2 hours at
`room temperature, the reaction mixture was filtered and
`concentrated under high vacuum (55° C.). The residue
`was dissolved in CI-!Cl3(150 ml) and washed twice with
`water (250 ml portions), brine (250 ml), dried over N32.
`S04, and concentrated to give 15.28 g (84.8%) of crude
`nitrile. Recrystallization from hot ethanol gave 10.70 g
`(59.4% overall) of product, m.p. 54°-S6" C. A second
`recrystallization of a 5.0 g sample afforded 2.74 g of
`a-(l-indolinyl)-m-tolunitrile, m.p. 54-.5°—56.0° C.
`ANALYSIS: Calculated for C151-I14N2: 82.02%C,
`6.02%I-I,
`ll.96%N, Found:
`82.07%C,
`5.96%H,
`11.94-%N.
`
`3-(5-Chloro-l -indolinyl)be-nzonitrile
`A slurry of 2.64 g (0.11 mole, 1.1 equivalents) sodium
`hydride in 15.36 g (0.1 mole) S-chloroindoline and 50 ml
`sieve dried DMSO was'permitted to stir at room tem-
`perature under nitrogen for 2 hours. While cooling in an
`
`b. 3-(1-Indolinyhnethyl)benzenemethanamine
`dihydrochloride
`A solution of 13.09 g (55.87 mmole) of u-(1-
`indolinyl)-m-tolunitrile of Example 5a in 120 ml dis-
`tilled THF was added dropwise to a rapidly stirred ice
`
`6of16
`
`PENN EX. 2190
`
`CFAD V. UPENN
`lPR20l5-01836
`
`

`
`4,448,734
`
`12
`indolyl)benzenemethana.rnine
`230°—233° C.
`for
`ANALYSIS: Calculated
`61.45%C,
`4-.8l%H,
`9.55%N,
`4.90%]-I, 9.66%N.
`
`11
`cold slurry of 8.43 g (223.5 mmole, 4 equivalents) of
`LiAIH4 in 110 ml distilled TI-I'F. After heating at reflux
`for 18 hours, the reaction mixture was cooled to 0.5" C.
`and treated dropwise with 8.5 ml water, 8.5 ml 10%
`NaOH, and 25.5 ml H10. The salts were filtered.
`washed thrice with 100 ml hot CHzCl2, and the filtrate
`was concentrated. The residue was dissolved in CI-ICI3
`and washed with dilute aqueous NaOH, with brine,
`dried (Na2S0a.). and concentrated to give 12.71 g
`(95.4%) of free base. A 4.85 g portion of the free base
`was converted to the hydrochloride salt as in Example
`1 (ethanol-ether/ethereal HCl] thus giving 5.75 g of
`3-(1-indolinylmethyflbenzenemethanamine
`dihydro-
`chloride, m.p. 160° C. dec.
`for
`ANALYSIS: Calculated
`61.74%-C,
`6.48%H,
`9.00%N,
`6.3S%H, 8.70%N.
`
`C15H:3Nz.2HCl:
`Found:
`6l.54%C,
`
`EXAMPLE 6
`
`a. 3-(5-Chloro—l-indolyl)benzonitrile
`
`To a stirred solution under nitrogen of 7.53 g (0.050
`mole) of 5-chloroindole in 50 ml of dimethylsulfoxide
`(DMSO) was added 1.51 g (0.063 mole) of sodium hy-
`dride in portions over a 0.5 hour period. When no more
`bubbles of hydrogen were visible (after 5 hours) a solu-
`tion of 7.63 g (0.063 mole) of 3-fluorobenzonitrile in 10
`ml DMSO was added dropwise over 1 hour. The solu-
`tion was stirred overnight, and then heated at 100° C.
`for 3 hours to complete the reaction. After cooling, the
`reaction fluids were slowly decanted into 1 liter of ice!‘-
`water, with good stirring. This caused the product to
`separate as chunks of a semi-solid. After 2 hours, the
`mixture was filtered and the cake washed repeatedly
`with water. This material was dissolved in 130 ml of
`boiling ethanol, charcoaled, filtered and allowed to
`stand overnight (about 16 hours). The crystals were
`collected, washed with ethanol, dried to afford 6.60 g of
`product (52.4%), having m.p.
`l16°—120° C. Recrystalli-
`zation from ethanol gave 3-(5-chloro-l-indoIyl)benz.oni-
`trile in an overall yield of 42%, m.p. 120"—122° C.
`ANALYSIS: Calculated for C15H9ClN2: 71.30%C,
`3.59%H,
`ll.09%N, Found:
`7l.29%C,
`3.50%H,
`1l.l7%N.
`
`b. 3-(5-Chloro-1-indolyl)benzenemethanamir1e
`hydrochloride
`To a stirred mixture of 1.67 g of lithium aluminum
`hydride in 100 ml of dry tetrahydrofuran (THF), kept at
`0"-5° C. under nitrogen, was added dropwise a solution
`of 5.60 g (0.022 mole) of 3-(5-chloro-l-indolyl)benzoni~
`trile of Example 6a in 150 ml of THF. The mixture was
`stirred 1 hour more at 0° C.,
`1 hour at room tempera-
`ture, and then refluxed for 5 hours. After cooling to 0°
`C., the reaction was quenched by slow and cautions
`addition of a solution of 25 ml of water in 25 ml of THF.
`The resulting mixture was stirred 1 hour at room tem-
`perature before filtering to remove the inorganic salts.
`The filtrate was concentrated to an oily residue which
`was partitioned between 250 ml of dichloromethane and
`250 ml of water. The organic phase was separated and
`extracted twice more with water before drying over
`NazSO4 and concentrating to an oil (5.8 3). This was
`dissolved in 20 ml of absolute ethanol and the stirred
`solution treated with 100 ml of ethereal hydrogen chlo-
`ride. The salt was collected and found to weigh 5.2 g
`(81% overall yield) m.p. 195° C.-sinter, 220"-228° C.
`melting. Recrystallization from boiling ethanol (char-
`coal) furnished 2.4 g (37% yield) of 3-(5-chloro—|-
`
`hydrochloride,
`
`m.p.
`
`C15}-I13ClN2.HCl:
`Found:
`6l.33%C,
`
`10
`
`30
`
`35
`
`45
`
`50
`
`55
`
`60
`
`65
`
`EXAMPLE 7
`
`a. 3-(1 -Indolyl)benzonitrile
`
`To a stirred solution, under nitrogen, of 17.6 g (0.150
`mole) of indole in 100 ml of dry dimethylsulfoxide
`(DMSO) was added 4.5 g (0.188 mole) of sodium hy-
`dride in portions over a 1.5 hour period. When no more
`bubbles of hydrogen were visible (4-5 hours), there was
`added dropwise a solution of 22.8 g (0.188 mole) of
`3-lluorobenzonitrile in 25 ml of dry DMSO. When the
`addition was complete (1 hour) the mixture was stirred
`overnight (about 16 hours) and then 3 hours at 100° C.
`The cooled mixture was poured into 1.5 liters of a
`stirred water-ice mixture to precipitate a semi-solid.
`The supernatent was poured off and the coagulated
`material was washed several times more with water. It
`was then dissolved in 500 ml of dichloromethane,
`washed twice with dilute brine, dried over l\lazS04, and
`concentrated in vacuo to an oil. This material weighed
`32 g (l00% yield). A portion was distilled yielding
`3-(1-indolyl)benzonitr-ile (160"/0.1 mm) in 75% overall
`yield. The product was a soft, crystalline material at
`room temperature, m.p. 33°—36° C.
`ANALYSIS: Calculated for C]3H1oN2: 82.55%C,
`4.62%H, Found: 82.29%C, 4.56%H.
`
`b. 3-(I-Indoly1)beI1zenemethanarni11e hydrochloride
`
`To a stirred mixture, kept at 0°—5° C. under nitrogen,
`of 3.8 g of lithium aluminum hydride in 150 ml of dry
`tetrahydrofuran was added dropwise a solution of 10.9
`g (0.050 mole) of 3-(l—iudolyl)benzonitrile of Example
`7a in 50 ml ofTHF. When the addition was complete (1
`hour), the mixture was stirred 1 hour at 0° C., 1 hour at
`room temperature and finally refluxed overnight. The
`mixture was then kept below 5° C. during cautious
`addition of a solution of 25 ml H30 and 25 ml THF.
`After the addition,
`the mixture was stirred at room
`temperature for 2 hours, filtered, the cake washed twice
`with THF, and the combined filtrates concentrated.
`The residue was dissolved in 250 ml of dichloromethane
`and this solution was washed twice with dilute brine,
`dried over Na2SO4 and concentrated to an oil weighing
`11.0 g (100%). The oil was dissolved in 25 ml of abso-
`lute methanol, and then treated in one portion with 50
`ml of ether saturated with HCl gas. To the initial solu-
`tion was added another 50 ml of ether. The salt crystal-
`lized rapidly and was immediately filtered, washed well
`with ether, and dried to yield 11.6 g (90%) of product,
`m.p. 189“—l9l° C. Recrystallization from isopropanol
`gave 10.0 g (73% overall yield) of pure 3-(1-indolyl)-
`benzenemethanamine hydrochloride, m.p. l90°—192"' C.
`ANALYSIS:
`Calculated
`for
`C151-[14,Ng.I-ICI:
`59.64-%C,
`5.34-%H,
`l0.83%N, Found:
`69.87%C,
`5.7l%H. l0.99%N.
`
`EXAMPLE 8
`a.
`
`N-Ethoxycarbonyl-3—(l -indolinyl)henzene-methanamine
`A slurry of 10.0 g (39.3 mmole of 3-(l-indolinyl)ben-
`zenemethanamine hydrochloride of Example 31: in 120
`ml CH2Cl2 was cooled in an ice bath and treated drop-
`
`7ufl6
`
`PENN EX. 2190
`
`CFAD V. UPENN
`IPR20l5-01836
`
`

`
`13
`
`4,448,784
`
`wise with a solution of 13.5 ml (958 mmole, 2.5 equiva-
`lents) of triethylarnine