LT3612B - Therapeutic agents - Google Patents

Abstract

This invention includes a description for formula I<IMAGE>and their saline, useful in pharmacy; where R50 is hydrogen or Cl-4 alkyl, A51 is oxygen, sulphur or NR52 formula group; where R52 is hydrogen of C1-4 alkyl; A50 correspond to 1) mono- or bicyclic aromatic ring, which can have one or several nitrogen, oxygen or sulphur atoms, ii) cycloalkenyl group, iii) non-cyclical bridge with a one, two or three atoms chain, which is located between the cyclobutanedione group and Xso, described as a chain, this is one or two carbon atom chain, or a chain, made from one carbon atom and one or several nitrogen, oxygen and sulphur atoms or iv) connection; X 50 is a connection or interim group, connecting a chain of one or several atoms length between A50 and B50; where B50 is a mono- or bicyclic aromatic ring, which can have one or more nitrogen, oxygen or sulphur atoms, r is an integer number from 1 to 6; and Het is a ring system, which can have one or more nitrogen, oxygen and sulphur atoms or is phosphinite or amine formation (where A50, X50, B50 and Het can be substituted).The compounds include angiotensin II antagonist activation and are used for treating blood vessel disorders such as hypertension.

Description

and pharmaceutically acceptable salts thereof;

wherein R 50 is hydrogen or C 1-4 alkyl, A 51 is oxygen, sulfur or NR 52 is a group of formula; wherein R 52 is hydrogen or C 1-4 alkyl; A50 corresponds to (i) a mono or bicyclic aromatic ring which may have one or more nitrogen, oxygen or sulfur atoms, (ii) a cycloalkendenyl group, (iii) a non-cyclic bridge having one, two or three atoms between the cyclobutendione group and means a chain of one or two carbon atoms or a chain of one carbon atom and one or more atoms of nitrogen, oxygen or sulfur; or (iv) a bond; Χ50 is a bond or an intermediate group linking a one or two atom long chain between A50 and B50; B50 is a mono or bicyclic aromatic ring having one or more nitrogen, oxygen or sulfur atoms, r is an integer from 1 to 6; and Het is a ring system which may contain one or more nitrogen, oxygen or sulfur atoms or is a derivative of a phosphonate, phosphinate or amino (where A50, Χ50, B50 and Het may be substituted).

The compounds have angiotensin II antagonist activity and are used to treat blood vessel disorders such as hypertension.

i

The present invention describes novel therapeutic agents as well as partially novel substituted cyclobut-3-en-1,2-diones, processes for their preparation, pharmaceutical compositions containing them and their therapeutic activity in the treatment of blood vessel disorders.

Angiotensin II is the primary mediator of the reninangiotensin system. Angiotensin II is known to be a vasoconstrictor whose action is mediated through interaction with specific receptors on cell membranes. Recently, several non-peptide compounds have been reported as angiotensin II antagonists as useful antihypertensive agents.

The present invention describes compounds of formula I

H £ t i

(CH 0) ri * fsc 0 _Ύ p and pharmaceutically acceptable salts thereof, wherein R ₅₀ is hydrogen or C _1-4 alkyl, A ₅₁ is oxygen, sulfur or -NR ₅₂ - wherein R ₅₂ is hydrogen or C _1-4 alkyl; A ₅₀ corresponds to (i) a mono or bicyclic aromatic ring which may have one or more nitrogen, oxygen or sulfur atoms, (ii) a cycloalkendenyl group, (iii) an acyclic bridge having one, two or three atoms between Cyclobutendio.no and X ₅₀ , the chain described is a chain of one or two carbon atoms or a chain of one carbon atom and one or more atoms of nitrogen, oxygen or sulfur; or (iv) a bond; X ₅₀ is a bond or a linking group linking a one or two atom long chain between A ₅₀ and B ₅₀ ; B _s0 is a mono or bicyclic aromatic ring having one or more nitrogen, oxygen or sulfur atoms, r is an integer from 1 to 6; and Het is a ring system which may contain one or more nitrogen, oxygen or sulfur atoms or is a phosphonate, phosphinate or amino derivative (wherein A ₅₀ , X ₅₀ , B ₅₀ and Het may be substituted).

A ₅₀ is preferably selected from groups (i) to (xi) given above (wherein in each case Z ₅₀ is a bond to X ₅₀ and the other free valences are linked to a cyclobutenedione group).

(i) wherein R ₇₀ and R ₇₁ are each independently hydrogen, hydroxy, alkyl (which may be substituted by halogen, C ₃ _ ₈ cycloalkyl or phenyl, C _{3rd 12} cycloalkyl or phenyl (both of which may be substituted by halogen), C ₁ _ ₆ alkyl or Ο ₃ _ ₆ alkoxy or R ₇₀ and R ₇₁ together form a 3, or 7 membered carbocycle (which may bear one or two Ο ₇ _ ₆ alkyl, 0 _Σ _ ₆ alkoxy, phenyl, hydroxy or halogen group is optionally substituted);

Ar, * 81 * 60 (ii), * 80 wherein A _{6 U} is nitrogen or methine; A _S1 is imino, oxygen or sulfur, and R ₈₀ and R ₈₁ are each a hydrogen, halo, fluoro, nitro, cyano, alkyl, ^C2-io (preferably C ₂ _ ₄₎ alkenyl, alkylthio, mono-, di- or trihalo- (C _{4th 6} alkyl), hydroxyalkyl, oxoalkyl, carboxy or esterified carboxyl group, or when R ₈₀ and R ₈₁ on adjacent carbon atoms, R ₈₀ and R ₈₁ may together form a 1,3-butadienileną, thereby connecting the condensed aromatic ring;

(iii)

OR

wherein R ₉ -R ₉₀ s are each a hydrogen, halo, fluoro, nitro, amino, C ₄ _ ₄ alkylamino, di- (C ₄ _ ₄ alkyl) amino, Trif luormetilo C ₄ _ ₄ alkyl, C ₄ _ ₄ alkoxyl or -SO ₂ NHR ₉₈ group (where R _ss is hydrogen, C _1-5 alkyl, aryl or arylmethyl);

(iv) wherein -A ₇₀ -A ₇₁ -A ₇₂ -A ₇₃ - is present

- NC (R ₁₀₀ ) c (R ₁₀₁ ) C (Rlu2) ~ ' - C (Rioo) NC (R ₁₀₁ ) C (R102) ~ r - C (Rioo) C (R ₁₀₁ ) NC ( ^R 102) ~ f - C (Rioo) C (Rioi) C (R ₁₀₂ ) N-, -NC (R ₁₀₀ ) NC (R ₁₀₁ ) - C (R ₁₀₀ ) NC (R ₁₀₁ ) N- 'r -NNC (R ₁₀₀ ) C (R ₁₀₁ ) -, - C (R ₁₀₀ ) NNC (R ₁₀₁ ) - 'f -C (R ₁₀₀ ) C (R ₁₀₁ ) NN-, - N C (Rioo) C (Rio! .) N -, - C (Rioo) C (R ₁₀₁ ) c (0) N (R ₁₀₃ ) - - C (Rioo) C (R ₁₀₁ ) N (R ₁₀₃ ) C (O) -, - C (O) N < ^R 103) C (R 100) C (R101) ~ t - N ( ^R 103) C (0) C (R 100) C (R ₁₀₁ ) -,

- C (O) N (R ₁₀₃ ) C (R ₁₀₀ ) N -, -C (R ₁₀₀ ) NC (O) N (R ₁₀₃ ) -,

- N (R ₁₀₃ ) C (O) NC (R ₁₀₀ ) -, -NC (R ₁₀₀ ) N (R ₁₀₃ ) C (O) -,

- C (O) N (R ₁₀₃ ) NC (R 100) - or

- C (R ₁₀₀ ) N N (R ₁₀₃ ) C (O) -;

a group of formula in which Rioo ^_r io2 are each independently hydrogen, halo, fluoro, nitro, amino, C ₃ _ ₄ alkylamino, di (C ₁ _ ₄ alkyl) amino, Trif luormetilo C _x _ ₄ alkyl, C _1-4 alkoxy or a group of formula SO ₂ NHR ₁₀₄ (wherein R ₁₀₄ is hydrogen, C _{x 6} alkyl, aryl, arylmethyl or -CH ₂ OC (O) CH ₃ ) or when two of R ₁₀₀ , R ₁₀₁ and R ₁₀₂ are attached to adjacent carbon atoms, they can combine to form a phenyl or naphthyl ring; and R ₁₀₃ is hydrogen, _Ο χ _ ₄ alkyl, phenyl or phenylmethyl (in which the phenyl or phenylmethyl substituted by one or two substituents selected from halogen, fluoro, C _{first 4} alkyl, C ₃ _ ₄ alkoxy, trifluoromethyl, amino, C _x _ ₄ alkylamino, di (C ₃ _ ₄ alkyl) amino, or -CO ₂ R ₁₀₄ of formula 'groups (wherein R ₁₀₄ is defined hereinbefore);

^A 8 O0) ^A S3 ^a 81 ~ ^a 82 where -A _S0 -A ₈₁ -A ₈₂ -A ₈₃ - is “Y50-C (Ruo) C (Rm) C (Ζ ₈₂ )

- c (Rno) Y ₅₀ C (Rni) c (Z ₅₂ ) - c (Rno) C (Rm) Y ₅ o c (Z52) ~ f - z 50 c (R ₁₁₀ ) C (Z ₅₂ ) c (R111) -Λ - c ( ^{R 10} ) Y 50 C (z ₅₂ ) c (R _1U ) - or

- C (R ₃₁₀ ) C (R _m ) C (Z ₅₂ ) Y ₅₀ -, a group of the formula wherein Y ₅₀ is oxygen, sulfur, sulfinyl or sulfonyl; R _{n = 0} and R _{1 U} are each a hydrogen, halo, fluoro, nitro, amino, formyl, Ci-4 alkylamino, di (C _x _ ₄ alkyl) amino, trifluoromethyl, C ₁ _ ₇ alkyl, C ^ g alkoxy, C ₃ _ ₇ cycloalkyl or -SO ₂ NHR _112, -O (CH ₂₎ CO (CH ₂₎ d CH _3, ~ (CH _{2) d} O (CH _{2) d} CH _3, - (CH ₂₎ N (R _{112) 2} , -CH (OR ₁₁₂ ) (C 1-7 alkyl), -CO ₂ R ₁₁₂ ,

-CH = CHR ₁₁₂ , -CH ₂ CR _{u 2} = C (R ₁₁₂ ) ₂ , - (CH ₂ ) _e NHC (O) R ₁₁₂ - (C _{x 4} ) alkylaryl or -CH (R ₁₁₂ ) ₂ group of formula ( wherein R ₁₁₂ is hydrogen, C _{x 6} alkyl, arylmethyl or aryl, c is an integer from 1 to 3, d is an integer from 1 to 5, and e is O or an integer from 1 to 2) or when R ₁₁₀ and R _{in, when} attached to adjacent carbon atoms, may combine to form a phenyl or naphthyl ring; and wherein Z ₅₂ represents the other free valence described above;

^R 120 ^A 90 ~~ ^r 121 (Vi) in which A ₉₀ is a bond, oxygen, sulfur, sulfinyl or sulfonyl, methylene or -NR ₁₂₂ - a group of formula wherein (R ₁₂₂ is hydrogen, C _x _ ₆ alkyl, aryl, arylC (C ₂ _ ₇₎ alkylcarbonyl, (C ₁ _ ₆₎ alkylcarbonyl, [(C ₂ _ ₅₎ alkenyl) methylene, [(C ₂ _ ₅₎ alkynyl] methylene or arilmetilenas) and R ₁₂₀ and R ₁₂₁ are each a hydrogen, 0χ_ ₆ alkyl (which may be aryl or C ₂ _ ₇ cycloakyl substituted), aryl (which may bear up to 5 substituents selected from halo, fluoro, Cą.g alkyl, (C ₂ _ ₅ alkenyl) methylene, (C ₂ _ ₅ alkynyl) methylene CTs alkoxy, alkylthio, nitro, trifluoromethyl, hydroxy, nitro, or -CO ₂ R ₁₂₃ group of formula (wherein R ₁₂₃ is hydrogen, Ο ₂ _ ₆ alkyl, aryl or arilmetilenas) ) or aryl (C ₁ _ ₂₎ alkyl (which may contain up to 5 »substituents selected from halo, fluoro, Ο ₃ _ ₆ alkyl, (C ₂ _ ₅ alkenyl) methylene, (C _2-5 alkynyl) methylene (Τ ₅ alkoxy, alkylthio, nitro, trifluoromethyl, hydroxy or -CO ₂ R ₁₂₃ group of formula (wherein R ₁₂₃ is as described above) or C ₃ _ ₇ cycloalkyl.

^R m

(vii) wherein R _130, R ₃₁ and R ₁₃₂ are each a hydrogen, halogen, fluorine, nitrogen, amino, C _x _ ₄ alkylamino, di (C _l _ ₄ alkyl) amino, trifluoromethyl, Ci_ ₄ alkyl, C _x _ ₄ aiLT 3612 B ί

koksilo or -SO ₂ NHR group of Formula ₁₃₃ (wherein R ₁₃₃ is hydrogen, C ₁ _ ₅ alkyl, aryl or arylmethyl);

z

R

OR \ - {k

^R 141

100 (viii), 'Ί4 2 wherein R ₁₄₀ is hydrogen, alkyl, aryl (denoting phenyl which may be substituted by halogen, fluorine, alkyl, alkoxyl, alkylthio, hydroxyl, alkanoyl, nitro, amino, dialkylamine, trifluoromethyl, C ₃ - C ₇ -cycloalkyl or arylalkyl; A ₁₀₀ is nitrogen (when the dotted line is a bond) or nitrogen substituted with a substituent selected from the list of R ₁₄₀ values given (where the dashed line is not a bond), and R ₁₄₁ and R _{142 are} each independently is hydrogen, halo, fluoro, nitro, amino, Ci_ ₄ alkylamino, di (Cj_ ₄ alkyl) amino, trifluoromethyl, C _x _ ₄ alkyl, C ₃ _ ₄ alkoxy, or -SO ₂ NHR group of formula ₁₄₃ (where hydrogen Ο ₇ - ₅ alkyl or arylmethylene);

R ₁₄₃ is present

^r 150 (ix) wherein R 1 _SO is hydrogen, C ₇ -C ₆ alkyl or a group of formula Y ₆₀ wherein Y ₆₀ is phenyl or naphthyl 1- or 2LT 3612 B (each may be methyl, methoxy, hydroxyl, bromine, chlorine, fluoro, nitro, amino, diethylamino, methylthio or sulfhydryl modified) _x C ₆ _ ₆₀ alkyl group of the formula Y (wherein Y ₆₀ is described above), Y a group of formula ₆₁ (wherein Y ₆₁ is a 5- or 6-membered ring, or 8-, 9- or 10-membered bicyclic system containing one or more heteroatoms optionally selected from nitrogen, oxygen and sulfur (including but not limited to pyrrole, imidazole, thiophene, furan, pyridine, thiazole, indole, morpholine and isoquinoline), which may be substituted by halogen, C _x _ ₆ alkyl, C _x _ ₆ alkoxy or hydroxy; or a C 1 -C 6 -alkyl-Y 4 - group of formula (wherein Y ₆₁ is as previously described);

* 111 ^Z 50 ^A no (x) wherein A _m is oxygen, sulfur imine or methylene; where A _m is oxygen, sulfur or an imino, and A ₁₁₀ is -CR ₁₆₀ R ₁₆₁ - a group of formula and, where A _{1 U} is methylene, then A ₁₁₀ is either nitrogen or -CR ₆ R ₁₆₀ i ^_ a group of formula wherein R ₁₆₀ and R ₁₆₁ are each a hydrogen, Ci_iq alkyl, C ₃ _ ₁₀ alkenyl, C ₃ _ ₁₀ alkynyl, C ₃ _ ₈ cycloalkyl, C ₄ _ ₁₀ c'ikloalkilalkilas C ₅ _ ₁₀ cikloalkilalkenilas, C _{5. 10} cycloalkylalkynyl or aryl optionally substituted by one or two halogen, C _x _ ₄ alkyl or C _x _ ₄ alkoxy substituents;

OH (CH ₂ ) b '50? 50

-V (xi) wherein b is 2, 3 or 4; or o

j'V ·

N-Z (XII) '171 wherein R ₁₇₁ is hydrogen, halo, fluoro, alkyl, or C _x _ ₄ alkoxy; and R ₁₇₀ is hydrogen, halogen, C ₄ _ ₄ alkyl, C ₄ _ ₄ alkoxy, nitro, C ₄ _ ₄ acyloxy, carboxy (which may be esterified), phenyl, furyl or -NHS ₂ Me, CF ₂ -NHS ₃ , -SO _? A group of formula NH ₂ or -CONHR ₁₇₂ (wherein R ₁₇₂ is hydrogen, methyl or benzyl).

Accordingly, when X ₅₀ is a linking group, it is carbonyl, oxygen, sulfur, vinylene, difluorvinylene, monofluorvinylene, ethylene, perfluoroethylene, oxymethylene, thiomethylene or -NR ₅₃ -, -CONR ₅₄ -,

-NR ₅₄ CO-, -nhcr ₅₅ r ₅₆ -, -nr ₅₅ so ₂ -, -so ₂ nr ₅₅ -, CR ₅₅ R ₅₆ NH-,

-CH (OR ₅₇₎ ~, -CH (OCOR ₅₈₎ or -C (NR ₅₉₎ - group of the formula (in which R ₅₃ is hydrogen, C ₂ _ ₄ acyl, C ₄ _ ₆ alkyl, allyl, C ₃ _ ₆ cycloalkyl , phenyl or benzyl, R ₅₄ is hydrogen or C ₄ _ ₄ alkyl, R ₅₅ is hydrogen, Ci_ ₅ alkyl, phenyl or benzyl, R ₅₆ is hydrogen or C ₄ _ ₁₄ alkyl, R ₅₇ is hydrogen, C ^ .g alkyl , Ο ₇ _ ₈ perfluoroalkyl, C ₃ _ ₆ cycloalkyl, phenyl or benzyl, R ₅₈ is hydrogen, Ο ₄ _ ₆ alkyl, C ₃ _ ₆ cycloalkyl, phenyl or benzyl, R ₅₉ is -NR ₅₅ R _56, -OR ₅₆ , NHC (O) NH ₂ , -NHC (S) NH ₂ , -NHSO ₂ benzyl or -NHSO ₂ phenyl (wherein R ₅₅ and R ₅₆ are as previously described);

The B ₅₀ group is best selected from the xv xxii groups described above (where, in each case, Z ₅₁ is a bond to a

X ₅₀ and the other free valence is bonded to a - (CH ₂ ) R -Het group);

wherein R ₁₈₀ is hydrogen, halogen (preferably bromo), fluoro, C _x _ ₆ alkyl, C ₂ _ ₆ alkenyl, C ₃ _g-alkyl, C ₁ _ ₆ alkoxy, formyl, carboxyl or a group of formula -COR ₁₈₃ (wherein R ₁₈₃ represents C ₃ _g alkyl, C ₂ _ ₆ alkenyl, alkoxy or -NR ₁₈₄ R ₁₈₅ group of the formula (wherein

R ₁₈₄ and R ₁₈₅ each independently is hydrogen or alkyl or together form a saturated heterocyclic ring containing. 5 or 6 ring members and capable of having one oxygen atom in the ring)); R ₁₈₁ and R ₁₈₂ are each a hydrogen, halo, fluoro, nitro, amino, C ₃ _ ₄ alkylamino, di (C ₃ _ ₄ alkyl) amino, Trif luormetilo, Cy_ ₄ alkyl, C ₃ _ ₄ alkoxy, or -SO ₂ A group of formula NHR ₁₉₁ (containing hydrogen, alkyl, aryl or arylmethyl); and A ₁₂₀ is oxygen, sulfur or a group of formula -NR ₁₈₆ wherein R ₁₈₆ is hydrogen or a group selected from C ^ .g alkyl, C ₃ _ ₆ alkenyl, Cj_ ₆ alkoxy or -COR _19? or -SO ₂ R ₁₈₈ group of the formula: [wherein R ₁₈₇ and R _I88 each Cj.g alkyl, C ₂ _ ₆ alkenyl, C ^ -g alkoxy or -NR ₁₈₉ R ₁₉₀ group of the formula (wherein R ₁₈₉ and R _190, which may be the same or different, each independently represents a hydrogen atom or a C _1-4 alkyl group, or together form a saturated heterocyclic ring having 5 or 6 ring members capable of having one oxygen atom in the ring)]} and wherein the previously described free valence is preferably is in the 5th position of the ring;

KjoO

(xvi) wherein R ₂₀₀ and R ₂₀ i are each independently selected from the above list for R ₁₈₀ , and R ₂₀₂ and R _{203 are} each independently selected from the above list for R ₁₈₁ and wherein the free valence described above is preferably when is in the 5th position of the ring;

(XVII) wherein R _210, R ₂ n and R212 are each a van25 bons, halo, fluoro, nitro, CJ.g alkyl, Cj.g acyloxy, C ₃ _ ₆ cycloalkyl, C ₂ _ ₆ alkoxy, hydroxy, -C ₃ _ ₄ allyl, ^ _ ₄ alkylthio, C _x _ ₄ alkylsulfinyl, C ₂ _ ₄ alkylsulfonyl, trifluoromethyl, aryl, furyl or

A group of formula -NHSO ₂ R ₂₁₃ , -SO ₂ NHR ₂₁₃ or -NR ₂₁₃ R ₂₁₄ wherein R ₂₁₃ and R _{214 are} each independently hydrogen, C 1-8 alkyl, benzyl or phenyl, or when R ₂₁₀ and R 211 are attached adjacent carbon atoms, they may together form an aromatic ring; ₁₃₀ and A is a carbonyl, methylene or -CH (CO ₂ C ₃ _ ₄ alkyl) -, -CH (CO ₂ H) -,

-CH (CN) -, -CH (tetrazolyl) - or -CH (R ₂ CONHSO ₂ i5) - a group of formula wherein R ₂₁₅ is an aryl, heteroaryl, C ₃ _ ₇ cycloalkyl or C ₄ _ ₄ alkyl (which may be substituted aryl, heteroaryl, hydroxyl, sulfhydryl, alkyl, Cj_ ₄ alkoxy, C ₄ _ ₄ alkylthio, methyl, halo, fluoro, nitro, carboxy, carboxy (C ₄ _ ₄ alkyl) amino, di (C ₄ _ ₄ alkyl) amino or -PO ₃ H or -PO (OH) [O- (C 1-6 alkyl)], and wherein the free valence described above is preferably in the 5-position of the ring;

140 (xviii) wherein R ₂₂ and R 221 are each hydrogen, halogen, fluoro, nitro, amino, C ₄ . ₄ alkylamino, di- (C ₄ _ ₄ alkyl) amino, Trif luormetilo C ₄ _ ₄ alkyl, C ₃ _ ₄ alkoxy, or -SO ₂ NHR group of Formula ₂₂₈ (wherein R ₂₂₈ is hydrogen, C ₃ _5 alkyl, aryl or arylmethyl ); o A ₁₄₀ -A ₁₄₁ - is a group of the formula -N = CR ₂₂₂ -, -CR ₂₂₂ = CR ₂₂₃ - or -CHR ₂₂₂ -CHR ₂₂₃ -;

wherein R ₂₂₂ and R _{223 are} each independently hydrogen, halo, fluoro, alkyl, haloalkyl; C ₃ _ ₇ cycloalkyl or arylalkyl (wherein aryl is phenyl, which may be substituted with halo, fluoro, alkyl, alkoxy, alkylthio, hydroxy, alkanoyl, nitro, amino, trifluoromethyl, alkylamino or dialkylamino, or a group of formula -COR224 (wherein R ₂₂ is 4 hydrogen, a C ₄ _ ₆ alkyl, C ₃ _ ₆ cycloalkyl, -OR ₂₂ or -NR 5 ₂ 2 _{6 2} R 27 group of formula wherein R ₂₂₅ is oxygen, C ₄ _ ₆ alkyl, C _{3rd 6} cycloalkyl, aryl, aralkyl, or a 5-7 membered carbocyclic ring which may have connected to it a 5-7 membered carbocyclic ring and R 6 and ₂₂ R227 are each a hydrogen, a C ₄ _ ₄ alkyl, phenyl, benzyl, α-methylbenzyl or together form a C ₃ _ ₄ cyclic group substituted on a ring nitrogen and / or oxygen) which as described above is a free valence 5JE ring position;

wherein R ₂₃₀ and R ₂₃₁ are each a hydrogen, halo, fluoro, nitro, amino, C ₄ _ ₄ alkylamino, di (C _x _ ₄ alkyl) amino, Trif lųormetilo, Cf_ ₄ alkyl, Cj. A group of formula ₄ alkoxy or -SO ₂ NHR ₂₃₄ (wherein R ₂₃₄ is hydrogen, alkyl, aryl or arylmethyl);

A _{15 °} and A ₁₅₁ each independently is oxygen, sulfur or -NR ₂₃₂ - or -CR ₂₃₂ R 3 _{2 3} - a group of formula wherein R ₂₃₂ and R ₂₃₃ are each a hydrogen, a C ₄ _ ₆ alkyl, C ₃ _ ₆ cycloalkyl , phenyl or benzyl and wherein the free valence described above is in the 5-position of the ring;

(xx) wherein -A ₁₆₀ -A ₁₆₁ - are = C (R ₂₃₂ ) -N = or = NC (R ₂₃₂ ) = wherein R ₂₃₀ z R ₂₃ i and ^R 232 are each independently hydrogen, halogen, fluoro, nitro, amino, C ₄ _ ₄ alkyl, Cf_ ₄ alkylamino, di- (C ₄ _ ₄ alkyl) amino, Cf_ ₄ alkoxy, Trif lųormetilo or -SO ₂ NHR group of formula ₂₃₃ (wherein R ₂₃₃ is hydrogen, alkyl Cf_ ₅ , aryl or arylmethyl);

wherein R ₂₄₀ -R _{243 are} each independently hydrogen, halogen, fluoro, C _{x- 6} alkyl, C _{x- 6} perfluoroalkyl, C _{x- 6} alkoxy or C _{x- 6} alkoxyalkyl; or

wherein -A = A _{170 171} - is -C (R ₂₅₀₎ = N- or -C (R ₂₅₁₎ = C (R ₂₅₂₎ group of formula wherein R ₂₅₀ is hydrogen or C _x _ ₇ alkyl and R ₂₅₁ and R ₂₅₂ are each hydrogen, halo, fluoro, C _x _ ₇ alkyl, C _x _ ₇ alkoxy, C ₂ _ ₇ alkenyloxy, phenoxy, benzyloxy, trifluoromethyl or -S (O) ₂ R _f group of formula 53 (wherein f is O or an integer from 1 to 2 and R ₂₅₃ is hydrogen or C _{x 7} alkyl).

Preferably, r is 1.

Het is preferably a single group of any given formula, wherein in each case the symbols are as defined in the corresponding patent publication cited in brackets. The disclosed and / or specific heterocycles are as defined in the relevant patent publication (s):

(DE-A-3928177, EP-A-0392317; THOMAE)

(DE-A-4006692; SCHERING)

(DE-A-4031287, DE-A-4105324 and EP-A-0468470; THOMAE) ^R \ (DE-A-4031601, DE-A-4105827 »(and EP-A-0470543; THOMAE)

........ n, (DE-A-4032522 and DE-A-4034728; SCHERING) cn r ~ σι σ

n o

I

I

CM ω

et

« 2 u u M cz oh O ω ω M s s • k CM LT) o m oo CO r * co o <y> o rd σ \ o O 00 * 3 * «Here o O O

L ¹ I <

I I I

CM CU cu W ω w

<0

\ O et cm o

rd r * o

o ¹ o

I

I cu w

ω z ^ <i

b>

i kO '• «X

M • H

UO rd m oo »- CO CM ω 00 o gC CM O rd «—1 ---. o .___ Lf) O H H □ 2 Di Di 1 1 Z 2 H ω ω <<o O > 1 1 i cu CU · *. < ω o D £> M * CQ 0Q D £ Q Q. rd 00 • k • k <*. · ». · «. rH CM CM co o r- r- rd CM O CO 00 rd <Λ Γ- * 3 » th uo LD uo ΟΟ rd CM 00 r * o CM rd 00 C0 O CO iH 1 • CO CM uo uo o CM rd < rd CM CM rd rd CO i 1 01 M * « O Lf) Ch O C ω 1 < i | 1 1 1 <<< 1 1 1 1 ω m ω ω 1 1 1 cu ui o 1 cu Q-H Q. Q. ω D S

OC /

O

rl cd

etc.

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a.

Het is accordingly a heterocyclic group which forms a closed organic ring system whose ring system contains one or more oxygen, nitrogen or sulfur atoms. Het primarily forms a stable monocyclic ring having a 5- to 7-membered or saturated or unsaturated bicyclic heterocyclic ring having from 7 to 10 members and containing up to five, preferably up to three, nitrogen, oxygen and / or sulfur atoms (wherein any nitrogen atom may be a ketine chain), and including any bicyclic group in which any one of the mono-heterocyclic rings defined above is linked to a benzene ring, and wherein the ring may be substituted. The following heterocyclic groups include, but are not limited to: thienyl, furyl, pyranyl, chromenyl, xanthenyl, pyrrolyl, 2H-pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, , purinyl, quinolizinyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinolinyl, pteridinyl, isothiazolyl, isoxazolyl, furazanyl, piperazinyl, pyrrolidinyl, oxazolyls, triazolyl and tetrazolyl, and, dihydro, tet25 rahydro, and their mono-, di- and tri-derivatives. Heterocyclic groups in the present invention also include fused rings based on any combination of up to three rings and / or benzene or naphthalene rings discussed above. Preferably, these heterocycles are based on benzimidazole and imidazopyridine.

Groups of formulas i, ii, iii, iv, viii, ix, x, xi and xii are described in (a) (Bayer); b) EP-A-0480204 (Fujisawa); c) (Merck); d) EP-A-0512676 (Merck); e) EP-A-0512675 (Merck);

f) WO-A-9112001 (Merck); g) WO-A-9215577 (Searle);

V, VI, VII, EP-A-0513533 US-A-5124335

h) EP-A-0501269 (Matter); i) WO-A-9206081 (Warner Lambert); j) US-A-5191086 (Matter); k) DE-A-4006693 (Schering) and 1) EP-A-0253310 (Du Pont) respectively, and preferably when these groups are as described in these publications.

Groups of formulas xv, xvi, xvii, xviii, xix, xx, xxi and

0514193,

0514197, (Glaxo);

(Merck);

(Squibb) (Merck) preferably xxii are described m) WO-A-9209600, EP-AEP-A-0514192, EP-A-043709, EP-A-0514198, EP-A-

EP-A-0514216, EP-A-0505954 and EP-A-0514217 n) EP-A-0429257 (Glaxo); 0) EP-A-0517357 P) EP-A-0488532 (Squibb); q) US-A-5190942 ; r) EP-A-0508393 (Searie); S) EP-A-0400974 and t) EP-A-0528762 (Ciba Geigy) respectively, and

wherein said groups are as described in these publications.

Het is preferably one of the groups of formula xxv, xxvi, xxvii or xxviii, shown below:

b r, f

. ^FU-,: 26I (XXV) wherein R ₂₆₀ is hydrogen or alkyl, and R _261, R 62 and R _{2 2} £ 3 in each case independently hydrogen, C ₁ _ ₄ alkyl, nitro, fluorine, chlorine, bromine, cyano, formyl or -sonr ₂₆₄ , -so ₂ nr ₂₆₅ r _266, or -COR ₂₆₇ (wherein R ₂₆₄ , R ₂₆ 65 and ^R 266 each independently are hydrogen or alkyl, n is 1 or 2, and R _{267 is 3}

C _1-4 alkyl or -OR ₂₆₈ or -NR ₂₆₉ R ₂₇₀ wherein R ₂₆₈ z R ₂₆₉ ^{and R} 27o are each independently hydrogen or C 1-4 alkyl);

T --- 36

UI ^R28! (xxvi) wherein R _{28 is} Y ^is hydrogen or C _{x 6} alkyl; R ₂₈₁ is * hydrogen, chloro, fluorinated (preferably perfluorinated) C _x _ ₂ alkyl (preferably trifluormertilas or pentafluoroethyl, aryl, C _x _ ₄ alkyl, C _x _ ₄ aikilsulf inyl C _x _ ₄ alkylsulfonyl, C _x _ ₄ alkylthio , arylsulfinyl, arylsulfonyl, arylthio, arilmetilsulfinilas, arilmetilsul15 arilmetiltio or sulfonyl (wherein aryl denotes phenyl or 1-, or 2-naphthyl, each of which may be substituted by C _r _ ₄ alkyl, C _x _ ₄ alkoxy or fluoro, chloro or bromo, and R ₂₈₂ is hydroxymethyl, formyl, carboxyl, C ₂ _ ₄ alkoxymethyl, C _2-4 alkoxycarbonyl bakarboksimetilas AR20;

^R 290

/ 291 p ^R 292 (XXVII) wherein R ₂₉₀ is hydrogen or C _x _ ₆ alkyl and R ₂₉₁ and 30 ^ 292 both individually is hydrogen, C _x _ ₄ alkyl or phenyl (which may be substituted with C _x _ ₄ alkyl C _x _ ₄ alkoxy, fluoro, chloro or bromo, or R ₂₉₁ and R ₂₉₂ together with the carbon atom to which they are attached form C ₃ _ ₆ spiro cycloalkyl ring; or ^R 30I

X ^N 5> ^ - ^R 300 IĮ Ί

I £ 10 SO (xxviii) wherein A ₁₈₀ is oxygen, sulfur or -NR ₃₀₂ - a group of formula wherein R ₃₀₂ is C _{x 6} alkyl, A ₁₈₁ is nitrogen or methine, R ₃₀₀ is hydrogen, C _x . ₄ alkyl, C _x _ ₄ alkylthio, or aryl C _x _ ₄ alkyl (wherein aryl denotes phenyl which may be substituted by C _x _ ₄ alkyl, C _x _ ₄ alkoxy, or fluorine, chlorine or bromine and R _30I hydrogen, carboxyl, carbamoyl or -C (O) NR ₃₀₃ R ₃₀₄ group of the formula (wherein R ₃₀₃ and R ₃₀₄ are each a C _x _ ₄ alkyl or a hydroxy-substituted C _x _ ₄ alkyl, or C _x _ ₄ alkyl).

In the groups of formula xxv, R _{260 is} preferably ethyl, R ₂₆₂ is hydrogen, and R ₂₆₁ and R _{263 are} both methyl.

In the groups of formula xxvi, R _{280 is} preferably butyl and R ₂₈₁ is chlorine.

In the groups of formula xxvii, R _{290 is} preferably butyl and R ₂₉₁ and R ₂₉₂ together with the carbon atom to which they are attached form a spirocycloheptane ring.

In the groups of formula xxviii, A 1 _{SO 2 is} preferably a -NBu formyl group, R ₃₀₀ is hydrogen and R ₃₀₁ is a carboxyl group.

In the preferred compounds of formula I, A ₅₀ is a group of formula (iii) above, X ₅₀ is a bond, B ₅₀ is a group of formula (xxi) above, and Het is a heterocyclic ring as defined previously.

T

Priority compounds of formula I are compounds of formula II

wherein R ₁₃₀ is hydrogen or C _x _ ₄ alkyl;

I9o ^A is oxygen, sulfur or -NR ₃₁₉ - a group of formula wherein R ₃₁₉ is hydrogen or C _x _ ₄ alkyl;

and R ₃₁₄ are each a vandeC _x _ ₄ alkoxy, nitro, cyano, carboxyl, C _2-4 alkoxycarbonyl, C _x _ ₄ alkylthio, C _x _ ₄ alkilsuifinilas C _x _ ₄ alkylsulfonyl, phenyl (which may be substituted with C _x _ ₄ alkyl, C _x _ ₄ alkoxy, fluoro, chloro or bromo, C _ _{x 4} alkylsulfonylamino or C _x _ ₆ alkylsulfonylamino group, R ₃₁₅ is hydrogen or C _x _ ₄ alkyl; and R _316, R31- and R318 * kiek311

312 * '313 Nilis, fluoro, chloro, bromo, C _x _ ₄ alkyl, _X ^ _ ₄ is independently fluoro, chloro, - SO ₂ NR ₃₂ 1R322 or hydrogen, 0 _χ _ ₄ alkyl, nitro, bromo, cyano, formyl or -SO "R _q g ^x '32O *

-COR ₃₂₃ group of the formula (wherein R320 * R321 * R322 each independently are hydrogen or C _x _ ₄ alkyl, g is 1 or 2 and R ₃₂₃ is C _x _ ₄ alkyl, or -OR ₃₂₄ or -NR ₃₂₅ R 3 ₂ 6 Formula group, wherein R _324, R ₃₂₅ and R 326 each independently are hydrogen or C _x _ ₄ alkyl);

and pharmaceutically acceptable salts thereof.

Particularly preferred compounds of formula I are represented by formula III

_19o A III wherein R _310, R _315, R _316, R ₃₁₇ and R ₃₁₈ are each as defined above;

and pharmaceutically acceptable salts thereof.

Particularly preferred compounds of formula I are represented by formula IV:

paIV wherein A ₁₉₀ and R ₃₁₀ are as previously defined;

and pharmaceutically acceptable salts thereof.

Priority compounds of formulas II, III and IV contain oxygen and R ₃₁₀ is hydrogen.

τ

Further preferred compounds of formula I are represented by formula V

and pharmaceutically acceptable salts thereof;

wherein R ₃₃₀ is C ₂ . _x0 alkyl, C ₃ _ _x0 alkenyl, or (CH _{2) h} C _{3rd 6} cycloalkyl or - (CH ₂ ) _h -phenyl groups wherein h is O or an integer from 1 to 8 (capable of containing up to three C _{x 6} alkyl, nitro, cyano, halogen, fluoro, C _{x 3} perfluoroalkyl, C _ _{x 3} perfluoralkilsulfonilo C _x _ ₆ alkylsulphonyl, C _x _ ₆ alkylthio, hydroxy, C _x _ ₆ alkoxy or - NR33.jP.335, -CO ₂ R _334, -CONR _{334 R-33} 5 - (oR ₃₃₄ ) ₂ ,

-NR ₃₃₄ CHO, -NR ₃₃₄ O (C _x _ ₆ alkyl) or -NR ₃₃₄ COR ₃₃₆ substitutes a group of formula (in which R ₃₃₄ and R ₃₃₅ each independently are hydrogen or C _x _ ₄ alkyl and R ₃₃₆ is C _x _ Perfluoroalkyl ₃ );

A ₂₀₀ is a bond, sulfur or oxygen; R _33x is hydrogen, halogen, fluoro, formyl, nitro, C _{x 3} perfluoroalkyl, cyano, C _{x 6} alkyl, phenyl, hydroxymethyl or -CO ₂ R ₃₃₈ , -CONR ₃₃₈ R ₃₃₉ or -NR ₃₃₈ R ₃₃₉ (wherein R ₃₃₈ and R ₃₃₉ each independently are hydrogen or C _x _ ₄ alkyl);

m is O or an integer from 1 to 4;

z

B ₆₀ is 1,4-phenylene, 1,4-naphthylene or 2,5-pyridylene, which may contain one or more halogens,

I fluoride Cf_ ₄ alkyl, nitro, hydroxy, C _x _ ₄ alkoxy, Cf_ ₄ alkylsulfonyl, C ₃ _ _x perf iuoralkilo, nitrile, or -SO ₂ NiIR _338, -NHS ₂ R ₃₃₈ or -CONR ₃₃₈ R ₃₃ group of formula G substituents (wherein R ₃₃₈ and R _{33s are} each as previously defined);

A ₂₀₁ is oxygen, sulfur or -NR ₃₃₇ - a group of formula (in which R ₃₃₇ is hydrogen or C _{x. 4} alkyl);

R ₃₃₃ is hydrogen or C _1-4 alkyl;

^{0 r} 332 Group Y ^is selected from the group xxxxxxiii above:

^R 34O'X ____ ^ 341 ^R <342 (XXX), nitro, Cj., 3 Cf_ ₆ alkilkurioje R ₃₄₀ and R ₃₄₁ are each a hydrogen, Cf_ ₆ alkyl, C ₃ _ ₆ cycloalkyl or phenyl-Y ₇₀ -, biphenyl Y ₇₀ -, naphthyl-Y ₇₀ -, thienyl-Y ₇₀ -, furyl-Y ₇₀ -, pyridyl-Y ₇₀ -, pyrazolyl-Y ₇₀ -, imidazolyl-Y ₇₀ -, pyrrolyl-Y ₇₀ -, triazolyl-Y ₇₀ -, oxazolyl-Y ₇₀ -, isoxazolyl-Y ₇₀ -, thiazolyl-Y ₇₀ - or tetrazolyl-Y ₇₀ - wherein each aryl or heteroaryl group may contain hydroxyl, perfluoroalkyl, C _{x 3} perfluoroalkylsulfonyl, thio , Cf.g alkylsulfonyl, C _x _ ₆ alkyl, C _x _ ₆ alkoxy, halogen, or -NR ₃₄₃ R _344, -CO ₂ R _343, -SO ₂ NHR _343, -SO ₃ K, -CONR ₃₄₃ R ₃₄₄ , -NR ₃₄₃ CHO, -NR ₃₄₃ CO ₍₃ Cf_ perfluoroalkyl), or -NR ₃₄₃ CO (Cj_ ₆ alkyl) group of the formula, wherein each R ₃₄₃ and R ₃₄₄ each independently are hydrogen or C _x _ ₆ alkyl; Y ₇₀ is a bond, oxygen, sulfur or C _x _ ₆ alkylene which may be substituted by phenyl or benzyl, (wherein each phenyl or benzyl group may be halogen, nitro, Trif lųormetilo C _x _ ₆ alkyl, _Ο χ _ ₆ alkokT pinewood, cyano or -CO ₂ R a group of formula _345, wherein each R ₃₄₅ is hydrogen or C _x _ ₄ alkyl); R ₃₄₂ is present

-Y ₇₁ -COOR ₃₄₆ (wherein R ₃₄₆ is hydrogen, C ₄ _ ₆ alkyl, or

2-di (C 1-6 alkyl) amino-2-oxoethyl); -Y ₇₁ -CONR ₃₄₇ R ₃₄₈ (where R ₃₄₇ and R _{348 are} each independently hydrogen or C ₇ -C ₆ alkyl), or -Y ₇₁ -tetrazol-5-yl (wherein Y ₇₁ is a bond, vinylene, methyleneoxymethylene, methylene ( may optionally be substituted by C ₃ _ _e alkyl, one or two benzyl groups, thienylmethyl, furylmethyl), or -C (O) NHCHR ₃₄₉ - a group of formula (wherein R ₃₄₉ is hydrogen, C _x _ ₆ alkyl, phenyl, benzyl, thienylmethyl or furylmethyl));

350 ^ 351 ^ - (CH ₂₎ n -N - em R ₃₅₂ ^R 353 in formula (XXXI) wherein R ₃₅₀ and R ₃₅₁ are each a hydrogen or Ο ₄ _ ₆ alkyl; R ₃₅₂ is hydrogen, Ci_ ₈ alkyl, or thienyl-Y ₈₀ ~ furyl-Y ₈₀ -, pyrazolyl-Y ₈₀ -, imidazolyl-Y _B0 -, thiazolyl-Y ₈₀ -, pyridyl-Y ₈₀ -, tetrazolyl-Y ₈₀ - , pyrrolyl-Y ₈₀ -, triazolyl-Y _80, oxazolyl-Y ₈₀ -, isoxazolyl-Y ₈₀ - or phenyl-Y ₈₀ - a group of formula (wherein Y ₈₀ is a bond or C ₃ _ ₆ alkylene) with each aryl or heteroaryl group may have a C _x _ ₆ alkyl, C ₄ _ ₆ alkoxy, C _4-4 perfluoroalkyl, C ₇ _ ₆ alkylthio, C ₇ _ ₆ alkylsulfonyl, C ₃ _ ₄ perfluoralkilsulfonilo, halogen, hydroxy, nitro or -NR ₃₅₄ r ₃₅₅ , -co ₂ r ₃₅₄ , -so ₂ nhr ₃₅₄ , -so ₃ h, -conr ₃₅₄ r ₃₅₅ ,

-NR ₃₅₄ CHO, -NR ₃₅₄ COR _356, or -NR ₃₅₄ COC ₁ _ ₆ alkyl substituted with a group of formula (wherein R ₃₅₄ and R ₃₅₅ each independently are hydrogen or C ₃ _ ₄ alkyl and R ₃₅₆ is C ₄ _ ₄ perfluoroalkyl) ; R ₃₅₃ is a group of formula -CO ₂ R ₃₅₈ , -CONR ₃₅₈ R _357, or tetrazol-5il (wherein R ₃₅₇ and R _{358 are} each hydrogen or C 1-6 alkyl); on is O or an integer from 1 to 5;

^ 3 60 - (CH ₂₎ n N -------- j ^K?, 2 ;; TCH ₂ 3 PU ₃₆ (xxxii), wherein R ₃₆₀ is hydrogen, C ₄ _ ₆ alkyl, C _{3rd 6} alkenyl, alkylcarbonyl or ~ (CH _{2) 3 0} _ a phenyl group of the formula;

R ₃₆₁ is hydrogen, C ₄ _ ₆ alkyl, C ₃ _ ₆ alkenyl, or - (CH _{2) 0} -3 phenyl; R ₃₆₂ is -CO ₂ R _364, R _{365 364} -CONHR a group of formula (wherein R ₃₆₄ and R ₃₆₅ each independently are hydrogen or C ₄ _ ₆ alkyl) or tetrazol-5-yl;

n and p are each independently O or an integer from 1 to 4; o

R ₃₆₃ is phenyl, naphthyl, thienyl, furyl, pyridyl, pyrimidyl, imidazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyrrolyl, oxazolyl, or isoxazolyl, wherein each aryl or heteroaryl group may be substituted with C ₄ _ ₆ alkyl, Cj_ ₆ alkoxy, halogen, fluorine, hydroxy, nitro, C _x _ ₄ perf luoralkilu C ₄ _ ₆ alkylsulfonyl, C ₄ _ ₄ perfluoralkilsulfonilu C _{first 6} alkylthio or -NR ₃₆₆ R ₃₆₇ , -CO ₂ R ₃₆₆ ,

-CONR ₃₆₆ R

366 ^ 367,

-SO ₃ H, -SO ₂ NHR ₃₆₆ , -NR ₃₆₆ CHO; -NR _36e CO (C ₄ _ ₄ luoralkilas perf) or _1G6 -NRCOC alkyl (wherein R ₃₆₆ and R ₃₆₇ each independently are hydrogen or C _{4th 6} alkyl);

(xxxiii) wherein R ₃₇₀ is a -CO ₂ R ₃₇₃ , CONR ₃₇₃ R _374, or tetrazol-5-yl group; A ₂₁₀ is a bond or a carbonyl group; R ₃₇₁ is hydrogen, C _x _ ₈ alkyl, C ₃ _ ₆ cycloalkyl, phenyl, phenyl C _x _ ₄ alkylene or biphenyl or biphenyl C _x _ ₃ alkylene wherein each phenyl group may have up to three substituents selected from C _X _ ₆ alkyl, nitro, halogen, fluorine, hydroxy, C _x _ ₆ alkyl or NR375R376 '-CO ₂ R ₃₇₆ or -CONR ₃₇₅ R ₃₇₆ group of formula (where

R ₃₇₅ and R ₃₇₆ each independently are hydrogen or C _x _ ₄ alkyl); R ₃₇₂ is hydrogen or C _x _ ₆ alkyl; R ₃₇₃ and R ₃₇₄ are each a hydrogen, a C _x _ ₄ alkyl or - (CH _{2) 4 O} _ a phenyl group of the formula; on is C or an integer from 1 to 4.

The preferred compounds of formula V, B _60, are 1,4-phenylene which may be substituted as defined above.

Priority compounds of formula V are represented by formula VI:

VI ^R 333 ~ ^α 201 wherein R ₃₃₀ , A ₂₀₀ , R ₃₃₁ , R ₃₃₂ , A ₂₀₁ and R _{333 are} each as previously defined and R ₄₀₀ and R _{401 are} each independently hydrogen, halogen, fluorine,

C _x _ ₄ alkyl, nitro, hydroxy, C _x _ ₄ alkoxy, C _x _ ₄ alkylsulfonyl, C _x _ ₃ perfluoroalkyl, nitrile, or

-SO ₂ NHR _402, -NHS ₂ R ₄₀₂ or -CONR ₄₀₂ R ₄₀₃ group of the formula (wherein R ₄₀₂ and R ₄₀₃ each independently are hydrogen or C _x _ ₄ alkyl); while the other substituents are as defined previously.

Unless otherwise indicated, the previously used terms alkyl, alkenyl and alkynyl refer to linear or branched radicals having from 1 to 10 carbon atoms, preferably from 1 to 6 carbon atoms, and more preferably from 1 to 4 carbon atoms.

Where there are no other indications previously used the term aryl means phenyl or naphthyl, which may have halogen, C _x _ ₄ alkyl, C _x _ ₄ alkoxy, nitro, trifluoromethyl, C _x _ ₄ alkylthio, hydroxy, amino, di ( C _x _ ₄ alkyl) amino, carboxyl or esterif ikuotą C _x _ ₄ alkyl substituted by carboxyl groups.

Unless otherwise indicated, the term heteroaryl as used herein refers to a five or six membered aromatic ring containing up to 3 oxygen, nitrogen and / or sulfur atoms and which may contain hydroxyl, sulfhydryl, C _{x 4} 4alkyl, C _x _ _{4 4} alkoxyl, trifluoromethyl, halogen, fluoro, nitro, carboxyl, esterified C _x . ₄ alkyl, carboxy, amino, C _x _ ₄ alkylamino or di (C _x _ ₄ alkyl) amino substituents.

It will be understood that a group having 3 or more carbon atoms may be linear or branched, for example, propyl includes n-propyl and isopropyl, and butyl includes n-butyl, secondary, butyl, isobutyl and tertiary, butyl. the term halogen means bromine, chlorine or iodine.

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Specific compounds of the present invention include:

3- [4 '- (2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyrid-3-ylmethyl) biphenyl-2-yl] -4-isopropoxycyclobut-3-en-1, 2dion;

3- [4 '- (2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyrid-3-ylmethyl) biphenyl-2-yl] -4-hydroxycyclobut-3-en-1, 2-dione;

3-Amino-4- [4 '- (2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyrid-3-ylmethyl) biphenyl-2-yl] cyclobut-3-en-1 , 2-dione;

3- [4 '- (5,7-Dimethyl-2-propyl-3H-imidazo [4,5-b] pyrid-3-ylmethyl) -biphenyl-2-yl] -4-isopropoxycyclobut-3-ene-1,2-dione;

3- [4 '- (5,7-Dimethyl-2-propyl-3H-imidazo [4,5-b] pyrid-3-ylmethyl) -biphenyl-2-yl] -4-hydroxy-cyclobut-3-ene-1,2-dione;

2-ethyl-3- ^[2-one 3,4--izopropoksi dioksociklobut-l-en-lil) biphenyl-4-ylmethyl] -5,7, N, N-tetramethyl-3H-imidazo [4,5-b ] pyridine-6-sulfonamide;

2-ethyl-3- [2 '- (2-hydroxy-3,4-dioxocyclobut-1-enyl) biphenyl-4-ylmethyl] -5,7, N, N-tetramethyl-3H-imidazo [4 , 5-b] pyridine-6-sulfonamide;

3- [4 '- (6-Chloro-2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyrid-3-ylmethyl) -biphenyl-2-yl] -4-hydroxy-cyclobut-3-ene , 2-dione;

2- [4 '- (2-Ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyrid-3-ylmethyl) -biphenyl-2-yl] -3,4-dioxocyclobut-1-en- l -yloxymef 'til pivalate;

4-ethyl-1- [2 '- (3,4-dioxo-2-isopropoxycyclobut-1-enyl) biphenyl-4-ylmethyl] -2-propyl-1H-imidazole-5-carboxaldehyde;

4-ethyl-1- [2 '- (2-hydroxy-3,4-dioxocyclobut-1-en-1-yl) biphenyl-4-ylmethyl] -2-propyl-1H-imidazole-5-carboxaldehyde;

3-Dimethylamino-4- [4 '- (2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyrid-3-ylmethyl) biphenyl-2-yl] cyclobut-3-en-1 , 2dion;

1- [2- [4 '- (2-Ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyrid-3-ylmethyl) biphenyl-2-yl] -3,4-dioxocyclobut-1-ene -1-yloxy] -ethyl pivalate;

ethyl 4- [N-butyl-N- [2- (2-isopropoxy-3,4-dioxocyclobut-1-en-1-yl) biphenyl-4-ylmethyl] amino] pyrimidine-5-carboxylate;

ethyl 4- [N-butyl-N- [2 '- (2-hydroxy-3,4-dioxocyclobutyl-en-1-yl) biphenyl-4-ylmethylamino] pyrimidine-5-carboxylate;

4- [N-butyl-N- [2 '- (2-hydroxy-3,4-dioxocyclobut-1-en-yl) -biphenyl-4-ylmethylamino] pyrimidine-5-carboxylic acid;

3- [4 '- (2-Butyl-5-oxo-2-imidazolin-4-spirocyclopent-1-ylmethyl) biphenyl-2-yl] -4-isopropoxycyclobut-3-ene-1,2-dione;

3- [4 '- (2-Butyl-5-oxo-2-imidazolin-4-spirocyclopent-1-ylmethyl) biphenyl-2-yl] -4-hydroxycyclobut-3-ene-1,2-dione;

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2-Butyl-4-chloro-1- [2 '- (2-isopropoxy-3,4-dioxocyclobut-1-en-1-yl) biphenyl-4-ylmethyl)] -1H-imidazole-5-carboxaldehyde;

2-butyl-4-chloro-1- [2 '- (2-hydroxy-3,4-dioxocyclobuten-1-yl) biphenyl-4-methyl-methyl] -1H-imidazole-5-carboxaldehyde;

3- [4 '- (2-Butyl-4-chloro-5-hydroxymethyl-1H-imidazol-1-ylmethyl) biphenyl-2-yl] -4-isopropoxycyclobut-3-ene-1,2-dione;

methyl 2-butyl-4-chloro-1- [2 '- (2-isopropoxy-3,4-dioxocyclobut-1-en-1-yl) biphenyl-4-ylmethyl] -1H-imidazole-5-carboxylate;

methyl 2-butyl-4-chloro-1- [2 '- {2-hydroxy-3,4-dioxocyclobut-1-en-1-yl) biphenyl-4-methylmethyl] -1H-imidazole-5-carboxylate;

2-Butyl-4-chloro-1- [2 '- (2-hydroxy-3,4-dioxocyclobut-1-yl-1-yl) biphenyl-4-ylmethyl] -1H-imidazole-5-carboxylic acid; and (E) -2-Benzyl-3- [2-butyl-4-chloro-1- [4- (2-hydroxy-3,4-dioxocyclobut-1-en-1-ylbenzyl] -1H-imidazol-5-yl ] -propenoic acid;

and, where appropriate, pharmaceutically acceptable salts and / or solutions thereof, such as alkali metal salts, preferably sodium salts, and hydrochlorides.

The present invention also provides compounds of Formulas I-VI wherein A _y , A ₁₉₀ and A _{201 are} each oxygenated, wherein R ₅₀ , R _310, and R ₃₃₃ are each group which may be hydrolyzed in vivo leaving it Formula I- Compounds VI wherein R ₅₀ , R ₃₁₀ and

R333 is hydrogen, such groups including groups of formula xxxv -choco ~ ₄₁₁ r 1 ^r 4) 0 (xxxv) wherein R ₄₁₀ is hydrogen or C ₃ _ ₄ alkyl and R ₄₁₁ is C _x _ ₄ alkyl or C ₃ _ ₆ cycloalkyl; xxxvi formula groups

(χχχνί) wherein R ₄₁₂ and fyn are each independently hydrogen or C _{x 4} alkyl; and xxxvii formula groups

(χχχνϋ) wherein R ₄₁₄ is hydrogen or C _{x 4} alkyl.

Compounds containing such groups are generally described as pro-drugs. Scientists should be aware that these pro-drugs can utilize many other groups that are eliminated in vivo. Examples of these groups and methods for their introduction can be found in H. Bundgaard's article (Drugs of the Future (1991), 16, 443) and in the Design of Prodrugs (edited by H. Bundgaart, 1985 Elsevier Science Publishers BV, Biomedical Division) and Pro -drugs as Novel Drug Delivery Systems (T. Higuchi and V. Stella publishers, 1975, ACS Symposium Series 14, American Chemical Society, Wasbington DC). Except as otherwise stated, all references to the compounds of formulas I-VI above, where applicable, include the following prodrugs of the compounds of formulas I-VI.

The compounds of formula I-VI with acids and alkalis form salts. The following references to compounds of Formulas I-VI include all of these pharmaceutically acceptable salts of compounds of Formulas I-VI. Particularly suitable salts of the compounds of Formulas I-VI are, for example, alkali metal salts (such as sodium and potassium salts), alkaline earth metal salts (such as magnesium and calcium salts), aluminum and ammonium salts, salts with suitable organic bases such as such as alkylamines, N-methyl-D-glutamine, and salts with amino acids such as arginine and lysine. Inorganic acid salts such as hydrochlorides, hydrobromides, sulfates and phosphates and organic acid salts such as maleate and fumarate are also suitable.

Scientists should be aware that certain compounds of Formulas I-VI, or salts thereof, have one or more chiral centers. When a compound of Formulas I-VI has a single chiral center, it may exist in two enantiomeric forms which may be obtained separately by methods known to those skilled in the art. These methods generally involve the separation of diastereoisomeric salts or complexes by reformulation, which may be separated, for example, by crystallization; formation of diastereomeric derivatives which can be separated, for example by crystallization, gas-liquid or liquid chromatography; selective isolation of one enantiomer by reaction with a specific enantiomeric reagent, such as enzymatic oxidation or reduction; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support or in the presence of a chiral solvent. Optionally, specific enantiomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts, or solvents, or by converting one enantiomer into another by asymmetric transformation. The present invention includes all enantiomers of Formulas I-VI and mixtures thereof. When a compound of formula I-VI has more than one chiral center, it may exist in diastereoisomeric forms. Diastereoisomers may be separated by methods known to those skilled in the art, such as chromatography or crystallization. The present invention includes all diastereoisomers of compounds of formula I-VI and mixtures thereof. It will be appreciated that where the active phase is transformed using the separation procedures described above, a further step is required to convert the product into the active phase.

Certain compounds of Formulas I-VI, or salts thereof, may have more than one crystalline form, and the present invention includes all crystalline forms and mixtures thereof.

Certain compounds of Formulas I-VI may have the form of zwitterions, and the present invention includes zwitterionic forms and mixtures thereof.

Certain compounds of Formulas I-VI, or salts thereof, may also exist in the form of solvates, for example, hydτ wheels, and the present invention includes all solvates and mixtures thereof.

The present invention also provides pharmaceutical compositions comprising compounds of formula I-VI or salts thereof together with a pharmaceutically acceptable diluent or carrier. Specific compounds that may be included in the compositions of the present invention are the novel compounds described above.

The term active compound as used hereinbefore refers to a compound of formula I-VI, more preferably of formula II. When used therapeutically, the active compound may be administered orally, rectally, parenterally or topically, preferably orally. Thus, the pharmaceutical compositions of the present invention may be any known pharmaceutical composition for oral, rectal, parenteral or topical administration. The compositions may be formulated according to methods known to those skilled in the art to control the administration of the compounds of this invention. Pharmaceutically acceptable carriers suitable for use in these compositions are well known in the pharmaceutical art. Accordingly, the compositions of the invention contain 0.190% by weight of the active compound. The compositions of the invention are generally formulated in unit dosage form.

Formulations for oral administration are preferred compositions of the invention and are in the form of conventional use, such as tablets, capsules, syrups, and aqueous or oily suspensions. The excipients used in preparing these pharmaceutical compositions are known in the pharmaceutical art.

Tablets may be prepared by mixing the active compound with an inert diluent such as lactose or calcium phosphate in the presence of disintegrating agents such as magnesium stearate, and preparing the tablet from the mixture by known methods. If desired, these tablets may be enteric-coated by known techniques, for example, using cellulose acetate phthalalate. In general, capsules, for example hard or soft gelatin capsules, containing the active compound with or without added excipients, may be formulated in conventional manner and, if desired, enteric-coated in a known manner. Enteric-coated compositions of the present invention may be superior depending upon the nature of the active compound. The tablets and capsules may each contain between 1 and 500 mg of the active compound. Other compositions for oral administration include, for example, aqueous suspensions comprising the compound of formula I-VI in aqueous medium in the presence of a non-toxic suspending agent such as sodium carboxymethylcellulose, and oily suspensions comprising the compound of the present invention in a suitable vegetable oil. such as in arachis oil.

The present invention includes compositions for rectal administration in the form of known pharmaceutical forms for this use, for example, suppositories with semisynthetic glycerides or polyethylene glycol.

The compositions of the present invention for parenteral administration include sterile solutions of known pharmaceutical forms for such administration, such as sterile suspension in aqueous or oily medium in a suitable solvent.

Compositions for topical administration may be comprised of a binding agent in which the active compound is dispersed so as to be in contact with the skin for the transdermal effect of the compound of formula I-VI.

i

The active compound may optionally be dispersed in a cream or ointment base.

In some technologies, it would be useful to use the compounds of the present invention in the form of very fine particles, such as those obtained by vigorously grinding liquids.

In the compositions of the present invention, the active compound may, if desired, be associated with other similar pharmacologically active ingredients, such as a β-adrenoceptor antagonist such as atenolol, propranol, oxoprenolol, nadolol or timolol and / or a diuretic such as co-fluazide, ethacrylic acid or frusemide and / or angiotensin converting protein inhibitors such as captopril or enalapril and / or vasodilators such as hydralazine hydrochloride, flosechinone, sodium nitroprusside, glyceryl trinitrate or molzidomine, and / or potassium channel activators such as lemacinocin or , such as prazosin or labetalol, and / or other hypotensive agents such as chloridine, diazoxide, α-methyldopa or ketanserin, and / or positive inotropes such as milrinone, digitalis or dobutamine, inhibitors such as zaprinast, cifin bradycardic agents such as alinidine or phalipamil, an endothelin antagonist and / or an endothelin converting protein inhibitor and / or a renin inhibitor and / or a thrombolytic agent such as streptokinase.

and / or PDE and / or specific therapeutic activity of the compounds of formulas I to VI was demonstrated in standard laboratory animals. This test includes, for example, oral administration of compounds to spontaneously hypertensive rats. Thus, compounds of Formulas I-VI may be used to reduce blood pressure in hypertensive mammals. Regardless of the exact amount of active compound consumed, its use depends on many factors, such as the age of the patient, the severity of the medical history, and the limits of its use must be correctly determined by the prescribing physician. For mammals, including humans, a suitable dose for the small intestine is usually in the range of 0.01 to 25 mg / kg / day, more typically 0.2 to 10 mg / kg / day in single or divided doses. For parenteral administration, the dose is usually in the range of 0.001 to 2.5 mg / kg / day, more typically 0.005 to 1 mg / kg / day in single or divided doses or in continuous administration. Oral administration is a priority.

The compounds of formula I-VI and their salts contain angiotensin

II antagonists are therefore used in the treatment of hypertension in mammals, including humans. Compounds of Formulas I-VI are also nurgically compatible with acute and chronic persistent heart failure, glaucoma, primary and secondary hyperaldosteronism, primary and secondary pulmonary hypertension, cor pulmonale, renal failure, renal vasohypertension, angina, migraine, left ventricular treatment of blood vessel diseases (such as Raynaud's disease), scleroderma, diabetic nephropathy and prophylaxis of coronary insufficiency after myocardial infarction.

Accordingly, the present invention further provides the use of any of the compounds of Formulas I-VI for the treatment of said disorders and the use of any of the compounds of Formulas I-VI in the manufacture of a medicament for the treatment of said disorders.

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Methods of preparing compounds of Formulas I-VI will now be described.

These methods form a further aspect of the present invention.

Compounds of formula I wherein R 5 _O is C _{x 4} alkyl, A ₅₁ is oxygen, or is 1 may be prepared by reacting a compound of formula X with ch ₂

wherein f. is a leaving group such as halogen (e.g., bromine); and R ₅₀ is C _{x 4} alkyl; with a corresponding compound of formula Het-H wherein Het is as defined in the above list of structural formulas; inert to the reaction conditions in the solvent; better at base.

The compounds of Formula Het-H may be prepared by the methods set forth in the relevant patents cited above. In particular, compounds of formula Het-H wherein Het is a group of formula xxv, xxvi and xxvii may be prepared as described in EP-A-0400974 (Merck), WO-A9114679 (Sanofi) and EP-A-0475206 (Abbott). respectively.

Compounds of formula Het-H where Het is a group of formula xxvi can be obtained by Schunack [Arch. Pharmaz. (1974) Vol. 307, p 46] (for compounds wherein R ₈ is hydrogen), EP-A-0253310 (for compounds wherein R ₈ is chloro or trifluoromethyl), EP-A-0324337 (for compounds wherein R ₈ is pentafluoroethyl), WO -A-9200977 (for compounds wherein R ₈ is C _x _ ₄ alkyl), and EP-A-0465368 (for compounds wherein R ₈ is C ₄ _ _x alkylsulphonylamino inyl, alkylsulfonyl, C _x _ ₄ alkylthio, arylsulfinyl, arylsulfonyl, arylthio , arilmetilsulfinilas, arilmetilsulfonilas arilmetiltio or group [wherein aryl represents phenyl, which can be a C _x _ ₄ alkyl, C _x _ ₄ alkoxy, or fluoro, chloro or bromo substituted])

Compounds of formula X wherein L is a halogen such as chlorine or bromine may be prepared by reacting a compound of formula XI

with a chlorinating agent such as benzitriethylammonium tetrachlorododate or with a brominating agent such as N-bromosuccinimide; inert to the reaction conditions in the solvent.

Compounds of formula XI wherein X ₅₀ is a bond such that A ₅₀ and B ₅₀ are directly bonded via a carbon carbon bond (e.g., when A ₅₀ is a group of formula ii, iii, iv or v as previously described and B ₅₀ is xv , xix, xx, xxi or xxii) may be obtained by reacting compound XII

XII,

58 where Hal with formi is flaps halogen, respectively, with compound XIII CH ₃ - b ₅₀ - q ₅₀ bromine or iodine; XIII, in which ^B 50 is xv, xix, xx, xxi or xxii formulas group, how stated above; o Q ₅₀ means of course

combining aromatic ring group such as a boronic acid group of formula -B (OH) ₂ or a boronic acid derivative of formula -B (OAlk) ₂ (wherein Alk is C _x _ ₄ alkyl group) or a trialkyltin group of the formula - Sn (Alk) ₃ (wherein Alk is C _x _ ₄ alkyl group); inert to the reaction conditions in the solvent; a better reaction in the presence of a base such as sodium carbonate; respectively, in the presence of a metal catalyst such as palladium (O) or nickel (O) or by reacting the compounds of formula XII and XIII in a similar manner, modifying the substituents Q ₅₀ and Hal.

Compounds of formula XIII wherein B ₅₀ is a group of formula xv, xix, xx, xxi, or xxii as hereinbefore defined, or are known from the patent publications designated by the letters (m) and (q) to (t) as above, or are readily available from compounds described therein by methods well known in the art (for example, during the reaction reaction, by modifying a compound of formula XIII such that Q ₅₀ is lithium or a MgHal group (where Hal is halogen) by reaction with trialkylborate (such as triisopropylborate ° C to 0 ° C) in an inert reaction to the reaction conditions in a solvent (such as tetrahydrofuran) Hydrolysis in the presence of an acid (such as hydrochloric acid) can be performed to give a -B (OH) ₂ substitution in formula XIII.

Compounds of formula XII may be prepared by reacting a compound of formula XIV

wherein T is a trialkyltin group of formula -Sn (Alk) ₃ wherein Alk represents C _x _ ₄ alkyl group (preferably butyl group); with a compound of formula XV

Hal - A 5 _C - I XV wherein Hal is bromine or iodine, preferably bromine; inert to the reaction conditions in a solvent, preferably in the presence of a metal catalyst such as palladium (O) or nickel (O).

Compounds of formula XIV may be prepared as described by Liebeskind and Fengl in Journal of Organic Chemistry (1990) Vol. 55 pp. 5359/5364.

The compounds of Formula XV are either known from the above-mentioned patent publications designated letters (b) to (e) or are readily derived from the compounds described therein, for example by the halogenation reactions described above, respectively.

Compounds of formula XI may also be prepared by reacting a compound of formula XVI

CH ₃ - B ₅₀ - X ₅₀ - A ₅₀ - Met

XVI wherein Met is lithium or a group of the formula MgX wherein X is chlorine, bromine or iodine; with a compound of formula XVII

XVII wherein Alk is alkyl; followed by treatment with an acylating agent such as trifluoroacetic anhydride; inert to the reaction conditions in the solvent.

Compounds of Formula XVII are available from Aldrich Chemical Co. (In the United Kingdom).

Compounds of formula XVI may be prepared by reacting a compound of formula XVIII

CH ₃ - B ₅₀ - X ₅₀ - A ₅₀ - Hal XVIII wherein Hal is halogen, preferably bromine; with the C _x _ ₄ alkyl-lithium compound or magnesium metal; inert to the reaction conditions in the solvent.

Compounds of Formula XVIII wherein X ₅₀ is a bond such that A ₅₀ and B ₅₀ are linked via a carbon-carbon bond (e.g. A ₅₀ is a group of formula ii, iii, iv or v above and B ₅₀ is xv, xix, xx, xxi or xxii) can be obtained by reacting a compound of formula XIII with a compound of formula XIX as described above

Hal - A ₅₀ - XIX wherein Hal is halogen or iodine and A ₅₀ is a group ii, iii, iv or v of the above formula; inert to the reaction conditions in the solvent; preferably in the presence of a base such as sodium carbonate; a better reaction in the presence of a metal catalyst such as palladium (O) or nickel (O); or by reacting compounds of formula XII and XIX in the same manner, modifying them so that the substituents Q ₅₀ and Hal are substituted.

Compounds of Formula XVIII wherein X ₅₀ is a bond such that A ₅₀ and E ₅₀ are bonded via a carbon-carbon bond (e.g., when A ₅₀ is a group of formula ii, iii, iv, or v above and B ₅₀ is xv , xix, xx, xxi or xxii) may also be prepared by reacting a compound of formula XIII wherein Q ₅₀ is a group -MgHal (wherein Hal is bromine or chlorine) with a compound of formula XX

Hal - A ₅₀ - Hal XX wherein A ₅₀ is a group of formula ii, iii, iv or v as previously described and each Hal is independently chloro, bromo or iodo; inert to the reaction conditions in the solvent; a better reaction in the presence of a base such as sodium carbonate; preferably in the presence of a metal catalyst such as palladium (O) or nickel (0) or by reacting the compounds of formula XIII and XX in the same manner so that the substituents Q ₅₀ and Hal are interchanged therein.

Compounds of formula XIX and XX are either known from the above-mentioned patent publications designated letters (b) to (e) or readily derived from the compounds described therein.

ι

Compounds of formula I wherein A ₅₀ is oxygen, r is 1 and R ₅₀ is C _{x 4} alkyl may also be prepared by reacting a compound of formula XXI

Het - CH ₂ - B ₅₀ - X ₅₀ - A _so - I XXI with the above compound of formula XIV; inert to the reaction conditions in the solvent; preferably in the presence of a metal catalyst; for example palladium (O) or nickel (O) catalyst.

Compounds of formula XXI may be prepared by reacting a compound of formula XXII

LCH ₂ - B ₅₀ - X ₅₀ - A ₅₀ - I XXII wherein L is a leaving group, preferably halogen (e.g. bromine or chlorine) with a Het-H compound of the formula as previously described; inert to the reaction conditions in the solvent; better at base.

Compounds of formula XXI may also be prepared by reacting a compound of formula XXII (or a corresponding compound wherein L is an amine) with a precursor of the corresponding Het group of the formula and subsequently generating the Het residue in situ. Suitable methods are described in the aforementioned patent publications.

Compounds of formula XXII wherein L is bromine or chlorine may be prepared by reacting a compound of formula XXIII

CH ₃ - B ₅₀ - X ₅₀ - A ₅₀ - I XXIII f

with a chlorinating agent such as benzyltriethylammonium tetrachloroiodate, or with a brominating agent such as N-bromosuccinimide, e.g. inert to the reaction conditions in the solvent.

The foregoing compounds of formula XXIII wherein X is a bond such that A ₅₀ and B ₅₀ are bonded via a carbon-carbon bond (e.g., when A ₅₀ is a group of formula ii, iii, iv or v above and B ₅₀ is of formula xv, xix, xx, xxi, or xxii) may be prepared by reacting a compound of formula XIII above with a compound of formula XIX above; inert to the reaction conditions in the solvent; preferably by reaction with a base such as sodium carbonate; preferably in the presence of a metal catalyst such as palladium (O) or nickel (O) or by reacting the compounds of formula XIII and XIX in the same manner, modifying them in such a way that the substituents Q ₅₀ and Hal are substituted.

It will be appreciated that when a readily reactive substituent, such as a carboxyl, is present in a compound of formula Het-H or in a Het group of the formula, it is necessary to block this substituent (e.g., in this case by esterification of the carboxyl group). Following such a reaction, the unit may be removed (for example, by acidic or alkaline hydrolysis) to provide a free substitution if required.

Compounds of formula I wherein A ₅₀ is a group of formula vii above, R ₅₀ is C _{x 4} alkyl, X ₅₀ is a bond, r is 1, and A ₅₁ is oxygen may be prepared by reacting a compound of formula XL ι

XL wherein L is a leaving group such as halogen (e.g., bromine); and R ₅₀ is C _1-4 alkyl; with an appropriate compound of formula Het-H wherein Het is as defined in the above list of structural formulas; inert to the reaction conditions in a solvent (such as dimethylformamide); preferably in the presence of a base such as sodium hydride.

The compounds of formula xt, wherein R ₅₀ is C _1-4 alkyl and L is halogen, for example chlorine or bromine, may be obtained by reaction of a compound of formula XLI

P.

\ V {.3 ' ^r 132

XLI with a chlorinating agent such as benzyltriethylammonium tetrachloroiodate or with a brominating agent such as N-bromosuccinimide; inert to the reaction conditions in the solvent.

Compounds of formula XLI may be prepared by reacting a compound of formula XLII

^K 130 \\ [_7 / ^r 132

XLII with a compound of formula XVII above, followed by treatment with an acylating agent such as trifluoroacetic anhydride; in an inert solvent under reaction conditions.

Compounds of formula XLII may be prepared by reacting a compound of formula XLIII

XLIII with C 1-4 alkylthiol reagent (such as butyl lithium); inert to the reaction conditions in the solvent.

Formula XLIII compounds are known from WO-A-9215577 (Searie).

Compounds of Formula I wherein X ₅₀ is a non-linking group, but a linking group as previously described, may be prepared by the reactions described above, modified by appropriate alternative aromatic or aliphatic linkage reactions as described in FR-A-2669928 (Labs UPSA), EP-A-0323841 (Du Pont), EP-A-0475206 (Abbot),

EP-A-0449699 (Labs UPSA), US-A-5091390 (Du Pont), US-A4880804 (Du Pont) and US-A-5043349 (Du Pont) and references therein.

Compounds of formula V wherein A _20X is oxygen and R ₃₃₃ is C _{x 4} alkyl may be prepared by reacting a compound of formula L _α ^ν ΊΓ ^{Κ 331 r} 330 * 200 \ 'L.

N ^r 332 L (CK _? ): N

I ^z ~ ^{nai B} 60 with the above compound of the formula XIV (wherein R ₅₀ is R ₃₃₃₎ with respect to the reaction conditions in an inert solvent; preferably in the presence of a metal catalyst such as palladium (O) or nickel (O).

Compounds of formula L wherein R ₃₃₂ is a group of formula xxx may be prepared by dehydrating a compound of formula LI ^R 330 * 200 µ _. n - e— <

<CH ₂ lrn ^r ? <5OR _34X LI ^b 60 ^—For example, by reaction with a salivating agent such as acetic anhydride and subsequent treatment with a base,

Such as diazobicyclo [5.4.0] undec-7-enu in the reaction inert to the solvent.

Compounds of formula Ll may be prepared by reacting a compound of formula LII

LII with a compound of formula R 34iCH ₂ R _{342 in} an inert reaction to the reaction in a solvent such as a base such as lithium diisopropylamide. Compounds of formula R ₃ 4] CH ₂ R ₃₄₂ are well known in the art (e.g., EP-A-0425211; Smithkline Beecham).

Compounds of formula LII may be prepared by reacting a compound of formula Lili

Lili with a compound of formula LIV

L (CH ₂ ) _ra - B ₆₀ - Hal

LIV wherein Hal is bromine or iodine and L is a leaving group such as bromine or chlorine; inert to the reaction conditions in the solvent; preferably in the presence of a base such as potassium carbonate. This reaction results in a mixture of isomeric products which can be separated by conventional techniques such as column chromatography.

Compounds of formula Lili are known from EP-A-0425211 (Smithkline Beecham) or are readily derived from the compounds described herein by methods well known in the art.

The compounds of formula LIV are well known.

Compounds of formula L, wherein R ₃₃₂ is a group of formula xxxi, may be prepared by reacting a compound of formula LV

(CH ₂ ) m I ²

B ₆₀ -Hal

LV wherein Hal is bromine or iodine with an LVI of formula ^R 350 H -N *? 351 j ~ ^R 352 ^r 3S3

LVI under inert reaction conditions preferably in the presence of a catalyst, succinimide.

with respect to the solvent; such as N-hydro69

Formula LV compounds may be prepared as described in EP-A-0437103 (Smithkline Beecham).

Compounds of Formula LVI EP-A-0437103 may be obtained (Smithkline Beecham).

as described

Compounds of formula L wherein R ₃₃₂ is a group of formula xxxii may be prepared by reacting a compound of formula LVII ^R 330 ~ ^A 200

I (CH ₂ ) ro B ₆₀ ~ Hal

LVII wherein Hal is bromine or chlorine and L is a leaving group such as chlorine; with a compound of formula LVIII

363

LVIII in a reaction inert solvent such as dimethylformamide; preferably in the presence of a base such as triethylamine.

Compounds of Formula LVIII may be prepared as described in EP-A-0427463 (Smithkline Beecham).

Compounds of Formula LVII wherein n is greater than 1 are known from US-A-4340598 (Takeda) or are readily derived from compounds described herein by methods well known in the art.

Compounds of formula LVII wherein L is halogen and n is 1 can be obtained by reacting a compound of formula LIX

LIX wherein Hal is bromine or chlorine; with a halogenating agent such as thionyl chloride; inert to the reaction conditions in the solvent.

Compounds of formula LIX may be prepared by reacting a compound of formula LX ^r 330 ^{a 2} C u

I (CK! M I ²

LX with a reducing agent such as sodium borohydride;

inert to the reaction conditions in the solvent.

T

Formula LX compounds may be prepared as described in EP-A-0427463 (Smithkline Beecham).

Formula L compounds in which R ₃₃₂ has the formula xxxiii group, wherein R ₃₇₀ is carboxyl, A ₂₁₀ is carbonyl and R372 ^{is not} Y ^c i-6 alkyl, may be prepared by hydrolysis of a compound of formula LXI

LXI wherein R ₃₇₂ is C _{x 6} alkyl and R ₃₇₃ is as defined above but not hydrogen; for example, with a base such as aqueous sodium carbonate solution; inert to the reaction conditions in the solvent.

Formula LXI compounds wherein R ₃₇₂ is C ₁ _ ₆ alkyl, may be prepared by reacting the corresponding compound in which R ₃₇₂ is hydrogen, with a base such as sodium hydride followed by treatment with C _x _ ₆ alkyl halide in an inert reaction conditions, in a solvent .

Compounds of formula LXI wherein R ₃₇₂ is hydrogen may be prepared by reacting the above compound LVII of formula LII wherein L is chloro with a compound of formula LXII jG to ₇₃ ccG> ₂ -c ···

Well

LXII wherein R ₃₇₃ is as defined above but is not hydrogen; inert to the reaction conditions in a solvent (such as dimethylformamide).

Compounds of formula LXII may be prepared as described in WO-A-9200068 (Smithkline Beecham).

Compounds of formula L wherein R ₃₃₂ is a group of formula xxxiii wherein R ₃₇₀ is a -CO ₂ R ₃ 73 group, A ₂₁₀ is a bond, and R ₃₇₁ and R _{372 are} both hydrogen may be obtained by hydrolysis of a compound of formula LXIII

Λ

Ph Ph (CH-Air! *

B _6c -Hal

LXIII wherein R ₃₇₃ is as defined above but not hydrogen, for example by hydrolysis with a dilute acid such as hydrochloric acid; inert to the reaction conditions in the solvent.

Compounds of formula LXIII may be prepared by reacting a compound of formula LVII wherein L is chlorine with a compound of formula LXIV

Ph / = N-ęH-co ₂ -R _27J Ph bi

LXIV wherein R ₃₇₃ is as defined above but is not hydrogen; inert to the reaction conditions in a solvent (such as tetrahydrofuran).

Compounds of formula LXIV may be prepared as described in WO-A-9200068 (Smithkline Beecham).

Compounds of formula II (in particular compounds of the present invention) wherein R ₃₁₀ is alkyl o

A ₁₉₀ is oxygen, may be obtained by reaction of a compound of formula LXX

wherein L is a leaving group such as halogen, and R ₃₁₀ is C ₃ _ ₄ alkyl; with a corresponding compound of formula Het-H wherein Het is a group of formula xxxviii

(xxxviii) in a solvent inert to the reaction conditions; better at base.

Compounds of formula LXX wherein L is a halogen such as chlorine or bromine may be prepared by reacting a compound of formula LXXI

^R 311

LXXI wherein R ₃₁₀ is C _{x 4} alkyl; with a halogenating agent such as a chlorinating agent such as benzyltriethylammonium tetrachloroiodate, or with a brominating agent such as N-bromosuccinamide in a solvent inert to the reaction conditions.

Compounds of formula LXXI may be prepared by reacting a compound of formula LXXII

LXXII wherein Hal is halogen, preferably bromine or iodine, and R ₃₁₀ Y ^is C 1-4 alkyl; with a compound of formula LXXIII

LXXIII ° 50 wherein Q ₅₀ represents a boronic acid group of formula -B (OH) ₂ or trialkilstanil group of formula -Sn (Alk) ₃ (wherein Alk represents C _x _ ₄ alkyl group); inert to the reaction conditions in the solvent; a better reaction in the presence of a base such as sodium carbonate; preferably in the presence of a metal catalyst such as palladium (O) or nickel (O).

The compounds of formula LXXIII are well known.

Compounds of formula LXXII may be prepared by reacting a compound of formula LXXIV

LXXIV wherein R ₃₁₀ is C _x _ ₄ alkyl and T is a trialkyltin group of formula -Sn (Alk) ₃ wherein Alk represents a C ₂ _ ₄ alkyl group (preferably butyl group); with a compound of formula LXXV

LXXV wherein Hal is bromine or iodine, preferably bromine, in a reaction inert solvent, preferably in the presence of a metal catalyst such as palladium (O) or nickel (O).

Compounds of formula LXXIV may be obtained as described by Liebeskind and Fengl, Journal of Organic Chemistry (1990) Vol. 55 pp. 5359/5364.

Formula LXXV compounds are well known and available from Lancaster Synthesis Ltd or Aldrich Chemical Co. (United Kingdom).

Compounds of formula LXXI may also be prepared by reacting a compound of formula LXXVI

LXXVI wherein Met is lithium or a group of the formula MgX wherein X is chlorine, bromine or iodine; with compound of formula LXXVII n

n

Alko

Lxxvii wherein R ₃₁₀ is C ₃ _ ₄ alkyl and Alk is a C _x _ ₄ alkyl; followed by reaction with an acylating agent such as

T with trifluoroacetic anhydride; inert to the reaction conditions in the solvent.

Compounds of formula LXXVII are well known and are available from Aldrich Chemical Co. (United Kingdom).

are obtained by reacting

Compounds of Formula LXXVI may be of Formula LXXVIII

CH,

U '312 Γ J

LXXVIII, ^K 3?., Wherein Hal is halogen, preferably with a fused silica or metal bromine; with almagnesium; inert to the reaction conditions in the solvent.

Compounds of formula LXXVIII are described by Gomberg and Pernert (J. Am. Chem. Soc. (1926) Vol 48, p. 1373) and may be prepared as described there.

They can also be obtained by reacting formulas

For compound LXXIII, modifying it such that Q ₅₀ is a group of the formula MgHal (where Hal is chloro, bromo or iodo) with 1,2-diiodobenzene, 1,2-bromoiodobenzene, 1,2-dibromobenzene or 1,2-bromochlorobenzene (substituted with R, respectively). ₃₁₁ and / or R ₃₁₂ ) in an inert reaction to solvent conditions in the presence of palladium (O) or nickel (0) catalyst.

Compounds of formula LXXIII, modified by such that Q ₅₀ is a group of formula MgHal, may be prepared by reacting the corresponding compounds wherein Q 5 _U is chlorine, bromine or iodine with metallic magnesium; inert to the reaction conditions in the solvent.

Compounds of formula II wherein A ₁₉₀ is oxygen and R ₃₁₀ is lower alkyl may also be prepared by reacting a compound of formula LXXIX

LXXIX wherein Het is a group of formula xxxviii above; with a compound of formula LXXIV above, in an inert reaction solvent, preferably in the presence of a metal catalyst such as palladium (O) or nickel (O).

Compounds of formula LXXIX may be prepared by reacting a compound of formula LXXX

LXXX,

Where L is a leaving group, preferably halogen {e.g. bromine or chlorine); with a compound of the formula Het-H (wherein Het is a group of formula pateiktaνίϋ above) in a solvent inert to the reaction conditions, preferably in the presence of a base.

Compounds of formula LXXX wherein L is bromine or chlorine may be prepared by reacting a compound of formula LXXX1

CH-,

LXXXI with a chlorinating agent, such as benzyltriethylammonium tetrachlorododate, or with a brominating agent, such as / Nbromo-succinimide.

Compounds of formula LXXXI are known from Hammerschmidt and Vogtle (Chem. Ber. (1979) Vol. 112, p. 1785) and may be prepared as described therein.

Formula Het-H, wherein Het is as described above formula χχχνίϋ group wherein R _316, R ₃₁₇ and R ₃₁₈ are each independently hydrogen, C _x _ ₄ alkyl, nitro, fluoro, chloro, bromo, cyano or formyl group may be prepared obtained by the methods described in EP-A-0400974 (merck).

Compounds of formula Het-H wherein Het is a group of formula anksčiauνί pateikta above, wherein R ₃₁₇ is a group of formula -SO ₂ NR 3 ₂₀ R ₃₂₁ , can be prepared by reacting a corresponding compound of formula 3612 B with R ₃₁₇ is a sulfonyl chloride group; with an amine of the formula HNR ₃₂₀ R ₃₂₁ or a salt thereof; inert to the reaction conditions in the solvent.

Compounds of formula Het-H wherein Het is a group of formula xxxviii, by modification such that R ₃₁₇ is a sulfonyl chloride group, may be prepared by reaction of the corresponding compound of formula Het-H wherein R ₃₁₇ is an amino group; with a diazotizing agent such as an alkali metal nitrite under appropriate conditions (e.g., concentrated hydrochloric acid at a temperature below 5 ° C); adding a source of copper (I) ions (e.g., by adding copper chloride) and sulfur dioxide in an inert solvent to the reaction conditions.

Compounds of Formula I-Het Het-H wherein Het is a group of formula xxxviii wherein R ₃₁₇ is an amino group may be prepared by reduction of the corresponding compound wherein R ₃₁₇ is a nitro group with an appropriate reducing agent such as hydrogen. gas with a catalyst such as metal palladium catalyst.

Compounds of formula I, by modification such that R ₅₀ is a group of formula χχχν, xxxvi or χχχνίί of the above formula (e.g., so-called prodrugs) may be prepared by reacting the alkali metal salts of the above compound of formula I wherein A ₅₁ is oxygen. and R ₅₀ is hydrogen, with the compounds of the above formulas of formula formulν, χχχνί or χχχνίί, wherein in each of the foregoing structures, the free valence is attached to a halogen, preferably chlorine, in an inert reaction solvent; preferably in the presence of an alkali metal iodide such as potassium iodide.

T

Compounds of formula I wherein A ₅₁ is oxygen and R ₅₀ is hydrogen may be obtained by hydrolysis of a compound of formula I wherein A ₅₁ is oxygen and R ₅₀ is lower alkyl (obtained as described above), for example by heating with acidic acids. or under alkaline conditions.

Furthermore, compounds of formula I in which A ₅₁ is oxygen and R50 is hydrogen may be prepared by removing the blocks from the compounds of formula I in which A ₅₁ is oxygen, by modifying them so that R ₅₀ is a protecting group, for example:

1) an aralkyl group during ether decomposition, for example using hydrobromic acid, in a reaction inert to the liquid;

2) an aralkyl group (e.g. benzyl or trityl), for example, by hydrogenolysis such as hydrogen over palladium on carbon; or

3) a trialkylsilyl group (e.g. t-butyldimethylsilyl) by known silicon removal methods, for example by reaction with a fluoride source; such as tetrabutylammonium fluoride).

Experts should be aware of the many protecting groups that can be used. Examples of these protecting groups and methods for their attachment and removal can be found in T. W. Greene, John Wiley & Sons, 1981 textbook, Protective Groups in Organic Synthesis.

It should also be known that the previously described reactions with compounds wherein R ₅₀ is alkyl may also be carried out using the corresponding compounds by modifying them so that R ₅₀ contains a protecting group as previously described.

Therefore, on the other hand, the present invention provides novel intermediates of formula XC.

XC wherein Z is a protecting group of the type described above.

Formula I compounds wherein A ₅₁ is sulfur or a group of formula NR ₅₂ may be prepared by reacting a compound of formula XCI (CH _{2) o} - Het ^ o * 50 50 ^a 50

XCI wherein Hal is halogen, preferably bromine or chlorine; with a compound of formula HSR ₅₀ or HNR ₅₀ R ₅₂ (or its alkali metal salts), respectively; inert to the reaction conditions in a solvent (such as pyridine). When A ₅₁ is sulfur, this reaction is followed by interaction with a strong acid such as concentrated hydrochloric acid. In order to obtain the corresponding free acid, any salt formed, if desired, must be neutralized.

Compounds of formula I wherein A ₅₁ is sulfur or a group of formula -NR ₅₂ and R ₅₁ is C _{x 4} alkyl may also be

It is prepared by reacting a compound of formula XCI with hydrogen sulfide or ammonia, respectively, followed by treatment with an alkylating agent if necessary.

Compounds of formula XCI may also be prepared by reacting a salt of a compound of formula I, preferably an alkali metal salt, wherein A ₅₁ is oxygen and R ₅₀ is hydrogen; with a halogenating agent, preferably a chlorinating agent such as oxalyl chloride; inert to the reaction conditions in the solvent.

Compounds of formula I wherein A ₆₁ is -NR ₅₂ - wherein R ₅₂ is as previously described may also be prepared by interaction of a compound of formula I wherein A ₅₁ is oxygen and R ₅₀ is Ο _{4 -4} alkyl. HNR ₅₀ R ₅₂ or its alkali metal salts in a solvent inert to the reaction conditions.

All novel intermediates described herein containing a cyclobutendione ring in the present invention are key mediators and form an additional aspect of the invention.

Novel intermediates corresponding to the above structures of Formula I are also provided (e.g., structures of Formulas II, III and IV, modified so that R ₃₁₀ is a protecting group as described above).

Salts of the compounds of Formula I, which are also encompassed by the present invention, may be prepared by conventional methods, such as by reacting a free acid or free base form of a compound of Formula I with one or more equivalents of the corresponding acid or base.

The therapeutic activity of the compounds of the formula I was demonstrated in these experiments. In Assay A, retention of angiotensin II reT receptor on the adrenal membrane was determined in vitro, and in Assays B and C, the antihypertensive effect of the compounds was measured in vivo. The tests are described in more detail below.

Test A

1) Preparation of membranes

New Zealand white rabbit male adrenal glands were homogenized on ice in 20 mM aqueous sodium bicarbonate solution containing 50 μΜ PMSF (phenylmethanesulfonyl fluoride) (2 mL / g wet weight) using a Polytron (trademark) homogenizer, 3x15 seconds, adjusted to 8. The homogenate was centrifuged at 900 g for 10 minutes at 4 ° C and the precipitate was removed. The supernatant was centrifuged again at 30,000 g for 30 minutes at 4 ° C and the resulting pellet was suspended in assay buffer (50 mM Tris-HCl, pH 7.4 containing 1 mM EDTA,

6.5 mM UgCl, 125 mM NaCl, 50 μΜ PMSF, 5 pg / mL pepstatin and 50 pg / mL each leupeptin, antipain, aprotinin and chymostatin): 10 mL per gram of starting wet tissue. Polyethylene glycol (30% final concentration) was added as a cryopreservant, and the membrane preparation was divided into samples stored at -80 ° C as needed. The protein was determined by a modified Lowry method. (Markwell et al., (1978) Anai. Biochem., 87: 206-210).

2) Binding assay

Rabbit adrenal membrane specimens containing 10-30. μρ of protein was incubated with 0.05 nM [I] -angiotensin II in the presence or absence of a potential angiotensin II antagonist in 1 ml polyamide tubes in a total volume of 200 μΐ of assay buffer. After incubation for 60 minutes at 25 ° C, the reaction was stopped by the addition of chilled ice assay buffer, and bound and free radioactivity were separated through Skatron (brand) receptor binding filters after pre-moistening with assay buffer using the Skatron cell cutter. The filters were washed with chilled ice-phosphate-buffered saline, dried, and radioactivity was determined using a gamma counter. Non-specific binding, measured with 2 μΜ unlabeled angiotensin II, was subtracted from total binding to obtain specific binding. Radioligand binding curves were assayed using EBDA and LIGAND (Cambridge Bioscit). Binding pull values were obtained by non-linear regression analysis of non-transformed data.

The activities of the compounds described in the examples herein are reported in Table A, column 1, below.

Test B

Female Aoki-Okamoto strains of self-hypertensive rats, weight range 180-240 g were used. Groups of rats, four at a time, were fasted overnight prior to administration of the test compound. Blood pressure was measured this way. The rats were placed in a box kept at 38 ° C and their tails protruded through the holes in the box. After 30 min, blood pressure in the box was measured using a swollen cuff placed around the base of the tail, and arterial pulsations were controlled by a pneumatic pulse transducer. Pressure greater than expected blood pressure was applied to the cuff and this pressure was gradually reduced. Cuff pressure, which recurs with arterial pulsation, was taken as blood pressure. Rats were removed from the box and each group was orally dosed with a fixed dose of the test compound in solution or suspension in 0.25% aqueous carboxymethylcellulose. With no additive before measurement, blood pressure was measured 1.5 and 5.0 hours after dosing. The degree of blood pressure reduction required to achieve a significant p <0.01 level comparable to control was 9% after correction for control changes over time. Thus, in this test, compounds were considered active if, after a correction of 9% or greater, they caused a drop in blood pressure.

Limit doses of antihypertensive compounds of formula I were determined as follows. The compounds were initially tested at different dose levels, for example 90 mg / kg. If the compound was considered sufficiently active (yielding a blood pressure reduction of 16% or more after correction), it was re-tested at a lower dose level, for example 30 mg / kg. During testing, further low dose levels were used to determine the threshold antihypertensive dose (the dose that causes a reduction in blood pressure between 9% and 16% after correction). Inactive at a certain dose level, compounds causing a blood pressure decrease equal to or greater than 16% after correction were classified at the next higher dose level as having a marginal antihypertensive dose within two dose levels.

The activity of the compounds described in the examples below is given in Table A, column 2, below.

Test C

Modification was performed by performing procedure B of the above test, after pretreating rats with cofluazide 10 mg / kg (oral diuretic), to ensure activation of the reninangiotensin sisLT 3612 B theme, 16 and 2 hours prior to receiving the test compound.

The activity of the compounds 5 described in the examples below is given in Table A, column 3, below.

The antihypertensive activity of the compounds of the present invention may also be demonstrated in rats in which the renin-angiotensin system has been activated by surgical intervention.

TABLE A

FINAL 1 COLUMN COLUMN 2 COLUMN 3 EXAMPLE (Off in test A) (Limit antihiper- (Limit antihiper- PRODUCT (x10 ^"9 M) tensile dose in test B) (mg / kg) tensile dose in test C) (mg / kg) 1 97.6 - 30th 2 97.6 - 30th 4 5 0.1 0.1 5 1.78 1 1 6th 400 - - 8th 3.19 10th <10 9th 3.71 10th 0.1 11th 393 - - 12th 13.3 - - 13th 19th 10th <10 15th 13.5 - 3 16th 1890 - - 17th 21.5 - -

TABLE A (cont'd)

FINAL 1 COLUMN COLUMN 2 COLUMN 3 EXAMPLE (Off in test A) (Limit antihiper- (Limit antihiper- PRODUCT (x10 ^"9 M) tensile dose in test B) (mg / kg) tensile dose in test C) (mg / kg) 20th 81.7 3 1 22nd 3.68 - 30th 24th 31.1 - 3 28th 27.7 - 10th 29th 13.7 > 3 3 30th 77.9 - <10

The invention is illustrated by the following non-limiting examples in which the mixed solvent compositions are provided by volume. The novel compounds were characterized by one or more of the following methods: elemental analysis, nuclear magnetic resonance and infrared spectroscopy.

Flash chromatography was carried out according to the method described by Stili et al., J. Org. Chem. (1978), Vol. 43, pp. 2923-5.

An example

a)

Mixture of 3-isopropoxy-4-tributyltin cyclobut-3-en-1,2-dione (4.68 g; preferably as described by Liebeskind and Fengl, Journal of Organic Chemistry (1990), Vol. 55, pp. 5359/5364). , l-bromo-2-iodobenzene (3.54 g), dry dimethylformamide (15 mL), tetrakis (triphenylphosphine) palladium (O) (0.606 g) and copper iodide (0.196 g) were stirred under nitrogen at room temperature for about 2.5 hours and then it is kept at room temperature for 3 days. Diethyl ether (225 mL) was added and the resulting mixture was washed first with saturated aqueous ammonium chloride solution (225 mL) followed by 10% aqueous potassium fluoride solution (3x225 mL). The organic phase was filtered through a pad of silica (5 cm diameter x 1 cm height) and the collected dry residue was washed with diethyl ether (50 mL). The resulting orange filtrate and washings were combined and evaporated. A semi-liquid brown oil was obtained, which was purified by flash chromatography on silica gel (eluting with dichloromethane and washing with 20% diethyl ether in petroleum ether (boiling point 40-60 ° C)). The resulting intermediate was 3- (2-bromophenyl) -4-isopropoxycyclobut-3-ene-1,2-dione - a yellow oil (2.16 g).

b)

The product of Example 1 above (2.16 g) was dissolved in toluene (170 mL) and 4-methylbenzenesulfonic acid (1.94 g), tetrakis (triphenylphosphine) palladium (O) (0.53 g), ethanol (8.3 mL) and aqueous solution were added to the solution. sodium carbonate solution (2M; 8.3 mL). The resulting mixture was heated in a rectifying flask under nitrogen for 3.5 hours. The resulting dark reaction mixture was left to cool to room temperature and then washed with water (2X50 mL). The organic phase was dried over magnesium sulfate and then evaporated. Obtained a brown oil (3.37 g) which was purified by flash chromatography on silica gel (eluting with dichloromethane). A yellow oil (1.48 g) was obtained and this oil was mixed with petroleum ether (boiling point 40-60 ° C): diethyl ether mixture 1: 1. A yellow suspension was obtained. The solution was filtered and the resulting solid residue was washed with petroleum ether (boiling 40-60 ° C) and dried in vacuo. Further intermediate was obtained

3-Isopropoxy-4- (4'-methyl-biphenyl-2-yl) -cyclobut-3-ene-1,2-dione-pale yellow solid (0.96 g; mp 120-130 ° C).

c)

3- Isopropoxy-4- (4'-methylbiphenyl-2-yl) cyclobut-3-ene-1,2-dione (1.24 g; preferably as described in the example).

1 (b)), carbon tetrachloride (40 ml), recrystallized N-bromosuccinimide (0.79 g) and AIBN (azobis (isobutyronitrile)) (40 mg) were heated in a rectifying column flask for 4.5 hours. AIBN (23 mg) was then added and the mixture heated for a further 4.5 hours. The mixture is kept at room temperature for about 16 hours and then quenched with ice-water. The yellow supernatant was separated. The resulting off-white solid was washed with cold carbon tetrachloride (about 3 mL). The resulting yellow supernatant and washings were combined and evaporated. The resulting yellow gum was dried in vacuo. The intermediate is obtained

3- (4'-Bromomethyl-biphenyl-2-yl) -4-isopropoxy-cyclobut-3en-1,2-dione (1.74 g).

d)

2-Ethyl-5,7-dimethyl-3H-imidazo [4.5-b] pyridine (0.66 g; obtained as described by Mantio et al., J. Med. Chem. 34, (1991), pp. A-0400974; Merck) and anhydrous potassium carbonate (1.02 g) were added to 3- (4'-bromomethylbiphenyl-2-yl) -4-isopropoxycyclobut3-en1,2-dione (1.88 g preferably as described in Example 1 (c)). dry dimethylformamide 910 mL) and the resulting mixture was stirred at room temperature for about 16 hours. To the resulting dark reaction mixture was added 2-ethyl-5,7-dimethyl-3H-imidazo [4.5-b] pyridine (0.33 g) and stirred for a further 24 hours at room temperature. The resulting dark mixture was partitioned between ethyl acetate (100 mL) and water (50 mL). The organic layer was separated, washed with water (50 mL) and dried over magnesium sulfate. The resulting solution was evaporated. Obtained a dark oil which was purified by flash chromatography on silica gel (eluting with 1% technical alcohol in dichloromethane), repeated chromatography on silica gel (elution with ethyl acetate), and chromatography again on silica gel (elution with 0% to 2% methanol in dichloromethane). The active compound of this invention, 3- [4'-2 (ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyrid-3-ylmethyl) -biphenyl-2-yl] -4-isopropoxycyclobut-3-en-1, was obtained. 2- Dione - Yellow foam slowly melting at 60 ° C or below.

An example

a)

A mixture of 1,2-diiodobenzene (6.6 g) and tetrakis (triphenylphosphine) palladium (O) (0.34 g) was stirred at room temperature in AR toluene under a nitrogen atmosphere. An aqueous solution of sodium corbonate (2 g) (15 mL) was added. The resulting orange mixture was heated under stirring in a flask with a screaming column and a solution of 4-methylbenzene boronic acid (1.36 g) in technical methyl alcohol was added portionwise over 40 minutes. The resulting mixture was heated in a flask with a rectification column for a further 4 hours, then cooled to room temperature. Aqueous hydrogen peroxide (30%; 1 mL) was added and the resulting mixture was stirred at room temperature for 1 hour. Saturated sodium chloride solution was added and the organic phase separated. The aqueous phase is extracted with ethyl acetate (2 x 50 mL) and the combined organic phases are washed with saturated sodium chloride solution (1 x 70 mL) and dried over magnesium sulfate. An orange gum was obtained. This resin was mixed with petroleum ether (boiling point 40-60 ° C) (200 mL). The resulting resin was partially purified by flash chromatography on silica gel (petroleum ether (boiling 40-60 ° C): ethyl acetate (4: 1)) and further purified by flash column chromatography on silica gel (petroleum ether (boiling petroleum ether)). 60-80 ° C) 200 ml / min). The intermediate 2'-iodo-4-methylbiphenyl was obtained as a colorless oil (1.3 g).

b)

The product of Example 2 (a) above (1.23 g) was dissolved in carbon tetrachloride (30 mL). N-Bromosuccinimide (0.82 g) was added followed by AIBN (33 mg). Heat the resulting mixture in a flask with a rectifying column for 4.5 hours and then keep it at room temperature for approximately 16 hours. The resulting bright pink supernatant solution was separated and the resulting solid white residue mixed with additional carbon tetrachloride (about 3 mL). The supernatant and subsequent washings were combined and then evaporated. Further intermediate 4- (bromomethyl) -2'-iodobiphenyl is obtained as a bright pink / red oil (1.69 g).

c)

2-Ethyl-5,7-dimethyl-3H-imidazo [4.5-b] pyridine (0.731 g) and anhydrous potassium carbonate (1.15 g) were stirred in dry dimethylformamide (10 mL) for 10 minutes. A solution of the product of Example 2 (b) (1.65 g) in dry dimethylformamide (10 mL) was added portionwise over about 5 minutes. The resulting suspension was stirred at room temperature for about 16 hours and then partitioned between diethyl ether (50 mL) and water (50 mL). The layers were separated and the aqueous phase was further extracted with diethyl ether (25 mL). The combined organic phases were dried over magnesium sulfate and evaporated. Obtained a brown oil. This π

the oil was purified by flash chromatography on silica gel (eluting with acetate) followed by vacuum drying. The intermediate 2-ethyl-3- (2'-iodobiphenyl-4-ylmethyl) -5,7-dimethyl-3H-imidazo [4.5-b] pyridine was obtained as a brown oil (1.07 g).

d)

A portion of the product of Example 2 (c) (97 mg) was dissolved in dry dimethylformamide (1 mL). 3-Isopropoxy-4-tributyl tin cyclobut-3-ene-1,2-dione (91 mg) was added followed by tetrakis (triphenylphosphine) palladium (O) (20 mg) followed by copper iodide (8 mg). and stirred under nitrogen for 70 minutes. Thereafter, tetrakis (triphenylphosphine) palladium (O) (16 mg) and copper iodide (9 mg) were added and stirring was continued at room temperature for another 50 minutes. Additional 3-isopropoxy-4-tributyltin-cyclobut-3-ene-1,2-dione (41 mg) was then added and stirring was continued for a further 72 hours. The solution was then combined treated (see f below).

e)

The product residue of Example 2 (c) (0.94 g) was dissolved in dry dimethylformamide (4 mL) and the resulting solution was stirred at room temperature under nitrogen until 3-isopropoxy-4-tributyltin cyclobut-3-ene-1,2-dione was added. 1.29 g), tetrakis (triphenylphosphine) palladium (O) (0.143 mg) and copper iodide (40 mg). The resulting mixture was stirred at room temperature for 5.5 hours. Tetrakis (triphenylphosphine) palladium (O) (0.14 g) and copper iodide (0.12 g) were then added. After stirring under nitrogen for a further 72 hours, the resulting solution was combined (see f below).

f)

The two red-brown reaction solutions of (d) and (e) above were combined, diluted with diethyl ether (75 mL) and washed with saturated aqueous ammonium chloride solution (50 mL) followed by 10% aqueous potassium fluoride solution (3 x 30 mL). ). A gray solid, insoluble in both phases, was obtained. The organic phase was filtered through diatomaceous earth (trade name Celite), separating a small aqueous phase. The organic phase was evaporated. An orange oil was obtained which was partially purified by flash chromatography on silica gel (eluting with methanol in dichloromethane 0 to 4% in ascending order). Further purification was carried out by chromatography on silica gel (eluting with diethyl ether). A semi-liquid foam was obtained, which was fractured and dried in vacuo. The resulting active compound of the present invention is 3- [4 '- (2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyrid-3-ylmethyl) biphenyl-2-yl) -4-isopropoxycyclobutyl. The 3-en-l, 2dione yellow solid (0.42 g) was substantially identical to the product of Example 1 (d).

An example

a)

To a solution of 1-bromo-2-iodobenzene (200 g) and 4-methylbenzene boric acid (105 g) in toluene (1 L) was added sodium carbonate (164.8 g), technical methyl alcohol (165 ml), water (165 ml) and after all, tetrakis (triphenylphosphine) palladium (O) (40.8 g). The resulting mixture was stirred at 95-100 ° C under nitrogen for hours. After cooling to room temperature, water (1 L) was added and the resulting mixture was stirred for minutes. The organic layer was separated and dried over magnesium sulfate 3612. The solvent was evaporated under reduced pressure to give a crude product.

The reaction described above was repeated at x0.45, and the crude products of both reactions were combined and stirred for 30 minutes in hexane (1 L). The insoluble material was filtered off, and the solvent was evaporated under reduced pressure through a fractionation column _; filled with glass spirals. The intermediate is obtained

2-Bromo-4'-methylbiphenyl (241.7 g) as a colorless oil (boiling 98-102 ° C at 0.8 mmHg).

b)

To a solution of 2-bromo-4'-methylbiphenyl (9.0 g; prepared as described in Example 3 (a) and Gomberg and Pernert, J. Am. Chem. Soc. (1926) Vol 48p 1373) in tetrahydrofuran (60 mL) was added. Butyl lithium (2.5M in hexane,

15.3 ml). The mixture was stirred at -70 ° C for 10 min and then a solution of 3,4-diisopropoxycyclobut-3-en-1,2-dione (7.6 g) in tetrahydrofuran (100 mL) was added over 1 min at -70 ° C. ). The resulting solution was stirred for an additional 30 minutes at -70 ° C and then treated with trifluoroacetic anhydride (6.4 mL) and saturated aqueous ammonium chloride (40 mL). The resulting mixture was allowed to warm to room temperature and then partitioned between diethyl ether (300 mL) and aqueous sodium bicarbonate (5%, 300 mL). The aqueous layer was extracted once more with diethyl ether (200 mL) and the combined organic layers were washed with brine, dried over magnesium sulfate and evaporated. A yellow oily solid was obtained which was purified by flash chromatography on silica gel (eluting with a gradient of 10% to 20% ethyl acetate in petroleum ether (boiling point 60-80 ° C)). The intermediate 3-isopropyl 3612B-oxy-4- (4'-methibiphenyl-2-yl) cyclobut-3-ene-1,2-dione is obtained as a yellow solid substantially identical to the product of Example 1 (b). The above method is described in Reed et al., Journal of Organic Chemistry (1988) Vol. 53, p 2477.

It is understood that this intermediate may react as described, for example, in Examples 1 (c) and 1 (d) to form the active compounds of the present invention, such as the active compound of Example 1.

An example

The final products of Examples 1 and 2 (0.35 g), glacial acetic acid (7.5 ml), and water (7.5 ml) were heated at 95-100 ° C under nitrogen for 5 hours. The resulting yellow solution was filtered through cotton wool and evaporated. A glassy brown oil was obtained. This oil was mixed with ethyl acetate (5 mL) to give a yellow solid which was dried in vacuo at 70 ° C. The resulting active compound of the present invention is 3- [4 '- (2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyrid-3-ylmethyl) biphenyl-2-yl] 4-hydroxycyclobut-3-en-1, 2-dione (0.23 g; m.p. 245-247 ° C).

An example

3- [4 '- (2-Ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyrid-3-ylmethyl) biphenyl-2-yl] -4-hydroxycyclobut-3-en-1, 2-Dione (1.3 g; preferably as described in Example 4) was suspended in distilled water (10 mL) and aqueous sodium hydroxide solution (0.1 M; 29 mL) was added portionwise. The resulting mixture was evaporated under reduced pressure (bath temperature% C or lower). A brown oil was obtained which was mixed with diethyl ether (50 mL). A yellow solid was obtained. This solid was collected and dried under vacuum at 60 ° C. The dried material was then mixed with diethyl ether (100 mL) and dried again in vacuo at 70 ° C. The resulting active compound of the present invention is 3- [4'- (2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyrid-3-ylmethyl) biphenyl-2-yl] -4-hydroxycyclobut-3. -en-i, 2-dione sodium salt (1.18 g). Juniper melts slowly at temperatures of 180 ° C or lower.

An example

3- [4 '- (2-Ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyrid-3-ylmethyl) -biphenyl-2-yl) -4-isopropoxy-cyclobut-3-ene -1.2dione (0.44 g; more preferably as in Example 2) was stirred in saturated ammonia ethanol solution (10 mL) for 3 hours at room temperature and then left at room temperature for an additional 16 hours. The solvent was evaporated and the resulting residue was mixed with diethyl ether. An off-white solid was obtained, which was dried in vacuo. The resulting active compound of the present invention is 3-amino20 4- [4 '- (2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyrid-3-ylmethyl) biphenyl-2-yl]. cyclobut-3-ene-1,2-dione (0.25 g; mp 217 ° C).

An example

To a stirred suspension of sodium hydride (0.15 g; 60% in mineral oil) in dry dimethylformamide (10 mL) was added 5,7-dimethyl-2-propyl-3H-imidazo- [4,5-b] pyridine (0.69 g) over 15 minutes. ) (preferably as described by Mantio et al., J. Med. Chem. 34, (1991), pp. 2919/2922 and EP-A-0400974; Merck) Stirring was continued for another 30 minutes. The resulting solution was added to a stirred solution of 3- (4'-bromomethylbiphenyl-2-yl) -4-isopropoxycyclobut-3-ene-1,2-dione (1.46 g; preferably as described in Example 1 (c) in dry dimethylformamide (10 mL)). Stirring at 0-5 ° C was continued for Ϊ an hour The resulting dark solution was poured into ethyl acetate (75 mL) and the resulting mixture was washed with water (60 mL) The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water (3x6 ml) and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure, and the resulting residue was purified by flash chromatography on silica gel (ethyl acetate / petroleum ether 40 ml). ° C) (4: 1)) to give the active compound of the present invention 3 [4 '- (5,7-dimethyl-2-propyl-3H-imidazo [4,5-b] pyrid-3-ylmethyl) -biphenyl. -2-yl] -4-isopropoxycyclobut-3-ene-1,2-dione - yellow gum (0.73 g).

An example

A solution of the final product of Example 7 in a mixture of acetic acid (30 mL) and water (17 mL) (0.73 g) was stirred at 95-100 ° C under nitrogen for 18 hours. The solvent was evaporated under reduced pressure and the resulting residue was mixed with ethyl acetate (20 mL). The active compound of the present invention is 3- (4 '- (5,7-dimethyl-2-propyl-3H-imidazo [4,5-b] pyrid-3-ylmethyl) biphenyl-2-yl] -4-hydroxycyclobut-3. -en-1,2-dione-yellow solid (0.44 g; mp 240 ° C, liquid from 210 ° C).

An example

The final product of Example 8 (0.40 g) was dissolved in a mixture of aqueous sodium hydrochloride solution (2.5M; 15 mL) and technical methyl alcohol (15 mL) and the resulting solution was extracted with dichloromethane (2 x 15 mL). The combined extracts were dried over magnesium sulfate and the solvent evaporated. 3- (4- (5,7-Dimethyl-2-propyl-3H-imidazo [4,5-b] pyrid-3-ylmethyl) -biphenyl-2-yl] -4-hydroxycyclobut-3-en-1 is obtained. Sodium 2-dione (0.4 g; m.p. 182 ° C, with slight decomposition) is the active compound of this invention.

TT

10 'Example

a)

2-Ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridine is added to the stirred sulfuric acid (2.17 g) and the resulting solution is heated to 80 ° C. Potassium nitrate (3.0 g) was added portionwise over 10 minutes and the resulting mixture was heated at 95-100 ° C for 10 minutes, cooled and then poured onto ice (about 25 g). The mixture was neutralized with concentrated ammonia solution and then extracted with dichloromethane (2 x 50 mL). The combined extracts were dried over magnesium sulfate and then the solvent was evaporated. The resulting residue was recrystallized from ethyl acetate (15 mL) to give the intermediate 2-ethyl-5,7-dimethyl-6-nitro-3H-imidazo [4,5-b] pyridine (1.01 g, m.p. 146-). 149 ° C).

A solution of the product of Example 10 (a) (1.01 g) in technical methanol (75 mL) is shaken at room temperature under a hydrogen palladium on carbon (10%; 120 mg) and pressure for 7 hours. The resulting mixture was filtered through diatomaceous earth (trade name 'Celite') and the filtrate was evaporated. A viscous pale brown oil was obtained. Trituration of this oil in diethyl ether (30 mL) gave the intermediate 6-amino-2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridine (0.88 g; mp 153-155 ° C). ).

c)

6-Amino-2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridine (1.89 g; more than 10 (b)) was dissolved in concentrated hydrochloric acid (2.6 mL) and water (2.6) by stirring. ml) in the mixture and the mixture was cooled to below 5 ° C. In support of inferior, neLT 3612 B

100 g at 5 ° C, a solution of sodium nitrite (0.76 g) in water (2.2 ml) was added portionwise. The resulting solution (A).

Copper iodide (0.26 g) was dissolved in saturated sulfuric acetic acid (10 mL) and the resulting solution (B) was cooled to 10 ° C. To 1 stirred cooled solution (B) at 0-10 ° C, add solution (A) in portions over 10 minutes. The resulting mixture was stirred for 3.5 hours at 10-15 ° C, ice (100 g) was added, followed by extraction with dichloromethane (3X50 ml). The combined extracts were dried over magnesium sulfate and the solvent evaporated. A pale yellow solid was obtained, which was added portionwise to aqueous dimethylamine solution (30%; 20 mL) at room temperature. The solvent was evaporated under reduced pressure and the resulting residue was stirred with water (5 mL). Intermediate 2-ethyl-5,7, N, N-tetramethyl-3H-imidazo [4,5-b] pyridine-6-sulfonamide (0.21 g; m.p. 179-182 ° C) was obtained.

d)

To a solution of the product of Example 10 (c) (0.19 g) in dry dimethylformamide (2 mL) under nitrogen was added sodium hydride (60% dispersion in mineral oil; 25 mg) and the resulting mixture was stirred for 10 minutes. The resulting solution was added dropwise at 0-5 ° C to a stirred solution of 3 (4'-bromomethyl-biphenyl-2-yl) -4-isopropoxycyclobut-3-ene-1,2-dione (0.289 g; preferably as in Example 1 (c)). solution in dry dimethylformamide (2 ml). ' The resulting mixture was stirred at room temperature for 1.5 hours, poured into ethyl acetate (50 mL) and then washed with water (2 x 25 mL). The washings were then extracted with ethyl acetate (40 mL). The combined organic solutions were dried over magnesium sulfate and the solvent evaporated under reduced pressure. The resulting residue was purified by silica gel flash chromatography (eluting with ethyl acetate / petroleum ether (boiling point 40-60 ° C) (4: 1)). Gau-r

The active compound of this invention is 2-ethyl-3- [2 '- (2-isopropoxy-3,4-dioxycyclobut-1-en-1-yl) biphenyl-4-ylmethyl] -5,7, N, N- hetramethyl-3H-imidazo [4,5-b] pyridine-6-sulfonamide (0.2 mp 80 ° C with slow decomposition).

Example A solution of the final product of the sample (0.19 g) in a mixture of acetic acid (8.3 ml) and water (3.7 ml) was heated at 95-100 ° C for 15 hours. The solvent was evaporated under reduced pressure and the resulting residue was mixed with ethyl acetate (5 mL). The resulting solid was collected and dried under vacuum at 70 ° C. The resulting active compound of the present invention is 2-ethyl-3- [2 '- (2-isopropoxy-3,4-dioxocyclobut-1-en-1-yl) biphenyl-4-ylmethyl] -5,7, N, N-tetramethyl-3H. - Imidazo [4,5-b] pyridine-6sulfonamide monoethyl acetate solvate (0.15 g; m.p. 195-197 ° C (by decomposition)).

a)

6-Amino-2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridine (0.85 g; preferably as in Example 10 (b)) was stirred with concentrated hydrochloric acid (1.15 mL) and water (1.15). ml> in the mixture, and the resulting solution was cooled to 0 [deg.] C. A solution of sodium nitrite (0.34 g) in water (1 ml) was added portionwise at an internal temperature below 5 [deg.] C. The resulting solution was stirred at this temperature for 10 minutes and it was added to a stirred solution of copper chloride (0.48 g) in concentrated hydrochloric acid (1.7 ehI) at a temperature below 10 [deg.] C. The resulting mixture was stirred at 70 [deg.] C. for 2 hours, then cooled to room temperature. The residue was washed with water (5 mL) and the second portion of the intermediate identified above (70 mg) was recrystallized from methanol.

102

b)

To a suspension of the product of Example 12 (a) (0.28 g) in dry dimethylformamide (4 mL) was added sodium hydride (60% dispersion in mineral oil; 91 mg), and the resulting mixture was stirred at room temperature under nitrogen for 30 minutes. The resulting mixture was added portionwise to a solution of 3- (4'-bromomethylbiphenyl-2-yl) -4-isopropoxycyclobut-3-en-1,2-dione (0.548 g; more preferably as described in Example 1 (c)) in dry dimethylformamide (5). ml). The resulting mixture was stirred at room temperature for 5 hours and then poured into ethyl acetate (70 mL). The resulting mixture was washed with water (2 x 25 mL) and the washings were extracted with ethyl acetate (20 mL). The combined organic phases were dried over magnesium sulfate and the solvent evaporated under reduced pressure. The resulting intermediate was 3- [4 '- <6-chloro-2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyrid-3-ylmethyl) biphenyl-2-yl] -4-isopropoxycyclobut-3. -en-l, 2-dione - a viscous oil (0.65 g).

c)

The product of Example 12 (b) (0.65 g) was heated for 18 hours in a mixture of acetic acid (7 mL) and water (2.5 mL) at 95-100 ° C under a nitrogen atmosphere. The solvents were evaporated under reduced pressure and the resulting residue was mixed with ethyl acetate (20 mL). Resin formed. Aqueous sodium hydroxide solution (5 mL) was added to the resin. The resulting suspension was acidified with concentrated hydrochloric acid. A yellow solid was obtained, which was collected on a filter and purified by flash chromatography on silica gel (eluting with ethyl acetate / 7: 3 methanol). The resulting active compound of the present invention is 3 [4 '(6-chloro-2-ethyl-5,7-dimethyl-3H-imidazol-4,5-b] pyridin-3-ylmethyl) biphenyl-2-yl] -4-hydroxycyclobut-3- en-1,2-dione hydrochloride, a yellow solid (70 mg; mp 205 ° C, with decomposition).

ΤΤΓ

103

An example

To the stirred 3- [4 '- (2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyrid-3-ylmethyl) biphenyl-2-yl] -4-hydroxycyclobut-3-ene, To a suspension of 2-dione (4.21 g; preferably as in Example 4) in dry N, N-dimethylacetamide (40 ml) was added portionwise chloromethyl pivalate (3.22 g) at room temperature. Potassium iodide (2.5 g) was added to the resulting mixture and it was stirred at room temperature for a further 2 days. Chloromethyl pivalate (3.7 g) was added and stirred for a further 2 days. The resulting mixture was poured into diethyl ether (500 mL). A resin was obtained which was separated and dissolved in a mixture of acetone (100 mL) and ethyl acetate (300 mL). The resulting solution was washed with a saturated aqueous solution of sodium bicarbonate (2 x 400 mL) followed by water (2 x 400 mL) and dried over magnesium sulfate. The solvents were evaporated under reduced pressure and the resulting residue was purified by flash chromatography on silica gel (ethyl acetate). The resulting active compound of the present invention was 2- [4 '- (2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyrid-3-ylmethyl) biphenyl-2-yl] -3,4-dioxocyclobut. -1-en-1-yloxymethyl] pivalate as a yellow foam (0.54 g), mp 60-80 ° C.

An example

Sodium hydride (60% dispersion in mineral oil; 36 mg) was added to a stirred solution of 4-ethyl-2-propyl-11 Himidazole-5-carboxaldehyde (0.15 g; preferably as described in WO92 / 00977; Dupont) in dry dimethylformamide (3 ml) and stirred. for another 45 minutes. The resulting solution was then added to a stirred solution of 3- (4-bromomethylbiphenyl-2-yl) -4-isopropoxycyclobut-3-ene-1,2-dione (0.35 g; preferably as in Example 1 (c)) in dry dimethylformamide (3 mL). . After stirring for 1 hour, 2-propanol (0.1 mL) was added. The resulting mixture was poured into ethyl acetate (20 mL) and then washed with water (15 mL). Wash waters ext. 3612 B

The reaction mixture was quenched with ethyl acetate (10 mL) and the organic phases were washed with water (5 x 15 mL) and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the resulting residue was purified by flash chromatography on silica gel (eluting with ethyl acetate / petroleum ether (boiling 60-80 ° C) (75:25)). The resulting active compound of the present invention is 4-ethyl-1- [2'- (3,4-dioxo-2-isopropoxycyclobut-1-en-1-yl) biphenyl-4-ylmethyl] -2-propyl-1H-imidazol-5-one. -Carboxaldehyde in the form of foam (0.194 g).

Sample product (0.19 g), acetic acid (2 mL), and water (2 mL) were heated at 95-100 ° C under nitrogen for about 5 hours and then left at room temperature for a further 17 hours. The solvents were evaporated under reduced pressure and the resulting residue was mixed with ethyl acetate (2 x 15 mL) and dried in vacuo at 80 ° C. The resulting active compound of the present invention is 4-ethyl-1- [2 '- (2-hydroxy-3,4-dioxocyclobuten-1-yl) biphenyl-4-ylmethyl] -2-propyl-1H-imidazole-5-carboxaldehyde. yellow solid (0.12 g; m.p. 241-245 ° C).

An example

The final product of Example 5 (0.463 g; dried under vacuum since it is a hygroscopic compound) was dissolved in dry dimethylformamide (3 mL). The resulting solution was added to a solution of chloromethyl pivalate (0.19 g) in dry dimethylformamide (3 mL). The resulting mixture was stirred for about 17 hours and then potassium iodide (21 mg) was added and stirred for a further 3 days. Additional chloromethyl pivalate (98 mg) was added and stirred for a further 4 days. The resulting solution was partitioned between water (25 mL) and diethyl ether (25 mL). The aqueous layer was separated and extracted with diethyl ether (2 x 25 mL).

T

105

The combined organic layers were dried over magnesium sulfate, the solvent was distilled off and the resulting residue was purified by flash chromatography on silica gel (ethyl acetate followed by ethyl acetate / 9: 1 methanol). The fractions containing the two major products were combined and evaporated under reduced pressure. The resulting residue was mixed with diethyl ether (2 mL). The resulting solid was collected and washed with diethyl ether (1 mL) and then dried. The active compound of the present invention is obtained [4 '- (2-ethyl-5,7-dimethyl-3H-imidazo [4,5-f] pyrid-3-ylmethyl) biphenyl-2-yl] cyclobut-3-en-1, 2dione - colorless solid (34 mg; m.p. 140142 ° C).

An example

The final product of Example 4 (1.01 g; dried under vacuum since it is a hygroscopic compound) was suspended in dry N, N-dimethylacetamide (10 mL). 1-Chloroethyl pivalate (0.9 g; preferably as described in J. Med. Chem. (1978), Vol. 21, p. 753) is added with stirring, followed by potassium iodide (0.77 g). Stirring is continued at room temperature for a further 3 days. The resulting suspension was diluted with ethyl acetate (50 mL) and washed with sodium bicarbonate solution (5%; 50 mL) followed by water (4 X 50 mL). The organic layer was dried over magnesium sulfate, the organic solvents evaporated under reduced pressure and the resulting residue was purified by flash chromatography on silica gel (ethyl acetate washing). The resulting active compound of the present invention is 1- [2- [4 '- (2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyrid-3-ylmethyl) biphenyl-2-yl] -3 , 4-Cyclobut-1-en-1-yloxy] ethyl pivalate 0.22 ethyl acetate solvate (0.55 g) as a yellow foam which is liquid and slowly melts at about 80 ° C.

106

An example

a)

A solution of 4-bromomethyl-2'-iodobiphenyl (4.0 g; preferably 2 (b)) and butylamine (40 mL) in dry tetrahydrofuran (55 mL) was stirred in a flask with a rectification column at room temperature for 45 minutes. The solvent was evaporated under reduced pressure and the resulting residue was dissolved in dichloromethane (100 mL). The resulting solution was washed with aqueous potassium hydroxide solution (1M; 2X50 mL), water (50 mL), followed by hydrochloric acid (5M; 2X50 mL). The organic layer was dried over magnesium sulfate and the organic solvent evaporated. The resulting residue was purified by flash chromatography on silica gel (dichloromethane / methanol (9: 1)). The intermediate N- (2'-iodobiphenyl-4-ylmethyl) butylamine (1.9 g; mp 134-136 ° C) was obtained.

b) '

To a solution of the product of Example 18 (a) (1.9 g) and triethylamine (2.5 ml) in dry tetrahydrofuran (10 ml) was added ethyl 4-chloropyrimidine-5-carboxylate (0.9 g, preferably as described by Bredereck et al., Chem. Ber.). 1962), Vol, 95, p 803) in dry tetrahydrofuran (2 mL) and the resulting mixture was stirred at room temperature for about 1.5 hours. The solvent was evaporated under reduced pressure and the resulting residue was dissolved in dichloromethane (50 mL), washed with saturated sodium bicarbonate solution (2 x 25 mL) and then dried over magnesium sulfate. The solvent was evaporated and the resulting residue was purified by flash chromatography on silica gel (eluting with ethyl acetate). The intermediate 4-tert-butyl-N- (2'-iodobiphenyl-4-ylmethyl) amino] pyrimidine-5-carboxylate was obtained as a viscous oil (1.5 g).

• ΗΓ

107

c)

3-Isopropoxy-4-tributylstanylcyclobut-3-ene-1,2-dione (1,626 g), tetrakis (triphenylphosphine) palladium (O) (0.348 g), copper iodide (0.138 g) and the product of Example 18 (b).

After stirring for 23.5 hours at room temperature under nitrogen, dry dimethylformamide (20 mL) was added. After dilution with ether (100 mL), the mixture was washed with saturated ammonium chloride solution (2 x 25 mL), aqueous potassium fluoride solution (10%; 2 x 25 mL), and water (2 x 25 mL). The organic phase was dried over magnesium sulfate and the solvent evaporated under reduced pressure. A brown solid was obtained. This solid was purified by flash chromatography on silica gel eluting with petroleum ether (boiling point 40-60 [deg.] C.) / ethyl acetate (1: 1) to give the active compound of the present invention ethyl 4- [N-butyl-N- [2 '- (2-Isopropoxy-3,4-dioxocyclobut-1-en-1-yl) biphenyl-4-ylmethyl] amino] -pyrimidine-5-carboxylate - Yellow oil (0.77 g).

Example (c) The product of Example (0.67 g) was heated at 96-100 ° C in a mixture of acetic acid (30 mL) and water (15 mL) under a nitrogen atmosphere for 22 h. The resulting solution was cooled and filtered. The solvents were evaporated under reduced pressure. The resulting active compound of the present invention is ethyl 4- [N-butyl-N- [2 '- (2-hydroxy-3,4-dioxocyclobut-1-en-1-yl) biphenyl-4-ylmethyl] amino] -pyrimidine-5-carboxylate. - Brown solid (0.59 g; m.p. 95 ° C (with decomposition)).

Example A solution of the final product of the sample (0.59 g) and sodium hydroxide (0.51 g) was stirred at room temperature for 7 hours in a mixture of methanol (20 ml) and water

108 (6 mL). The stirred solution was left at room temperature for a further 18 hours and then acidified to pH 2 by the addition of concentrated hydrochloric acid. The resulting mixture was diluted with water (20 mL) and filtered. A solid product (400 mg) was obtained, which was then stirred in a solution of sodium hydroxide (0.5 g) and water (10 ml) at room temperature for 6 hours, and the resulting mixture was acidified to pH 2 with concentrated hydrochloric acid. A pale brown precipitate was obtained. This precipitate was collected and dried. The resulting active compound of the present invention is 4- [N-butyl-N- [2'-hydroxy-3,4-dioxocyclobut-1-en-1-yl) biphenyl-4-ylmethyl] amino] -pyrimidine-5-carboxylic acid 0.6. hydrochloride (0.2 g; m.p. 172-175 ° C (with decomposition)).

An example

To a stirred solution of 2-butyl-2-imidazolin-4-spirocyclopentan-5 (1 H) -one (3.9 g; preferably as described in WO 91/14679; Sanofi) in dry dimethylformamide (68.5 mL) was added sodium hydride ( 60% dispersion in mineral oil; 0.804 g). Stirring was continued for another 45 minutes. The resulting solution was then added to a stirred solution of 3 (4'-bromomethylbiphenyl-2-yl) -4-isopropoxycyclobut-3-en1,2-dione (11.17 g; preferably as described in Example 1 (c)) in dry dimethylformamide and stirring was continued. for another 2 hours. 2-Propanol (2.6 mL) was added and the resulting mixture was poured into ethyl acetate (450 mL) and washed with water (250 mL). The aqueous layer was separated and extracted with ethyl acetate (300 mL). The combined organic layers were washed with brine (5 x 200 mL) and dried over magnesium sulfate. The organic solvent was evaporated under reduced pressure and the resulting residue was purified by flash chromatography on silica gel (eluting with ethyl acetate / petroleum ether (boiling point 60-80 ° C) (7: 3)). Obtained akLT 3612 B

109 Compounds of the Invention 3- [4 '- (2-Butyl-5-oxo-2-imidazolin-4-spirocyclopent-1-ylmethyl) biphenyl-2-yl] -4-isopropoxycyclobut-3-ene-1,2-dione - yellow resin (3.6 g).

Example A mixture of the sample product (3.6 g) in acetic acid (35.2 ml) and water (35.2 ml) was heated at 95-100 ° C under a nitrogen atmosphere for about 4.5 hours. The solvents were evaporated under reduced pressure. The resulting resin was mixed with ethyl acetate (2 x 90 mL) and dried in vacuo at 60 ° C. The active compound of the present invention is 3- [4 '- (2-butyl-5-oxo-2-imidazolin-4-spirocyclopent-1-ylmethyl) biphenyl-2-1] -4-hydroxycyclobut-3-ene-1,2-dione (1.91). g; m.p. 197199 ° C).

An example

a)

To a stirred mixture of 2-butyl-4-chloro-1H-imidazole-5-carboxaldehyde (preferably as described in Drugs of the Future (1991), Vol. 16, p. 305), anhydrous potassium carbonate (6.9 g) and dry dimethylformamide (100 mL) ) at room temperature was added 4- (bromomethyl) -2'-iodobiphenyl (9.23 g; preferably as described in Example 2 (b)) in dry dimethylformamide (50 mL). Stirring was continued at room temperature for another 24 hours. Water (200 mL) was added and the resulting mixture was extracted with diethyl ether (500 mL then 200 mL). The combined extracts were washed with water (2 x 100 mL) and dried over magnesium sulfate. The organic solvent was evaporated and the residual orange oil was purified by silica gel thin layer chromatography (eluting with 5% then 30% ethyl acetate in petroleum ether (boiling 60-80 ° C)).

110

The intermediate 2-butyl-4-chloro-1- (2'-iodobiphenyl-4-ylmethyl) -1H-imidazole-5-carboxaldehyde was obtained as a yellow oil (8.06 g).

b)

To a solution of Example 23 (a) (0.5 g) in dry dimethylformamide (5 mL) was added 3-isopropoxy-4-tributyltin cyclobut-3-ene-1,2-dione (0.67 g; preferably as described by Liebeskind & Fengl, Journal of Organic Chemistry (1990), Vol 55, pp 5359/5364)), tetrakis (triphenylphosphine) palladium (O) (0.145 g) and copper iodide (48 mg). The resulting mixture was stirred at room temperature. in a nitrogen atmosphere for 24 hours. Diethyl ether (50 mL) was added and the resulting mixture was washed with saturated aqueous ammonium chloride solution (35 mL) followed by aqueous potassium fluoride solution (10%; 3 x 20 mL) and the organic layer was dried over magnesium sulfate. The organic solvents were evaporated in vacuo and the remaining orange / brown oil was purified by flash chromatography on silica gel (20% ethyl acetate in petroleum ether (boiling point 60-80 ° C)) to give the active compound of the present invention 2-butyl-4-chloro. 1- [2 '- (2-Isopropoxy-3,4-dioxocyclobut-1-en-1-yl) biphenyl-4-ylmethyl) -1H-imidazole-5-carboxaldehyde - Semi-solid yellow oil (0.22 g).

Example A solution of the final product of the sample (0.20 g) in a mixture of glacial acetic acid (5 ml) and water (5 ml)

Heat at 95-100 ° C for 4.5 hours. Glacial acetic acid (2 mL) and water (2 mL) were added and the mixture was heated for a further 5 hours. The resulting solution was cooled to room temperature and filtered. The solvents were evaporated in vacuo. The resulting active compound of the present invention is 2-butyl-4-chloro-1- [2 '- (2-hydroxy-3,4-dioxocyclobuten-1-yl) biphenyl-4-ylmethyl)] -1H-imidazol-5-one. carboxaldeLT 3612 B

111 Hydra is a yellow solid that melts and melts at 50 ° C or below.

An example

a)

To a solution of the product of Example 23 (a) (0.5 g) in methanol (5 ml) at room temperature was added sodium borohydride (39 mg) and the resulting solution was stirred for 1.5 hours. The solvent was evaporated in vacuo and water (50 mL) was added to the resulting residue. The resulting mixture was extracted with ethyl acetate (2 x 50 mL) and the combined extracts dried over magnesium sulfate. The solvent was evaporated in vacuo. The intermediate 2-butyl-4-chloro-5-hydroxymethyl-1- [2'-iodobiphenyl-4-ylmethyl] -1H-imidazole was obtained as a yellow oil (0.33 g).

b)

To a solution of the product of Example 25 (a) above (0.30 g) in dry dimethylformamide (5 mL) under nitrogen was added 3-isopropoxy-4-tributyltin cyclobut-3-ene-1,2-dione (0.402 g), tetrakis (triphenylphosphine). palladium (O) (86 mg) and copper iodide (28 mg). The resulting mixture was stirred for 40 hours. Diethyl ether (50 mL) was added and the resulting mixture was washed with saturated aqueous ammonium chloride solution (30 mL) followed by aqueous potassium fluoride solution (10%; 2x20 mL). The organic solution was dried over magnesium sulfate and the solvents evaporated in vacuo. The resulting residue was dissolved in diethyl ether (10 mL), the insoluble material was removed by filtration, and the solvent was again evaporated in vacuo. The resulting residue was purified by flash chromatography on silica gel (eluting with ethyl acetate / petroleum ether (boiling point 60-80 ° C) (1: 1)). The resulting active compound of the present invention is 3- [4 '- (2-butyl-4-chloro-5-hydroxymethyl-1H-imi [beta]

112 dazol-1-ylmethyl) -biphenyl-2-yl] -4-isopropoxycyclobut-3en-1,2-dione - yellow oil (80 mg).

Example A solution of sodium hydride (60% dispersion in mineral oil; 35 mg) in dry dimethylformamide (2 ml) was added methyl 2-butyl-4-chloro-1H-imidazole-5-carboxylate under nitrogen at room temperature and stirring was continued for another 30 minutes. . 3- (4'-Bromomethylbiphenyl-2-yl) -4-isopropylcyclobut-3-ene-1,2-dione (0.64 g; better than 1 (c)) in dry dimethylformamide (3 mL) was then added. ) and stir for another 24 hours. The reaction mixture was partitioned between water (20 mL) and diethyl ether (20 mL). The aqueous layer was separated and extracted with diethyl ether (20 mL). Combined ethereal. the solutions were dried over magnesium sulfate and the solvent evaporated in vacuo. The resulting residue was purified by flash chromatography on silica gel (eluting with 20% ethyl acetate in petroleum ether (boiling point 4060 ° C) (1: 1)). The resulting active compound of the present invention is 2-butyl-4-chloro-1- [2 '- (2-isopropoxy-3,4-dioxocyclobut-1-en-1-yl) biphenyl-4-ylmethyl] -1H-imidazole-5-carboxylate - yellow oil (0.17 g).

An example

(a) A solution of sodium chlorite (1.02 g) and sodium dihydrogen phosphate (1.02 g) in water (24 ml) is added at room temperature to a solution of product 23 (0.5 g) in t-butanol and the resulting mixture is stirred vigorously for 40 hours. Subsequently, enough sodium metabisulphite is added to make the solution yellow. Then, most of the solvents were evaporated in vacuo. Water (75 mL) was added to the resulting residue and the resulting mixture was added

T

113 was extracted with dichloromethane (2X50 mL). The combined extracts were dried over magnesium sulfate and the organic solvent was evaporated in vacuo. Mixing the resulting residue with diethyl ether (5 mL) gave the intermediate 2-butyl-4-chloro-1- (2'-iodobiphenyl-4-ylmethyl) -1H-imidazole-5-carboxylic acid as a colorless solid (0.27 g; m.p. mp 175 ° C).

b)

To a stirred suspension of sodium hydride (60% dispersion in mineral oil; 41 mg) in dry dimethylformamide (5 mL) was added methyl 2-butyl-4-chloro-1- (2'-iodobiphenyl-4-dimethyl) -1- imidazole-5-carboxylic acid (0.43 g; preferably as described in Example 27 (a)) and stirring was continued for another 30 minutes. Iodomethane (0.06 mL) was then added and stirred for a further 2 hours. Diethyl ether (20 mL) was then added and the resulting mixture was washed with water (20 mL). The washings were extracted with diethyl ether (2 x 20 mL) and the combined organic phases were dried over magnesium sulfate. The organic solvent was evaporated. Another intermediate methyl 2-butyl-4-chloro-1- (2'-iodobiphenyl-4-ylmethyl) -1H-imidazole-5-carboxylate was obtained as an oil (0.43 g).

c)

To a solution of the product of Example 27 (b) (0.42 g) in dry dimethylformamide at room temperature under nitrogen was added 3-isopropoxy-4-tributyltin cyclobut-3-ene-1,2-dione (0.53 g), tetrakis (triphenylphosphine) palladium (O). (0.12 g) and copper iodide (38 mg).

The mixture is stirred for 18 hours. Diethyl ether (30 mL) was then added and the resulting mixture was washed with saturated aqueous ammonium chloride solution (20 mL) followed by aqueous potassium fluoride solution (10%; 2x20 mL). OrLT 3612 B

The organic phase was dried over magnesium sulfate and the solvent evaporated in vacuo. The resulting residue was purified by flash chromatography on silica gel eluting with a gradient of 20% to 50% ethyl acetate in petroleum ether (boiling point 40-60 ° C) to give the active compound of the present invention (substantially identical to Example 26) methyl 2-butyl. -4-Chloro-1- [2 '- (2-isopropoxy-3,4-dioxocyclobut-1-en-1-yl) biphenyl-4-ylmethyl] -1H-imidazole-5-carboxylate - yellow oil (0.1 g) ).

An example

Methyl 2-butyl-4-chloro-1- [2'-isopropoxy-3,4-dioxocyclobut-1-en-1-yl) biphenyl-4-ylmethyl] -1H-imidazole-5-carboxylate (0.26 g; preferably as described in Example 27 (c)) was heated in a mixture of glacial acetic acid (5 ml) and water (5 ml) at 95-100 ° C for 5 hours. The solvents were evaporated in vacuo and the resulting residue was purified by flash chromatography on silica gel (eluting with 10% to 30% ascending order in technical methyl alcohol in ethyl acetate). The resulting active compound of the present invention is methyl 2-butyl-4-chloro-1- [2 '- (2-hydroxy-3,4-dioxocyclobut-1-en-1-yl) biphenyl-4-ylmethyl] -1H-imidazol-5- Carboxylate - Yellow oil (0.1 g).

An example

To a solution of the product of Example 28 (90 mg) in methanol (3 mL) was added aqueous sodium hydroxide solution (2M; 1 mL) at room temperature. The resulting mixture was stirred for 2 hours. The solvent was evaporated in vacuo, and water (2 mL) was added to the resulting residue, and the resulting solution was acidified with hydrochloric acid (5M) to pH 1. The resulting yellow precipitate was filtered off, washed with water and dried. The resulting active compound of the present invention is 2-butyl-4-chloro-1- [2 '- (2-hydroxy-3,4-dioxocyclobut-1-en-1-yl) biphenyl-4-ylmethyl] -1H-imidazol-5 -karLT 3612 B

115 Boxylic acid 0.4 hydrochloride - a pale yellow solid (70 mg; m.p. 168 ° C).

An example

a)

A mixture of 2-butyl-4-chloro-1H-imidazole-5-carboxaldehyde (4.0 g; preferably as described in Drugs of the Future (1991), Vol. 16, p. 305), potassium carbonate and dry dimethylformamide (50 ml) was stirred at room temperature for 15 minutes. at temperature. To the resulting mixture was added 4-iodobenzyl bromide (6.34 g) and stirring was continued for about 17 hours. The solvent was then evaporated under reduced pressure at 80 ° C. Water (200 mL) was added to the resulting residue, which was then extracted with diethyl ether (2 x 100 mL). The combined extracts were washed with water (50 mL) and dried over magnesium sulfate. The solvent was evaporated. The resulting residue was purified by flash chromatography on silica gel (eluting with dichloromethane / methanol (80: 1)). The intermediate 2-butyl-4-chloro- (4-iodobenzyl) -1H-imidazole-5-carboxaldehyde was obtained as an oil (6.9 g).

b) To a stirred solution of lithium diisopropylamide tetrahydrofuran adduct (16.4 mL; 1.5M in cyclohexane) in dry tetrahydrofuran (50 mL) at -70 ° C was added methyl 3-phenylpropanoate (4.03 g) in dry tetrahydrofuran (50 mL) over 15 min. ). Stirring at -70 ° C is continued for about 1 hour. A solution of the product of Example 30 (a) (6.6 g) in dry tetrahydrofuran (50 mL) was then added over 15 minutes and the resulting mixture was stirred at -70 ° C for 4 hours. The mixture was allowed to warm to 0 ° C and poured into a saturated aqueous solution of ammonium chloride (250 mL) and extracted with ethyl acetate (3 x 150 mL). Combine

The 116 extracts were washed with brine (50 mL), dried over magnesium sulfate and evaporated to dryness under reduced pressure. The resulting residue was mixed with petroleum ether (boiling 60-80 ° C; 2x100 mL) and further purified by flash chromatography on silica gel (eluting with dichloromethane / methanol (50: 1)). The intermediate methyl 2-benzyl-3- [2-butyl-4-chloro- (4-iodobenzyl) -1H-imidazol-5-yl] -3-carboxypropenoate (5.7 g, mp 155-159 ° C) is obtained. ) - a solid mixture of diastereomers.

c)

A solution of the product of Example 30 (a) (5.7 g), acetic anhydride (11 ml) and 4-dimethylaminopyridine (0.5 g) in dichloromethane (250 ml) was stirred at room temperature for about 17 hours and then washed with saturated sodium bicarbonate solution (2x300 ml). ). The organic layer was dried over magnesium sulfate and the solvent evaporated. The resulting residue was dissolved in dry toluene (300 mL) and added

1,8-diazabicyclo [5.4.0] talc-7-eno (6 mL). The resulting mixture was heated to 95-100 ° C under nitrogen for about 8 hours and then cooled. The solvent was then evaporated under reduced pressure and the resulting residue was purified by flash chromatography on silica gel (60: 1 dichloromethane / methanol). The intermediate (E) -methyl 2-benzyl-3- [2-butyl-4-chloro-1- (4-iodobenzyl) -1H-imidazol-5-yl] propenoate was obtained as an oil (3.5 g).

d)

A mixture of the product of Example 30 (c) '(0.8 g), 3-isopropoxy-4-tributyltin cyclobut-3-ene-1,2-dione (0.9 g), tetrakis (triphenylphosphine) palladium (O) (0.2 g) ), copper iodide (0.1 'g) and dry dimethylformamide (5 mL) were stirred at room temperature under nitrogen for about 17 hours. The solvent was evaporated under reduced pressure and the resulting residue was dissolved in diethyl ether iii

117 (150 mL). The resulting solution was washed with a saturated aqueous solution of ammonium chloride (50 mL) followed by a saturated aqueous solution of potassium fluoride (2 x 50 mL) and dried over magnesium sulfate. The solvent was evaporated and the resulting residue was purified by flash chromatography on silica gel (eluting with dichloromethane / methanol (50: 1)). The intermediate (E) -methyl 2-benzyl-3- [2-butyl-4-chloro-1- [4- (2-isopropoxy-3,4-dioxocyclobut-1-enyl) benzyl] -1H-imidazole is obtained. 5-yl] Propenoate - Oil (0.4 g).

(E) -methyl 2-benzyl-3- [2-butyl-4-chloro-1- [4- (2-isopropoxy-3,4-dioxocyclobut-1-en-1-yl) benzyl] -1H- imidazol-5-yl] propenoate (1.2 g; preferably as described in Example 30 (d)) and aqueous acetic acid (50%; 20 ml) was heated at 95-100 ° C for 6 hours. The solvents were evaporated under reduced pressure and the resulting residue was mixed with diethyl ether (2 x 20 mL). The resulting solid was dissolved in technical methyl alcohol (20 mL). Aqueous sodium hydroxide solution (0.5M, 22 mL) was then added and the resulting mixture was stirred at room temperature for 1 hour and then neutralized with hydrochloric acid (5 M). The solvent was evaporated under reduced pressure, and the resulting residue was extracted with aqueous sodium hydroxide solution (1M; 60 mL) and then acidified with hydrochloric acid (5M). The resulting precipitate was collected, washed with water (2 x 10 mL) and dried. The active compound of the present invention is obtained (E) methyl 2-benzyl-3- [2-butyl-4-chloro-1- [4- (2-hydroxy-3,4-dioxocyclobut-1-en-1-yl) benzyl] -1H. -imidazol-5-yl] propenoic acid - solid (0.54 g; m.p. 155160 ° C).

Claims (9)

DEFINITION OF INVENTION 1. Compound of Formula II: or a pharmaceutically acceptable salt thereof: where R ₃₁₀ is hydrogen or C ₁ . _4- alkyl; A ₁₉₀ is oxygen, sulfur or a group of the formula -NR ₃₁₉ - wherein R ₃₁₉ is hydrogen or C ₁ _ ₄ alkyl; R _311, ^R 3i2 ^<r 3i3 3i4 and ^R are not taken Cl ausomai from each other hydrogen, fluoro, chloro, bromo, C ₁ _ ₄ -alkyl, C ₁ _ ₄ -alkoxy, nitro, cyano, carboxyl, C ₂ _ ₄ alkoxycarbonyl, C ₁ _ ₄ -alkiltiogrupė C _{first 4-} alkylsulfinyl, C ₁ . ₄ -alkįlsulfonilogrupė, phenyl (which is optionally substituted by alkyl Cj.ų C _x _ ₄ -aikoksigrupė fluorine, chlorine or bromine), C ₁ _ ₄ -alkilsulfonilaminogrupė or C ^ -alkilaminosulfonilo group; R ₃₁₅ is hydrogen or C ₁ _ ₄ alkyl; and fTT 119 R ₃₁₆ , ^R 31i ^{and R} 31i independently of one another are hydrogen, C 1-4 alkyl, nitro, fluoro, chloro, bromo, cyano, formyl or a group of the formula -SOgR320, -SO2NR321R322 or -COR323 (wherein R32o < ^R 32i, ^R 322, independently of one another are hydrogen or a C1_ ₄ alkyl, g is 1 or 2 and R ₃₂₃ is C _{first 4} alkyl or a group of the formula -OR ₃₂₄ or -NR ₃₂₅ R _326, wherein R _324, R 325 and R ₃₂₆ independently of one another are hydrogen or C ₁ _ ₄ alkyl). Compound according to claim 1, characterized in that it has the structural formula III: wherein ^A 19O / ^r 310 < ^r 315z ^R 316, ^R 3m and ^R 3i8 are as defined in claim 1; or a pharmaceutically acceptable salt of the compound. 3. A compound according to claim 2, which has the structural formula IV: 120 Me No. N Me O \ V _ // ^A 190. ^R 310 (IV) in which A ₁₉₀ and R _31o are as in point 2; or a pharmaceutically acceptable salt of the compound. 4. A compound according to any one of claims 1 to 3, wherein A ₁₉₀ is oxygen and R ₃₁₀ is hydrogen. 5. A compound selected from: 3- [4 '- (2-Ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyrid-3-ylmethyl) -biphenyl-2-yl] -4-isopropoxycyclobut-3-en-1 , 2dione; 3- [4 '- (2-Ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyrid-3-ylmethyl) -biphenyl-2-yl] -4-hydroxycyclobut-3-en-1 , 2-dione; 3-Amino-4- [4 '- (2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyrid-3-ylmethyl) biphenyl-2-yl] cyclobut-3-en-1 , 2-dione; z 3- [4 '- (5,7-Dimethyl-2-propyl-3H-imidazo [4,5-b] pyrid-3-ylmethyl) -biphenyl-2-yl] -4-isopropoxycyclobut-3-en-1,2-dione ; 121 3- [4 '- (5,7-Dimethyl-2-propyl-3H-imidazo [4,5-b] pyrid-3-ylmethyl) -biphenyl-2-yl] -4-hydroxycyclobut-3-ene-1,2-dione ; 2-ethyl-3- [2-isopropoxy-3,4-dioxocyclobut-1-en-yl) biphenyl-4-ylmethyl] -5,7, N, N-tetramethyl-3H-imidazo [4,5-b] pyridine-6-sulfamide; 2-ethyl-3- [2 '- (2-hydroxy-3,4-dioxocyclobut-1-en-1-yl) biphenyl-4-ylmethyl) -5,7, N, N-tetramethyl-3H-imidazo [ 4,5-b] pyridine-6-sulfamide; 3- [4 '- (6-chloro-2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyrid-3-ylmethyl) biphenyl-2-yl] -4-hydroxy. icyclobut-3-en1,2-dione; 2- [4 '- (2-Ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyrid-3-ylmethyl) -biphenyl-2-yl] -3,4-dioxocyclobut-1-ene -1-yl-oxymethyl pivalate; 3-Dimethylamino-4- [4'- (2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyrid-3-ylmethyl) biphenyl-2-yl] cyclobut-3-en-1 , 2-dione; 1- [2- [4 '- (2-Ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyrid-3-ylmethyl) -biphenyl-2-yl] -3,4-dioxocyclobut-1 -en-1-yloxy] -ethyl pivalate; or pharmaceutically acceptable salts thereof. 6. A pharmaceutical composition comprising a compound of formula II, III or IV according to any one of the preceding claims, together with a pharmaceutically acceptable carrier or diluent. A compound of formula II, III or IV according to any one of claims 1 to 5 for use in the treatment of hypertension. 122 Use of a compound of formula II, III or IV according to any one of claims 1 to 5 for the manufacture of a medicament for the treatment of hypertension. A compound of (II) wherein R ₃₁₀ is hydrogen or C _i _ ₄ alkyl; A ₁₉₀ is oxygen, sulfur or a group of the formula -NR ₃₁₉ - wherein R ₃₁₉ is hydrogen or C 1-6 alkyl; R _3n, R ₃ i2z it R313 R ₃₁₄ independently of one another are hydrogen, fluoro, chloro, bromo, C ₁ _ ₄ -alkyl, C ₁ _ ₄ -alkoxy, nitro, cyano, carboxyl, C _2-4 - alkoxycarbonyl, C ₁ _ ₄ -alkiitiogrupė C ₁ _ ₄ alkylsulfinyl group, a C ₁ _ ₄ -alkilsulf onyl group, phenyl (which is optionally substituted by C ₁ _ ₄ -alkyl, C ₃ _ ₄ -alkoxy, fluorine , chlorine or bromine), C ₁ _ ₄ -alkilsulfonilaminogrupė or C ^ -alkilaminosulfonilo group; R ₃₁₅ is hydrogen or C ₁ . _4- alkyl; and R _316, ^R 317 ^{R r} 3i8z in offline Klaus pendently of one another, are hydrogen, C ₁ _ ₄ alkyl, nitro, fluoro, chloro, JI 123 bromine, cyano, formyl or a group of the formula -SO _g R ₃₂₀ ^_ SO2NR321R322 or -COR323 (wherein R32q ^R 32i, ^R 322 <independently of one another are hydrogen or C4_ ₄ alkyl, g is 1 or 2, and R ₃₂₃ is C ₁ _ ₄ alkyl or a group of the formula -OR ₃₂₄ or -NR ₃₂₅ R _326, wherein R _324, ^R 325 and R ₃₂₆ independently 'from one another, are hydrogen or C ₁ _ ₄ alkyl ); or a pharmaceutically acceptable salt thereof, characterized in that the compound of formula LXX: (LXX) in which L is a leaving group acts on a compound of formula Het-H (Het-H) by reaction in a solvent inert to the reaction conditions.