Methods and compositions for the prophylactic and/or therapeutic treatment of organ hypofunction

Claim 2

The composition according to claim 1, wherein the organ is a liver.

Claim 3

The composition of according to claim 1, wherein the compound having antagonistic activity on the endothelin receptor is a cyclic peptide represented by the following formula [A] or a pharmaceutically acceptable salt thereof: wherein X and Y each represent α-amino acid residues having D- or L-form, A represents a D-acidic-α-amino acid residue, B represents a neutral-α-amino acid residue having D- or L-form, C represents an L-α-amino acid residue and D represents a D-α-amino acid residue having an aromatic ring group.

Claim 4

The composition according to claim 3, wherein the cyclic peptide is (i) a peptide in which A is a C₃₋₅-D-acidic-α-amino acid residue, preferably a C₃₋₅-D-α-aminodicarboxylic acid residue, (ii) a peptide in which X is a C₃₋₁₁-L-α-amino acid residue which may be substituted, preferably a C₃₋₅-L-α-aminodicarboxylic acid which may be substituted by a heterocyclic group which may have a substituent group, (iii) a peptide in which Y is an L-acidic-α-amino acid residue, preferably a C₃₋₅-L-α-aminodicarboxylic acid residue, (iv) a peptide in which B is a C₂₋₆-D-neutral-α-amino acid residue which may have a heterocyclic group, preferably a C₂₋₆-D-α-aminomonocarboxylic acid residue which may be substituted by a sulfur-containing heterocyclic group, (v) a peptide in which C is an L-neutral-α-amino acid residue, preferably a C₅₋₆-L-α-aminomonocarboxylic acid residue, or (vi) a peptide in which D is a D-neutral-α-amino acid residue having an aromatic heterocyclic group, which may be acylated, preferably a D-neutral-α-amino acid residue having a nitrogen-containing aromatic heterocyclic group.

Claim 5

The composition according to claim 3, wherein the cyclic peptide is Cyclo[-D-Asp-Asn(CH₂CH₂-Ind)-Asp-D-Leu-Leu-D-Trp-], Cyclo[-D-Asp-Trp-Asp-D-Leu-Leu-D-Trp(For)-], Cyclo[-D-Asp-Trp-Asp-D-Thg(3)-Leu-D-Trp-], Cyclo[-D-Asp-Trp-Asp-D-γMeLeu-Leu-D-Trp-], Cyclo[-D-Asp-Trp-Asp-D-Thg(2)-Leu-D-Trp-], Cyclo[D-Asp-Gln(CH₂Ph)-Asp-D-Leu-Leu-D-Trp-], Cyclo[-D-Asp-Asp(R1)-Asp-D-Leu-Leu-D-Trp-], Cyclo[-D-Asp-Asp(R2)-Asp-D-Leu-Leu-D-Trp-], Cyclo[-D-Asp-Orn(COCH₂Ph)-Asp-D-Leu-Leu-D-Trp-], Cyclo[-D-Asp-Orn(COCH₂-Ind)-Asp-D-Leu-Leu-D-Trp-], Cyclo[-D-Asp-Hyp(Bzl)-Asp-D-Thg(2)-Leu-D-Trp-], Cyclo[-D-Asp-Gln(Bzl)-Asp-D-Thg(2)-Leu-D-Trp-], Cyclo[-D-Asp-Asn(CH₂CH₂-Ind)-Asp-D-Thg(2)-Leu-D-Trp-], Cyclo[-D-Asp-Asp(R1)-Asp-D-Thg(2)-Leu-D-Trp-], Cyclo[-D-Asp-Asp(R7)-Asp-D-Thg(2)-Leu-D-Trp-], Cyclo[-D-Asp-Asp(R10)-Asp-D-Thg(2)-Leu-D-Trp-], Cyclo[-D-Asp-Asp(R12)-Asp-D-Thg(2)-Leu-D-Trp-], Cyclo[-D-Asp-Asp(R13)-Asp-D-Thg(2)-Leu-D-Trp-], Cyclo[-D-Cta-Asp(R1)-Asp-D-Thg(2)-Leu-D-Trp-], Cyclo[-D-Cta-Asp(R7)-Asp-D-Thg(2)-Leu-D-Trp-], Cyclo[-D-Cta-Asp(R10)-Asp-D-Thg(2)-Leu-D-Trp-], Cyclo[-D-Cta-Asp(R12)-Asp-D-Thg(2)-Leu-D-Trp-], Cyclo[-D-Cta-Asp(R13)-Asp-D-Thg(2)-Leu-D-Trp-], Cyclo[-D-Asp-Asp(R1)-Asp-D-Cpg-Leu-D-Trp-], or Cyclo[-D-Cta-Asp(R1)-Asp-D-Cpg-Leu-D-Trp-].

Claim 6

The composition according to claim 1, wherein the compound having antagonistic activity on the endothelin receptor is a peptide represented by formula [B] or a salt thereof: wherein R₁ represents a fat-soluble group, R₂ and R₅ each represent hydrogen atoms or lower alkyl groups, R₃ represents an aliphatic group which may contain an oxygen atom or a sulfur atom, R₄ represents a heterocyclic-lower alkyl group which may be substituted, R₆ represents a hydrogen atom, a lower alkyl group which may be substituted, or an aromatic ring group which may be substituted, X represents a group having an aromatic ring, n represents an integer of 0, 1 or more, and m represents an integer of 2 or more.

Claim 7

The composition according to claim 6, wherein the peptide or the salt thereof is hexamethylene-imino-CO-Leu-(D)Trp-(D)Ala-βAla-Tyr-(D)Phe-OH or salts thereof, hexamethyleneimino-CO-Leu-(D)Trp-(D)Ala-βAla-Tyr(I)-(D)Phe-OH or salts thereof, or hexamethyleneimino-CO-Leu-(D)Trp-(D)Ala-βAla-Try-NH-Ind-OH or salts thereof.

Claim 8

The composition according to claim 1, wherein the compound having antagonistic activity on the endothelin receptor is a peptide represented by formula [C] or pharmaceutical-ly acceptable salts thereof: wherein M represents a mercaptoacyl group; P, Q, R, S, T, U, V, W, X, Y and Z each represent amino acid residues, wherein an amino acid side chain of Y is either a substituted saturated aliphatic hydrocarbon group having 1 to 15 carbon atoms or an unsubstituted saturated aliphatic hydrocarbon group having 4 to 15 carbon atoms other than (1S)-1-methylpropyl.

Claim 9

The composition according to claim 8, wherein the peptide is

Claim 10

The composition according to claim 1, wherein the compound having antagonistic activity on the endothelin receptor is a peptide represented by formula [D] or salts thereof: wherein A, B, C, D, E and F each represent amino acid residues, and satisfy any one condition of (i) A=Ser, C=ser, D=Leu, E=Met and F=Phe, (ii) A=Ser, B=Ser; C=Ser, D=Trp, E=Leu and F=Phe, and (iii) A=Thr, B=Phe, C=Thr, D=Tyr, E=Lys and F=Tyr; and W, X, Y and Z each represent amino acid residues, and at least one of W and Y is an amino acid residue other than an L-alanine residue or other than an L-cysteine residue, or X is an amino acid residue other than an L-lysine residue, or Z is an amino acid residue other than an L-aspartic acid residue.

Claim 11

The composition according to claim 1, wherein the compound having antagonistic activity on the endothelin receptor is a cyclic pentapeptide represented by formula [E] or pharmaceutically acceptable salts thereof: Cyclo(-X¹-X²-X³-X⁴-X⁵)   [E] wherein X n represents an amino acid residue (wherein n represents an integer of 1 to 5); X¹ represents D-Phe, D-Tyr, D-Tha, D-Tza, D-Nal, D-Bta, D-Trp, D-Trp(O), D-Trp(CHO) or D-Trp[(CH₂) m COR¹] (wherein m represents an integer of 0 to 6, and R¹ represents a hydroxyl group, a C₁₋₆ alkoxyl group, an amino group or a C₁₋₆ monoalkylamino group); X² represents D-Asp, D-Glu or D-Cys(O₃H); X³ represents Pro, Hys, Pip, Thz, β-Ala, Gly, Ala, α-Aba, Aib, Val, Nva, Leu, Ile, alle, Nle, Met, Met(O), Met(O₂), Phe, Tza, Tha, Tyr, Trp, His, Arg, Lys, Lys(CHO), Orn, Orn(CHO), Asn, Gln, Asp, Glu, Cys(O₃H), Cys, Ser or Thr, and a hydrogen atom on an α-amino group may be substituted by a C₁₋₆ alkyl or C₃₋₇ cycloalkyl group which may have a group selected from the group consisting of a imidazolyl group, a carboxyl group and a hydroxyl group; X⁴ represents D-Ala, D-Thr, D-αAba, D-Val, D-Nva, D-Leu, D-Ile, D-alle, D-Nle, D-tertLeu, D-Cpg, D-Chg, D-Cpg, D-Pen, Aib, Ac3c, Ac4c, Ac5c, Ac6c, Ac7c, D-Phg, D-Thg, D-Fug, D-Tzg or D-Itg, and a hydrogen atom on an α-amino group may be substituted by a C₁₋₃ alkyl group; and X⁵ represents Pro, Pip, Thz, His, Ala, αAba, Val, Nva, Leu, Ile, alle, Nle, Met, C3al, C4al, C5al or C6al, and a hydrogen atom on an α-amino group may be substituted by a C₁₋₆ alkyl group.

Claim 12

The composition according to claim 11, wherein the peptide or the salt thereof is Cyclo(-D-Asp-Pro-D-Val-Leu-D-Trp-), Cyclo(-D-Cys(O₃H)-Pro-D-Val-Leu-D-Trp-), Cyclo(-D-Asp-Pro-D-Thg(2)-Leu-D-Trp-), or Cyclo(-D-Asp-Pro-D-Cpg-Leu-D-Trp-).

Claim 13

The composition according to claim 1, wherein the compound having antagonistic activity on the endothelin receptor is a peptide represented by formula [F] or salts thereof: wherein R¹ represents a hydrogen atom or an acyl group; R² represents a lower alkyl group, an ar(lower)alkyl group which may be substituted, a cyclo(lower)alkyl(lower)alkyl group or a heterocyclic (lower) alkyl group which may be substituted; R³ represents a heterocyclic (lower) alkyl group or an ar(lower)alkyl group which may be substituted; R⁴ represents a hydrogen atom or a lower alkyl group which may be substituted; R⁵ represents a carboxyl group, a protected carboxyl group, a carboxyl(lower)alkyl group or a protected carboxyl(lower)alkyl group; R⁶ represents a hydrogen atom or a lower alkyl group which may be substituted; R⁷ represents a hydrogen atom or a lower alkyl group; and A represents -O-, -NH-, a lower alkylamino group or a lower alkylene group; with the proviso that the peptide of formula [F] has an absolute configuration represented by the following partial formulae: when R² is an (S)-isobutyl group, R³ is an N-(dichlorobenzyloxycarbonyl)indole-3-ylmethylene group, R⁴ is a methyl group, R⁵ is a methoxycarbonyl group, R⁶ is a hydrogen atom, R⁷ is a hydrogen atom, and A is -NH-.

Claim 14

The composition according to claim 1, wherein the compound having antagonistic activity on the endothelin receptor is a compound represented by formula [G] or salts thereof: wherein R¹ represents a lower alkyl group, a lower alkoxyl group, a lower alkylthio group, a halogen atom or a trifluoromethyl group; R² represents a halogen atom, a lower alkoxyl group, a hydroxy-lower alkoxyl group or a trifluoromethyl group; R³ represents a hydroxyl group, a halogen atom, an alkylthio group, a cycloalkyl group, a hydroxy-lower alkyl group, a hydroxy-lower alkoxyl group, a hydroxyimino-lower alkyl group, a lower alkenyl group, an oxy-lower alkyl group, a trifluoromethyl group, a trifluoromethoxyl group, a lower alkoxyl group, a lower alkoxy-lower alkoxyl group or an aryl-lower alkoxyl group, and R² and R³ may form butadienyl; R⁴ represents a lower alkyl group, an aryl group or heterocyclic aryl group; R⁵ represents a lower alkanoyl group, a benzoyl group, a heterocyclic carbonyl group or a tetrahydropyran-2-yl group; R⁶ represents R⁷ represents a lower alkoxyl group or a nitro group; R⁸ represents a halogen atom, a lower alkyl groups a lower alkoxyl group, a lower alkylthio group, a nitro group, a hydroxyl group, an amino group or a trifluoromethyl group, and R⁷ and R⁸ may form butadienyl; R⁹ represents a halogen atom, a lower alkyl group, a lower alkoxyl group, a lower alkylthio group or a trifluoromethyl group; R¹⁰ represents a halogen atom, a lower alkyl group, a lower alkoxyl group or a lower alkylthio group; X and Y each represent O, S or NH; and n represents 2, 3 or 4.

Claim 15

The composition according to claim 1, wherein the compound having antagonistic activity on the endothelin receptor is a tritylpen derivative represented by formula [H]: wherein R¹ represents a hydrogen atom or a metabolic ester residue; R³ represents an aryl group which may be substituted or an aromatic heterocycle which may be substituted; one of X and Y is hydroxyl and the other is hydrogen, or both X and Y are combined to form oxo; and Z represents an oxygen atom or two hydrogen atoms.

Claim 16

The composition according to claim 1, wherein the compound having antagonistic activity on the endothelin receptor is a Endothelin derivative represented by formula [I]: wherein Xaa1 represents Tyr, Phe or Ala; Xaa2 represents Asp or Gly; and Xaa3 represents Trp or Phe.

Claim 17

The composition according to claim 1, wherein the compound having antagonistic activity on the endothelin receptor is a peptide represented by formula [J]:

Claim 18

The composition according to claim 1; wherein the compound having antagonistic activity on the endothelin receptor is a compound represented by formula [K]: wherein R¹ represents a hydrogen atom, a lower alkyl group, a lower alkoxyl group, a lower alkylthio group, a halogen atom or a trifluoromethyl group; R² represents a hydrogen atom, a halogen atom, a lower alkoxyl group, a trifluoromethyl group or -OCH₂COOR a ; R³ represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkylthio group, a trifluoromethyl group, a cycloalkyl group or a lower alkoxyl group, and R² and R³ may form butadienyl, methylenedioxy, ethylenedioxy or isopropylidene; R⁴ represents a hydrogen atom, a lower alkyl group, a cycloalkyl group, a trifluoromethyl group, a lower alkoxyl group, a lower alkylthio group, a lower alkylthio-lower alkyl group, a hydroxy-lower alkyl group, a hydroxy-lower alkoxyl group, a lower alkoxy-lower alkyl group, hydroxy-lower alkoxy-lower alkyl group, hydroxy-lower alkoxy-lower alkoxyl group, a lower alkylslufinyl group, a lower alkylsulfonyl group, a 2-methoxy-3-hydroxypropoxyl group, a 2-hydroxy-3-phenylpropyl group, an amino-lower alkyl group, a lower alkylamino-lower alkyl group, a di-lower alkylamino-lower alkylamino group, a lower alkylamino group, a di-lower alkylamino group, an arylamino group, an aryl group, an arylthio, an aryloxy group, an aryl-lower alkyl group or a heterocycle; R⁵ represents a hydrogen atom, a lower alkyl group, a lower alkanoyl group, a benzoyl group, a heterocyclic carbonyl group, a heterocyclic methyl group or a tetrahydropyran-2-yl group; R⁶ to R⁹ each represent hydrogen atoms, halogen atoms, trifluoromethyl groups, lower alkyl groups, lower alkoxyl groups, lower alkylthio groups, hydroxyl groups, hydroxymethyl groups, cyano groups, carboxyl groups, formyl groups, methylsulfinyl groups, methylsulfonyl groups, methylsulfonyloxy groups or lower alkoxycarbonyloxy groups; R⁷ may combine with R⁶ or R⁸ to form butadienyl, methylenedioxy, ethylenedioxy or isopropylidenedioxy; Z represents -O-, -S-, ethylene, vinylene, -CO-, -OCHR¹⁰-or -SCHR¹⁰-, wherein R¹⁰ represents a hydrogen atom or a lower alkyl group; X and Y each represent O, S or NH; YR⁵ represents a lower alkylslufinyl group or -OCH₂CH(OR c )CH₂-OR d ; R a , R b , R c and R d each represent hydrogen atoms or lower alkyl groups; R c and R d each represent methylene, ethylene or isopropylidene; and n represents 1, 2 or 3.

Claim 19

The composition according to claim 1, wherein the compound having antagonistic activity on the endothelin receptor is a compound represented by formula [L] or a pharmaceutically acceptable salt thereof: wherein A¹ is a group represented by formula (1), R¹¹-CO-, [wherein R¹¹ represents a lower alkyl group, a cycloalkyl group, a cycloalkyl-lower alkyl group, a group represented by Ar¹-(CH₂) p - (wherein Ar¹ represents a phenyl group, a furyl group or a thienyl group, and p represents 0, 1 or 2), a 1,3-dithio-2-iridenemethyl group or 1,3-dithiol-2-iridene(lower alkoxycarbonyl)methyl group], a group represented by formula (2), R¹²O-CO-, (wherein R¹² represents a lower alkyl group, a cycloalkyl group, a cycloalkyl-lower alkyl group or a phenyl group), a group represented by formula (3), R¹³R¹⁴N-C(=X¹)- [wherein X¹ represents an oxygen atom or a sulfur atom; R¹³ represents a lower alkoxycarbonyl group, a cycloalkyl group, a lower alkynyl group, a 1-adamantyl group, a pyrrolidino group, a piperidino group, a perhydroazepine-1-yl group, a perhydroazocine-1-yl group, a perhydroazonine-1-yl, a group represented by Ar²-(CH₂) q - [wherein Ar² represents a phenyl group (a hydrogen atom or each of two hydrogen atoms on the benzene ring may be substituted by a halogen atom, a lower alkyl group or a lower alkoxyl group), a furyl group or thienyl group, and q represents 0, 1 or 2]; R¹⁴ represents a hydrogen atom, a hydroxyl group, a cycloalkyl group or a group represented by Ar³-(CH₂) r - (wherein Ar³ represents a phenyl group, a furyl group or thienyl group, and r represents 1 or 2), R¹³ and R¹⁴ may form a 5- to 9-membered nitrogen-containing saturated heterocycle having 4 to 8 carbon atoms together with the adjacent nitrogen atom, one methylene group not adjacent to a nitrogen atom in a methylene group forming the heterocycle may be substituted by an oxy group, a thio group or -NR¹⁵- (wherein R¹⁵ represents a lower alkyl group), 1 to 4 hydrogen atoms on a carbon atom or carbon atoms of the heterocycle may each be substituted by hydroxyl groups or lower alkyl groups which may be substituted by hydroxyl groups, two adjacent carbon atoms of the heterocycle may form a double bond or a benzo condensed ring, and R¹³ and R¹⁴ may form a group represented by formula (LII) together with B: wherein R¹⁶ represents a hydrogen atom, a lower alkyl group or a cycloalkyl group, and R¹⁷ and R¹⁸ each represents hydrogen atoms or lower alkyl groups, independently; B represents an oxygen atom or a group represented by -NR²- (wherein R² represents a hydrogen atom or a methyl group), and forms the group represented by the above-mentioned formula (LII) together with A¹; R³ represents a lower alkyl group having 3 to 5 carbon atoms; R⁴ represents a hydrogen atom or a methyl group; R⁵ represents (1) a 3-indolylmethyl group, (2) a (2,3-dihydro-2-oxo-3-indolyl)methyl group, (3) a 3-indolylmethyl group in which the indole ring is substituted at the 1-position by a group represented by R⁵¹-CO-(CH₂) s - (wherein R⁵¹ represents a hydrogen atom, a lower alkyl group, a hydroxyl group, a lower alkoxyl group, a benzyloxy group, an amino group or a mono-lower alkylamino group, s represents an integer of 0 to 6, and when s is 0, R⁵¹ represents a group other than a hydroxyl group) or a group represented by (R⁵²O)₂P(=O)-(CH₂) t - (wherein R⁵² represents a hydrogen atom, a lower alkyl group or a benzyl group, and t represents an integer of 0 to 6), (4) a benzyl group in which any hydrogen atom on the benzene ring may be substituted by a group represented by R⁵³O-CO-(CH₂) u -(wherein R⁵³ represents a hydrogen atom or a lower alkyl group, and u represents an integer of 0 to 6), (5) a benzyl group in which one or two hydrogen atoms on the benzene ring are substituted by hydroxyl groups, or two hydrogen atoms on the benzene ring are substituted by a hydroxyl group and a sulfo group, (6) a 3-benzothienylmethyl group, a (1-oxo-3-benzo-thienyl)methyl group or (7) a (1,1-dioxo-3-benzothienyl)-methyl group; X² represents an oxygen atom or a sulfur atom; and A² represents a group selected from the group consisting of groups represented by formulae (LIII), (LIV), (LV), (LVI) (LVII) and (LVIII): wherein Y represents a sulfo group, a group represented by -CO₂R⁹¹ (wherein R⁹¹ represents a hydrogen atom, a lower alkyl group or a benzyl group) or a group represented by - CONR⁹²R⁹³ (wherein R⁹² represents a hydrogen atom, a lower alkyl group, a lower alkylsulfonyl group, a phenylsulfonyl group in which 1 to 5 arbitrary hydrogen atoms on the benzene ring may each be substituted by lower alkyl groups or halogen atoms, or a carboxymethyl group, and R⁹³ represents a hydrogen atom or a lower alkyl group); R⁶¹ represents a hydrogen atom or a lower alkyl group, or represents a methylene group together with R⁷¹; R⁷¹ represents a hydrogen atom, a lower alkyl group which may be substituted by a hydroxyl group, a phenyl group, a thienyl group, a phenyl-lower alkyl group in which any hydrogen atom on the benzene ring may be substituted by a hydroxyl group or a benzyloxy group, a thienyl-lower alkyl group, a thiazolyl-lower alkyl group, a 4-imidazolylmethyl group, a (lower alkyl-substituted 4-imidazolyl)methylthiomethyl group, a 3-indolylmethyl group, a carbamoyl-lower alkyl group or an N-benzyloxycarbonyl-ω-amino-lower straight chain alkyl group, or represents a methylene group together with R⁶¹, with the proviso that when R⁶¹ is a lower alkyl group, R⁷¹ represents a group other than a hydrogen atom; R⁶² represents a hydrogen atom, a phenyl group, a benzyl group, a carboxyl group, a carbamoyl group or an N-phenylcarbamoyl group, or represents a single bond together with R⁸; R⁷² represents a hydrogen atom, a lower alkyl group, a phenyl group, a benzyl group, a 3-indolylmethyl group, a carbamoyl group or an N-phenylcarbamoyl group, with the proviso that when R⁶² is a group other than a hydrogen atom, R⁷² represents a hydrogen atom or a lower alkyl group; R⁸ represents a hydrogen atom, a lower alkyl group, a lower alkoxyl group or a hydroxyl group, or represents a single bond together with R⁶²; V represents 3, 4 or 5; R⁶³ represents a hydrogen atom, a lower alkyl group, a carboxy-lower alkyl group or a group represented by Ar⁴-(CH₂) w - (wherein Ar⁴ represents a phenyl group, a furyl group or a thienyl group, and w represents 1 or 2; Z represents CH or N; and X represents 1, 2 or 3.

Claim 20

The composition according to claim 1, wherein the compound having antagonistic activity on the endothelin receptor is a peptide represented by formula [M] or a pharmaceutically acceptable salt thereof: AA¹-AA²-AA³-AA⁴-AA⁵-AA⁶   [M] wherein AA¹ represents D-Dip, D-Bip, D-His, D-His(Dnp), D-2-Nal, D-1-Nal, D-Phe, D-Pgl, D-Tyr, D-Tyr(OMe), D-Tyr(OEt), D-Tyr(OtBu), D-Trp, D-Trp(For), D-Tic, D-Tza, D-Pyr, Ac-D-Dip, Ac-D-Bip, Ac-D-His, Ac-D-His(Dnp), Ac-D-2-Nal, Ac-D-1-Nal, Ac-D-Phe, Ac-D-Pgl, Ac-D-Tyr, Ac-D-Tyr(OMe), Ac-D-Tyr(OEt), Ac-D-Tyr(OtBu), Ac-D-Trp, Ac-D-Trp(For), Ac-D-Tic, Ac-D-Tza, Ac-D-Pyr, Ada-D-Dip, Ada-D-Bip, Ada-D-His, Ada-D-His(Dnp), Ada-D-2-Nal, Ada-D-1-Nal, Ada-D-Phe, Ada-D-Phe, Ada-D-Pgl, Ada-D-Tyr, Ada-D-Tyr(OMe), Ada-D-Tyr(OEt), Ada-D-Tyr(OtBu), Ada-D-Trp, Ada-D-Trp(For), Ada-D-Tic, Ada-D-Tza, Ada-D-Pyr, Adoc-D-Dip, Adoc-D-Bip, Adoc-D-His, Adoc-D-His(Dnp), Adoc-D-2-Nal, Adoc-D-1-Nal, Adoc-D-Phe, Adoc-D-Pgl, Adoc-D-Tyr, Adoc-D-Tyr(OMe), Adoc-D-Tyr(OEt), Adoc-D-Tyr(OtBu), Adoc-D-Trp, Adoc-D-Trp(For), Adoc-D-Tic, Adoc-D-Tza, Adoc-D-Pyr, Boc-D-Dip, Boc-D-Bip, Boc-D-His, Boc-D-His(Dnp), Boc-D-2-Nal, Boc-D-1-Nal, Boc-D-Phe, Boc-D-Pgl, Boc-D-Tyr, Boc-D-Tyr(OMe), Boc-D-Tyr(OEt), Boc-D-Tyr(OtBu), Boc-D-Trp, Boc-D-Trp(For), Boc-D-Tic, Boc-D-Tza, Boc-D-Pyr, Z-D-Dip, Z-D-Bip, Z-D-His, Z-D-His(Dnp), Z-D-2-Nal, Z-D-1-Nal, Z-D-Phe, Z-D-Pgl, Z-D-Tyr, Z-D-Tyr(OMe), Z-D-Tyr(OEt), Z-D-Tyr(OtBu), Z-D-Trp, Z-D-Trp(For), Z-D-Tic, Z-D-Tza, Z-D-Pyr, Fmoc-D-Dip, Fmoc-D-Bip, Fmoc-D-His, Fmoc-D-His(Dnp), Fmoc-D-2-Nal, Fmoc-D-1-Nal, Fmoc-D-Phe, Fmoc-D-Pgl, Fmoc-D-Tyr, Fmoc-D-Tyr(OMe), Fmoc-D-Tyr(OEt), Fmoc-D-Tyr(OtBu), Fmoc-D-Trp, Fmoc-D-Trp(For), Fmoc-D-Tic, Fmoc-D-Tza or Fmoc-D-Pyr; AA² represents Ala, Alg, Arg, Asn, Asp, Dab, Glu, Gln, Gly, homoArg, homoGlu, homoLys, Ile, Leu, D-Leu, Lys, Met, Met(O), Met(O₂), Nva, Nle, Orn, Phe, Tyr or Val, or AA² is lacking; AA³ represents Ans, D-Ans, N-MeAns, Glu, Gln, homoPhe, Phe or Tyr, or AA³ is lacking; AA⁴ represents Ala, Chx, Gly, Glu, Ile, D-Ile, Leu, Nle, Nva or Val, or AA⁴ is lacking; AA⁵ represents Ala, Chx, Gly, Ile, D-Ile, Leu, Nle, Nva or Val, or AA⁵ is lacking; and AA⁶ represents 2-Nal, 1-Nal, Pyr, Trp, Tyr(OMe), Tyr(OEt), Tyr(OtBu), Tyr, Trp-Gly, Trp-Asp, Trp(For), Dip, Phe, Bza or

Claim 21

The composition according to claim 1, wherein the compound having antagonistic activity on the endothelin receptor is a compound represented by formula [N] or a pharmaceutically acceptable salt thereof: wherein: R₁ is -X(CH₂) n Ar or -X(CH₂) n R₈ or R₂ is hydrogen, Ar or (c); P₁ is -X(CH₂) n R₈; P₂ is -X(CH₂) n R₈, or -XR₉Y; R₃ and R₅ are independently hydrogen, R₁₁, OH, C₁₋₈alkoxy, S(O) q R₁₁, N(R₆)₂, Br, F, I, Cl, CF₃, NHCOR₆, -XR₉-Y or -X(CH₂)nR₈ wherein the methylene groups of -X(CH₂) n R₈ may be unsubstituted or substituted by one or more -(CH₂) n Ar groups; R₄ is hydrogen, R₁₁, OH, C₁₋₅alkoxy, S(O) q R₁₁, N(R₆)₂, - X(R₁₁), Br, F, I, Cl or NHCOR₆ wherein the C₁₋₅alkoxy may be unsubstituted or substituted by OH, methoxy or halogen; R₆ is independently hydrogen or C₁₋₄alkyl; R₇ is independently hydrogen or C₁₋₆alkyl or (CH₂) n Ar; R₈ is hydrogen, R₁₁, COOH, PO₃H₂, P(O)(OH)R₇ or tetrazole; R₉ is C₁₋₁₀alkyl, C₂₋₁₀alkenyl or phenyl all of which may be unsubstituted or substituted by one or more OH, N(R₆)₂, COOH, halogen or XC₁₋₅alkyl; R₁₀ is R₃ or R₄; R₁₁ is C₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkynyl all of which may be unsubstituted or substituted by one or more OH, CH₂OH, N(R₆)₂ or halogen; X is (CH₂) n , O, NR₆ or S(O) q ; Y is CH₃ or -CH₂X(CH₂) n Ar; Ar is: naphthyl, indolyl, pyridyl or thienyl, oxazolidinyl, oxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, thiadiazolyl, morpholinyl, piperidinyl, piperazinyl, pyrrolyl, or pyrimidyl; all of which may be unsubstituted or substituted by one or more R₃ or R₄ groups; A is C=O, or [C(R₆)₂] m ; B is -CH₂- or -O-; Z₁ and Z₂ are independently hydrogen, C₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkynyl, OH, C₁₋₈alkoxy, S(O) q C₁₋₈alkyl, N(R₆)₂, Br, F, I, Cl, CF₃, NHCOR₆, -X(CH₂) n R₈, phenyl, benzyl or C₃₋₆cycloalkyl wherein the C₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkynyl may be optionally substituted by COOH, OH, CO(CH₂) n CH₃, CO(CH₂) n CH₂N(R₆)₂ or halogen; or Z₁ and Z₂ together may be -O-A-O- on contiguous carbons; Z₃ is Z₁ or XR₉Y; q is zero, one or two; n is an integer from 0 to six; m is 1, 2 or 3; and the dotted line indicates the optional presence of a double bond; or a pharmaceutically acceptable salt thereof; provided that · R₂ is not hydrogen when X is S(O) q ; · when the optional double bond is present there is only one R₁₀ and there is no P₁; · the compound Formula I is not (1RS)-1,3-diphenylylindene-2-carboxylic acid; (cis,cis)-(1RS,3SR)-1,3-diphenylidindane-2-carboxylic acid; (1RS)-3-[3-Methyl-1-pheyl-(1H)-ind-2-en-1-yl]propionic acid; or (1RS)-2-[1,3-dipheyl-(1H)-ind-2-en-2-yl]ethanoic acid.

Claim 22

The composition according to claim 1, wherein the compound having antagonistic activity on the endothelin receptor is a compound represented by formula [O] or a pharmaceutically acceptable salt thereof: AA¹-AA²-AA³-AA⁴-AA⁵-AA⁶   [O] wherein AA¹ is wherein R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, fluorenylmethyl, wherein R² and R³ are each the same or different and each is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, or fluorenylmethyl, wherein R² is as defined above, -OR², wherein R² is as defined above, wherein R² and R³ are as defined above, wherein R⁹ is F, Cl, Br, or I, -CH₂-OR², wherein R² is as defined above, wherein R 2a is hydrogen or alkyl and R³ is defined above, wherein R 2a and R³ are as defined above excluding R³ is hydrogen, or wherein R² is defined above, R¹ is hydrogen or alkyl, Z is -O-, -S(O) m -, wherein m is zero or an integer of 1 or 2, -N-, wherein R² is as defined above, R² -(CH₂) n -, wherein n is zero or an integer of 1, 2, 3, or 4, -(CH₂) n -CH=CH-(CH₂) n -, wherein n is as defined above, -CO-, wherein R¹ and R² are as defined above, or wherein R² and R³ are each the same or different and each is as defined above, X and Y are the same and each represent substituents located at the same position on the aromatic ring and each may be one, two, three, or four substituents selected from the group consisting of hydrogen, halogen, alkyl, -CO₂R², wherein R² is as defined above, wherein R² and R³ are as defined above, wherein R² and R³ are as defined above, nitro or wherein R, Z, X, and Y are as defined above; AA² is wherein R⁴ is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, wherein R 2b and R 3b are each the same or different and each is hydrogen, alkyl, cycloalkyl, aryl, or heteroaryl, -OR 2b , wherein R 2b is as defined above, wherein R 2b and R 3b are each the same or different and each is as defined above for R 2b and R 3b , wherein R 2b is as defined above, wherein R 2b is as defined above, or wherein R 2b is as defined above, and R¹ and n are as defined above, AA² can be absent; AA³ is wherein R⁵ is hydrogen, alkyl, aryl, heteroaryl, wherein R 2b and R 3b are each the same or different and each is as defined above, wherein R 2b is as defined above, or wherein R 2b is as defined above, and R¹ and n are as defined above, AA³ can be absent; AA⁴ and AA⁵ are each independently absent or each is independently wherein R⁶ is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, or heteroaryl, and R¹ and n are as defined above, AA⁶ is wherein R⁷ is aryl or heteroaryl, R⁸ is wherein R¹ is as defined above, -OR¹, wherein R¹ is as defined above, wherein R¹ is as defined above, or -CH₂-OR¹, wherein R¹ is as defined above, and R¹ and n are as defined above; wherein the stereochemistry at C* in AA¹, AA², AA³, AA⁴, or AA⁵ is D, L, or DL and wherein the stereochemistry at C* in AA⁶ is L; or a pharmaceutically acceptable salt thereof.

Claim 23

The composition according to claim 1, wherein the compound having antagonistic activity on the endothelin receptor is a peptide represented by formula [P] or pharmaceutically acceptable salts thereof: X-A-Trp-B-Gly-Thr-E-G-Y   (P) wherein A represents Asn or Asp; B represents His or Lys; E represents Ala or Ser; G represents Ala or Pro; X represents X¹-Gly or Y represents hydroxyl, lower alkoxyl, amino, [wherein X¹ and X³ each represent hydrogen, benzyloxycarbonyl, t-butyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, or carbonyl-substituted or unsubstituted lower alkanoyl; X² and Y² each represent hydrogen; Y¹ represents hydroxyl, lower alkoxyl or amino, or X¹ and Y¹, and X² and Y² each combine to form X¹-Y¹ and X²-Y², respectively, which represent single bonds; Z represents hydroxyl, lower alkoxyl, benzyloxy or benzhydryloxy, Gly-Z¹ (wherein Z¹ represents hydroxyl, lower alkoxyl, benzyloxy or benzhydryloxy, or forms X¹-Z¹ together with X¹, which represents a single bond), Ala-Z¹ (wherein Z¹ has the same meaning as given above), Val-Z¹ (wherein Z¹ has the same meaning as given above), Trp-Z¹ (wherein Z¹ has the same meaning as given above), Trp-Gly-Z¹ (wherein Z¹ has the same meaning as given above), Trp-Asn-Tyr-Tyr-Trp-Z¹ (wherein Z¹ has the same meaning as given above), Trp-Phe-Phe-Asn-Tyr-Tyr-7Hyt-Z¹ (wherein Z¹ has the same meaning as given above, and 7Hyt represents 7-hydroxytryptophan), Trp-Ile-Ile-Trp-Z¹ (wherein Z¹ has the same meaning as given above), Trp-Val-Tyr-Phe-W-His-Leu-Asp-Ile-Ile-Trp-Z¹ (wherein Z¹ has the same meaning as given above; and W represents Ala, Ser or Cys), Trp-W-His-Leu-Asp-Ile-Ile-Trp-Z¹ (wherein Z¹ and W have the same meanings as given above), Trp-Val-Tyr-Tyr-W-His-Leu-Asp-Ile-Ile-Trp-Z¹ (wherein Z¹ and W have the same meanings as given above), Trp-Leu-Tyr-Phe-W-His-Gln-Asp-Val-Ile-Trp-Z¹ (wherein Z¹ and W have the same meanings as given above), Trp-Val-Tyr-Phe-W-Phe-Phe-Asn-Tyr-Tyr-Trp-Z¹ (wherein Z¹ and W have the same meanings as given above), Trp-Phe-Phe-Asn-Tyr-Tyr-W-His-Leu-Asp-Ile-Ile-Trp-Z¹ (wherein Z¹ and W have the same meanings as given above), Trp-Phe-Phe-Asn-Tyr-Tyr-Asn-Ile-Ile-Trp-Z¹ (wherein Z¹ has the same meaning as given above), or J-Phe-M-Q-Tyr-R-T-Z¹ (wherein J represents Trp or a single bond; M represents Phe a single bond; Q represents Asn or a single bond; R represents Tyr or a single bond; T represents Trp, Ala, Phe, Tyr, Trp-Trp, Asn-Tyr-Tyr-Trp, Trp-Asn-Tyr-Tyr-Trp, Trp-Val-Tyr-Phe-W-His-Leu-Asp-Ile-Ile-Trp (wherein W has the same meaning as given above) or a single bond; at least two or more of J, M, Q, R and T do not concurrently form a single bond; and Z¹ has the same meaning as given above).

Claim 24

The composition according to claim 1, wherein the compound having antagonistic activity on the endothelin receptor is a compound represented by formula [Q] or a pharmaceutically acceptable salt thereof: wherein A is a group of the formula R¹¹OCO-(wherein R¹¹ is a lower alkyl group or a phenyl group), or a group of the formula R¹²R¹³N-C(=O)-(wherein R¹² is a lower alkyl group, a cycloalkyl group, a 1-adamantyl group, a phenyl group wherein one or two optional hydrogen atoms on the benzene ring may independently be replaced by a halogen atom, a trifluoromethyl group, a nitro group, an amino group or a formylamino group, a pyridyl group, or a thienyl group, R¹³ is a hydrogen atom, a lower alkyl group or a cycloalkyl group, or R¹² and R¹³ form, together with the adjacent nitrogen atom, a 5- to 9-membered nitrogen-containing saturated heterocyclic ring having 4 to 8 carbon atoms, wherein among methylene groups forming the ring, one optional methylene group not adjacent to the above nitrogen atom may be replaced by a thio group, and one to four optional hydrogen atoms on the carbon atoms of the heterocyclic ring may independently be replaced by a lower alkyl group, and further two adjacent carbon atoms in the heterocyclic ring may form a benzo-fused ring); B is an oxygen atom or a group of the formula -NR²- (wherein R² is a hydrogen atom or a lower alkyl group); R³ is a lower alkyl group, a cycloalkyl group, an anyl group, a heterocyclic group, a cycloalkyl lower alkyl group, an aryl lower alkyl group or a heterocyclic lower alkyl group; X¹ is an oxygen atom or a group of the formula -NR⁴- (wherein R⁴ is a hydrogen atom or a lower alkyl group); R⁵ is a 3-indolylmenthyl, 3-benzothienylmethyl, 1-naphthylmethyl or benzyl group wherein one or two optional hydrogen atoms on the ring may be replaced by a hydroxyl group, a halogen atom, a formyl group, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a lower alkoxycarbonyl group, a nitro group or a group of the formula R⁵¹-CO-X² (wherein R⁵¹ is a lower alkyl group, a lower alkoxy group, or an amino group which may be substituted by a lower alkyl group, and X² is an oxygen atom or a group of the formula -NR⁵²- (wherein R⁵² is a hydrogen atom or a lower alkyl group)); X³ is an oxygen atom or a sulfur atom; R⁶ is a hydrogen atom, or a lower alkyl or lower alkenyl group which may have a substituent selected from the group consisting of a hydroxyl group, a lower alkoxy group, a lower alkylthio group and a heterocyclic group; n is O or 1; Y is a hydroxymethyl group, a group of the formula CO₂R⁷¹ (wherein R⁷¹ is a hydrogen atom or a lower alkyl group), a group of the formula CONHR⁷² (wherein R⁷² is a hydrogen atom or a lower alkyl group which may have a substituent selected from the group consisting of a hydroxyl group, a carboxyl group and a sulfo group), a 1H-tetrazol-5-yl group, a sulfo group and a phosphono group; or a pharmaceutically acceptable salt thereof.

Claim 25

The composition according to claim 1, wherein the compound having antagonistic activity on the endothelin receptor is a compound represented by formula [R] or a pharmaceutically acceptable salt thereof: wherein R¹ is a lower alkyl group, a cycloalkyl group, a cycloalkyl lower alkyl group, an aralkyl group, an aryl group, a 5- to 10-membered heterocyclic ring, a 5- to 10-membered heterocyclic lower alkyl group, in which on the chain and/or the ring, the lower alkyl group, the cycloalkyl group, the cycloalkyl lower alkyl group, the aralkyl group, the aryl group, the 5- to 10-membered heterocyclic ring, the 5- to 10-membered heterocyclic lower alkyl group may be each independently substituted by a lower aklyl, halogen, OH, a lower alkoxy, nitro, trifluoromethyl, cyano, formyl, a lower alkanoyl, carboxyl, a lower alkoxy carbonyl group, amino, monoloweralkylamino, diloweralkylamino, formylamino, alkanoylamino, aroylamino, carbamoyl, N-mono-loweralkylcarbamoyl or N,N-diloweralkylcarbamoyl, mercapto, loweralkylthio or loweralkanoylthio; p is an integer of 0 to 2; A¹ is a single bond or a divalent lower alkylene group which may be substituted with a lower alkyl; R² is a lower alkyl group, a cycloalkyl group, a cycloalkyl lower alkyl group, an aralkyl group, an aryl group, a 5- to 10-membered heterocyclic ring, a 5- to 10-membered heterocyclic lower alkyl group; X¹ is an oxygen atom or -NR³- wherein R³ is hydrogen or a lower alkyl group; R⁴ is a 5- to 10-membered heterocyclic lower alkyl group which may have on the ring a lower alkyl group; R⁴¹-CO-(CH₂) q wherein R⁴¹ represents hydrogen, a lower alkyl group, OH, a lower alkoxy group, aralkyloxy, amino, a monolower alkylamino group or a dilower alkylamino group; q is an integer of 0 to 6; an aryl lower aklyl group which may have on the ring nitro, R⁴²-CO-(CH₂) r - wherein R⁴² represents a lower alkyl group, a lower alkoxy group, amino, a mono lower alkylamino group or a dilower alkylamino group; r is an integer of 0 to 6; R⁴²-CO-X²- wherein R⁴² has the same meaning as above, X² is an oxygen atom or -NR⁴³- wherein R⁴³ is hydrogen or a lower alkyl group; or R⁴⁴O-(CH₂) s - wherein R⁴⁴ is hydrogen or a lower alkyl group and s is an integer of 0 to 6; X³ represents an oxygen or sulfur atom; A² represents any group selected from a group consisting of the following [RII] to [RVII]: wherein Y represents a hydroxy loweralkyl group, a sulfo group, a phosphono group, -CO₂R⁸¹ wherein R⁸¹ is hydrogen or a carboxyl protective group, or -CONR⁸²R⁸³ wherein R⁸² and R⁸³ each independently represents hydrogen, a lower alkyl group, a lower alkyl sulfonyl group, a phenyl sulfonyl group in which 1 to 5 hydrogen atoms on the benzene ring may be independently substituted by a lower alkyl group or halogen, or a carboxy lower alkyl group; R⁵¹ is hydrogen or a lower alkyl group, or forms a methylene group together with R⁶¹ described below; R⁵³, R⁶¹ and R⁶² each independently represents a lower alkyl group, a lower alkenyl group, an aryl group, an aryl lower alkyl group, a 5- to 10-membered heterocyclic ring, a 5- to 10-membered heterocyclic lower alkyl group; in which, on the chain and/or the ring, the lower alkyl group, the lower alkenyl group, the aryl group, the aryl lower alkyl group, the 5- to 10-membered heterocyclic ring, the 5- to 10-membered heterocyclic lower alkyl group may be each independently substituted by OH, a lower aklyl group, halogen, a lower alkoxy group, an aryloxy group, an acyloxy group, a carboxyl group, a protected carboxyl group, an amino group, a monoalkylamino group, a diloweralkylamino group, a carbamoyl group, an N-mono-loweralkylcarbamoyl group, an N,N-diloweralkylcarbamoyl group, a loweralkoxy carbonylamino group or an aryloxy carbonylamino group; further R⁶¹ and R⁵¹ may form together a methylene group in the proviso that R⁶¹ is other than hydrogen when R⁵¹ is a lower alkyl, and R⁶² is hydrogen or a lower alkyl group when R⁵² is other than hydrogen; R⁵² represents hydrogen, an aryl group, an aralkyl group, a carboxyl group, a carbamoyl group, an N-monoloweralkyl carbamoyl group, an N,N-diloweralkyl carbamoyl group or an N-arylcarbamoyl group; or forms a single bond with R⁷; R⁷ represents hrdrogen, a lower alkyl group, a lower alkoxy group or OH, or forms a single bond with R⁵²; t is an integer of 2 to 6; Z is CH or N; v is an integer of 1 to 3.

Claim 26

The composition according to claim 25, wherein the compound is represented by the formula:

Claim 27

The composition according to claim 1, wherein the compound having antagonistic activity on the endothelin receptor is a cyclic pentapeptide represented by formula [S] or a pharmaceutically acceptable salt thereof: cyclo(-Dtrp(COOCH₃)-Dasp-Pro-DtertLeu-γMeLeu-)   [S].

Claim 28

The composition accroding to claim 1, wherein the compound having antagonistic activity on the endothelin receptor is a compound represented by formula [T] or a pharmaceutically acceptable salt thereof: wherein one of X and Y is N and the other is O; R is naphthyl or naphthyl substituted with R¹, R² and R³; R¹, R² and R³ are each independently hydrogen; alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl or aralkyl, any of which may be substituted with Z¹, Z² and Z³; halo; hydroxyl; cyano; nitro; -C(O)H; -C(O)R⁶; COOH; COOR⁶; -SH; -S(O) n R⁶; -S(O) m -OH; S(O) m -OR⁶; -O-S(O) m -R⁶; O-S(O) m -OH; -O-S(O) m -OR⁶; -Z⁴-NR⁷R⁸; or -Z⁴-N(R¹¹)-Z⁵-NR⁹R¹⁰; R⁴ and R⁵ are each independently hydrogen; alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, or aralkyl, any of which may be substituted with Z¹, Z² and Z³; halo; hydroxyl; cyano; nitro; -C(O)H; -C(O)R⁶; COOH; COOR⁶; -SH; -S(O) n R⁶; -S(O) m -OH; -S(O) m -OR⁶; -O-S(O) m -R⁶; -O-S(O) m -OH; -O-S(O) m -OR⁶; -Z⁴-NR⁷R⁸; or -Z⁴-N(R¹¹)-Z⁵-NR⁹R¹⁰; or R⁴ and R⁵ together are alkylene or alkenylene (either of which may be substituted with Z¹, Z² and Z³), completing a 4- to 8-membered saturated, unsaturated or aromatic ring together with the carbon atoms to which they are attached; R⁶ is alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, or aralkyl, any of which may be substituted with Z¹, Z² or Z³; R⁷ is as defined for R⁶ or is H, CN, OH, COH, COR⁶, CO₂R⁶; or in Z is not SO n , R⁷ can be SH, COR⁶, SO m OH, SO m OR⁶, OSO m R⁶, OSO m OH or OSO m OR⁶; R⁸ is as defined for R⁶ or H or if Z⁴ is not CO and R⁷ is not COH, COR⁶ or CO₂R⁶, R⁸ can be COH or COR⁶; or NR⁷R⁸ is alkylene or alkenylene (each opt. substituted with Z¹, Z² or Z³) completing a 3-8 membered optionally saturated, unsaturated, or aromatic ring; R⁹ is as defined for R⁶ or H, OH, COH or COR⁶, CO₂R⁶, SH, SO n R⁶, SO m OH, SO m OR⁶ , OSO m R⁶, OSO m OH or OSO m OR⁶; R¹⁰ is as defined for R⁶ or H or if Z⁵ is not CO and R⁹ is not COH, COR⁶ or CO₂R⁶, R¹⁰ can be COH or COR⁶; R¹¹ is as defined for R⁶ or H, OH, COH, COR⁶ or CO₂R⁶; or any 2 of R⁹, R¹⁰ and R¹¹ together form alkylene or alkenylene (each opt. substituted with Z¹, Z² or Z³) completing a 3-8 membered optionally saturated, unsaturated, or aromatic ring, with the atoms to which they are attached; Z¹, Z² and Z³ are H, halogen, OH, alkyl, alkenyl, aralkyl, alkoxy, aryloxy, aralkyloxy, SH, SO n Z⁶, SO m OH, SO m OZ⁶, OSO m OH, OSO m OZ⁶, oxo, NO₂, CN, COH, COZ⁶, CO₂H, CO₂Z⁶, Z⁴NZ⁷Z⁸, Z⁴NZ¹¹Z⁵Z⁶, Z⁴NZ¹¹Z⁵NZ⁷Z⁸; Z⁴,Z⁵ are a vinyl bond, Z⁹SOnZ¹⁰, Z⁹COZ¹⁰, Z⁹CSZ¹⁰, Z⁹OZ¹⁰, Z⁹SZ¹⁰ or Z⁹OCOZ¹⁰; Z⁶, Z⁷, Z⁸ are H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aralkyl; or NZ⁷Z⁸ is alkylene or alkenylene completing a 3-8 membered optionally saturated, unsaturated, or aromatic ring; Z⁹, Z¹⁰ are a single bond, alkylene, alkenylene or alkynylene; Z¹¹ is as defined for R⁶ or H, OH, COH, COZ⁶ or CO₂Z⁶; or any 2 of Z⁷, Z⁸ and Z¹¹ together form alkylene or alkenylene completing a 3-8 membered optionally saturated, unsaturated, or aromatic ring, with the atoms to which they are attached; m is 1 or 2, n is 0, 1 or 2.

Claim 29

The composition according to claim 28, wherein the compound is

Claim 30

The composition according to claim 1, wherein the compound having antagonistic activity on the endothelin receptor is a compound represented by formula [U] or pharmaceutically acceptable salts thereof: wherein Ar is a substituted or unsubstituted aromatic or heterocyclic group; R is H or a substituted or unsubstituted straight or branched chain, cyclic or mixture of straight, branched and cyclic alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkoxyalkyl or alkoxycarbonyl group having from 1-20 carbon atoms; A is a functional group that bears a polar moiety, and is preferably COOH or RNH; R₁ is R, R-C=O, R substituted with one or more heteroatoms, a substituted or unsubstituted aryl group, or is aryl-(CH₂) n ; R₂ is (CH₂) n , CHR, C(R)₂, COO, OCO, NHCO, CONH, SO, SO₂ or NR; R₃ and R₄, which are the same or different or each may be absent, and are =O, H, O-aryl, OR, O-alkyl or alkyl, aryl, SR, S-aryl, NHR, NH-aryl, NR, or are other heteroaromatic groups; R₅ is H, OH or R; E and F, which are the same or are different, are either N or (CH₂) p ; p is an integer or 0 between 0 and 5; m and n are integers or 0 between 0 and 10; T is O, S, NCOR or NR; U and V, which may be the same or different, are (CH₂) n ; W is CO, (CH₂) n , (CH₂) n -CHR or CHR-(CH₂) n ; X and Y, which may be the same or different, are H, alkyl or aryl or X and Y form a saturated or unsaturated homocyclic or heterocyclic ring containing 3-15 members; and Z is H, SR, NHR or N(R)₂.

Claim 31

The composition according to claim 30, wherein the compound is represented by the formula:

Claim 32

The composition according to claim 1, wherein the compound having antagonistic activity on the endothelin receptor is a compound represented by formula [V] or a pharmaceutically acceptable salt thereof: One of X, Y is N and the other is O; R₁, R₂, R₃ = independently H (R₁ is not H); alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl(alkyl), cycloalkenyl(alkyl), aryl, aryloxy, aralkyl or aralkoxy; halo, hydroxyl; cyano; nitro; -C(O)H; -C(O)R₆; COOH; COOR₆; -SH; -S(O) n R₆; -S(O) m -OH; -S(O) m -OR₆; -O-S(O) m -R₆; -O-S(O) m -OH; -O-S(O) m -OR₆; -Z₄-NR₇R₈; or -Z₄-N(R₁₁)-Z₅-NR₉R₁₀; R₄, R₅ = as defined for R₁-R₃ or together form a 4-8 membered saturated, unsaturated or aromatic ring; R₆ is alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cylcoalkenylalkyl, aryl or aralkyl, any of which may be substituted with Z₁, Z₂ and Z₃, R₇ is H; alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cylcoalkenylalkyl, aryl or aralkyl, any of which may be substituted with Z₁, Z₂ and Z₃; cyano; hydroxyl; -C(O)H; -C(O)R₆; COOH; COOR₆; -SH; - S(O) n R₆; -S(O) m -OH; -S(O) m -OR₆; -O-S(O) m -R₆; -O-S(O) m -OH; -O-S(O) m -OR₆ except when Z₄ is -S(O) n -; R₈ is H; -C(O)H or -C(O)R₆ except when Z₄ is -C(O)- and R₇ is -C(O)H, -C(O)R₆, COOH or COOR₆; alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cylcoalkenylalkyl, aryl or aralkyl, any of which may be substituted with Z₁, Z₂ and Z₃; or R₇ and R₈ together are alkylene or alkenylene (either of which may be substituted with Z₁, Z₂ and Z₃), completing a 3- to 8-membered saturated, unsaturated or aromatic ring together with the nitrogen atom to which they are attached; R₉ is H; hydroxyl; -C(O)H or -C(O)R₆; COOH or COOR₆; -SH; - S(O) n R₆; -S(O) m -OH; -S(O) m -OR₆; -O-S(O) m -R₆; -O-S(O) m -OH; -O-S(O) m -OR₆; alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cylcoalkenylalkyl, aryl or aralkyl, any of which may be substituted with Z₁, Z₂ and Z₃; R₁₀ is H; -C(O)H or -C(O)R₆ except when Z₅ is -C(O)- and R₉ is -C(O)H, -C(O)R₆, COOH or COOR₆; alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cylcoalkenylalkyl, aryl or aralkyl, any of which may be substituted with Z₁, Z₂ and Z₃; R₁₁ is H; hydroxyl, -CO₂R₆ or COOH, except when one of R₉ and R₁₀ is hydroxyl, -CO₂R₆ or COOH; -C(O)H, -C(O)R₆; or alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cylcoalkenylalkyl, aryl or aralkyl, any of which may be substituted with Z₁, Z₂ and Z₃; any 2 of R₉, R₁₀ and R₁₁ together form alkylene or alkenylene (each opt. substituted with Z₁, Z₂ and Z₃) completing a 3-8 membered optionally saturated, unsaturated, or aromatic ring, with the atoms to which they are attached; Z₁, Z₂ and Z₃ are each independently H; halogen; OH; alkoxy, SH, SO n Z₆, SO m OH, SO m OZ₆, OSO m Z₆, OSO m OH or OSO m OZ₆; oxo; NO₂, CN, COH, COZ₄, CO₂H, CO₂Z₄, NZ₇Z₈, CONZ₇Z₈ or S(O) n Z₇Z₈; Z₄ and Z₅ are each independently a single bond; -S(O) n ; - C(O)-; -C(S)-; or alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cylcoalkenylalkyl, aryl or aralkyl, any of which may be substituted with Z₁, Z₂ and Z₃; Z₆, Z₇ and Z₈ are each independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cylcoalkenylalkyl, aryl or aralkyl, or Z₇ and Z₈ together form alkylene or alkenylene completing a 3-8 membered saturated, unsaturated, or aromatic ring, with the nitrogen atom to which they are attached; m is 1 or 2; and n is 0, 1, or 2.

Claim 33

The composition according to claim 32, wherein the compound is represented by the formula:

Claim 34

The composition according to claim 1, wherein the compound having antagonistic activity on the endothelin receptor is a cyclic pentapeptide represented by formula [W1], [W2] or [W3] or a pharmaceutically acceptable salt thereof: X= an α-amino acid with a conformationally restricted 4-16C side chain. Y= Ser, Z= an α-amino acid with a conformationally restricted side chain. The side chain, C-amino and N-amino groups of X form 1-3 separate or fused rings with the amino groups being members of one the rings. TCC is 1,2,3,4-tetrahydro-2-carboline-3-caroxylic acid; and

Claim 35

The composition according to claim 1, wherein the compound having antagonistic activity on the endothelin receptor is a compound represented by formula [X1], [X2] or [X3] or a pharmaceutically acceptable salt thereof:

Claim 36

The disodium salt of a compound cyclo(D-Asp-Asp(R1)-Asp-D-Thg(2)-Leu-D-Trp-).