United States Patent
`
`{19]
`
`Karjalainen et a1.
`
`[11] Patent Number:
`
`[45] Date of Patent:
`
`4,544,664
`* Oct. 1, 1985
`
`[54] ANTIHYPERTENSIVE SUBSI'ITUTED
`[MIDAZOLE DERIVATIVES
`
`Attorney, Agent, orFirm—Annstrong, Nikaido,
`Marmelstein Kt Kubovcik
`
`[75]
`
`Inventors: Arto J. Karjalalnen; Kauko O. A.
`Kurlrela, both of Oulu, Finland
`
`[73] Assignee:
`[ ‘ ] Notice:
`
`Farmos Group, Ltd, Turku, Finland
`The portion of the term of this patent
`subsequent to Jun. 8, 1999 has been
`disclaimed.
`
`[21] Appl. No.: 396,000
`[22] Filed:
`Jul. 7, 1982
`
`Foreign Application Priority Data
`[30]
`Jul. 10, 1981 [GB] United Kingdom ................. 8121333
`
`[51]
`
`Int. Cl.‘ .................. A61K 31/415; C07D 233/56;
`CO7D 233/64
`[52] US. Cl. .................................... 514/396; 514/397;
`514/400; 548/335; 548/336; 548/342
`[58] Field of Search ............. .. 548/335. 336. 341. 342,
`548/345; 542/458. 400. 468; 424/273 R;
`514/397, 400, 396
`
`[56]
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`7/1960 Zaugg et a]. ........................ 548/342
`2,946,804
`
`4.333.947 6/ 1982 Karjalainen er al.
`..
`.. 542/548
`4,443,466 4/ 1984 Karjalaincn cl :1.
`424/274
`FOREIGN PATENT DOCUMENTS
`
`0024829
`0034474
`0034473
`
`3/ 1981 European Pat. Off.
`8/1981 European Pat. 01'1'.
`8/1981 European Pat. Off.
`OTHER PUBLICATIONS
`
`..
`..
`
`
`I 548/335
`
`Kelley. 1., et al.. J. Pharm. Sci, 70(3), 341—343, (1981).
`
`[57]
`
`ABSTRACT
`
`The invention provides novel compounds of the for-
`mula:
`
`R3
`
`/
`
`C
`
`\h
`R2
`
`I
`
`.
`h
`
`N
`1H
`
`R —<
`I
`
`Of
`
`H I
`1"
`H
`
`R‘
`
`(1)
`
`(11)
`
`R5
`Re
`
`M
`
`R
`
`5
`
`R7
`
`wherein the various substituents are defined herein be-
`low. Processes for the preparation of these compounds
`are described, as are novel pharmaceutical compositions
`comprising at least one of the compounds of their salts.
`The compounds and their non-toxic salts exhibit valu-
`able pharmacological activity and are useful
`in the
`treatment of mammals, especially as antihypertensive
`agents. Furthermore, some of the compounds have
`proved to possess antithrombotic and diuretic activity.
`Antimycotic and antifungal properties have also been
`found.
`
`Primary Examiner—Richard A. Schwartz
`
`12 Claims, No Drawings
`
`Petition for Inter Partes Review of US 8,242,158
`Amneal Pharmaceuticals LLc — Exhibit 1004 - Page 1
`
`

`

`1
`
`4,544,664
`
`ANTIHYPERTENSIVE SUBSTITUTED
`IMIDAZOLE DERIVATIVES
`
`CH3
`/
`—CH(-CH—CH3)—.
`
`DESCRIPTION
`
`The present invention relates to substituted imidazole
`derivatives and their non-toxic, pharmaceutically ac-
`ceptable acid addition salts, and their preparation, to
`pharmaceutical compositions containing the same, and
`to their use.
`The imidazolc derivatives of the present invention
`have the general formula:
`
`5
`
`IO
`
`or
`—CH(—CH2CH2CH2CH3)—
`> C-=CH—CH3. > C=CH-CH2CH3.
`
`> Cin,
`
`\
`
`CH3
`/
`CBC—CH3,
`
`>C=CH—CH2CH2CH3; R9 is H, —CH3. —CH2CH3,
`—CH2CH2CH3,
`
`15
`
`/R’
`w I R4
`N
`lH
`
`R:
`
`or
`
`R5
`R7
`
`(0
`
`CH3
`/
`—CH—CH 3.
`
`20
`
`—CH2CH2CH2CH3 or OH; R10
`—CHZCH3. —CH2CH2CH3,
`
`is H,
`
`_CH3I
`
`Rs
`
`(II) 25
`
`CH:
`/
`_CH—CHJ
`
`N
`R'_< I
`1'1
`H
`
`x-(CHzil.~@Ro
`K7
`
`R2
`
`or ——CH2CH2CH2CH3; Rn is H, —CH3, -CH2CH3.
`—-CH2CH2CH3,
`
`30
`
`CH3
`/
`-CH—CH3
`
`wherein R1 is H, an alkyl of I to 4 carbon atoms. eg.
`methyl or —-CH20H; R1 is H or CH3; R3 is —-—CH3, 35
`-—CH2CH3, —CH2CH2CH3.
`
`or —CH2CH2CH2CH3; n is 0 to 4; provided that
`when R4 is OH, R] is H or CH3 and R3 is
`
`CH
`/ J
`-CH-CH3.
`
`—CHzCHzCHzCH3, —CH2CH=CH2, or
`
`Rs
`
`R6
`
`R7
`
`4O
`
`45
`
`and R4 is H or OH; or R3 and R4 together represent 50
`in. =CH—CH5, =CH—CH2—CH3,
`
`CH3
`
`/
`=C—CH3.
`
`or =CH—CH2CH2CH3: X is
`
`ll?” 1ro
`1'19
`5'1:
`-CH-CH- or -C=C-:
`
`55
`
`6°
`
`R5, R6. and R7, which can be the same or different are
`H, —~CH3, —CH;CH3‘, halogen, OH or —OCH3 or R5
`is hydrogen and R6 and R7 together form an —O—CH- 65
`2—O—bridge between two adjacent carbon atoms in
`the phenyl group; —CHRs—— is —-CH2—, —CH(CH-
`3)—. —CH(—CH2CH3)-. —CH(—CH2CH2CH3)—.
`
`R5
`
`R7
`
`then R5, Rsand R7 are not all simultaneously hydro-
`BC“;
`when R], R2 and R4 all are hydrogen and R5 is
`
`R5
`
`R7
`
`then R5, R5. R7 are not all simultaneously hydrogen;
`R3 and R9 are not simultaneously hydrogen; and
`R” and R10 are not simultaneously hydrogen.
`Because of the tautomerism in the imidazole ring the
`campounds of the general formula I and II are 4(S)-sub-
`stituted irnidazole derivatives.
`The non-toxic pharmaceutically acceptable acid addi-
`tion salts of these compounds are also within the scope
`of the invention.
`The compounds of the formula (I) and (II) form acid
`addition salts with both organic and inorganic acids.
`They can thus form many pharmaceutically usable acid
`addition salts, as, for instance, chlorides, bromides. sul—
`fates, nitrates, phosphates, sulfonates,
`formates,
`tar-
`irates, maleates, citrates. benzoates, salicylates, ascor-
`bates and the like.
`
`Petition for Inter Partes Review of US 8,242,158
`Amneal Pharmaceuticals LLc — Exhibit 1004 - Page 2
`
`

`

`4,544,664
`
`4
`
`3
`The invention includes within its scope pharmaceuti-
`cal compositions comprising at least some of the com-
`pounds of formula (I) or (II) or a non-toxic. pharmaceu-
`tically acceptable salt thereof. and a compatible phar-
`maceuticall
`accc table carrier therefor.
`The invezttion grovides, for example. the Following
`specific compounds of formula (1):
`4-[a.a-bis(2-methylphenyl)hydroxymethylhmidazole
`4~[[a-(2-methylphcnyl)]-2-mcthyIbenzyl]imidazolc
`4-(a-phcnylbcnzyl)-S-methylimidazole
`4-[[a—(2,Gdimethylphenyl)]—a-methyl]hydroxymethyl-
`]imidazole
`4—[[_a-_(2.3-dimethylphenyl)l-a-methylihydroxymethyl-
`JImIdélole
`4'[a’fib'figtg‘figfiz‘Pheny‘)hyd'°xym“hyu‘s‘
`L[Ezzf'meé‘ylphenyl)]_2_methylbenzyl]_5_
`methy'imidazole
`4-[(a-methyl)-2.6-dimethylbenzyl1imidazole
`4-[(a-mcthyl)—2.3-dimctl’tylbcnzyl]imidazolc
`4-[(a-ethyl)—3-methylbenzyl]imidazole
`4-[(a-butyl)-2,3-dimethylbenzyl]imidazole
`4-[(a-methyl)-2,3-dimethylbenzyl]-Z-methylimidazole
`4'[(G-Pf0Pyl)‘2‘m¢lhYlbenlylllmifllawlc
`4'lia'mcthYD'Z'mcfhylbcnlylllml‘ihfdc
`f[(°'";let:‘ynf’s'dfitiylberzglgm‘dazoleh I
`{fr-rieiilayzofj -met y p my )- y roxyme‘ y '
`4.[a_butyl_a_(2.3_dimemylphenyl)_hydmxymethy1_
`1imidazole
`4_[a_mcthyi-a-(2'3_dimethylphenyi)-hydfoxymethyng-
`methylimidazole
`4-[a-propyl-a-(2—methylphenyl)-hydroxymethyl-
`]imidazole
`HG-melhyl'Z'CthI'ObenZyllimidalOlC
`lml azo e
`4‘5?"rf’sthyra‘a'methylphc"YD'hydroxyme‘hyl'
`4-[a-methyl-a-(2,S-dimethylphenyl)—hydroxymethyI-
`limidazole
`4-[a.a-bis-(Z.3-dimethylphcnyl)hydroxymethyl-
`Fmiduolc
`4-[a-(2,3-dimethylphenyl)-2.3-dimethylbenzyl—
`]imidazole
`4-[(a-ethyl)-2,é-dimethylbenzyllimidazole
`‘4-[(a-ethyl)-2,3-dimethylbcnzyl]imidazole
`l-(4-imidazolyl)‘ l~(2,3-dimethylphenyl)ethylene
`l-(4-imidazolyl)—l-(2,6—dimethylphenyl)ethylene
`l-(4-imidazolyD-l-(2.3-dimethylphenyl)propene
`l—(4-imidazolyl)-l~(2.3-dimethylphenyl)pemene
`The following specific compounds of formula (II):
`4'[2-(2y5-dimelhylPhenyl)‘I‘melhylemyllimidaZOle
`4-[2-(2.6-dimethylphenyl)propyllimidazolc
`g‘glmetgfipflgnl/g’f‘:YJAIT‘dgzmfiimauolc
`-
`,
`-
`tmc
`n
`- c
`r
`t
`4‘[2_(2’6_dimethylghcn;l)_2-hydrgx§et:;]]imidazole
`4-(2-phenylpropyl)imidazole
`4-[2-(2,6-dimethylphenyl)- l -methylethenyl]imidazole
`4-[2-(2,6-dimethylphcnyl)-l-propcnyl]imidazolc
`4-(2-mcthyl-4—phenyl— l-butenyl)imidazole
`4-[2-(4-chlorophenyl)-l-methylpropyllimidazole
`
`4-[5-(2,6-dimethylphenyl)- 1 -methyl- l -pentenyl-
`]imidazole
`4-{3-(2,6-dimethylphcnyl)-2-methyl-l-propcnyl-
`]imidazole
`4-[2-(2,6-dimethylphenyl)- l -ethylethenyl]imidazole
`4-[2-(2.3-dimethylphenyl)-l-methyletheny11imidazole
`4-[2-(2.6-dimethylphenyl)— l -isopropylethenyIIimidazole
`
`5
`
`2°
`
`4-[2-(2,6—dimethylphenyl)—l-methylethenyl]-2-
`methylimidazole
`4~[2-(2,6—dimethylphenyl)- Lmethylethenyl]-5-
`methylimidazole
`.
`.
`.
`A'Ii'(2'6'dfchlorolpheny13'l‘metzylf‘henymmlfazom
`LI .'(?’6'd‘me‘hy pheny H‘met y '1'pemeny '
`.
`l‘m'daz9le
`_
`.
`Ll3'(2v6'dlm3thylphenyl)' I “Ethyl' I'Pml’enylll""daZOIe
`‘0 4-[5-(2.6-dimethylphenyl)-l-methyl-l-pentenyl]-S.
`methylimidazole
`4—[5-(2.6—dimethylphenyl)-l-methylpentyl]imidazole
`4-[4-(2,6-dichlorophenyl)—l-methy1-l-butenyl]imidazole
`,5 4-{2-(2,6—dimethylphenyl)-l-ethylethyl]imidazole
`4-[2-(2,6-dimethylphenyl)—2-ethylethyl]imidazole
`4-[2-(3.4-methylenedioxyphenyl)propyl]imidazole
`¢[z-(g-bromo4,S-methylenedioxyphenyl)pr0pyl-
`llmldazole
`The compounds of the present invention have been
`found to possess excellent antihypertensive activity.
`Preliminary tests have shown that
`they also possess
`other valuable pharmacological properties. for exam-
`25 pie, antithrombotic and diuretic effect. Antimycotic and
`antifungal properties have also been found.
`While all of the compounds of formula (I) and (Il)
`essentially satisfy the objectives of the present inven-
`30 tion. certain groups of compounds remain preferred.
`One such preferred group Isrepresented by formula (I)
`wherein R4 is hydrogen. R3 is alkyl and R5. R1, and R7.
`which can be the same or different, each are hydrogen.
`methyl, ethyl or halogen. Another preferred group of
`35 compounds is represented by formula (11). wherein R5.
`R6 and R7. which can be the same or different, each are
`-
`-
`-
`-
`hydrogen, methyl, ethyl or halogen.
`In such com-
`pounds' those m thh R' ‘S hqugen or methyl‘ R} ls
`40 hydrogen or methyl. Rs or Ru IS methyl. ethyl or Iso-
`Pr°P¥'v R9 “3‘5 “{0 3“ “ydmgcn and n '5 ° {nay b?
`mentioned. bspecrally the compounds wherein n lS
`greater than 0 possess valuable antimycotic properties.
`Especially good antihypertensive properties have been
`45 found in compounds of formula (ll) wherein n is 0 and
`x is
`
`50
`
`If" 11'”
`—C=C—v
`
`According to the feature of the invention, the corn-
`pounds of formula (I) wherein R4 is OH and the com-
`pounds of formula (II) are made by a Grignard reaction,
`55 .
`-
`.
`-
`in which an imtdazolylltetone of the formula
`
`N
`Rl—< I
`
`60
`
`65
`
`0
`g_RJ
`
`R;
`
`N
`|
`H
`wherein Ri, R2 and R; are as defined before. is reacted
`with an arylalkyl magnesium halide derivative or aryl
`magnesium halide derivative of the formula;
`
`Petition for Inter Partes Review of US 8,242,158
`Amneal Pharmaceuticals LLc — Exhibit 1004 - Page 3
`
`

`

`5
`
`4,544,664
`
`R:
`
`R6
`
`R7
`
`(CHyn. ~Mgflal
`
`wherein R5, R5 and R7 are as defined before, n' is 0 to S
`and Hal is a halogen atom to give compounds of the
`formula (Ill)
`
`0H
`
`H In:
`N
`lH
`
`R2
`
`(Ill)
`
`“5
`
`m
`
`wherein R1, R2, R3, R5. R6. R7 and n' are as before.
`The arylalkylmagnesium halide derivative can be. for
`example. an arylalkylmagnesiumbromide derivative.
`which is prepared by reacting the corresponding ary-
`lalkylbromide derivative with magnesium. Suifable sol-
`vents for the reaction include a variety of ethers, prefer-
`ably tetrahydrofuran. The arylalkylmagnesiumhalide
`derivative is prepared in the usual way by adding the
`arylalkylmagnesiumhalide derivative in a suitable sol-
`vent, e.g. tetrahydrofuran. dropwise onto magnesium
`turnings covered by tetrahydrofuran, at
`the boiling
`point of the reaction mixture. When the magnesium
`tumings have reacted. the mixture is cooled slightly and
`the 4-imidazole derivative is added in solid form in small
`
`portions or in tetrahydrofurane solution. After the addi-
`tion, the reaction mixture is refluxed until all of the
`4-imidazole derivative has reacted. The reaction time
`varies between one and five hours.
`Another process for the preparation of compounds of
`formula (III) is a Grignard reaction in which a com-
`pound of the formula (IV)
`
`5
`
`l0
`
`15
`
`20
`
`25
`
`35
`
`40
`
`45
`
`wherein R: and R2 are as before, is reacted in a first
`step/with a Grignard reagent of the formula
`
`(CHzln- "MBHIl
`
`wherein R5, R5, R7 and n‘ are as before. to give a com-
`pound of formula (IV). which in a second step without
`isolation is reacted with a Grignard reagent of the for—
`mula
`
`R3MgHal
`
`wherein R3 is as defined before.
`Compounds of formula (I) wherein R4 is H can be
`prepared by reduction of compounds of formula (III)
`wherein n' is 0 with hydrogen. A suitable catalyst is e.g.
`palladiumon-carbon.
`Unsaturated compounds of formula (I) wherein R3
`and R4 are =CH2, =CH—CH3, =CH—CH2CH3,
`
`CH]
`-C—CH3
`
`or =CH—CH2CH2CH3 or formula (II) wherein R10 is
`hydrogen are prepared by dehydrating compounds of
`formula (Ill):
`
`R5
`
`(111)
`
`R1
`
`.
`
`(W)
`
`SO
`
`55
`
`H: I
`
`H
`
`r
`"’
`C—(CHz)..@&
`at
`
`R:
`
`I
`
`N
`
`NI
`
`H
`
`/H
`
`wherein Rl—R‘} and n’ are as before. is reacted with a
`compound of the formula
`
`RgMgHal
`
`wherein R3 is an alkyl or aryl as defined before and Hal
`
`is halogen. Yet another process for the preparation of 6
`compounds of formula (III) is a Grignard reaction in
`which an imidazolc carboxylic acid alkyl ester, prefera-
`bly the methyl ester of the formula
`
`. “14:1
`
`H
`
`wherein R1, R2, R5. R5, R7 are as defined before, R3 is
`an alkyl or aryl as defined before and n' is 0 to 5, to give
`a compound of the formula (V)
`
`R5
`
`(V)
`
`Rn
`C=CH—(CH1),.
`
`R2
`
`
`
`Petition for Inter Partes Review of US 8,242,158
`Amneal Pharmaceuticals LLc — Exhibit 1004 - Page 4
`
`

`

`4,544,664
`
`8
`Thus, according to this embodiment of the invention, a
`starting material of the formula (VI) or (VII)
`
`R_
`i
`R6
`R7
`or
`
`Rs
`R5
`R7
`
`flktz if”
`1'13
`CH—?-f‘-Rg
`Ru fins
`
`if” If”
`(CH5),,"X—(l:—(II—R1
`R14 Ru
`
`VI
`
`i
`
`,
`
`(vm
`
`wherein R2, R3, R5. R5, R7 and n are as hereinbefore
`defined; wherein Rlz. R13. R14 and R;5, which can be
`the same or different, are each hydrogen, hydroxy,
`mercapto, halogen, amino, —0— alkyl of] to 7 carbon
`atoms or
`
`0l
`
`l
`—o-—c- R.
`
`wherein R is an alkyl; or wherein R]: and R” can be
`combined to form a keto group, or R13 and ms can be
`combined to form a keto group. or both Ru and RH and
`R13 and R15 can simultaneously form keto groups;
`is
`reacted with a reagent capable of converting said start-
`ing material to the corresponding imidazole of the for-
`mula:
`
`R3
`I
`CH
`
`R:
`
`R5 or
`
`Rb
`
`R7
`
`R5
`
`,0
`
`R7
`
`x—(cnl).
`
`I
`
`R:
`
`N
`
`N
`lH
`
`IH
`
`.
`h
`
`/
`
`R’—< I
`N
`|H
`
`5
`
`[0
`
`)5
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`wherein R1. R2. R3. R5. R6. R7. X and n are defined as
`before. Reagents capable of converting the depicted
`starting material to the corresponding imdidnzole in»
`55 elude NH3+CH20 (or a source of ammonia and form-
`aldehyde);
`
`if
`ii
`HN=c~—Nriz. H—C—0——NH4*; HCONHg; Rl—C—Nll;;
`I
`
`IR
`
`or RICHO and NH3. Choice of an appropriate reagent
`varies with the particular starting material employed.
`When R. is hydrogen it is preferable to employ form-
`amide as the reagent in cases where,
`in place of the
`bromine atom in the aforementioned starting materials.
`there is instead a hydroxyl, amino or acetyl group. In
`
`60
`
`65
`
`Petition for Inter Partes Review of US 8,242,158
`Amneal Pharmaceuticals LLc — Exhibit 1004 - Page 5
`
`7
`-continued
`
`i“
`C—(Cflzh.
`
`.4: I
`
`R2
`
`H
`
`“’
`Ra
`
`R7
`
`wherein R1. R2, R5, R6, R7, and n and n’ are as defined
`before; R11 is an alkyl as defined before and R3 is an
`alkcnyl as defined before.
`The dehydration is preferably performed by refluxing
`in an apprOpriate acidic solution. e.g. concentrated hy-
`drochloric acid or heating for example with potassium-
`hydrogen sulfate.
`The compounds of formula (V) can further be re-
`duced with hydrogen in the presence of a palladium-on-
`carbon catalyst
`to the corresponding saturated com-
`pounds of formulae (I) and (II).
`Compounds of formula (11) wherein R" is hydrogen
`are prepared by a Wittig reaction which comprises
`reacting an imidazole aldehyde of the formula
`
`CHO
`
`R:
`
`N
`
`N
`IH
`
`wherein R1 and R2 are as before. with an aralkylidene-
`triphenylphosphorane of the formula:
`
`lllm
`(Colli)JP=C'(CHz)n
`
`R5
`Ra
`
`R7
`
`wherein R5. R6, R1, Rm and n are as defined before, to
`give the unsaturated compounds of formula (II), which
`in a further step can be reduced to the corresponding
`saturated compounds of formula (II) as described
`above.
`The aralkylidenetriphenylphosphoranes are prefera-
`bly prepared by reacting the corresponding aralkyltri-
`phenylphosphonium halide of the formula:
`
`R
`
`5
`Rs
`
`R1
`
`Rio
`6
`l
`(CH2).—CH- P—(CeHm Hale
`
`wherein R5, R5. R7. Rio and n are as before and Hal is
`halogen, with a basic reagent, preferably butyllithium.
`In the Grignard- and Wittig-synthcscs dcsoribed
`above, the free nitrogen atom in the imidazole starting
`material can be protected by different methods. Suitable
`protecting groups are for example benzyl. triphenylsilyl
`or dinlkoxyrnethane. The removal of the protecting
`group can be performed in different ways, and depends
`on the kind of protecting group used. For example, a
`dialkoxymethane group is removed by acidic hydrolysis
`and a benzyl group by sodium in liquid ammonia.
`The present invention further provides yet another
`method for preparing compounds of the invention.
`
`

`

`$54£664
`
`10
`
`Y
`
`Rlc
`
`|N
`
`N
`
`=o
`
`l
`
`{for x
`=0w—o—z
`
`where Y is the arylalkylresidue determined by the for-
`mula (I) and (II), R is an alkyl group of l to 7 carbon
`atoms or an aryl radical of 6 to 10 carbon atoms
`Preferably, the hydrolysis is carried out by boiling
`the starting material, an N-acylated imidazole deriva-
`tive, in an aqueous solution of an inorganic acid until the
`reaction is completed.
`Yet another process for the preparation of the com-
`pounds of formula (I) and (II) comprises hydrogenating
`a starting material of the formula;
`
`9
`these instances, fonnamide is used in excess and acts in
`part as the solvent. Generally, the reaction is run at the
`boiling point of formamide for a period of time ranging
`from one to five hours.
`
`Yet another process for the preparation of the com-
`pounds of formula (I) and (II) comprises reacting form-
`amide with a benzene derivative of the formula:
`
`Rs
`Ro
`
`K7
`
`1'“
`Rs
`CH—Qor hflX—(Cflzln—Q
`
`R7
`
`wherein R5. R6. R7, R3, n and X are as defined herein-
`above, and Q is a radical of formula:
`
`O
`O
`O
`ll
`II
`II
`—C—(|:H—NH—C—R, C—‘(IZHNHCHZ
`R2
`R2
`
`0
`/ \
`or —CH'—(':—R1
`Hal
`
`5
`
`10
`
`| 5
`
`20
`
`25
`
`wherein R is a substituted and unsubstituted alkyl, ary- 30
`lalkyl or aryl group, and R1, and Hal are as defined
`hereinabove. Preferably the reaction is performed by
`vigorously boiling the benzene derivative in formarnide,
`the reaction time varying with the particular material
`employed.
`Reaction times typically are from 30 minutes to 8
`hours. Obviously, the formamide treatment will be fol-
`lowed by reaction with an appropriate acid (cg. HCl)
`when Q in the starting material is
`
`40
`
`35
`
`45
`
`50
`
`55
`
`60
`
`65
`
`0
`o
`ll
`ll
`~C—CH—NH—C—R
`
`|R
`
`:
`
`in order to obtain the corresponding compound of for-
`mula (I) and (II).
`Similarly, when a starting material wherein Q is
`
`i’—C—(lIHNHCH2‘@
`
`R2
`
`is employed, then the formamidc treatment will be fol-
`lowed by hydrogenation.
`thus affording the desired
`compound of formula (I) and (II).
`A further process for the preparation of the com-
`pounds of the formula (I) and (II) comprises hydroly-
`sing a corresponding N—acetylated compound of the
`formula (1) and (ll)
`
`Y
`
`R1
`
`R"
`
`I i
`
`’”
`N
`R'5—< I . R|—< I or R|—< I
`N
`R:
`:1
`R:
`N
`$111R"
`
`v
`
`N
`
`Y
`
`N
`
`l H
`
`wherein Y is as defined before and R' is an aryl or alkyl
`and R” is an aryl group. The hydrogenation is conve-
`niently conducted in the presence of a suitable catalyst
`and under a hydrogen atmosphere, with stirring or
`using metallic sodium in liquid ammonia. Suitable cata-
`lysts include platinum oxide, palladium-on-carbon and
`Raney nickel. Reaction temperatures vary with the
`particular starting material employed, with typical tem-
`peratures being 25‘-70° C.
`Yet another method for the preparation of the com-
`pounds of formula (1) or (II) wherein X is
`
`l"
`i“
`—CH—CH-
`
`comprises reacting a N-trialkylsilylimidazole of the
`formula
`
`[I
`
`Y—f—YY
`
`wherein Y is an alkyl group, preferably methyl. with an
`arylalkylhalogenide of the formulae
`
`
`
`Petition for Inter Partes Review of US 8,242,158
`Amneal Pharmaceuticals LLc — Exhibit 1004 - Page 6
`
`

`

`11
`
`R5
`Ills
`CPI—Hal or R5
`
`R7
`
`R5
`R5
`
`R:
`
`4,544,664
`
`12
`wherein R3 is an alkyl as before, in the presence of a
`Lewis acid, for example zinc (II) chloride, to give a
`compound of the formula (XII)
`
`Ellis
`1119
`CH—CH‘Hal
`
`wherein R3, R5, R6. R1, R3 and R9 are as before and Hal
`is a halogen atom, in the presence of a Lewis acid, for
`example titanium tetrachloride, aluminium chloride or
`zinc chloride. As solvent can be used for example rneth-
`ylene chloride or chloroform. The reaction is prefera-
`bly carried out at room temperature stirring the starting
`materials for 6-12 hours.
`The intermediates of formula (VI) and (V II) can be
`prepared for example as follows:
`An aldehyde of the formula
`
`)1,
`
`“fl(CH3),—CHO
`
`R1
`
`wherein R5. R6, R7 and n are as before, is reacted in
`alkaline or acidic conditions with a ketone, preferably
`acetone, to give a compound of the formula (VIII) via
`direct aldol condensation:
`
`R6
`
`i“ ii
`(CH2).—CH=C—C—CH3
`
`(Vlll)
`
`wherein Rx is an alkyl as defined before. which com-
`pound in a second step is catalytic-ally reduced to give
`the corresponding saturated compound of the formula:
`
`Rs
`
`if
`i“
`(CH2).—CH2—CH—C-CHJ
`
`(9‘)
`
`l0
`
`is
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`which compound in a third step is regioselectively bro-
`minated in methanol to give compounds of formula VII. 50
`Another method for the preparation of the com-
`pounds of the general formula (VII) is the regioselec-
`tivc alkylation process of ketoncs in whih for example a
`halide compound of the formula (X)
`
`55
`
`R9
`|
`(Cfllh—CH—Hal
`
`iiR7
`
`00
`
`Rt 0
`R9
`ll
`(CH1)Ir—'CH—CH—C—CH3
`
`(xm
`
`The compound of formula (XII) is further bromi-
`nated as before to give compounds of the formula (VII)
`When R5 and R2 are hydrogen yet another method
`for the preparation of compounds of the formula (VII)
`can be applied. In this method a halide of the general
`formula (XIII)
`
`RV
`|
`(Cflzln-CH— H3]
`
`(Xlll)
`
`is reacted with lithiated N,N-dimethylhydrazone of
`acetone followed by hydrolysis to give a compound of
`the general formula (XIV)
`
`R5
`
`R6
`
`R7
`
`0
`R9
`ll
`(CHILI—CH—CH;C—CH3
`
`(XIV)
`
`which compounds are brominated as before to give
`compounds of the formula (VII).
`According to another method for the preparation of
`compounds of the formula (VII), compounds of the
`formula (VIII) are selectively brominated using as bro—
`minating agent for example 2-carboxyethyltriphenyl-
`phosphonium perbromide, Wthh has the formula (XV)
`
`O
`ll
`(CoiIm—Pe—CHzCl-lgC-—OH one
`
`(XV)
`
`the preparation of com-
`Yet another method for
`pounds of the formula (VII) is possible Via a directed
`aldol condensation. in which for example a compound
`of the formula (XVI)
`
`RS
`
`Rs
`
`R7
`
`3
`(CH1)..—C-R in
`
`(XVI)
`
`60
`
`is reacted with the compound (XI) in the presence of a
`Lewis acid followed by dehydration to give a com-
`pound of the formula (XVII)
`
`is reacted with a trimethylsilylenolether derivative of
`the general formula (XI)
`
`OTMS
`
`5
`
`(XI) 6
`
`Rs
`
`Re
`
`R7
`
`Rica” 0
`(CH2)~—C=C—C—C HJR]
`
`V
`(x m
`
`
`
`Petition for Inter Partes Review of US 8,242,158
`Amneal Pharmaceuticals LLc — Exhibit 1004 - Page 7
`
`

`

`(XXIII)
`
`(XXIV)
`
`(xxv)
`
`o
`CH=CH—(li—CH;Rm
`
`It
`im ’
`it
`C—C=C‘H I
`
`‘
`
`”
`TH
`
`RI
`
`7
`In the first step this condensation gives unsaturated
`ketones of the formulae XV and
`XVI
`(x
`)
`(x
`)
`
`R
`R1.
`R
`
`"
`a.
`R,
`
`R’
`R.
`
`R7
`
`4,544,664
`
`13
`which compound is further brominatcd as before to
`give a compound of the formula (VII).
`When R“ is hydrogen, compounds of the formula
`
`(VII) can be Prepared from compounds ofthe formula 5
`
`(XVI), wherein these are reacted with I-lithiated N,N—
`dimethylhydrazone of methylalkylketone of the for-
`mula (XVIII)
`
`14
`
`0
`ll
`
`R5
`
`R7
`
`“QC—CH2“)
`
`CH3
`
`(xvm)
`
`m
`
`/
`fil—N—CH;
`“CH2_C_CH2R2'
`Here in the first step compounds of the formula '5
`(XIX) are achieved,
`
`(I,
`IMO
`Rs
`Rb@(CH2)n—C=CH_C_CH1RZ
`
`R7
`
`(xxx) 20
`
`the bromination of which compounds are performed 25
`following the method above.
`The preparation of compounds of the general formula
`(VII) can be accomplished from compounds of the
`general formula (XVII) by hydrogenation of the car-
`boo-carbon bouble bond as well. The bromination in the m
`second step leads to compounds of the formula (VII).
`Alkylation of compounds of the general
`formula
`(XVII) when R2 and R10 are hydrogen can be aceom.
`plished, too. In this method a compound of the formula 35
`(XX)
`
`Rs
`R5
`R?
`
`R5 0
`I
`II
`(CH2),—CH=c—c—CH,
`
`(x20
`
`40
`
`.
`.
`.
`.
`.
`.
`is reacted With an alkylation reagent such a dialkyllithi- 45
`ocuprate (XXI) which undergoes 1,4—conjugate addi-
`tion
`
`(1010!“
`
`(20(1)
`
`50
`
`to form compounds of the formula (XII).
`Condensation of an arylalkylkelone or its vinylogue
`with 4-imidazole aldehydes of the formula (XXII)
`
`CHO
`
`'
`N
`H I
`i
`H
`
`xxu 55
`l
`
`(
`
`60
`
`R
`
`o Rm
`CH=CH_II:_(':=CH I
`
`(XXVI)
`
`\ N
`
`N
`
`I]
`H
`
`which compounds are then hydrogenated to the end
`products according to the formulae (XXVII) and
`(XXVHI)
`
`Rs
`Re
`R1
`
`R5
`k.
`R7
`
`(xxvu)
`
`R2
`
`If")
`CHz—CH—cri,
`
`I
`
`N
`
`N
`IH
`
`>411
`
`“1
`I‘m
`cuzcuchzc};—CHZ I
`
`(xxvm)
`
`>_RL
`
`N
`
`N
`I
`H
`
`Yet another method for the preparation of com-
`pounds of formula (I) wherein R4 is H comprises react-
`ing a compound of the formula
`
`/R
`o
`a
`
`R:
`
`us
`M
`R7
`
`~
`H I
`N
`|H
`
`provides further another method for the preparatIOn of
`.
`.
`com ounds accordin this invention. The condensation
`wherein R1, R2, R3, R6 and R7 are as before and R is an
`p
`8
`is Performed for example in aqueous alwho’ “.mXRd 65 alkyl of 1 to 4 carbon atoms with a Grignard reagent of
`by sodium hydroxide. Arylalltylketones or their vmy-
`the formula
`logues have the general formulae (XXIII) and (XXIV)
`
`Rg—CflzMgHIl
`
`
`
`Petition for Inter Partes Review of US 8,242,158
`Amneal Pharmaceuticals LLc — Exhibit 1004 - Page 8
`
`

`

`15
`
`4,544,664
`
`in a mixture of tetrahydrofuran and toluene with reflux-
`ing to give a compound of the formula
`
`R)
`
`CIH
`
`R2
`
`N
`R1—< I
`N
`iH
`
`“5
`ReR
`
`7
`
`As stated herein above, the compounds of the general
`formula (I) and (II) and their non-toxic, pharmaceuti-
`cally acceptable acid addition salts have valuable phar-
`macological properties and have been found to possess
`excellent antihypertensive properties.
`Tests have shOWn that they also possess other phar-
`macological properties as well, for example, antithrom-
`bolic activity. Furthermore, antimycotic and antlfungal
`properties have been found, too.
`The processes described above for the preparation of
`compounds of formula (ll) wherein X is
`
`‘fll lilto
`_@C_
`
`result mainly in the trans isomer of the compound. The
`trans isomer can be converted to the cis isomer aceord-
`ing to known methods, e.g. by heating it in the presence
`of an acid or by irradiating it with ultraviolet light.
`Administration of isomeric compounds of formula (I)
`and (II), their non-toxic, pharmaceutically acceptable
`salts or mixtures thereof may be achieved parenterally,
`intravenously or orally. Typically, an effective amount
`of the derivative is combined with a suitable pharma-
`ceutical carrier. As used herein.
`the term “effective
`amount" encompasses those amounts which yield the
`desired activity without causing adverse side-effects.
`The precise amount employed in a particular situation is
`dependent upon numerous factors such as method of
`administration. type of mammal. condition for which
`the derivative is administered. etc., and of course the
`structure of the derivative.
`The pharmaceutical carriers which are typically em-
`ployed with the derivatives of the present invention
`may be solid or liquid and are generally selected with
`the planned manner of administration in mind. Thus, for
`example. solid carriers include lactose, sucrose, gelatin
`and agar, while liquid carriers include water, syrup.
`peanut oil and olive oil. Other suitable carriers are well-
`known to those skilled in the art of pharmaceutical
`formulations. The combination of the derivative and the
`carrier may be fashioned into numerous acceptable
`forms, such as tablets, capsules, suppositories, solutions,
`emulsions. and powders.
`The anti-hypertensive properties of the imidazole
`derivatives of the present invention have been deter-
`mined by the following procedure. Sprague-Dawley
`rats of normal weight were first anesthetized with ure-
`thane. After this, the femoral artery was connected by
`way ofa. polyethylene tube with a blood pressure trans-
`ducer. The test substance was then injected into the
`femoral vein or given intraperitoneally and the blood
`pressure and the pulse frequency were registered with a
`recorder.
`
`l0
`
`15
`
`20
`
`25
`
`30
`
`35
`
`4O
`
`45
`
`55
`
`65
`
`16
`In a further test for anti-hypertensive properties un-
`anesthetized Wistar
`spontaneous hypertensive rats
`(SHR) were used. The test derivative was administered
`pcrorally by way of a tube into the stomach. The blood
`pressure was measured from the tail using an indirect
`bloodless method.
`The diuretic activity was studied in rats by collecting
`the urine output during 0—5 hours after i.p. injection of
`the compounds. Before the test the animals were fasting
`overnight and got l0 ml water p.o. immediately before
`the injection.
`The antithrombotic activity was investigated in vitro.
`The inhibiting activity ofthc compounds against ADP-
`and collagen-induced aggregatiOH of thrombocytes was
`measured. In the test thrombocytes from a cow was
`used. To 1.2 ml of plasma containing 250000 throm-
`bocytes/mm3 were added 50 ul of a solution of the
`compound to be tested. After 10 min incubation either
`ADP or collagen was added. The aggregation of the
`thrombocytes was
`turbidimetrically determined at
`X=605 n m.
`The antimicrobial activity was determined in vitro
`according to a qualitative test for antibacterial and anti-
`fungal activity, using the agar diffusion method, against
`the following standard organisms: Staphylococcus au-
`reus. Streptococcus pyogenes, Escherichia coli. Proteus
`mirabilis, Pseudomonas aeruginasus Candida albicans
`and Aspergi‘llus m‘ger.
`The antifungal activity was determined in vitro
`against the following fungi: Trt'chopltyron mbrum. Trich-
`opkyton mentagropliylis, Microsporum canis, Epidermoph-
`yton floccosum. Chrysosporum, Candida albicans. Can-
`dida gut'lliermondt’ and Saccaramyces cerevisiae. The
`fungi were cultured by plating on an agar nutrient me-
`dium. The compound to be tested was added before the
`incubation. A measure of the efficiency of the com-
`pound tested is the radius of the circle, within which the
`growth of the fungi has been inhibited.
`Acute toxicity was determined by using female mice
`of NMRl-Strain with an age of about 7 months and
`weighing 30—40 g. The administration of the test com-
`pound was i.v.
`Thus
`the compound 4-[2-(2.6-dimethylphenyl)—l-
`rnethylethenyl]imidazole, which has a LDso value of40
`mg/kg i.v.
`in mice, was found in the blood pressure
`study with anesthetized rats of normal weight described
`above to cause a registrable lowaring of the blood pres-
`sure at a dose of 3 rig/kg i.e. At a dose of IO rig/kg i.v.
`the blood pressure lowering was quite clear and at a.
`dose of [00—300 pig/kg i.v. the reduction of the blood
`pressure was on an average 38%. The duration of the
`effect was at least 30 minutes (after which time the
`determination was interrupted). A blood pressure low-
`ering of more than 40% was obtained when 2 mg/kg of
`the compound was administered perorally. The dura-
`tion of the effect was at least 5 h.
`The compound 4—{2-(2.6~dimethylphenyl)—l-methyle-
`thyl]imidazole (LD50=40 mg/kg i.v. in mice) caused a
`blood pressure lowering of 20 percent measured 30
`minutes after the administration at a dose of mo tag/kg
`i.v. When 10 mg/kg of the compound was given per-
`orally, a blood pressure drop of 25% was obtained.
`Duration was at least 5 h.
`The
`compound 4-[(a-methyl)-2,6—dimethylbenzyl-
`]imidazole (LD50=ISO mg/kg i.v.
`in mice) caused a
`blood pressure lowering of 30% at a dose of 1—10
`mg/kg i.v. (30 min. after administration).
`
`Petition for Inter Partes Review of US 8,242,158
`Amneal Pharmaceuticals LLc — Exhibit 1004 - Page 9
`
`

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