United States Patent
`
`[19]
`
`Karjalainen et al.
`
`[11] Patent Number:
`
`[45] Date of Patent:
`
`4,544,664
`* Oct. 1, 1985
`
`[54] ANTIHYPERTENSIVE S D
`IMIDAZOLE DERIVATIVES
`
`Attorney, Agent, orFirm—Armstrong, Nikaido,
`Marmelstein K: 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.2 396,000
`[22] Filed:
`Jul. 7, 1982
`
`Foreign Application Priority Data
`[30]
`Jul. 10. 1981 [GB] United Kingdom ................. 8121333
`
`[51]
`
`Int. Cl.‘ .................. A6lK 31/415; C07D 233/56;
`C07D 233/64
`[52] U.S. 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, 4(X), 396
`
`[56]
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`7/1960 Zaugg et al. ........................ S48/342
`2,946,804
`
`4.333.947 6/ 1982 Karjalainen et al.
`..
`.. 542/548
`4,443,466 4/ 1984 Karjalaincn el al.
`424/Z74
`FOREIGN PATENT DOCUMENTS
`
`0024829
`0034474
`0034473
`
`3/ 1981 European Pat. Off.
`8/1981 European Pat. Ol'l'.
`8/1981 European Pat. Off.
`OTHER PUBLICATIONS
`
`..
`..
`
`
`I S48/335
`
`Kelley. 1., et al.. J. Pharm. Sci, 70(3), 341-343, (1981).
`
`[57]
`
`ABSTRACT
`
`The invention provides novel compounds of the for-
`mula:
`
`R3
`
`R4
`
`C
`
`/
`
`\
`
`R2
`
`N
`
`N
`
`.
`N
`IH
`
`Rr—<
`
`01'
`
`“'4' I
`‘F
`H
`
`R’
`
`(1)
`
`(ll)
`
`R5
`R5
`R7
`
`R5
`
`av
`
`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 8,338,470
`Amneal Pharmaceuticals LLC — Exhibit 1004 — Page 1
`
`

`
`1
`
`4,544,664
`
`2
`
`ANTIHYPERTENSIVE SUBSTITUTED
`IMIDAZOLE DERIVATIVES
`
`CH,
`/
`—ct-t(-ct-t—ct-i,)—.
`
`5
`
`DESCRIPTION
`The present invention relates to substituted imidazolc
`derivatives and their non-toxic, pharmaceutically ac-
`ceptable acid addition salts, and their preparation, to
`pharmaceutical compositions containing the same, and to
`to their use.
`The imidazolc derivatives of the present invention
`have the general formula:
`
`or
`—CH(—CH2CH2CH2CHg)—
`> C=CH—CH3. >C=CH——CH2CH3_
`
`>ciH2,
`
`CH3
`\C_CficH3
`
`'
`
`_
`>%C}I—CH2CH2CH3; R9 is H, —CH3, —CHzCH3,
`15 ——CH2CH2CH3,
`
`R3
`
`RI_< I R‘
`
`R:
`
`N
`I
`H
`
`R5
`
`R7
`
`—CH—CH3.
`2° —CH2CH2CH2CH3 or on; no is H, —CH3.
`—CH2CH3. —CHzCHzCH3,
`
`or
`
`R5
`
`(ll) 25
`
`CH,
`
`/
`-CH-CH3
`
`N X‘(C”llIv “°
`R,_( I
`K7
`1'1
`R2
`"
`
`or -——CHzCH2CH2CH3; Rn is H, —CH3, —CH2CH3.
`—-CHzCHzCH3,
`/0”
`-CH—CH3
`
`30
`
`wherein R; is H, an alkyl of I to 4 carbon atoms. e.g.
`methyl or —-CH2OH; R1 is H or CH3; R3 is —--CH3,
`-CH2CH_1, —CH2CH2CH3.
`
`_
`V
`.
`_
`.
`,5 °'whE,?§f:’gEf%{§; ',‘{'f,f’g‘;,‘};;,°{;§‘;°;‘ ‘hm
`
`Rs
`
`/CH3
`-CH-CH3.
`
`—CHzCHzCl-IzCH3, —CHzCH=CI-I2, or
`
`Rs
`
`4°
`
`"5R
`7
`then R5, Rsand R7 are not all simultaneously hydro-
`gen;
`
`when R1, R2 and R4all are hydrogen and R3 is
`45
`‘
`and R4 is H or OH; or R3 and R4 together represent 50 —
`
`R5
`R6
`
`R7
`
`Rs
`
`R7
`
`1]-I2, =CH—CH3, =CH—CH2—CH3,
`
`CH3
`
`/
`=C'C"3'
`
`or =CH—CH2CH2CH3: X is
`
`55
`
`than 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
`compounds of the general formula I and II are 4(S)-sub-
`stituted imidazole derivatives.
`
`‘
`
`The non-toxic pharmaceutically acceptable acid addi-
`R” Rm
`R9
`R‘
`60 tion salts of these compounds are also within the scope
`I
`I
`I
`l
`of the invention.
`-'CH"CH" °’ -C=c-‘
`The compounds of the formula (I) and (II) form acid
`_
`,
`addition salts with both organic and inorganic acids.
`R5’ R°- ‘“'d R71 “’h'°h °‘“‘ be ‘he 53"” °" d‘ff°"°"t 3"’
`They can thus form many pharmaceutically usable acid
`H- “CH3: —CH2CH5v h31°8°“- OH °" ‘OCH! °‘ R5
`55 hYd"°89“ 3"d R6 and R7 ‘°89‘he" 70"" 3“ —O—CH‘ 6S addition salts, as, for instance, chlorides, bromides. sul-
`2—O—bridge DSIWCEH 1W0 adjacent Carbon atoms in
`fates, nitrates, phosphates, sulfonates,
`formates,
`tar-
`the phenyl group; —CI-lRs—— is —CH2—, —CH(CH-
`(rates, maleates. citrates, benzoates, salicylates, ascor-
`3)—. —CH(-CH2CH3)—. -—-CH(-CH2CH2CH3)—.
`bales and the like.
`
`Petition for Inter Partes Review of US 8,338,470
`Amneal Pharmaceuticals LLc — Exhibit 1004 — Page 2
`
`

`
`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-
`
`4,544,664
`
`4
`
`4—[2—(2,6‘-dimethylphenyl)—l-methylethenyl]-2-
`methylimidazole
`4~[2-(2,6-dimethylphenyl)- l«methylethenyl]-5-
`metliylimidazole
`
`‘
`
`20
`
`40
`
`so
`
`T" '|""’
`—C=c—,
`
`0
`g_R,
`
`[S.-(?,6-dimethylphenyl)-1-methyl-l-pentenyl-
`_
`]‘""d"‘?'°
`_
`4'i3'(2v5'dlm‘3'hY]PhE"Y')' I 'elhY" "PV°P°”)"]|m'da2°l9
`10 4-(5-(2.6-dimethylphenylyl-methyl-l-pentenyl]-S-
`methylimidazole
`4—[S-(2,6-dimethylphenyl)-I-methylpentyl]imidazole
`4—[4-(2,6-dichlorophenyl)-l-methy1-l-butenyl]imidazole
`4- 2- 2,6-dimeth I henyl)-l-eth lethyl imidazole
`15 4-E2-é2,6-dimethyllghenyl)-2-eth:I,lethyliimidaz0le
`442 (3 4-meth lenediox
`hen I)
`to
`l]i
`‘dazol
`'3
`‘
`-
`V
`V1’
`Y P
`P3’
`'"'
`4—[2.-Q-bromo-4,5-methylenedioxyphenyl)propyl-
`l"'"d3Z°'e
`_
`V
`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 (1) and (Il)
`essentially satisfy the OUJCCIIVCS of the present inven-
`30 tion. certain groups of compounds remain preferred.
`One such preferred group is represented by formula (I)
`wherein R4 is hydrogen. R3 is alkyl and R5. R5 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-
`:°:ndS' those In \l;vhllc:R' lsllhyqrogenhof m‘:h'yl' R} ls
`y rogen or met y.
`ii or
`ii IS met 3' . et y or Iso-
`P'°PY'~ R9 3"” R10 3“ “>’d'°8'~‘" and " '5 ° ‘Pay be
`mentioned. Especially the compounds wherein n is
`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
`
`specific Compounds of fonnula (D:
`4-[a..a-bis(2-methylplienyl)hydroxymethyflimidazole
`4-[[a-(2-methylphcny1)]-2-mcthy|benzyl]imidazo1c
`4-(at-phcnylbcnzyl)-5-methylimidazole
`4-[[a—(2,6—dimethylphenyl)]—a-methyl]hydroxymethyl-
`]imidazole
`4—[][_a-_(§.3-c:imeIhy|phenyI)l-a-methyl]hydroxymethyl-
`"m 31°C
`4'[a’°"b'§(2'.mcthylPh°nyDhydr°xym°thyl]"5‘
`“‘°‘hV"""d“‘°'°
`4-[[a-(2-methylphenyl)]-2-methylbenzyl]-5-
`methynmidazole
`4-[(a-methyl)-2.6-dimethylbenzyl]imidazole
`4-[(a-methyl)-2.3-dimethylbenzyl]ii-nidazolc
`4-[(a-ethyl)—3-methylbenzyl]imidazole
`4-[(a—butyl)-2,3-dirnethylbenzyl]imidazole
`4-[(0-methyl)-2,3-dimethylbellZ3/ll-Z-methylimidazole
`4-[(G'Pl'0DyU‘2°m¢l1'lY1bBI“IZ)'1]i_mif1aZ01€
`tggflgzgYg:§';‘j§?:‘);'3‘°'}?;2;"‘;§;'§L°z°le
`4_[a_ethyll_(3:methylph3;nyl)_:ydroxymethyh
`limiduole
`4.[a_bmy1_a_(2.3_dimemy1phenyD_hydwxymemyb
`limidazole
`4,.[a-mcthyi-a_-(2,3.d1me,hyiphenyiyhyd,°,(yme;hy]].2-
`meghylimidazole
`4-[a-propyl-a-(2-methylphenyl)-hydroxymethyl—
`]imidazole
`4-(G-melhY1-2'Ch10l'0b¢nlyllimidfllok
`4'[]‘:;'r:’£:g:;“‘(2'm“hY[Phc"Y1)‘hyd"°"Y“"°‘hYl'
`4-[a-methyl-a-(2,S-dimethylphenyl)-hydroxymethy|—
`limidazole
`4-[a..a—bis-(2.3-dimethylphcnyl)hydroxymethyl-
`]im;du°|c
`4-[at-(2,3-dimethylphenyl)-2.3-dimetliylbenzyl—
`]imidazole
`4-[(a-ethyl)-2.6-dimeihylbenzyllirnidazole
`4-[(0-ethyl)-2,3-dirneihylbenzyl]imidazole
`l-(4-imidazolyl)-1~(2,3-dimcthylphenyl)ethylene
`l-(4-imidazolyl)-I-(2.6-dimethylphenyl)ethylene
`l-(4-imidazolyl)-l-(2.3-dimethylphenyl)propene
`l—(4-imidazolyl)-l-(2.3-dimeihylplienyl)pemene
`The following specific compounds of formula (II):
`4'[2‘(2y5-dlmelhflPh¢“Yl)‘1‘me‘h)’lelhY1]imid37-01¢
`According to the feature of the invention, the com-
`‘[2'(2-5'df""elhYlPh°"Yl)P"°PYl]Emidazolc
`pounds of formula (I) wherein R4 is OH and the com-
`dazolc 55 pounds of formula (II) are made by a Grignard reaction,
`4_[2_(2’6_dimethy1phenyl)_2_hydr°xyethy]]imidaz°!e
`in which an imidazolylketone of the formula
`4-(2-phenylpropyl)imidazole
`4»-[2-(2,6-dimethylphenyl)- l -methylethenyllimidazole
`4-[2-(2,6-dimethylphcnyl)-l-propcnyflimidazolc
`4-(2-methyl-4-—phcnyl- l-butenyl)imidazole
`4-[2-(4-chlorophenyl)-l-methylpropyllimidazole
`
`4-[5-(2.6-dimethylphenyl)- l -methyI- l -pentenyl-
`Iimidazole
`4-{J-(2,6-dimethylphenyl)-2-methyhl-propcnyl-
`]imidazole
`4-[2-(2,6-dimethylpheny|)- l -ethylethenyllimidazole
`4-[2-(2.3-dimethylphenyl} 1 -methylethenyl]imidazole
`4-[2-(2.6-dimethylplienyl} l -isopropylethenyflimidazole
`
`co
`
`65
`
`N
`R1“< I
`
`R;
`
`N
`|
`H
`wherein Ri, R2 and R; are as defined before. is reacted
`with an arylalkyl magnesium halide derivative or aryl
`magnesium lialidc derivativc of the formula;
`
`Petition for Inter Partes Review of US 8,338,470
`Amneal Pharmaceuticals LLc — Exhibit 1004 — Page 3
`
`

`
`5
`
`4,544,664
`
`R:
`
`K(,
`
`R7
`
`(CH;),,. -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 (III)
`
`R’
`
`(H!)
`
`on
`
`R2
`
`(::‘(CH2)n- 6
`N
`..._( IR;
`R,
`N
`IH
`
`wherein R1, R2, R3, R5. R5. R7 and n’ are as before.
`The arylalkylmagncsium 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)
`
`R5
`R6
`
`-
`
`(W)
`
`S0
`
`55
`
`R;—<: I
`
`H
`
`0
`II
`C-(CH2)...
`
`N
`
`R:
`
`H I
`
`NI
`
`H
`
`5
`
`I0
`
`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
`
`(CHz)n. —Mgl-Ial
`
`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.
`palladium-on-carbon.
`Unsaturated compounds of formula (I) wherein R;
`and R4 are =CI-I2, =CH—CI-I3, =CH—CH2CI-I3,
`
`CH3
`-‘C’-‘CH3
`
`or =CH—CH2CH2CH3 or formula (II) wherein R10 is
`hydrogen are prepared by dehydrating compounds of
`fonnula (III):
`
`R:
`
`(Ill)
`
`C—(CHz).. eR1
`
`_
`
`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 fonnula (V)
`
`wherein Ri—R7 and n’ are as before. is reacted with a
`compound of the formula
`
`R3MgHal
`
`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 imidazole carboxylic acid alkyl ester, prefera-
`bly the methyl ester of the formula
`
`. «-4: I
`
`H
`
`R5
`
`(V)
`
`Rn
`C=CH—(CH1),.
`
`R2
`
`Petition for Inter Partes Review of us 8,338,470
`Amneal Pharmaceuticals LLC — Exhibit 1004 — Page 4
`
`

`
`4,544,664
`
`8
`Thus, according to this embodiment of the invention, a
`starting material of the fonnula (VI) or (VII)
`
`RS
`R.
`R7
`O!
`
`R5
`R5
`R7
`
`FIH2 9'11:
`1'13
`ct»t—<l:-~p-R3
`Ru R15
`
`llltz flit:
`lCHs),,'°X""(l:—(|I-‘R1
`R14 Ru
`
`W”
`
`iv”)
`
`wherein R2, R3, R5, R5, R7 and n are as hereinbefore
`defined: wherein R11. R13. R14 and R;5, which can be
`the same or different, are each hydrogen, hydroxy,
`mercapto, halogen, amino, —O— alkyl ofl to 7 carbon
`atoms or
`
`0l
`
`l
`—o-c- R.
`
`wherein R is an alkyl; or wherein R]: and R14 can be
`combined to form a keto group, or R1; and Rug can be
`combined to form a keto group. or both Ru and Ru 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;
`
`r
`
`.
`7‘
`
`N
`IH
`
`R5 or
`
`R7
`
`N
`
`X-(CH;).,
`
`I
`
`.4 I
`T
`H
`
`R3
`
`R5
`
`,0
`
`R1
`
`7
`-continued
`
`N
`
`c-(cum.
`
`.._< I
`i‘
`H
`
`“’
`
`R.
`
`@z“
`R,
`
`wherein R1. R3, 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-
`hydrogcn 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:
`
`V
`
`N
`IH
`
`wherein R; and R2 are as before, with an aralkylidene-
`triphenylphosphorane of the formula:
`
`l|?-tn
`(C6"5)JP=C‘lCHZ)n
`
`R5
`R1:
`
`R7
`
`wherein R5. R(,, 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
`sattirated compounds of formula (II) as described
`above.
`The aralkylidenetriphenylphosphoranes are prefera-
`bly prepared by reacting the corresponding aralkyltri-
`phenylphosphonium halide of the formula:
`
`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+Cl-120 (or a source of ammonia and form-
`aldehyde);
`
`if
`ii
`HN=c~—NH;, H—C—0'—NH.;“; HCO-NH;; R.—C—Nll;;
`1
`
`|R
`
`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
`
`co
`
`65
`
`Rs
`Rs
`
`R1
`
`R10I
`e
`(CHz).—Cl-l- P—(C6Hs)i 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—synthescs described
`above, the free nitrogen atom in the imidazole starting
`material can be protected by different methods. Suitable
`protecting groups are for example bcnzyl. triphenylsilyl
`or diallcoxymethane. 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 compouncb of the invention.
`
`Petition for Inter Partes Review of US 8,338,470
`Amneal Pharmaceuticals LLC — Exhibit 1004 — Page 5
`
`

`
`10
`
`Y
`
`RlC
`
`IN
`
`N
`
`=O
`
`I
`
`<"IY« \
`=0W-O—'Z
`
`4,544,664
`
`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-acylatcd imidazolc 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 (It) comprises hydrogenating
`a starting material of the formula-
`
`Ru
`
`“
`l\I5’< I .R|—< I orR1—< I
`N
`R:
`iii
`R:
`N
`$111R"
`
`y
`
`N
`
`y
`
`N
`
`I H
`
`y
`
`R1
`
`I 9
`
`N
`
`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 cate-
`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|19
`Iii:
`—CH—CH-
`
`comprises reacting a N-trialkylsilylimidazole of the
`fonnula
`
`<NI
`
`Y-?i-YY
`
`wherein Y is an alkyl group, preferably methyl. with an
`arylalkylhalogenide of the formulae
`
`Petition for Inter Panes Review of us 8,338,470
`Amneal Pharmaceuticals LLC — Exhibit 1004 — Page 6
`
`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:
`
`R5
`Re
`
`R7
`
`II“
`R;
`CH—QOr Ro ~X'-(CHz)n—Q
`
`R7
`
`wherein R5. R5. R7, R3, n and X are as defined herein-
`above, and Q is a radical of formula:
`
`0
`O
`0
`II
`II
`II
`-C-(|2H—NH—C—R, C--<|:HNHCl-lg
`R,
`It;
`
`0
`I \
`or —CH--<'2—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 (c.g. HCI)
`when Q in the starting material is
`
`40
`
`35
`
`45
`
`50
`
`55
`
`60
`
`65
`
`0
`0
`ll
`ll
`-C-Cl-l—NH—C—R
`
`IR
`
`:
`
`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 fonnula (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 (I) and (II)
`
`

`
`11
`
`R5
`II‘)
`CH--Hal or R5
`
`R7
`
`R’
`R5
`
`R7
`
`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)
`
`I'M
`1'19
`CH—CH-Hal
`
`R; O
`R9
`ll
`(CH1)Ir"CH—'CH—C—CI'{3
`
`(xm
`
`The compound of formula (XII) is further bromi-
`nated as before to give compounds of the formula (VII).
`When R3 and R3 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)
`
`(CH:)n~CH— Hal
`
`(XIII)
`
`is reacted with lithiated N,N-dimethylhydrazone of
`acetone followed by hydrolysis to give a compound of
`the general formula (XIV)
`
`R5
`
`R6
`
`R7
`
`R
`R9
`(CH:)n"CH—CH;C—CFl3
`
`(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-carboxyethyltriphenyh
`phosphonium perbromide, which has the formula (XV)
`
`O
`ll
`tC¢,H;);—P9—Cl~IgCl-lgc--OH Due
`
`(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)
`
`R5
`
`R4»
`
`R7
`
`R
`(CH1)..—C-R in
`
`(XVI)
`
`wherein R3, R5, R5. R7, 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 meth-
`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 (V1) and (VII) can be
`prepared for example as follows:
`Arr aldehyde of the formula
`
`)1,
`
`R (CI‘I3),.—CHO
`
`R7
`
`wherein R5. R45, 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
`
`'1“ ii
`(CHzln“QH=C—C-‘CH3
`
`(VIII)
`
`wherein Rx is an alkyl as defined before. which com-
`pound in a second step is catalytically reduced to give
`the corresponding saturated compound of the formula:
`
`Rs
`
`in’
`‘F’
`(CH2).—CH2—CH—C—CH3
`
`( IX)
`
`l0
`
`,5
`
`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-
`live alkylation process of ketones in whih for example a
`halide compound of the formula (X)
`
`55
`
`R9
`I
`
`(cH2).~cr-t—r-iaI@R7
`
`(X)
`
`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 trimethylsilylenoletlrer derivative of
`the general formula (XI)
`
`OTMS
`
`5
`
`(XI) 6
`
`Rs
`
`Re
`
`R7
`
`Rw R” 0
`(CH2l».—C=C'-C—C HJRJ
`
`(xvm
`
`Petition for Inter Partes Review of US 8,338,470
`Amneal Pharmaceuticals LLc — Exhibit 1004 — Page 7
`
`

`
`R1.
`C”
`/
`R7
`fi—N—cH;
`In the first step this condensation gives unsaturated
`uCH2_c_cH’R"
`Here in the first step compounds of the formula '5 kcmncs of the formulae (XXV) and (XXVI)
`(XIX) are achieved,
`R
`O Rm R;
`N
`II
`I
`0
`Rm
`Rs
`R.
`c—c=c-rijl
`Rt (cHg).-c=cH-c—cH,Rg
`R,
`
`RI
`
`‘
`
`T
`
`H
`
`(XXV)
`
`(XXVI)
`
`R‘
`
`\
`
`N
`
`id
`H
`
`R
`0 R“;
`cH=CH_y:_(':=CH l
`
`R’
`R6
`
`R7
`
`which compounds are then hydrogenated to the end
`products according to the formulae (XXVII) and
`(XXVHI)
`
`R5
`R4.
`R1
`
`Rs
`R.
`R7
`
`R2
`lliio
`CHz—CH—CHz
`
`I
`
`XXV"
`
`(
`
`)
`
`N
`
`'
`IfH
`
`»_Rl
`
`“1
`'l‘|0
`CHgCHgCHzCH—CH;
`
`I
`
`(xxvin)
`
`>—Ri.
`
`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
`
`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 of the formula 5
`(XVI), wherein these are reacted with Hithiated N,N-
`dimethylhydrazone oi‘ methylalkylketone of the for-
`mula (XVIII)
`
`R5
`
`R5
`R7
`
`R
`
`14
`
`0
`[1
`C-C”’R'°
`
`0
`II
`
`(XXIII)
`
`(XXIV)
`
`J
`
`(xvm) W
`
`CH=CH-C-CH2Rio
`
`I
`
`I
`
`(xix)
`
`20
`
`R7
`
`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-
`bon-carbon bouble bond as well. The bromination in the 30
`second step leads to compounds of the formula (VII).
`Alkylation of compounds of the general
`formula
`(XVII) when R; and R10 are hydrogen can be acoom-
`plished, too. In this method a compound of the formula 35
`
`R5
`R.
`R7
`
`R8 0
`I
`ll
`(CH-,i).--CH=C-C-CH;
`
`(xx)
`
`4°
`
`.
`.
`.
`.
`.
`.
`is reacted with an alkylation reagent such 3 clialkyllithi- 45
`ocuprate (XXI) which undergoes 1,4-conjugate addi-
`tion
`
`(R)1CuLi
`
`(XXI)
`
`50
`
`to fomi compounds of the formula (XII).
`Condensation of an arylalkylkeione or its vinylogue
`with 4-imidazole aldehydes of the formula (XXII)
`
`N
`‘CHO
`R'_< I
`‘7
`
`H
`
`(xxu) 55
`
`60
`
`O/R
`<l:i-i< ’‘5
`I:
`
`R:
`
`N
`“'4 I
`N
`1!!
`
`provides further another method for the preparation of
`.
`.
`d
`co d'
`th's'
`e to .Thc eo dcnsation
`wherein R1, R2, R3, R5 and R7 are as before and R is an
`compo“ 5 ac
`I mg
`I my n I n
`n
`is Pcrfonncd for example in aqueous alcohol camlyud 55 alkyl of I to 4 carbon atoms with a Grignard reagent of
`by sodium hydroxide. Arylalkylketones or their viny-
`the formula
`logues have the general formulae (XXIII) and (XXIV)
`
`R;i—CH1MgHal
`
`Petition for Inter Partes Review of us 8,338,470
`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
`
`N
`R1—< I
`71
`H
`
`R:
`
`CIH
`
`R2
`
`R’
`R5R7
`
`As stated herein above, the compounds of the general
`formula (I) and (I1) and their non-toxic, pharmaceuti-
`cally acceptable acid addition salts have valuable phar-
`macological properties and have been found to possess
`excellent antihypertcnsive properties.
`Tests have shown that they also possess other phar-
`macological properties as well, for example, antithrom-
`botic activity. Furthermore, antimycotic and antlfungal
`properties have been found, too.
`The processes described above for the preparation of
`compounds of formula (II) wherein X is
`
`FIN: ‘flu
`_}C._
`
`result mainly in the trans isomer of the compound. The
`trans isomer can be converted to the cis isomer accord-
`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 (1)
`and (II), their non-toxic, phannaceutically 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 phamiaceutical 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 of a. 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
`
`40
`
`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
`perorally 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 ip. 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 ofthe compounds against ADP-
`and collagen-induced aggregation of thrombocytes was
`measured. In the test thrombocytes from a cow was
`used. To l.2 ml of plasma containing 250000 throm-
`bocytes/mm3 were added 50 l.l.l 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
`)\=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, Pseudamonas aeruginasus Candida albicans
`and Aspergillus mger:
`The antifungal activity was determined in vitro
`against the following fungi: Trfchopltyton rubrum. Trich-
`opliytort mt-ntagropliylis, Microsporum canis, Epi'dermoph-
`yton floccosum. Chrysosporum, Candida albitans. Can-
`dida guilliermondi 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 NMRI-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-
`tnethyleihenyl]imidazole, which has a LD5o 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 lowering of the blood pres-
`sure at a dose of 3 pg/kg i.e. At a dose of IO p.g/kg i.v.
`the blood pressure lowering was quite clear and at a.
`dose of lO0—300 pg/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-climethylphenyl)-l-methyle-
`thyl]imidazole (LD5o=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 pg/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 (LD5o=lS0 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 8,338,470
`Amneal Pharmaceuticals LLC — Exhibit 1004 — Page 9
`
`

`
`4,544,664
`
`18
`stated. The compounds which are indicated as bases are
`tested in deuterium methanol, deu terium acetone or
`deuterium chloroform, while the values for compounds
`which are indicated as hydrochlorides were determined
`in deuterium oxide. The presented I3C-NMR-spectrum
`were determined with a Bruker WP80DS apparatus.
`T he mass-spectra were determined with a Perkin(cid:173)
`Elmer RMU-6E apparatus using direct inlet system.
`The temperature employed was the fowest temperature
`10 needed for the evaporation of the compound as base. In
`the examples the strongest and the most essential frag(cid:173)
`ment-ions from a structural viewpoint are given as m/e
`values. In parenthesis is given the intensity of the frag-
`ment-ion in relation to the main peak.
`
`.
`17
`The compound 4-((a-methyl)-2,3-dimethylbenzyl(cid:173)
`]imidazole (LDso=40 mg/kg i.v. in mice) caused a
`blood pressure drop of 55% at IO µ.g/kg i.v. (after 30
`min.). Given perorally (I mg/kg) the compound gave a
`blood pressure drop of 20%. The duration was at least 5
`5 h.
`The compound 4-[2-(2,6-dimethylphenyl)propyl(cid:173)
`]i'!'idazole, which has a LDsovalue of200 mg/kg i.v. in
`mice gave a blood pressure drop of 30% at a dose of 3
`mg/kg i.v., measured 30 min. after administration.
`The compound 4-(2-(2,6-dimethylphenyl)-2-ethyle(cid:173)
`thyl]imidazole gave a blood pressure drop of about 25%
`at a dose of 3 mg/kg i.v., measured 30 min. after admin(cid:173)
`istration.
`The compound 4-[2-(2,6-dimethylphenyl)-1-ethyle- 15
`thenyl]-imidazole which has a LDso value of 110 mg/kg
`i. v. in mice, gave a blood pressure drop of 35% at a dose
`of 3 mg/kg intraperitoneally measured 30 min. after
`administration.
`4.9 ~ (0,2 mo!) of dry magnesium turnings are cov-
`4-(a-methyl-2-methyl