United States Patent
`
`[19]
`
`[11] Patent Number:
`
`5,399,578
`
`Biihlmayer et a1.
`Mar. 21, 1995
`[45] Date of Patent:
`
`USOOS399578A
`
`[54] ACYL COMPOUNDS
`
`[75]
`
`Inventors: Peter Biihlmayer, Arlesheim; Franz
`Ostermayer, Riehen; Tibur
`Schmidlin, Basel, all of Switzerland
`
`[73] Assignee: Ciba-Geigy Corp, Ardsley, NY.
`
`[21] App1.No.: 998,755
`
`[22] Filed:
`
`Dec. 29, 1992
`
`Related U.S. Application Data
`
`[63]
`
`Continuation of Ser. No. 654,479, Feb. 13, 1991, aban-
`doned.
`
`Foreign Application Priority Data
`[30]
`
`...... 518/90
`.
`Feb. 19, 1990 [CH]
`Switzerland ..........
`Jul. 5, 1990 [CH]
`Switzerland ......................... 2234/90
`
`Int. Cl.6 .................... C07D 257/04; A61K 31/41
`[51]
`[52] U.S. Cl. ..................................... 514/381; 548/253
`[58] Field of Search ......................... 514/381; 548/253
`
`[56]
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`.............. 424/269
`6/1982 Kurchacova et al.
`4,333,943
`5/1988 James ......................
`544/316
`4,748,245
`
`4,755,518 7/1988 Rafferty et a1. .........
`514/269
`5,260,325 11/1993 Markwalder et a1.
`.............. 514/381
`
`FOREIGN PATENT DOCUMENTS
`2014008 10/1990 Canada .
`0148752
`7/1985 European Pat. Off.
`0324377
`8/1985 European Pat. Off.
`9114679 10/1991 WIPO .
`
`.
`.
`
`Primary Examiner—David B. Springer
`Attorney, Agent, or Firm—Irving M. Fishman; Karen G.
`Kaiser
`
`[57]
`
`ABSTRACI
`
`Compounds of the formula
`
`R1_X1—1;1“X3
`Xz—Rz
`
`in which R] is an aliphatic hydrocarbon radical which is
`unsubstituted or substituted by halogen or hydroxyl, or
`a cycloaliphatic or araliphatic hydrocarbon radical; X1
`is CO, 802, or —-O—C(=O)—— with the carbon atom of
`the carbonyl group being attached to the nitrogen atom
`shown in formula I; X2 is a divalent aliphatic hydrocar-
`bon radical which is unsubstituted or substituted by
`hydroxyl, carboxyl, amino, guanidino or a cycloali-
`phatic or aromatic radical, or is a divalent cycloali—
`phatic hydrocarbon radical, it being possible for a car-
`bon atom of the aliphatic hydrocarbon radical to be
`additionally bridged by a divalent aliphatic hydrocar-
`bon radical; R2 is carboxyl which, if desired, is esterified
`or amidated, substituted or unsubstituted amino, formyl
`which, if desired, is acetalized,
`lH-tetrazol-S-yl, pyri-
`dyl, hydroxyl which, if desired, is etherified, S(O)m—R
`where m is 0, l or 2 and R is hydrogen or an aliphatic
`hydrocarbon radical, alkanoyl, unsubstituted or N—sub-
`stituted sulfamoyl or POnHz where n is 2 or 3; X3 is a
`divalent aliphatic hydrocarbon; R3 is carboxyl, S-tet-
`razolyl, SOgH, P02H2, PO3H2 or haloalkylsulfamoyl;
`and the rings A and B independently of one another are
`substituted or unsubstituted; in free form or in salt form,
`can be prepared in a manner known per se and can be
`used, for example, as medicament active ingredients.
`
`7 Claims, No Drawings
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`

`

`1
`
`ACYL COMPOUNDS
`
`5,399,578
`
`This application is a continuation of application Ser.
`No. 654,479, filed Feb. 13, 1991, now abandoned.
`The invention relates to compounds of the formula
`
`5
`
`(I)
`
`@@
`
`RI—Xl—lf-ng
`Xz—Rz
`
`in which R1 is an aliphatic hydrocarbon radical which is
`unsubstituted or substituted by halogen or hydroxyl, or
`a cycloaliphatic or araliphatic hydrocarbon radical; X1
`is CO, S02, or —O-—C(.—_O)— with the carbon atom of
`the carbonyl group being attached to the nitrogen atom
`shown in formula I; X2 is a divalent aliphatic hydrocar-
`bon radical which is unsubstituted or substituted by
`hydroxyl, carboxyl, amino, guanidino or a cycloali—
`phatic or aromatic radical, or is a divalent cycloali-
`phatic hydrocarbon radical, it being possible for a car-
`bon atom of the aliphatic hydrocarbon radical to be
`additionally bridged by a divalent aliphatic hydrocar-
`bon radical; R2 is carboxyl which, if desired, is esterified
`or amidated, substituted or unsubstituted amino, formyl
`which, if desired, is acetalised,
`lH-tetrazol-S-yl, pyri-
`dyl, hydroxyl which, if desired, is etherified, S(O)m—R
`where m is O, l or 2 and R is hydrogen or an aliphatic
`hydrocarbon radical, alkanoyl, unsubstituted or N-sub-
`stituted sulfamoyl or POnHz where n is 2 or 3; X3 is a
`divalent aliphatic hydrocarbon; R3 is carboxyl, S-tet-
`razolyl, SO3H, P02H2, PO3H2 or haloalkylsulfamoyl;
`and the rings A and B independently of one another are
`substituted or unsubstituted; in free form or in salt form,
`to a process for the preparation of these compounds, to
`the use of these compounds and to pharmaceutical prep-
`arations containing such a compound I in free form or in
`the form of a pharmaceutically acceptable salt.
`The compounds I can be present as salts, in particular
`pharmaceutically acceptable salts. If the compounds I
`have, for example, at least one basic centre, they can
`form acid addition salts. These are formed, for example,
`with strong inorganic acids, such as mineral acids, for
`example sulfuric acid, a phosphoric acid or a hydrohalic
`acid, with strong organic carboxylic acids, such as
`C1—C4 alkanecarboxylic acids which are unsubstituted
`or substituted, for example, by halogen, for example
`acetic acid, such as saturated or unsaturated dicarbox-
`ylic acids, for example oxalic, malonic, succinic, maleic,
`fumaric, phthalic or terephthalic acid, such as hydrox-
`ycarboxylic acids, for example ascorbic, glycolic, lactic,
`malic, tartaric or citric acid, such as amino acids, for
`example aspartic or glutamic acid, or such as benzoic
`acid, or with organic sulfonic acids, such as C1-C4al-
`kane- or arylsulfonic acids which are unsubstituted or
`substituted, for example by halogen, for example me-
`thane- or p-toluenesulfonic acid. Corresponding acid
`addition salts can also be formed having, if desired, an
`additionally present basic centre. The compounds I
`having at least one acid group (for example COOH or
`5-tetrazolyl) can also form salts with bases. Suitable
`salts with bases are, for example, metal salts, such as
`alkali metal or alkaline earth metal salts, for example
`sodium, potassium or magnesium salts, or salts with
`ammonia or an organic amine, such as morpholine,
`thiomorpholine, piperidine, pyrrolidine, a mono-, di- or
`
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`2
`tert—butyl-,
`tri-lower alkylamine, for example ethyl-,
`diethyl-, diisopropyl-, triethyl-, tributyl- or dimethyl-
`propylamine, or a mono-, di- or trihydroxy lower alkyl-
`amine, for example mono-, di- or triethanolarnine. Cor-
`responding intemal salts may furthermore be formed.
`Salts which are unsuitable for pharmaceutical uses but
`which can be employed, for example, for the isolation
`or purification of free compounds I or their pharmaceu-
`tically acceptable salts, are also included.
`An aliphatic hydrocarbon radical is, for example,
`lower alkyl, lower alkenyl or secondarily lower alky—
`nyl.
`An aliphatic radical substituted by halogen or hy-
`droxyl is, for example, halo-lower alkyl, -lower alkenyl
`or -lower alkynyl, or hydroxy-lower alkyl, -lower alke-
`nyl or -lower alkynyl.
`A cycloaliphatic hydrocarbon radical is in particular
`cycloalkyl and secondarily cycloalkenyl.
`A suitable araliphatic radical is in particular phenyl-
`lower alkyl, also phenyl-lower alkenyl or -lower alky-
`nyl.
`A divalent hydrocarbon radical which bridges a C
`atom of an aliphatic radical X2 is, for example, C2—C-
`(,alkylene, in particular C4-C5alkylene.
`A cycloaliphatic radical is, for example, a cycloalkyl
`or, secondarily, cycloalkenyl which is unsubstituted,
`monosubstituted or, furthermore, polysubstituted, for
`example disubstituted, for example by carboxyl which,
`if desired, is esterified or amidated or formyl which, if
`desired, is acetalised.
`An aromatic radical is, for example, a carbocyclic or
`heterocyclic aromatic radical, in particular phenyl or in
`particular an appropriate 5- or 6-membered and mono-
`cyclic radical which has up to four identical or different
`hetero atoms, such as nitrogen, oxygen or sulfur atoms,
`preferably one, two, three or four nitrogen atoms, an
`oxygen atom or a sulfur atom. Appropriate 5-membered
`heteroaryl radicals are, for example, monoaza», diaza-,
`triaza-,
`tetraaza—, monooxa— or monothia-cyclic aryl
`radicals, such as pyrrolyl, pyrazolyl, imidazolyl, triazo-
`lyl, tetrazolyl, furyl and thienyl, while suitable appro-
`priate 6-membered radicals are in particular pyridyl.
`Appropriate aromatic radicals are radicals which may
`be monosubstituted or polysubstituted, for example di-
`or trisubstituted, for example by identical or different
`radicals, for example selected from the group compris-
`ing: halogen, hydroxyl which, if desired, is etherified,
`S(O)m—R and an aliphatic hydrocarbon radical which
`may be interrupted by —O— and which is unsubsti-
`tuted or substituted by halogen or hydroxyl and which
`may be additionally substituted, for example by car-
`boxyl which, if desired,
`is esterified or amidated or
`formyl which, if desired, is acetalised.
`A divalent aliphatic hydrocarbon radical (X2) is, for
`example, alkylene or alkylidene.
`A divalent cycloaliphatic hydrocarbon radical is, for
`example, cycloalkylene.
`'
`Esterified carboxyl is, for example, carboxyl which is
`esterified by an alcohol which is derived from an ali-
`phatic or araliphatic hydrocarbon radical, such as lower
`alkyl, phenyl-lower alkyl, lower alkenyl and second-
`arily lower alkynyl, and which may be interrupted by
`—O—, such as lower alkoxy-lower alkyl, -lower alke—
`nyl and -lower alkynyl. Examples which may be men-
`tioned are lower alkoxy—, phenyl-lower alkoxy-, lower
`alkenyloxy— and lower alkoxy-lower alkoxy-carbonyl.
`
`,_
`
`g
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`

`5,399,578
`
`3
`in
`is, for example, carbamoyl
`Amidated carboxyl
`which the amino group is unsubstituted or monosubsti-
`tuted or, independently of one another, disubstituted by
`an aliphatic or araliphatic hydrocarbon radical or disub-
`stituted by a divalent aliphatic hydrocarbon radical
`which may be interrupted by O or may be condensed at
`two adjacent carbon atoms with a benzene ring, in par-
`ticular lower alkylene or lower alkyleneoxy-lower a1-
`kylene. Examples of appropriately substituted amino
`groups which may be mentioned are lower alkyl-, lower
`a1kenyl-, lower alkynyl-, phenyl-lower alkyl-, phenyl-
`lower alkenyl-, phenyl-lower alkynyl-, di—lower alkyl-,
`N-lower alkyl-N-phenyl-lower alkyl- and diphenyl-
`lower alkylamino and also quinol-l-yl, isoquinol-Z—yl,
`lower alkylene- and lower alkyleneoxy-lower alkylene-
`amino.
`
`Substituted amino has the meanings indicated in con-
`nection with substituted carbamoyl and is furthermore
`acylamino, such as lower alkanoyl-, phenyl-lower al-
`kanoyl-, benzoyl-, lower alkanesulfonyl- or benzenesul-
`fonylamino.
`Acetalised formyl is, for example, di-lower alkox-
`ymethyl or oxy-lower alkyleneoxymethylene.
`Etherified hydroxyl is, for example, hydroxyl etheri-
`fied by an alipahtic alcohol, in particular lower alkoxy
`or lower alkenyloxy, and is also a phenyl-lower alkoxy
`or phenoxy radical.
`the substituted amino
`In N—substituted sulfamoyl,
`group has the meanings indicated in connection with
`substituted carbamoyl.
`An aliphatic hydrocarbon radical which is inter-
`rupted by --O— is in particular lower alkoxy-lower
`alkyl, -lower alkenyl or-lower alkynyl, or lower al-
`kenyloxy-lower alkyl, -lower alkenyl or -lower alkynyl.
`Above and below, Unsaturated aliphatic, cycloali-
`phatic and araliphatic substituents are primarily not
`linked to an aromatic radical Via the C atom from which
`
`a multiple bond extends.
`(Hetero)aromatic radicals, if not defined differently,
`are in particular in each case unsubstituted or mono- or
`polysubstituted, for example disubstituted or trisubstitu-
`ted, in particular, for example, by a substitutent selected
`from the group comprising halogen, hydroxyl which, if
`desired,
`is etherified, S(O)m—-R and a hydrocarbon
`radical which is unsubstituted or substituted, for exam-
`ple by halogen or hydroxyl, and which may be inter-
`rupted by —O-—.
`The rings A and B are primarily a 4—biphenylyl, also
`a 2- or 3-biphenylyl ring system, where the radical R3 is
`preferably located in the ortho-position of ring B. Cor-
`respondingly, the rings A and B are unsubstituted or
`monosubstituted or polysubstituted, for example disub-
`stituted or trisubstituted, for example by identical or
`different radicals, for example selected from the group
`comprising: halogen, hydroxyl which, if desired, is eth-
`erifred, S(O)m—R and a hydrocarbon radical which is
`unsubstituted or substituted by halogen or hydroxyl and
`which may be interrupted by ——O—.
`The general definitions used above and below, unless
`defined differently, have the following meanings:
`The expression “lower” means that corresponding
`groups and compounds in each case in particular com-
`prise not more than 7, preferably not more than 4, car-
`bon atoms.
`
`Halogen is in particular halogen of atomic number
`not more than 35, such as fluorine, chlorine or bromine,
`and also includes iodine.
`
`4
`Alkanoyl is, for example, lower alkanoyl and is in
`particular C2-C7 alkanoyl, such as acetyl, propionyl,
`butyryl, isobutyryl or pivaloyl. C2-C5alkanoyl is pre-
`ferred.
`
`is in particular halo-C1-C7alk-
`Haloalkylsulfamoyl
`anesulfamoyl and is, for example,
`trifluoromethane-,
`difluoromethane-,
`1,1,2-trifluoromethane- or
`hepta—
`fluoropropanesulfamoyl. Halo-Cl—C4alkanesulfamoyl is
`preferred.
`Lower alkyl is in particular C3-C7alkyl, for example
`methyl, ethyl, n-propyl,
`isopropyl, n-butyl,
`isobutyl,
`sec-butyl, tert-butyl, and also includes corresponding
`pentyl, hexyl and heptyl radicals. C1—C4alkyl
`is pre-
`ferred.
`
`Lower alkenyl is in particular Cg—C7alkenyl and is,
`for example, 2—propenyl or 1-, 2- or 3-butenyl. C3—C-
`5alkenyl is preferred.
`Lower alkynyl is in particular C3-C7alkynyl and is
`preferably propargyl.
`Halo-lower alkyl
`is in particular halo-Cl-C4alkyl,
`such as trifluoromethyl, l,1,2—trifluoro-2-chloroethyl or
`chloromethyl.
`Halo-lower alkenyl is in particular halo-C3—C5alke-
`nyl, such as 3-chloroa11yl.
`Halo-lower alkynyl is in particular halo-C3—C5alky-
`nyl, such as 3-chloropropargyl.
`Hydroxy-lower alkyl is in particular hydroxy-Cl—C-
`4alky1, such as hydroxymethyl, 2-hydroxyethyl or 3-
`hydroxypropyl.
`is in particular hydroxy—
`Hydroxy-lower alkenyl
`C3—C5alkenyl, such as 3-hydroxyallyl.
`Hydroxy-lower alkynyl
`is in particular hydroxy-
`C3—C5alkyny1, such as 3-hydroxypropargyl.
`Cycloalkyl is in particular C3-C7cycloalkyl and is,
`for example, cyclopropyl, cyclobutyl, cyclopentyl, cy-
`clohexyl and cycloheptyl. Cyclopentyl and cyclohexyl
`are preferred.
`Cycloalkenyl is in particular C3—C7cycloalkenyl and
`is preferably cyclopent-Z- and -3-eny1, or cyclohex-Z—
`and -3-en-yl.
`Phenyl-lower alkyl is in particular phenyl-Cl—C4al-
`kyl and is preferably benzyl, l— and 2-phenethyl, while
`phenyl-lower alkenyl and phenyl-lower alkynyl are in
`particular phenyl-C3-C5alkenyl and-alkynyl, in particu-
`lar 3-phenylally1 and 3—phenylpropargyl.
`Pyrrolyl is, for example, 2- or 3-pyrrolyl. Pyrazolyl is
`3— or 4-pyrazolyl. Imidazolyl is 2- or 4-imidazolyl. Tri-
`azolyl
`is, for example, 1,3,5-1H-triazo1-2-yl or 1,3,4-
`triazol-Z-yl. Tetrazolyl is, for example, l,2,3,4—tetrazol-
`5-yl, furyl is 2— or 3—furyl and thienyl is 2- or 3-thienyl,
`while suitable pyridyl is 2—, 3— or 4-pyridyl.
`Alkylene is in particular C1—Cloalkylene or lower
`alkylene, such as Cl—C7alkylene, and is straight-chain or
`branched and is in particular methylene, ethylene, prop-
`ylene and butylene and also 1,2-propylene, 2-methyl-
`1,3-propylene and 2,2-dimethyl-l,3-propylene. C1-C-
`5alkylene is preferred.
`Alkylidene is in particular C2—C10alkylidene, such as
`ethylidene, 1,1- or 2,2—propylidene, also l,l- or 2,2-
`butylidene or 1,1-, 2,2- or 3,3-pentylidene. C2—C5a1kyli-
`dene is preferred.
`Cycloalkylene is in particular C3—C7cycloalkylene
`and is, for example, 1,2-cyclopropy1ene, 1,2- or 1,3-
`cyclobutylene, 1,2- or 1,3-cyclopentylene, 1,2-, 1,3- or
`1,4-cyclohexylene and 1,2-, 1,3- or 1,4-cyclohepty1ene.
`1,3Ccyclopentylene and 1,4-cyclohexylene are pre-
`ferred.
`
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`

`5
`Lower alkoxy is in particular C1—C7alkoxy and is, for
`example, methoxy, ethoxy, n-propyloxy, isopropyloxy,
`n-butyloxy,
`isobutyloxy,
`sec-butyloxy,
`tert-butyloxy
`and also includes corresponding pentyloxy, hexyloxy
`and heptyloxy radicals. Cl—C4alkoxy is preferred.
`Lower alkoxy-lower alkyl is in particular C1—C4alk-
`oxy-Cl—C4alkyl,
`such as 2-methoxyethyl,
`2-ethox—
`yethyl, 2-n-propyloxyethyl or ethoxymethyl. Lower
`alkoxy-lower alkenyl or -lower alkynyl is in particular
`C1—C5alkoxy-C3—C5alkenyl or —C3—C5alkynyl.
`Lower alkoxycarbonyl is in particular,C2—Cgalkox-
`ycarbonyl and is,
`for example, methoxy-, ethoxy-,
`propyloxy- or pivaloyloxycarbonyl. C2—C5alkoxycar-
`bonyl is preferred.
`Phenyl-lower alkoxycarbonyl is in particular phenyl-
`C1—C4alkoxycarbonyl and is, for example, benzyloxy-,
`l- or 2-phenylethoxy—, 3-phenylpropyloxy- or 4-phenyl—
`butyloxy—carbonyl. Benzyloxycarbonyl
`is preferred.
`Lower alkenyloxycarbonyl is in particular C3—C5alk-
`enyloxycarbonyl, preferably allyloxycarbonyl, while
`lower alkynyloxycarbonyl is in particular C3-C5alk-
`ynyloxycarbonyl, such as propargyloxycarbonyl.
`Lower alkoxy-lower alkoxycarbonyl is in particular
`C1—C4a1koxy-C1—C4alkoxycarbonyl, preferably ethox-
`yethoxycarbonyl, methoxyethoxycarbonyl
`and iso-
`propyloxyethoxycarbonyl.
`Lower alkyleneoxy-lower alkylene is in particular
`C1-C4alkyleneoxy-C2-C4alkylene,
`preferably
`ethyleneoxyethylene.
`Lower alkylamino is in particular C1—C7a1kylamino
`and is, for example, methyl-, ethyl-, n-propyl- and iso-
`propyl-amino. C1—C4alkylamino is preferred.
`Lower alkenylamino is preferably C3—C5a1kylamino,
`such as allyl- and methallylamino.
`Lower
`alkynylamino
`is
`preferably
`ynylamino, such as propargylamino.
`Phenyl-lower alkylamino is preferably phenyl—Cl—C-
`4alkylamino,
`in particular benzy1-,
`land 2-phenyle-
`thylamino.
`Phenyl-lower alkenylamino is preferably phenyl-
`C3—C5alkenylamino,
`in particular 3-phenylallylamino
`and 3-phenylmethallylamino.
`Phenyl-lower alkynylamino is preferably phenyl-
`C3—C5alkynylamino,
`in particular
`3-phenylpropar-
`gylamino.
`Di-lower alkylamino is in particular di-Cl—C4alk-
`ylamino, such as dimethyl-, diethyl-, di-n-propyl-, me-
`thylpropy1-, methylethyl—, methylbutyl-amino
`and
`dibutylamino.
`N-lower alkyl-N-phenyl-lower alkyl amino is in par-
`ticular N—C1—C4alkyl-N-phenyl-C1—C4alkylamino, pref-
`erably methylbenzylamino and ethylbenzylamino.
`Di-phenyl lower alkylamino is in particular di-phe-
`nyl-C1-C4alkylamino, preferably dibenzylamino.
`Lower alkyleneamino is
`in particular C2—C6a1k-
`yleneamino, preferably pyrrolidin-l-yl or piperidin-
`l-yl.
`Lower alkyleneoxy-lower alkyleneamino is in partic-
`ular C2-C3-alkyleneoxy-Cz-C3alkyleneamino, in partic-
`ular morpholino.
`in particular C1—C5a1k-
`Lower alkanoylamino is
`anoylamino, such as formyl-, acetyl-, propionyl-, buty-
`ryl- or pivaloylamino. C2-C5alkanoylamino is pre-
`ferred.
`
`C3—C5a1k-
`
`Phenyl-lower alkanoylamino is in particular phenyl-
`C2—Csalkanoylamino, such as phenylacetyl- or phenyl-
`propionylamino.
`
`5,399,578
`
`6
`Lower-alkanesulfonylamino is in particular C1-C-
`7alkanesulfonylamino, such as methane-, ethane-, pro-
`pane— or
`butanesulfonylamino.
`C1—C4alkanesul—
`fonylamino is preferred.
`Lower alkenyloxy is in particular C3—C7a1kenyloxy
`and is, for example, allyloxy or but-2-enyloxy or but-3-
`enyloxy. C3—C5alkenyloxy is preferred.
`Phenyl-lower alkoxy is in particular phenyl~C1—C-
`4alkoxy, such as benzyloxy, 1- or 2—phenylethoxy, 3-
`phenylpropyloxy or 4-phenylbutyloxy.
`Lower alkenyloxy-lower alkyl is in particular C3-C—
`5alkenyloxy-C1—C4alkyl, such as 2—allyloxyethyl, and
`lower alkenyloxy-lower alkenyl or—lower alkynyl is in
`particular C3-C5a1kenyloxy-C3—C5alkenyl or —-C3—C-
`salkynyl.
`have
`investigations
`pharmacological
`Extensive
`shown that the compounds I and their pharmaceutically
`acceptable salts, for example, have pronounced angio-
`tensin II antagonist properties.
`As is known, angiotensin II has strong vasoconstric-
`tor properties, additionally stimulates aldosterone secre—
`tion and thus causes distinct sodium/water retention.
`The consequence of angiotensin II activity is mani-
`fested, inter alia, in an increase in blood pressure. The
`importance of angiotensin II antagonists is in suppress-
`ing the vasoconstrictor and aldosterone secretion-
`stimulating effects caused by angiotensin II by competi-
`tive inhibition of the binding of angiotensin II to the
`receptors.
`The angiotensin II antagonist properties of the com-
`pounds of the formula I and their pharmaceutically
`acceptable salts can be detected in the angiotensin II
`binding test. Rat smooth muscle cells from homoge-
`nized rat aorta are used here. The solid centrifugate is
`suspended in 50 mM tris buffer (pH 7.4) using peptidase
`inhibitors. The samples are incubated for 60 minutes at
`25° C. with 25I-angiotensin 11 (0.175 nM) and a varying
`concentration of angiotensin II or test substance. The
`incubation is then ended by addition of saline buffered
`with ice-cold phosphate, and the mixture is filtered
`through Whatman GF/F filters. The filters are counted
`using a gamma counter. The IC50 values are determined
`from the dose-effect curve. IC50 values from about 10
`nM are determined for the compounds of the formula I
`and their pharmaceutically acceptable salts.
`For the determination of angiotensin II-induced vaso-
`constriction, investigations on the isolated rabbit aorta
`ring can be used. For this purpose, aorta rings are dis-
`sected from each chest and fixed between two parallel
`clamps at an initial tension of 2 g. The rings are then
`immersed in 20 ml of a tissue bath at 37° C. and aerated
`with a mixture of 95% 02 and 5% C02. The isometric
`reactions are measured: At 20-minute intervals,
`the
`rings are alternately stimulated with 10 nM angiotensin
`II (Hypertensin-CIBA) and 5 nM noradrenaline chlo-
`ride. The rings are then incubated with selected concen-
`trations of the test substances before treatment with the
`agonists. The data are analysed using a Buxco digital
`computer. The concentrations which cause a 50% inhi—
`bition of the initial control values are given as IC50
`values. IC50 values from about 5 nM are determined for
`the compounds of the formula I and their pharmaceuti-
`cally acceptable salts.
`The fact that the compounds of the formula I and
`their pharmaceutically acceptable salts can reduce high
`blood pressure induced by angiotensin II can be verified
`in the normotensive anaesthetized rat test model. After
`calibration of the preparations with 0.9% NaCl
`(1
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`45
`
`50
`
`55
`
`65
`
`BIOCON PHARMA LTD (IPR2020-01263) EX. 1008, p. 004
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`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1008, p. 004
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`

`7
`ml/kg i.v.), noradrenaline (1 ug/kg i.v.) or angiotensin
`II (0.3 ug/kg i.v.) in each case, increasing doses (3-6) of
`the test substance are intravenously injected by bolus
`injection, after which angiotensin II or noradrenaline is
`administered after each dose at 5 minute intervals. The
`blood pressure is measured directly in the carotid artery
`and recorded using an on-line data recording system
`(Buxco). The specificity of the angiotensin II antago-
`nism is shown by the selective inhibition of the pressure
`effect produced by angiotensin II, but not that pro-
`duced by noradrenaline. In this test model, the com-
`pounds of the formula I and their pharmaceutically
`acceptable salts show an inhibiting effect from a dose of
`about 0.3 mg/kg iv.
`.
`The antihypertensive activity of the compounds of
`the formula I and their pharmaceutically acceptable
`salts may also be manifested in the renally hypertensive
`rat test model. High blood pressure is produced in male
`rats by constricting a renal artery according to the
`Goldblatt method. Doses of the test substance are ad-
`ministered to the rats by means of a stomach tube. Con-
`trol animals receive an equivalent volume of solvent.
`Blood pressure and heart beat are measured indirectly
`at
`intervals in conscious animals by the tail clamp
`method of Gerold et al. [I-Ielv. Physiol. Acta 24, (1966),
`58] before administration of the test substances or of the
`solvent and during the course of the experiments. It was
`possible to detect
`the pronounced antihypertensive
`effect from a dose of about 30 mg/kg p.0.
`The compounds of the formula I and their pharma-
`ceutically acceptable salts can therefore be used, for
`example, as pharmaceutical active ingredients in antihy-
`pertensives which are employed, for example, for the
`treatment of high blood pressure and cardiac insuffi-
`ciency.
`The invention thus relates to the use of the com-
`pounds according to the invention and their pharma-
`ceutically acceptable salts for the production of appro-
`priate medicaments and to the therapeutic treatment of
`high blood pressure and cardiac insufficiency. The in-
`dustrial production of the active substances is also in-
`cluded in the production of the pharmaceuticals.
`The invention relates especially to compounds of the
`formula I and their salts in which R1 is an aliphatic
`hydrocarbon radical which is unsubstituted or substi-
`tuted by halogen or hydroxyl, or a cycloaliphatic or
`araliphatic hydrocarbon radical; X1 is CO or S02; X2 is
`a divalent aliphatic hydrocarbon radical which is un-
`substituted or substituted by hydroxyl or a cycloali-
`phatic or aromatic radical, or is a divalent cycloali-
`phatic hydrocarbon radical, it being possible for a car-
`bon atom of the aliphatic hydrocarbon radical to be
`additionally bridged by a divalent aliphatic hydrocar-
`bon radical; R2 is carboxyl which, if desired, is esterified
`or amidated, substituted or unsubstituted amino, formyl
`which, if desired, is acetalised, hydroxyl which, if de-
`sired, is etherified, S(O)m——R where m is 0, l or 2 and R
`is hydrogen or an aliphatic hydrocarbon radical, alkan-
`oyl, unsubstituted or N-substituted sulfamoyl or POnH2
`where n is 2 or 3; X3 is a divalent aliphatic hydrocarbon;
`R3 is carboxyl, 5-tetrazolyl, SO3H, P02H2, PO3H2 or
`haloalkylsulfamoyl; and the rings A and B indepen-
`dently of one another are substituted or unsubstituted.
`The invention relates in particular to compounds of
`the formula I and their salts in which R1 is an aliphatic
`hydrocarbon radical which is unsubstituted or substi-
`tuted by halogen or hydroxyl, or a cycloaliphatic or
`araliphatic hydrocarbon radical; X1 is CO or $02; X2 is
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`4O
`
`45
`
`50
`
`55
`
`65
`
`5,399,578
`
`8
`a divalent aliphatic hydrocarbon radical which is un-
`substituted or substituted by hydroxyl or a cycloali-
`phatic or aromatic radical; R2 is carboxyl which,
`if
`desired, is esterified or amidated, substituted or unsub-
`stituted amino, formyl which, if desired, is acetalised,
`hydroxyl which, if desired,
`is etherified, S(O)m—R
`where m is 0, 1 or 2 and R is hydrogen or an aliphatic
`hydrocarbon radical, alkanoyl, unsubstituted or N-sub-
`stituted sulfamoyl or POnH2 where n is 2 or 3; X3 is
`—CH2—; R3 is carboxyl, 5-tetrazolyl, SO3H, PO2H2,
`PO3H2 or haloalkylsulfamoyl; and the rings A and B
`independently of one another are substituted or unsub-
`stituted.
`The invention relates in particular to compounds of
`the formula I and their salts in which R1 is lower alkyl,
`lower alkenyl, lower alkynyl, halo-lower alkyl, -lower
`alkenyl or -lower alkynyl, hydroxy-lower alkyl, -lower
`alkenyl or —lower alkynyl, cycloalkyl, cycloalkenyl,
`phenyl-lower alkyl, phenyl-lower alkenyl or phenyl-
`lower alkynyl; X1 is CO or $02; X2 is alkylene or alkyli-
`dene which is unsubstituted or substituted by hydroxyl,
`a cycloalkyl or cycloalkenyl radical, a phenyl radical or
`a 5- or 6-membered, monocyclic heteroaromatic radical
`having up to four identical or different hetero atoms,
`where the cyclic radicals, for their part, are unsubsti-
`tuted or substituted by carboxyl which is free or esteri-
`fied by an alcohol which is derived from lower alkyl,
`phenyl-lower alkyl, lower alkenyl, lower alkynyl or
`lower alkoxy-lower alkyl, -lower alkenyl or -lower
`alkynyl, carbamoyl in which the amino group is unsub-
`stituted or monosubstituted or, independently of one
`another, disubstituted by lower alkyl, lower alkenyl,
`lower alkynyl, phenyl-lower alkyl, phenyl-lower alke-
`nyl or phenyl-lower alkynyl or disubstituted by lower
`alkylene- or lower alkyleneoxy-lower alkylene, formyl,
`di-lower
`alkoxymethyl or oxy-lower
`alkyleneox-
`ymethylene; R2 is carboxyl which is free or esterified by
`an alcohol which is derived from lower alkyl, phenyl-
`1ower alkyl,
`lower alkenyl,
`lower alkynyl or lower
`alkoxy-lower alkyl, -lower alkenyl or -lower alkynyl;
`carbamoyl in which the amino group is unsubstituted or
`monosubstituted or, independently of one another, di-
`substituted by lower alkyl, lower alkenyl, lower alky-
`nyl, phenyl-lower alkyl, phenyl-lower alkenyl or phe-
`nyl-lower alkynyl or disubstituted by lower alkylene- or
`lower alkyleneoxy—lower alkylene; amino in which the
`amino group is unsubstituted or monosubstituted or,
`independently of one another, disubstituted by lower
`alkyl, lower alkenyl, lower alkynyl, phenyl-lower alkyl,
`phenyl-lower alkenyl or phenyl-lower alkynyl or disub-
`stituted by lower alkylene- or lower alkyleneoxy-lower
`alkylene;
`lower alkanoyl-, phenyl-lower alkanoyl-,
`benzoyl-,
`lower alkanesulfonyl— or benzenesulfonyl-
`amino; formyl, di-lower alkoxymethyl, oxy-lower a1-
`kyleneoxymethylene, hydroxyl,
`lower alkoxy,
`lower
`alkenyloxy, phenyl-lower alkoxy, phenoxy, S(O)m—R
`where m is 0, 1 or 2 and R is hydrogen, lower alkyl,
`lower alkenyl or lower alkynyl; lower alkanoyl, sulfa-
`moyl in which the amino group is unsubstituted or mon-
`osubstituted or, independently of one another, disubsti-
`tuted by lower alkyl, lower alkenyl, lower alkynyl,
`phenyl-lower alkyl, phenyl-lower alkenyl or phenyl-
`1ower alkynyl or disubstituted by lower alkylene- or
`lower alkyleneoxy-lower alkylene, or is P0,.H2 where ,n
`is 2 or 3; X3 is —CH2—; R3 is carboxyl, 5-tetrazolyl,
`SO3H, PO2H2, P03H2 or halo-lower alkylsulfamoyl;
`where (hetero)aromatic radicals including the rings A
`and B are independently of one another in each case
`
`BIOCON PHARMA LTD (IPR2020-01263) EX. 1008, p. 005
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`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1008, p. 005
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`

`

`9
`unsubstituted or substituted by one or more substituents
`selected from the group comprising halogen, hydroxyl,
`lower alkoxy, lower alkenyloxy, or lower alkyl, lower
`alkenyl,
`lower alkynyl,
`lower alkoxy-lower alkyl,
`-lower alkenyl,-lower alkynyl, lower alkenyloxy—lower
`alkyl, lower alkenyl and -lower alkynyl which are in
`each case unsubstituted or substituted by halogen or
`hydroxyl.
`The invention relates in particular to compounds of
`the formula I and their salts, in which X2 is alkylene or
`alkylidene which is unsubstituted or substituted by hy-
`droxyl, a cycloalkyl or cycloalkenyl radical, a phenyl
`radical or a 5- or 6-membered, monocyclic heteroaro-
`matic radical having up to four identical or different
`hetero atoms, it being possible for a C atom of alkylene
`or alkylidene to be bridged by C2—Csalkylene and the
`cyclic radicals, for their part, being unsubstituted or
`substituted by carboxyl which is free or esterified by an
`alcohol which is derived from lower alkyl, phenyl-
`lower alkyl, lower alkenyl, lower alkynyl, or lower
`alkoxy-lower alkyl, -lower alkenyl or -lower alkynyl,
`carbamoyl in which the amino group is unsubstituted or
`monosubstituted or, independently of one another, di-
`substituted by lower alkyl, lower alkenyl, lower alky-
`nyl, phenyl-lower alkyl, phenyl-lower alkenyl or phe-
`nyl-lower alkynyl or disubstituted by lower alkylene- or
`lower alkyleneoxy—lower alkylene,
`formyl, di-lower
`alkoxymethyl or by oxy—lower alkyleneoxymethylene,
`or X2 is C3—C7cycloalkylene; X3 is lower alkylene or
`lower alkylidene; and the variables X1, R1, R2 and R3
`have the meanings indicated immediately above and the
`(hetero)aromatic rings including the rings A and B can
`be substituted as indicated immediately above.
`The invention relates in particular to compounds of
`the formula I and their salts, in which R1 is lower alkyl,
`lower alkenyl, halo-lower alkyl or -lower alkenyl, hy-
`droxy-lower alkyl, 3- to 7-membered cycloalkyl or phe-
`nyl-lower alkyl; X1 is CO, $02, or —O—C(=O)— with
`the carbon atom of the carbonyl group being attached
`to the nitrogen atom shown in formula 1; X2 is C1—C1-
`oalkylene or C1—C7alkylidene which is unsubstituted or
`substituted by hydroxyl, carboxyl, amino, guanidino, a
`3- to 7-membered cycloalkyl, 3- to 7-mernbered cy-
`cloalkenyl, phenyl, pyrrolyl, pyrazolyl,
`imidazolyl,
`triazolyl, tetrazolyl, fury], thienyl or pyridyl radical
`which, for its part, can be unsubstituted or additionally
`substituted by carboxyl, lower alkoxycarbonyl, phenyl-
`lower alkoxycarbonyl, carbamoyl in which the amino
`group is unsubstituted or monosubstitut