United States Patent 19
`Danielewicz et al.
`
`3,890,319
`[11]
`(45) June 17, 1975
`
`(54)
`
`75
`
`(73)
`22
`21
`
`(30)
`
`(2-IMIDAZOLIN-2-YLAMINO)
`SUBSTITUTED QUINOLINES,
`-QUINOXALINES AND -QUINAZOLINES AS
`ANTHYPERTENSIVE AGENTS
`Inventors: John C. Danielewicz; Michael
`Snarey; Geoffrey N. Thomas, all of
`Kent, England
`Assignee: Pfizer Inc., New York, N.Y.
`Filed:
`Feb. 14, 1973
`Appl. No.: 332,485
`
`Foreign Application Priority Data
`Feb. 29, 1972 United Kingdom................. 9196/72
`Nov. 8, 1972
`United Kingdom............... 51629/72
`
`52
`
`U.S. Cl. 260/250 Q; 260/256.4 R: 260/286 R;
`260/288 C; 260/289 C; 260/309.6; 424/250;
`
`424/258
`I51) int. Cl............................................. C07d 51/78
`58) Field of Search.................. 260/250 O, 2.56.4 O
`
`56)
`
`3,560,501
`3,594,380
`3,736,297
`
`References Cited
`UNITED STATES PATENTS
`2/1971
`Walker........................ 260/256.4 O
`7/1971
`Sulkowski.................... 260/256.4 O
`5/1974 Bracke......................... 260/256.4 O
`
`
`
`Primary Examiner-Donald G. Daus
`Assistant Examiner-David E. Wheeler
`Attorney, Agent, or Firm-Connolly and Hutz
`
`ABSTRACT
`(57)
`Novel (2-imidazolin-2-ylamino)substituted quinolines,
`-quinoxalines and -quinazolines, their preparation and
`use as antihypertensive agents are described.
`9 Claims, No Drawings
`
`Eye Therapies Exhibit 2190, 1 of 12
`Slayback v. Eye Therapies - IPR2022-00142
`
`

`

`1.
`(2-IMIDAZOLIN-2-YLAMINO) SUBSTITUTED
`QUINOLINES,-QUINOXALINES AND
`-QUINAZOLINES AS ANTIHYPERTENSIVE
`AGENTS
`BACKGROUND OF THE INVENTION
`The invention relates to therapeutic agents which are
`novel derivatives of quinoline, quinoxaline or quinazo
`line, and is particularly concerned with derivatives
`thereof having a 2-imidazoline-2-ylamino group at
`tached to the homocyclic ring which are useful as regu
`lators of the cardiovascular system and, in particular,
`in the treatment of hypertension.
`SUMMARY OF THE INVENTION
`The novel compounds according to the invention are
`those having the general formulae:
`
`3,890,319
`2
`responding 6-aminoethyl-thioureidoquinoline, -qui
`noxaline or -quinazoline, and (3) cyclizing to form the
`corresponding 2-imidazolin-2-ylamino compound, ac
`cording to the reaction sequence:
`
`-
`
`2
`
`(l)
`CSCl
`
`(2)
`
`HNCHCH-NH
`
`e (-HS)
`
`(R-NH.CS. NHCHCHNH
`
`g-i-
`
`O
`
`5
`
`X
`
`- N
`
`-N-C-E,
`
`-
`
`N
`
`Y
`
`Z
`
`H
`
`N
`
`X
`
`20
`
`NS
`
`– HRC3-,
`
`Y
`
`Z.
`
`where Q represents a group of the formula:
`X
`X
`X
`
`--R ,
`N22 ls
`Y Z.
`
`R2 O
`
`N2
`
`Y Z.
`
`Y
`
`Z
`
`SN R
`32
`
`H
`
`X
`
`w
`
`N 2' 2
`
`N
`
`Y Z
`
`In step (1) the reaction with thiophosgene can be
`carried out in aqueous solution or in dilute aqueous hy
`drochloric acid solution at room temperature in a pe
`riod of about 2 hours. Alternatively, the thiophosgene
`can be added to a mixture of an aqueous solution of a
`weak base, e.g., sodium carbonate, and a solution of
`the amine Q-NH in a water-immiscible solvent, e.g.,
`chloroform. In the first alternative, the isothiocyanate
`precipitates from the reaction mixture and precipita
`in which the 2-imidazolin-2-ylamino group may be in
`tion can be completed by neutralization with excess al
`kali; the precipitate is recovered by filtration and, if
`any of the 5-, 6-, 7- or 8-positions in the quinoline, qui
`necessary, basified, and may then be dissolved in a suit
`noxaline or quinazoline nuclei;
`able solvent, e.g., chloroform. In the second alterna
`X, Y and Z represent up to 3 optional substituents in
`tive, the isothiocyanate is formed in solution in the wa
`any of the remaining 5-, 6-, 7- or 8-positions, each of
`ter-immiscible solvent which is then separated. In ei
`X, Y and Z being selected from the group consisting of
`40
`ther case, the solution of the isothiocyanate is dried, fil
`hydrogen, halogen, lower alkyl, lower alkoxy or trifluo
`tered, and evaporated to yield the isothiocyanate prod
`romethyl; and
`R represents an optional substituent in any of the 2-,
`uct as the free base.
`In step (2) the isothiocyanate is reacted with an ex
`3- or 4-positions of the quinoline nucleus, or in either
`cess (e.g., 5 moles) of ethylene diamine in a suitable
`of the 2- or 3-, or 2- or 4-positions of the quinoxaline
`solvent, e.g., diethyl ether, benzene, chloroform or di
`or quinazoline nuclei, respectively, R2 being selected
`oxan. The reaction is carried out at room temperature
`from the group consisting of hydrogen, lower alkyl or
`in a period of about 2 hours. The g-aminoethyl
`lower alkoxy;
`thioureido compound precipitates and is recovered by
`and their pharmaceutically acceptable acid addition
`filtration and washing with further solvent.
`salts.
`50
`In step (3) the cyclization may be effected by heating
`In this specification "lower' alkyl or alkoxy groups
`a suspension of the thioureido compound with mercu
`are those containing up to 6 carbon atoms, and "halo
`ric or cupric oxide in a suitable organic solvent mess,
`gen' means fluorine, chlorine, bromine or iodine.
`dium, e.g., ethanol. The mercuric or cupric oxide can
`Pharmaceutically acceptable acid addition salts of
`be replaced by an organic mercuric or cupric salt solu
`the compounds of the invention are those formed from
`55
`ble in the medium, e.g., mercuric or cupric acetate.
`acids which form non-toxic addition salts containing
`pharmaceutically acceptable anions, such as the hydro
`The reaction mixture is filtered, to remove the mercu
`ric or cupric sulphide formed as by-product, and the
`chloride, hydrobromide, hydroiodide, sulphate or bi
`filtrate is evaporated to dryness. The product may then
`sulphate, phosphate or acid phosphate, acetate, male
`be recrystallized as the free base or converted to an
`ate, fumarate, oxalate, lactate, tartrate, citrate, gluco
`60
`acid addition salt by reaction with a suitable acid by
`nate, saccharate and p-toluene sulphonate salts.
`conventional means.
`DETAILED DESCRIPTION OF THE INVENTION
`In certain cases, the cyclization may be successfully
`effected by simply refluxing the thioureido compound
`The compounds of the invention may be prepared by
`in a suitable organic solvent medium, e.g., methanol, in
`(1) reaction of the appropriate amino-quinoline, -qui
`noxaline or -quinazoline (Q-NH2) with thiophosgene
`the absence of mercuric or cupric oxide.
`The compounds of the invention can also be pre
`to form the corresponding isothiocyanate, (2) reacting
`pared by (1) reaction of the corresponding amino
`the latter with excess ethylene diamine to form the cor
`
`25
`
`30
`
`35
`
`45
`
`65
`
`Eye Therapies Exhibit 2190, 2 of 12
`Slayback v. Eye Therapies - IPR2022-00142
`
`

`

`3,890,319
`3
`quinoline, -quinoxaline or -quinazoline with benzoyl
`isothiocyanate to form the corresponding N-benzoyl
`thioureido compound, followed by hydrolysis to the
`thioureido compound, or reaction of the aminoquin
`oline, -quinoxaline or -quinazoline with ammonium thi- 5
`ocyanate to form the thioureido compound directly;
`(2) methylation to form the S-methyl derivative of the
`thioureido compound; and (3) reaction with ethylene
`diamine, according to the reaction sequence:
`
`O
`
`m
`
`(l)
`
`Q-N, -v- Q-Ni, S.N.
`(2) tly
`
`15
`
`Q-NH. (-NHSP
`N
`Q-NH -( <-9- 2
`N
`HNCHCH-NH2
`
`H
`
`20
`
`4
`diamine in the same solvent. The reaction is promoted
`by heating the solution for several hours, and the result
`ing precipitate collected by filtration and basified, e.g.,
`using concentrated acqueous ammonium hydroxide so
`lution, to afford the free base form of the required (2-
`imidazoline-2-ylamino)-quinoline, -quinoxaline
`or
`-quinazoline product.
`The product may then be recrystallized to purity as
`the free base or converted to an acid addition salt by
`reaction with a suitable acid by conventional means.
`The amino-quinoline, -quinoxaline or -quinazoline
`starting materials for these reaction sequences are ei
`ther readily available materials or are readily prepara
`ble from such materials, e.g., by reduction of the corre
`sponding nitro-quinoline, -quinoxaline or -quinazoline
`and by halogenation of amino-quinolines, -quinoxalines
`or -quinazolines.
`"" -
`Compounds of the invention in which at least one of
`X, Y or Z is halogen can also be prepared from the cor
`responding des-halo compounds by conventional halo
`genation procedures.
`The invention is illustrated by the following exam
`ples, in which all temperatures are given in C.
`EXAMPLE I
`A.
`To a vigorously stirred solution of 5-amino-8-bromo
`6-methylquinoline hydrobromide (6.4g.) in distilled
`water (100 ml.) was added thiophosgene (1.6 ml.) in
`one portion. During a period of 2 hours, a brown solid
`precipitated. The suspension was poured into iced 4N
`aqueous sodium hydroxide solution (50 ml.) and the
`resulting brown solid was filtered off. The solid was dis
`solved in chloroform and the solution was dried over
`sodium sulphate, filtered and evaporated to yield 4.2g.
`of 8-bromo-5-isothiocyanato-6-methylduinoline as free
`base, m.p. 145.
`
`40
`
`45
`
`50
`
`25
`where Q is as previously defined.
`For step (1), the benzoyl isothiocyanate starting ma
`terial can be prepared in situ by reacting benzoyl chlo
`ride with ammonium thiocyanate. This may be conve
`niently carried out by heating under reflux a mixture of
`the reagents dissolved in a suitable organic solvent, 30
`e.g., acetone, for a short period, e.g., 20 minutes. To
`the cooled solution is then added the appropriate
`amino-quinoline, -quinoxaline or -quinazoline, and
`heating under reflux continued for a further period.
`35
`Precipitation of the product, if it has not already oc
`curred, can then be induced by adding the cooled reac
`tion mixture to water, and the crude product is suitably
`collected by filtration and used directly in the subse
`quent hydrolysis step.
`Hydrolysis is conveniently achieved by heating the
`(3-benzoylureido)-quinoline, -quinoxaline or -quinazo
`line in aqueous sodium hydroxide solution for several
`hours, and the product isolated by filtering the reaction
`mixture to remove any precipitated sodium benzoate
`and other solid material and collection of the precipi
`tate formed in the cooled filtrate, if necessary, after fur
`ther basification. Purification of the resulting thi
`oureido product by recrystallization from a suitable sol
`vent, e.g., butan-2-one, may optionally be effected.
`In the alternative method the amino-quinoline, -qui
`noxaline or -quinazoline is reacted with ammonium thi
`ocyanate to form the thioureido compound directly.
`This can be achieved by heating a solution of the rea
`gents in water until the product has precipitated. The
`55
`product, the thioureido compound, is then separated
`by filtration and optionally purified by crystallization
`before use in the next step.
`In step (2), the thioureido compound is reacted with
`methyl iodide in a suitable solvent, e.g., methanol. The
`reaction is conveniently carried out by heating, e.g., in
`a steam bath, for a short period, e.g., 1 hour, and the
`product isolated by evaporation of the filtrate from fil
`tration of the reaction mixture.
`In step (3), the crude product of the previous stage,
`conveniently used without the necessity for purifica
`tion, is dissolved in a suitable solvent, e.g., methanol,
`and the solution added to a boiling solution of ethylene
`
`B.
`The isothiocyanate (3.5 g.) was dissolved in benzene
`(50 ml.) and added dropwise to a well-stirred solution
`of ethylene diamine (4.5 g.) in benzene (50 ml.). Dur
`ing a period of 1% hours a light brown solid precipi
`tated, which was filtered off and washed with fresh ben
`Zene (20 ml.) to give 4.1 g of 1-(2-aminoethyl)-3-(8-
`bromo-6-methyl-quinolin-5-yl)-thiourea, m.p. 205.
`C.
`A suspension of the thiourea (3.4 g) in ethanol (100
`ml.) was stirred under reflux conditions (78) with mer
`curic oxide (3.25 g.) for 2% hours and filtered while
`hot. Evaporation of the filtrate yielded a yellow solid
`which was recrystallized from an isopropanol/methanol
`mixture to give 2.0 g. of pure 8-bromo-5-(2-imidazolin
`2-ylamino)-6-methyl-quinoline as the free base, m.p.
`>340°.
`
`60
`
`65
`
`Analysis: Found:
`Required for CahabrN: C,
`
`; H, 4.37; N, 18.44%
`3
`37
`H. 4
`.16; H, 4.29; N, 18.36%.
`
`Eye Therapies Exhibit 2190, 3 of 12
`Slayback v. Eye Therapies - IPR2022-00142
`
`

`

`3,890,319
`
`S
`EXAMPLES II TO XVI
`The following compounds were prepared by the
`method described in Example I from the appropriately
`substituted amino-quinoline, the product being isolated
`in each case as the free base.
`
`6
`EXAMPLE XVIII
`A.
`6-Amino-5-bromoquinoxaline hydrobromide (10 g.)
`5 was dissolved in water (150 ml.) and thiophosgene (3
`ml.) was added. The solution was stirred for 2 hours at
`
`H
`
`-() N
`
`NH N
`
`X
`
`Y
`
`a.
`
`N1
`
`Example X
`
`Y Z.
`
`Z
`
`n.p.
`oC.
`
`C-CH H 8-Cl
`
`278-280
`
`6-CH H H
`
`230-232
`
`6-Br
`
`H 8-CH, 271
`
`6-C
`
`H 8-CH 251-253
`
`6-CHO H H
`
`H
`
`H H
`
`6-Br
`
`H. H
`
`209-22
`
`218-220
`
`243-245
`
`H
`
`H 8-CH 234
`
`II
`
`V
`
`V
`
`V
`
`V
`
`VIII
`
`IX
`
`Analysis
`(required)
`figures in brackets)
`% H % N
`% C
`
`59.67
`(59.88
`69.08
`(69.00
`5.38
`(51.16
`59.60
`(59.88
`64.49
`(64.44
`67.94
`(67.90
`49.7
`(49.49
`68.86
`(69.00
`
`5.09
`5,03
`6.29
`6.24
`4.52
`4.29
`5.20
`5.03
`S.81
`5.82
`559
`5.70
`4.20
`3.80
`6.25
`6.24
`
`221
`21,49)
`24.89
`24.76)
`18.6
`18.36)
`2.41
`22.49)
`23.05
`23.13)
`26.03
`26.40)
`1933
`19.24)
`24.52
`24.76)
`
`C H
`
`N
`
`N
`
`X
`
`Y
`
`Z.
`
`m.p.
`C.
`
`Example X Y
`
`Z
`
`NS
`
`/
`N
`
`X
`
`X
`
`XII
`
`XII
`
`XIV
`
`XV
`
`H
`
`H
`
`H
`
`H
`
`-Cl
`
`-Br
`
`H
`
`H
`
`H
`
`207-20
`
`23-216
`
`240-241
`
`H
`
`7-CF. H
`
`232-233
`
`H
`
`H
`
`-Cl
`
`-Br
`
`8-Cl
`
`243-245
`
`8-Cl
`
`265-266
`
`XV
`
`H
`
`7-Br H
`
`232-234
`
`Analysis
`(required
`figures in brackets)
`% H
`% C
`% N
`
`67.97
`(67.90
`58.37
`
`(58.42
`49.17
`
`(49.50
`55.28
`(55.71
`55
`
`(5.26
`44.9
`
`(44.26
`49.38
`(49.50
`
`5.80
`5.70
`453
`
`4.49
`3.84
`
`3.81
`4.09
`3.96
`3.65
`
`3.59
`3.15
`
`3.09
`3.96
`3.81
`
`26.46
`26.40)
`22.56
`
`22.73)
`1927
`
`19.24)
`20.40
`1999)
`20.06
`
`19,92)
`17.7
`
`17.21)
`19.38
`19.24)
`
`EXAMPLE XVII
`By a similar procedure to that described in Example
`I,
`8-chloro-7-(2-imidazolin-2-ylamino)-4-
`methoxyquinazoline, m.p. 238-239, was prepared,
`starting from 7-amino-8-chloro-4-methoxyquinazoline.
`
`room temperature, and the resultant precipitate col
`lected by filtration, washed with water, and dried to af.
`60 ford 9 g. of 5-bromo-6-isothiocyanatoquinoxaline,
`which was used without further purification in the next
`Stage.
`
`Analysis:
`Found: C, 51.73; H, 4.64; N, 25.06%
`Required for CHCINO: C, 51.90; H, 4.36; N, 25.22%.
`
`B.
`65 The product of (A) (9 g.) was dissolved in benzene
`w
`(400 ml.) and the solution added to a stirred solution
`of ethylene diamine (15g.) in benzene (50 ml.). Dur
`
`Eye Therapies Exhibit 2190, 4 of 12
`Slayback v. Eye Therapies - IPR2022-00142
`
`

`

`3,890,319
`7
`ing a period of 2 hours with continual stirring an oil
`separated as a lower layer. The upper benzene layer
`was poured off and the oil washed with diethyl ether
`and then dissolved in methanol (approximately 500
`ml.). After the methanolic solution had been refluxed
`until hydrogen sulphide evolution had ceased, it was
`concentrated by evaporation in vacuo to a volume of
`approximately 100 ml., by which stage a yellow precipi
`tate had formed. The precipitate was collected by fil
`tration and recrystallized from methanol to afford 3 g.
`of
`5-bromo-6-(2-imidazolin-2-ylamino) quinoxaline,
`m.p. 250°-251.
`
`O
`
`8
`steam bath with stirring for 45 minutes. The solution
`was then filtered and the filtrate evaporated in vacuo
`to a gum, which was triturated in diethyl ether to afford
`5.1 g of 5,7-dichloroquinoline-8-(S-methylthiouroni
`um) iodide as a brown solid.
`C.
`A solution of the product of the previous stage (4.1
`g.) in methanol (45 ml.) was added dropwise to a boil
`ing solution of ethylene diamine (1.5 g.) in methanol (5
`ml.). Heating under reflux with stirring was continued
`for 6 hours, after which the mixture was twice allowed
`to stand at room temperature for 16 hours and then
`heated under reflux for a further 8 hours. By this stage
`a white precipitate had formed, and this was filtered
`from the cooled reaction mixture and crystallized from
`a mixture of dimethylacetamide and water. After dry
`ing in vacuo at 60 for 6 hours, the solid was basified
`by addition of concentrated aqueous ammonium hy
`droxide solution and the solid collected by filtration
`and crystallized from methanol.
`The free base product so obtained was converted to
`the hydrochloride salt by bubbling hydrogen chloride
`through a suspension of the solid in methanol. The re
`sulting solution was evaporated in vacuo to dryness and
`the solid residue was crystallized from isopropanol to
`afford
`1.0 g. of 5,7-dichloro-8-(2-imidazolin-2-
`ylamino) quinoline hydrochloride as colorless crystals,
`m.p. 335 with decomposition.
`
`Analysis:
`Found: C, 45. 39; H,
`5;
`3.35; N,
`25.55%
`Required for CHBrns: C, 45.22;
`3.45; N,
`23.97%.
`; H, 3.45;
`
`15
`
`20
`
`EXAMPLES XIX AND XX
`By similar procedures to that described in Example
`XVIII, the corresponding 5-chloro- and 5-iodo- com
`pounds,
`5-chloro-6-(2-imidazolin-2-
`ylamino) quinoxaline, m.p. 240, and 6-(2-imidazolin
`25
`2-ylamino)-5-iodoquinoxaline, m.p. 227, with decom
`position,
`were
`prepared
`from
`6-amino-5-
`chloroquinoxaline and 6-amino-5-iodoquinoxaline, re
`spectively, in each case as the hydrochloride salt.
`
`Analyses:
`Found:
`Required for CHCINs
`(5-chloro- compound) :
`Found:
`Required for CHINs
`(5-iodo- compound) :
`
`C, 52.98; H, 4.09; N, 28.09%
`C, 53.34; H, 4.07; N, 28.28%
`C, 38.69; H, 3.08; N, 21.01%
`C, 38.95; H, 2.97; N, 20.65%.
`
`30
`
`35
`
`Analysis:
`Found: C, 45.09; H,
`; N, 17.45%
`355
`Required for CHCl, N.HCl: C, 45.38; H
`N
`, 3.49; N, 17.64%.
`
`EXAMPLE XXI
`A.
`To a stirred solution of ammonium thiocyanate (3.9
`g.) in acetone (200 ml.) at room temperature and
`under an atmosphere of nitrogen was added benzoyl
`chloride (6.95 g.). The mixture was refluxed for 20
`minutes in a steam bath and then, after cooling to room
`temperature, added over a period of 5 minutes to a so
`lution of 8-amino-5,7-dichloroquinoline (10.6 g.) in ac
`etone (250 ml.). Refluxing of the mixture was carried
`50
`out for 45 minutes, after which it was cooled to room
`temperature and poured into water (1 litre). The re
`sulting solid was filtered off, washed with water and dis
`solved in approximately 2.5N aqueous sodium hydrox
`ide solution (750 ml.) and the resulting slurry was
`stirred at 80° for 1% hours. Immediately thereafter the
`reaction mixture was filtered through a celite pad, and
`the cooled (0) filtrate was acidified with concentrated
`hydrochloric acid to about pH 2 and rebasified with
`ammonium hydroxide, whereupon precipitation oc
`60
`curred. The precipitate was collected by filtration and
`dried in vacuo. Recrystallization from butan-2-one
`yielded 6.1 g of 5,7-dichloro-8-thioureidoquinoline as
`a cream colored solid; m.p. 145-150.
`B.
`A mixture of the product of (A) (5.4 g.) and methyl
`iodide (2.9 g.) in methanol (75 ml.) was heated in a
`
`40
`
`45
`
`EXAMPLE XXII
`By a similar procedure to that described in Example
`XXI, 8-(2-imidazolin-2-ylamino)-7-methylquinoline
`was prepared from 8-amino-7-methylquinoline, and
`isolated as the hydroiodide, m.p. 289-291.
`
`Analysis:
`Found: C, 43.93; H, 4.29; N, 15.86%
`Required for CH-NHI: C, 44.08; H, 4.27; N, 15.82%
`
`EXAMPLE XXIII
`The following compounds are prepared by the
`method of Example I from the appropriately substi
`tuted aminoquinoline, the product being isolated in
`each case as the free base.
`
`55
`
`N y-N:
`
`N
`H
`
`Y
`
`Z
`
`rS R2
`
`N
`
`X
`
`Y
`
`Z
`
`6-Br
`6-CHs
`6-CH
`
`H
`H
`H
`
`8-CHs
`8-Br
`H
`
`R
`
`H
`H
`2-CH
`
`65
`
`A.
`
`5-
`5-
`5-
`
`Eye Therapies Exhibit 2190, 5 of 12
`Slayback v. Eye Therapies - IPR2022-00142
`
`

`

`3,890,319
`
`10
`EXAMPLE XXV
`Repetition of the procedure of Example I, but using
`the appropriate aminoquinoxaline hydrochloride in
`place of 5-amino-8-bromo-6-methylguinoline hydro
`bromide produces the following compounds:
`
`5
`
`O
`
`15
`
`2O
`
`25
`
`r
`
`X
`
`)-NH
`
`- N
`H
`
`Y
`
`Z
`
`R2
`
`N
`
`X
`
`Z
`
`R
`
`O
`
`2-CH
`2-CH
`H
`H
`2-CH
`2-CH
`
`9
`-Continued
`R
`Z
`2-OCH
`H
`H
`8-OCH
`H
`H
`8-O-n-CHg H
`H
`2-O--
`n-CH
`H
`H
`H
`H
`H
`3-CH
`3-CH
`2-i-CH
`H
`2-O--
`n-CHg
`2-CH
`3-OCH
`2-O--
`n-CH
`H
`H
`H
`H
`H
`2-O--
`n-CHs.
`H
`H
`3-n-CH
`3-n-CHg
`H
`3-CH
`H
`H
`3-CH
`H
`4-n-C5H1
`3-CH
`H
`H
`2-O-
`n-CHg
`H
`H
`3-CHis
`4-CHs
`
`AI
`5-
`5-
`5-
`5-
`5-
`
`X
`H
`H
`H
`H
`H
`
`5-
`S-
`S-
`6-
`6-
`6-
`6-
`6-
`6-
`6-
`
`6-
`6-
`6-
`
`7-
`7-
`7.
`7.
`7.
`7.
`
`7-
`8-
`8-
`8-
`8-
`8.
`8-
`8-
`8-
`8-
`8-
`8-
`8-
`8-
`8.
`
`8-
`8.
`8.
`8-
`8-
`8-
`8-
`
`H
`H
`H
`5-OCH
`5-OCH
`5-OCH
`5-OCH
`H
`H
`H
`
`H
`H
`H
`
`H
`5-Cl
`5-Cl
`5-F
`5-OCH
`H
`
`5-CH
`H
`H
`5-CH
`5-OCH
`5-CH
`H
`H
`H
`H
`H
`5-CH
`6-BI
`5-C
`H
`
`H
`5-Br
`H
`H
`H
`5-Br
`5-Cl
`
`Y
`H
`H
`7-CH
`H
`H
`
`7-CH
`H
`H
`H
`H
`H
`H
`H
`H
`H
`
`7-CH
`H
`H
`
`8-CH
`8-OCH
`8-OCH
`8-OCH
`8-OCH
`8-OCH
`8-OCH
`H
`8-OCH
`H
`
`H
`H
`H
`
`H
`H
`6-OCH 8-OCH
`6-C
`8-C.
`6-F
`8-F
`6-OCH
`8-OCH
`H
`H
`
`H
`H
`6-Br
`6-CH
`6-OCH
`6-CH
`6-
`6-OCH
`H
`6-CH
`H
`6-CH
`H
`6-Br
`H
`
`8-CH
`H
`H
`H
`H
`H
`H
`H
`H
`H
`H
`H
`H
`7-Cl
`H
`
`H
`6-Cl
`7-Br
`6-C
`H
`H
`H
`H
`6-CHH H
`6-Br
`7-Br
`6-Cl
`7-C
`
`3O
`
`35
`
`The quinolines, quinoxalines and quinazolines substi
`tuted in the homocyclic portion of the nuclei with both
`an amino group and one or two halogen atoms, which
`were used as starting materials in the above prepara
`tions, are either known compounds or were themselves
`prepared from known starting materials according to
`the following methods, in which all temperatures are
`given in C.
`
`H
`H
`
`40
`
`EXAMPLE XXVI
`Salt Formation
`The free base form of the appropriate (2-imidazolin
`2-ylamino) substituted quinoline, quinoxaline or quin
`azoline compound in a suitable solvent, e.g., methanol,
`ethanol, benzene, ether or water, is treated with a stoi
`chiometric amount of the appropriate acid, warming if
`necessary to achieve reaction. The acid salt is recov
`ered by filtration or evaporation of the solvent.
`In this manner, the hydrochloride, hydrobromide, hy
`droiodide, acetate, maleate, fumarate, oxalate, lactate,
`tartrate, citrate, gluconate, saccharate, p-toluenesul
`phonate, sulfate, bisulfate, phosphate and acid phos
`phate salts of the herein described products are pre
`pared.
`In instances such as Examples XIX-XXII wherein the
`product is obtained as a hydrohalide salt, the free base
`is obtained by careful neutralization of the acid compo
`nent with ammonium hydroxide, and the base recov
`ered as in Example XXI.
`Method A
`To a stirred solution of 5-amino-6-methylquinoline
`(6.4g.) in glacial acetic acid (75 ml.) at room tempera
`ture was added dropwise a solution of bromine (6.4g.)
`in glacial acetic acid (25 ml.). The solution was then
`stirred at room temperature for a further 2 hours, and
`the resulting precipitate filtered off, washed with iso
`propanol and dried at 60 in vacuo for 4 hours. Pro
`duced was 9.0
`g.
`of
`5-amino-8-bromo-6-
`
`A = 2-Imidazolin-2-ylamino.
`
`EXAMPLE XXIV
`45
`The following compounds are prepared from the ap
`propriately substituted aminoquinazoline by the proce
`dure of Example I, the product being isolated in each
`case as the free base.
`
`()- NCC; ,
`
`X
`
`N N
`
`Y
`
`Z.
`
`N.
`
`N
`H
`
`AI
`
`5.
`6-
`6-
`6-
`7-
`8-
`8-
`7.
`7.
`
`X
`
`Y
`
`Z
`
`R
`
`H
`H
`H
`H
`H
`H
`5-OCH H
`H
`H
`H
`H
`H
`H
`H
`6-OCH
`H
`6-OCH
`
`H
`H
`H
`8-OCH
`H
`H
`H
`H
`H
`
`H
`H
`4-OCH
`H
`H
`H
`4-OCH
`H
`4-OCH
`
`50
`
`55
`
`60
`
`65
`
`Eye Therapies Exhibit 2190, 6 of 12
`Slayback v. Eye Therapies - IPR2022-00142
`
`

`

`3,890,319
`11
`methylquinoline hydrobromide, as a red-brown solid,
`m.p. 239.
`This compound was used directly, without further
`purification, in Example I.
`The following amino- and bromo- substituted quino
`lines were prepared from the corresponding, previously
`known, des-bromo compounds by a similar bromina
`tion procedure to that described above. In each case
`the Example in which the compound was used is indi
`cated.
`
`10
`
`and
`
`2
`
`X
`
`n
`N 1
`
`HBr
`
`Y
`
`Z
`
`Position of
`amino group
`
`X
`
`Y Z
`
`m.p.
`C.
`
`Used in
`Example
`
`5.
`5-
`6- .
`6-
`
`6-Br
`6-Br
`5-Br
`5-Br
`
`H 8-CH 262
`H H
`235-236
`H.
`H.
`230
`H 8-Cl
`248-251
`
`IV
`VI
`X
`XV
`
`15
`
`20
`
`and the pharmaceutically acceptable acid addition salts
`thereof wherein X is selected from the group consisting
`of hydrogen, halogen, lower alkyl, lower alkoxy and tri
`fluoromethyl and R2 is selected from the group consist
`ing of hydrogen, alkyl having 1 to 6 carbon atoms and
`alkoxy having 1 to 6 carbon atoms.
`2. A compound according to claim 1, formula II.
`3. A compound according to claim 1, formula III.
`4. A compound according to claim 2 wherein R is
`hydrogen.
`5. A compound according to claim 2 wherein R is
`hydrogen, X is halogen and the 2-imidazolin-2-ylamino
`group is located at the 6-position.
`6. A compound according to claim 5 wherein X is 5
`bromo.
`7. A compound according to claim 5 wherein X is 5
`chloro.
`8. A compound according to claim 3 wherein R is
`hydrogen or 4-methoxy.
`9. A compound according to claim 3 wherein R2 is
`hydrogen or 4-methoxy, X is hydrogen and the 2
`imidazolin-2-ylamino group is located at the 7-position.
`2k
`k
`-k,
`-k
`sk
`
`In a similar manner, 6-amino-5-bromoquinoxaline
`hydrobromide was prepared by bromination of 6
`aminoquinoxaline, a small portion of which was char
`acterized as the free base, with m.p. 155-156. The hy
`30
`drobromide salt was used in Example XVIII.
`What is claimed is:
`1. A compound selected from the group consisting of
`those having the formulae
`
`25
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`Eye Therapies Exhibit 2190, 7 of 12
`Slayback v. Eye Therapies - IPR2022-00142
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`CERTIFICATE OF CORRECTION
`PATENT NO. : 3,890,319
`DATED
`: June 17, 1975
`INVENTOR(S) : John C. Danielewicz et all
`It is Certified that error appears in the above-identified patent and that said Letters Patent
`are hereby COrrected as shown below:
`
`Col. 11, between lines 31 and 32, should read
`
`as
`
`a
`
`METHOD B
`
`A mixture of 3-bromo-4-nitroaniline (66 g. ), arsenic
`(A)
`oxide (55 g. ), glycerol (112.5 ml.) and concentrated Sulphuric aci
`(73 ml.) was gently heated with stirring to reflux temperature.
`At the first sign of Vigorous gas evolution, the heating Source was
`removed from the reaction vessel for about 3 minutes. Thereafter,
`heating was continued for 3 hours and the reaction mixture was
`cooled and poured onto ice. Once the latter had melted, the brown
`O solid was filtered off and suspended in water, which was then
`basified by addition of aqueous sodium hydroxide solution. The
`solid was collected by filtration, washed with water, and dried,
`yielding 35 g. of brown solid.
`The latter was recrystallized from methanol and then
`O three times from petroleum ether (b. p. 80-100) to afford 9.2 g.
`of 7-bromo-6-nitroquinoline, m. p. 144-145.
`(B)
`The product of (A) (6.05 g. ) was dissolved in con
`centrated hydrochloric acid (50 ml.), and to the stirred Solution
`at room temperature was added portionwise a solution of Stannous
`chloride (18. l. g. ) in concentrated hydrochloric acid (50 ml.).
`After stirring the mixture for 5 minutes, the solid was filtered
`off, washed with concentrated hydrochloric acid and dried in air.
`A suspension of the solid in water was then basified by addition
`of 4N aqueous Sodium hydroxide solution, and the solid filtered
`off, to be washed with distilled water, dried in air and then
`in vacuo at 60 for 6 hours.
`
`
`
`
`
`
`
`
`
`
`
`Eye Therapies Exhibit 2190, 8 of 12
`Slayback v. Eye Therapies - IPR2022-00142
`
`

`

`
`
`O
`
`O
`
`O
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`CERTIFICATE OF CORRECTION
`3,890,319 (page 2)
`PATENT NO. :
`June 17, 1975
`DATED
`John C. Danielewicz et all
`INVENTOR(S) :
`It is Certified that error appears in the above-identified patent and that said Letters Patent
`are hereby COrrected as shown below:
`The yellow solid (3.8 g. ) was finally recrystallized
`rom petroleum ether (b. p. 100-120) to afford 3.2 g . of 6-amino
`7-bromoquinoline as Straw-colored needles, m. p. 135-136.
`This compound was used in Example XVI.
`
`METHOD C
`To a stirred solution of 5-amino-8-methylquinoline
`(4 g. ) in glacial acetic acid (90 ml.) at room temperature was
`added a solution of Sulphuryl chloride (3.5 g. ) in glacial acetic
`O acid (10 ml.) dropwise. The solution was stirred for 2 hours
`at room temperature, and then poured into aqueous sodium acetate
`solution, resulting in the formation of a precipitate. The latter
`was collected by filtration and recrystallized from aqueous
`ethanol solution to afford 2.5 g. of 5-amino-6-chloro-8-methyl
`quinoline as a brown solid, m.p. 113-114.
`i
`This compound was used directly, without further
`purification, in Example W.
`The following amino- and chloro-substituted quinolines
`quinoxalines and quinazolines were prepared by a similar chlorina
`tion procedure to that described above. In cases where the hydro
`lchloride salt was isolated, the basification by sodium acetate
`step was omitted. The example in which the compound was used
`is indicated in each case.
`
`i
`
`O
`
`
`
`Eye Therapies Exhibit 2190, 9 of 12
`Slayback v. Eye Therapies - IPR2022-00142
`
`

`

`
`
`O
`
`O
`
`O
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`CERTIFICATE OF CORRECTION
`3,890, 319 (page 3)
`PATENT NO. :
`June 17, 1975
`DATED
`INVENTOR(S) : John C. Danielewicz et all
`It is Certified that error appears in the above-identified patent and that said Letters Patent
`are hereby Corrected as shown below
`
`m. p.
`oC.
`
`Used in
`Example
`
`Compound
`5-amino-8-chloro-6-methyl
`quinoline
`6-amino-5-chloroquinoline
`hydrochloride
`
`142-145
`
`XT
`
`6-amino-5,8-dichloro
`quinoline hydrochloride
`(from the 8-chloro compound) 236-238
`7-amino-8-chloro-4-methoxy
`quinazoline hydrochloride
`6-amino-5-chloroquinoxaline
`8-amino-5, 7-dichloro
`quinoline (from 8-amino
`quinoline)
`
`66-67
`139-140
`
`METHOD D
`To a stirred solution of 6-aminoquinoxaline (3 g. ) in
`O
`glacial acetic acid at room temperature was added dropwise over
`a period of one minute a solution of iodine monochloride (4.5 g.)
`in glacial acetic acid (15 ml.). Stirring at room temperature
`was continued for a further 30 minutes, after which the precipitat
`Solid was collected by filtration and washed with diethyl ether to
`Olafford 6.5 g. of 6-amino-5-iodoquinoxaline hydrochloride, as a
`complex with iodine, m.p. 167-169 with decomposition.
`
`
`
`Eye Therapies Exhibit 2190, 10 of 12
`Slayback v. Eye Therapies - IPR2022-00142
`
`

`

`UNITED STATES PATENT AND TRADEMARK OFFICE
`CERTIFICATE OF CORRECTION
`3, 890, 319 (page 4)
`PATENT NO. :
`June 17, 1975
`DATED
`:
`John C. Danielewicz et all
`NVENTOR(S) :
`It is Certified that error appears in the above-identified patent and that said Letters Patent
`are hereby Corrected as shown below:
`Analysis:
`C, 21.79; H, 1.58; N, 9.66%
`Found:
`Required for C3H6 IN.I.HCl: C, 22.11; H, 1.63; N, 9.67%
`This compound was used in Example XX.
`The starting materials for Examples III, VI, VII, IX,
`X, XIII and XXIII-XXV are all previously known compounds.
`The antihypertensive activity of the compounds of the
`invention is shown by their ability to lower the blood pressure
`of conscious hypertensive rats and dogs, when administered sub
`cutaneously and orally, respectively, within the dosage range
`0.025-10 mg. /kg.
`By virtue of their performance in such trials in
`animals, the preferred compounds of the invention are those in
`which at least one of X, Y or Z is a halogen atom, and those in
`which the 2-imidazolin-2-ylamino group is in either the 6- or the
`7-position in the quinoline, quinoxaline or quinazoline nucleus.
`When any of X, Y or Z is a halogen atom, this is preferably a
`bromine atom.
`Particularly preferred compounds of the invention are
`those of any of the three formulae given hereinbefore in which the
`2-imidazolin-2-ylamino group is in the 6-position and one of X,
`Y or Z represents a single halogen atom in the 5-position or in
`which the 2-imidazolin-2-ylamino group is in the 7-position and one
`of X, Y or Z represents a single halogen atom in the 8-position.
`
`
`
`Eye Therapies Exhibit 2190, 11 of 12
`Slayback v. Eye Therapies - IPR2022-00142
`
`

`

`
`
`O
`
`O
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`CERTIFICATE OF CORRECTION
`PATENT NO. :
`3,890,319 (page 5)
`DATED
`June 17, 1975
`INVENTOR(S) :
`John C. Danielewicz et all
`It is Certified that error appears in the above-identified patent and that said Letters Patent
`are hereby COrrected as shown below:
`Of particular value as antihypertensive agents have
`been found to be the compounds of Examples XI, XII, XVIII and XIX.
`The compound