Use of non-peptidyl compounds for the treatment of insulin related ailments

• US 6,933,272 B1
• Filed: 09/22/1999
• Issued: 08/23/2005
• Est. Priority Date: 09/22/1998
• Status: Expired due to Fees

• Current Assignee: Brian Scott Plewright, Erik Helmerhorst
• Original Assignee: Brian Scott Plewright, Erik Helmerhorst
• Inventors: Helmerhorst, Erik, Plewright, Brian Scott
• Primary Examiner(s): Weber, Jon
• Assistant Examiner(s): Robinson, Hope A.
• Application Number:
  US09/400,769
• Time in Patent Office: 2,162 Days
• Field of Search: 530/350, 530/326, 530/323, 530/325, 530/327, 530/324, 514/2, 514/3, 514/12, 514/13, 514/14, 514/21, 424/464
• US Class Current: 514/75
• CPC Class Codes: A61K 31/19 Carboxylic acids, e.g. valproic acid salicylic acid A61K31/60
• CPC Class Codes: A61K 31/35 having six-membered rings with one oxygen as the only ring hetero atom

Abstract

The present invention relates to the use of at least a non-peptidyl compound as a biological modulator of insulin activity or insulin-related activity, which compound possesses ionic and hydrophobic chemical moieties spatially located so as to mimic at least an ionic and hydrophobic amino acid residue of insulin, which amino acids are associated with the binding of insulin to its receptor.

Claims

1. A method for treating a patient suffering from one or more insulin related ailments selected from the group consisting of hyperglycemia and hyperglycemia associated with diabetes mellitus, which method comprises the step of:

administering to a patient in need thereof a therapeutically effective amount of a non-peptidyl compound, which possesses one or more ionic and hydrophobic chemical moieties spatially located so as to mimic the spatial location of at least an ionic or a hydrophobic amino acid residue of insulin and which binds to the insulin binding site of the insulin receptor, wherein said compound is an insulin agonist.

2. A method according to claim 1, wherein the ionic amino acid residue is selected from the group consisting of:

A21 Asn, B21 Glu and A17 Glu.

3. A method according to claim 1, wherein the ionic and hydrophobic amino acid residue(s) is(are) selected from the group consisting of:

A21 Asn, B21 Glu, A17 Glu, B24 Phe, B25 Phe, A19 Tyr, B12 Val, B16 Tyr, A2 Ile, A3 Val and A1 Gly.

4. A method according to claim 1, wherein at least one amino acid is selected from the group consisting of:

A17 Glu, B21 Glu and A21 Asn; and

at least one amino acid is selected from the group consisting of;

B24 Phe, B25 Phe, A19 Tyr, B12 Val and B16 Tyr.

5. A method according to claim 1, wherein the non-peptidyl compound possesses ionic and hydrophobic chemical moieties spatially located so as to mimic ionic and hydrophobic residues associated with at least one of the following groups of amino acid residues:

(i.) A21 Asn, B21 Glu, A17 Glu, B24 Phe, B25 Phe;

(ii.) A21 Asn, B21 Glu, B24 Phe, B25 Phe;

(iii.) A21 Asn, B21 Glu, B24 Phe, B25 Phe, A1 Gly, A2 Ile, A3 Val;

(iv.) A21 Asn, B21 Glu, A17 Glu, A19 Tyr, A1 Gly, A2 Ile, A3 Val;

(v.) A21 Asn, B21 Glu, A17 Glu, B12 Val, A1 Gly, A2 Ile, A3 Val;

(vi.) A21 Asn, B21 Glu, B12 Val, A1 Gly, A2 Ile, A3 Val;

(vii.) A21 Asn, B21 Glu, A17 Glu, B16 Tyr, A1 Gly, A2 Ile, A3 Val;

(viii.) A21 Asn, B21 Glu, A17 Glu, A19 Tyr, B12 Val, B16 Tyr;

(ix.) A21 Asn, B21 Glu, A19 Tyr, B12 Val, B16 Tyr;

(x.) A21 Asn, B21 Glu, A17 Glu, B24 Phe, B25 Phe, A19 Tyr, B132 Val, B16 Tyr;

(xi.) A21 Asn, B21 Glu, B24 Phe, B25 Phe, A19 Tyr, B12 Val, B16 Tyr;

(xii) A21 Asn, B21 Glu, B24 Phe, B25 Phe, B12 Val, B16 Tyr;

(xiii.) A21 Asn, B21 Glu, A17 Glu, B24 Phe, B25 Phe, A19 Tyr;

(xiv.) A21 Asn, B21 Glu, B24 Phe, B25 Phe, A19 Tyr;

(xv.) A21 Asn, A17 Glu, B24 Phe, B25 Phe, A19 Tyr;

(xvi.) B21 Glu, A17 Glu, B24 Phe, B25 Phe, A19 Tyr;

(xvii.) A21 Asn, B21 Glu, A17 Glu, B24 Phe, B25 Phe, B12 Val;

(xviii.) A21 Asn, B21 Glu, B24 Phe, B25 Phe, B12 Val;

(xix.) A21 Asn, A17 Glu, B24 Phe, B25 Phe, B12 Val;

(xx.) B21 Glu, A17 Glu, B24 Phe, B25 Phe, B12 Val;

(xxi.) A21 Asn, B21 Glu, A17 Glu, B24 Phe, B25 Phe, B16 Tyr;

(xxii.) A21 Asn, B21 Glu, B24 Phe, B25 Phe, B16 Tyr;

(xxiii.) A21 Asn, A17 Glu, B24 Phe, B25 Phe, B16 Tyr;

(xxiv.) B21 Glu, A17 Glu, B24 Phe, B25 Phe, B16 Tyr;

(xxv.) A21 Asn, B21 Glu, A17 Glu, B24 Phe, A19 Tyr, B12 Val, B16 Tyr;

(xxvi.) A21 Asn, B21 Glu, B24 Phe, A19 Tyr, B12 Val, B16 Tyr;

(xxvii.) A21 Asn, A17 Glu, B24 Phe, A19 Tyr, B12 Val, B16 Tyr;

(xxviii.) B21 Glu, A17 Glu, B24 Phe, A19 Tyr, B12 Val, B16 Tyr;

(xxix.) A21 Asn, B21 Glu, A17 Glu, B25 Phe, A19 Tyr, B12 Val, B16 Tyr;

(xxx.) A21 Asn, B21 Glu, B25 Phe, A19 Tyr, B12 Val, B16 Tyr;

(xxxi.) A21 Asn, A17 Glu, B25 Phe, A19 Tyr, B12 Val, B16 Tyr; and

(xxxii.) B21 Glu, A17 Glu, B25 Phe, A19 Tyr, B12 Val.

6. A method according to claim 1, wherein the non-peptidyl compound has the following formula:

AXYXZ_n 

 

(formula

     1)

where A is W or VXW;

V is V₁ or V₂;

V is substituted with up to two X groups;

V₁ is a phenyl or 6 membered heteroaromatic ring, optionally substituted with up to 5 R₁ groups;

V₂ is a 5 member ring system which may incorporate up to 4 hetero atoms which may be independently a nitrogen atom, a nitrogen atom optionally substituted with R₂, oxygen or sulfur, the ring system being optionally substituted with up to 4 R₁ groups;

W is W₁ or W₂ or W₃;

W is substituted with up to two X groups;

W₁ is V₁;

W₂ is a fused bicyclic ring system comprising rings of 5 or 6 atoms, which may incorporate up to 4 hetero atoms, which may be independently a nitrogen atom, a nitrogen atom optionally substituted with R₂, oxygen or sulfur, the system being optionally substituted with up to seven R₁ groups;

W₃ is —

N(R₂)R′

₂;

R₁ is independently H, OH, alkyl, alkenyl, alkynyl, alkoxy, alkanol, hydroxyalkoxy, haloalkyl, haloalkoxy, halogen, SH, thioalkyl, cyano (—

CN), N(R₂)R′

₂, phenyl, phenyl optionally substituted with up to five alkyl groups of 1 to 3 carbon atoms or up to five halogen atoms, benzyl, phenethyl, nitro, —

COR₃, —

R₅COR₃, —

R₅SOR₃, —

R₅SO₂R₃, —

SO₂N(R₂)R′

₂ or azido;

R₂ and R′

₂ are independently H, alkyl of 1 to 6 carbon atoms, alkenyl of 3 to 6 carbon atoms, alkynyl of 3 to 6 carbons, hydroxyalkyl of 2 to 6 carbons, alkoxy of 2 to 6 carbons, haloalkyl, haloalkenyl, haloalkoxy, benzyl, benzyl optionally substituted with up to four R₁ groups, phenylethyl, phenylethyl optionally substituted with up to four R₁ groups, arylalkyl, and where R₂ and R′

₂ can also be joined to form cyclic structures;

R₃ is independently H, OH, alkyl, alkenyl, alkynyl, alkoxy, alkanol, hydroxyalkoxy, —

R₄N(R₂)R′

₂, mesyl, triflouromesyl, —

NHSO₂CH₃ or —

NHSO₂CF₃;

R₄ is independently a bond, alkyl, alkenyl or alkynyl;

X is independently, a bond, —

R₄N(R₂)R₄—

, —

R₄N═

NR₄—

, —

R₄N(R₂)—

N(R₂)R₄—

, —

R₄OR₄—

, —

R₄SR₄—

, —

R₅—

, —

R₅O—

, —

R₅S—

, —

R₅N(R₂)—

, —

SO—

, sulfonyl (—

SO₂—

), —

CO—

, —

CONH—

, —

NHCONH—

, —

NHCO—

, —

CONHCO—

, —

CON(R₂)—

, —

RCOR₅—

, —

R₅COR₅N(R₂)R₅—

, —

N(R₂)CO—

or —

R₄N(R₂)R₄COR₄—

;

R₅ is independently alkyl, alkenyl, alkynyl, alkoxy, alkanol, hydroxyalkoxy;

Y is either Y₁, Y₂ or Y₃;

Y is substituted with at least two, but optionally up to four X linking groups;

Y₁ is a fused bicyclic ring system comprising rings of 5 or 6 atoms which may incorporate up to 4 hetero atoms, which may be independently a nitrogen atom, a nitrogen atom optionally substituted with R₂, oxygen or sulfur, the ring system optionally independently incorporating a sulfoxide (SO), sulfone (SO₂) or carbonyl (CO) group and optionally up to seven R₁ groups;

Y₂ is a 6;

6;

6 or a 6;

5;

6 fused tricyclic system which may incorporate up to 4 hetero atoms which may be independently a nitrogen atom, a nitrogen atom optionally substituted with R₂, oxygen or sulfur, the ring system optionally independently incorporating a sulfoxide (SO), sulfone (SO₂) or carbonyl (CO) group, and the ring system being substituted with at least two, but optionally up to four X linking groups and optionally up to seven R₁ groups;

Y₃ is V₁;

Z is independently —

R₆COOH, —

R₆SO₃H, —

R₆NO₂, —

R₆SO₂H, —

R₆SO₂NHR₂;

—

R₇SO₂NHCOR₄—

N-trifluoromesylsulfonanidate, —

OH, -2-yl-hydroxyethanoic acid (—

CH(OH)COOH), -3-yl-2-hydroxypropanoic acid (—

CH₂CH(OH)COOH)-2-yl-2-hydroxypropanoic acid (—

CH(CH₃)(OH)COOH), -3-yl-2,3-dihydroxypropanoic acid (—

CH(OH)CH(OH)COOH), -2-yl-2,3-dihydroxypropanoic acid (—

C(CH₂(OH))(OH)COOH), -3-yl-2-hydroxypropan-3-one-1-oic acid (—

COCH(OH)COOH, 2-yl-2-hydroxypropandioic acid (—

C(COOH)(OH)COOH), -2-yl-propandioic acid (—

C(COOH)(H)COOH), -4-yl-2-hydroxybutan4-one-1-oic acid (—

COCH₂CH(OH)COOH, 2-yl-2-hydroxybutan-1,4-dioic acid (—

C(OH)(COOH)CH₂COOH), 3-yl-2-hydroxybutan-1,4-dioic acid (—

CH(CH(OH)COOH)COOH), 5-yl-tetrazole,

R₆ is independently a bond, alkyl, alkenyl, alkynyl, alkoxy, —

CO(CH₂)_n—

, where n is an integer between 0 and 4, alkanoic, alkenoic or alkynoic;

with the exception that where W₁ is an optionally substituted phenyl then Y₃ cannot be an optionally substituted phenyl.

7. A method according to claim 6, wherein the non-peptidyl compound is a dimer or heterodimer wherein the compounds are joined through a X linking group by way of their V or W groups.

8. A method according to claim 6, wherein when V is V₁ or V₂, then:

V₁ is selected from the group consisting of, benzene, pyridine, pyridazine, pyrimidine, pyrazine and triazine and is optionally substituted with up to 5 R₁ groups; and

V2 is selected from the group consisting of, cyclopenta-1,3-diene, pyrrole, furan, thiophene, oxazole, isoxazole, pyrazole, imidazole, thiazole, isothiazole and triazole and is optionally substituted with up to 4 R₁ groups;

and W is W₂ then

W₂ is selected from the group consisting of naphthalene, quinoline, isoquinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, indole, benzothiophene, benzofuran, benzimidazole, indazole, benzoxazole, benzisooxazole, henzthiazole, benzisothiazole, purine, indoline and isoindoline and is optionally substituted with up to seven R₁ groups;

and Y is either Y₁ or Y₂ then

Y₁ is selected from the group consisting of croman, isochroman, benzofuran, cromene, 1,2,3,4-tetrahydronaphthalene, 1,4-dihydronaphthalene, indan, indene, benzopiperidine, indoline, isoindoline, quinoline, isoquinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline or pteridine, coumarin and 2,3-dihydrocoumarin and is optionally substituted with up to seven R₁ groups; and

Y₂ is selected from the group consisting of 9H-xanthone, 9H-xanthene, phenoxathiin, phenoxathiin-10-oxide, phenoxathiin-10-dioxide, acridine, phenazine, phenothiazine, phenoxazine, phenothiazine-5-oxide, phenothiazine-5-dioxide, thiathrene-5-dioxide, thiathrene-5-oxide, carbazole, dibenzo[b,d]furan and dibenzo[b,d]thiophene and is optionally substituted with up to seven R₁ groups.

9. A method according to claim 6, wherein when A is VXW then:

V is phenyl or pyrazole, optionally substituted with up to 5 R₁ groups;

and when A is W or VXW then W is W₁, W₂ or W₃ wherein W₁ is phenyl optionally substituted with up to 5 R₁ groups;

W₂ is naphthalene or quinoline optionally substituted with up to seven R₁ groups wherein R₁ is independently H, OH, methyl, ethyl, propyl, nitro, methoxy, ethoxy, 2-hydroxyethoxy, chloro, fluoro or acetyl;

W₃ is —

N(R₂)R₂ wherein R₂ is propyl;

X is independently, a bond, methoxy (—

OCH₂), oxypropoxy (—

O(CH₂)₃O—

), hexenyloxy (—

O(CH₂)₄CH═

CH—

), sulfonyloxy (—

SO₂O—

), methyl (—

CH₂—

), arnidyl (—

CONH—

) or —

NHCONH—

; and

Y is either Y₁ or Y₂ then Y₁ is croman, 4-H-chromen-4-one or napthalene optionally substituted with up to seven R₁ groups wherein R₁ is independently H, OH, methyl, ethyl, propyl, nitro, methoxy, ethoxy, 2-hydroxyethoxy, chloro, fluoro or acetyl;

Y₂ is 9H-xanthone optionally substituted with up to seven R₁ groups wherein R₁ is independently H, OH, methyl, ethyl, propyl, nitro, methoxy, ethoxy, 2-hydroxyethoxy, chloro, fluoro or acetyl;

Y₃ is phenyl optionally substituted with up to 5 R₁ groups wherein R₁ is independently H, OH, methyl, ethyl, propyl, nitro, methoxy, ethoxy, 2-hydroxyethoxy, chloro, fluoro or acetyl; and

Z is independently —

R₆COOH, —

R₆SO₃H or —

N-trifluoromesylsulfonarnidate wherein R₆ is independently a bond or propyl.

10. A method according to claim 6, wherein the non-peptidyl compound is selected from the following group of compounds:

(i.) 4,4′

-Methylenebis[3-hydroxy-2-naphthalenecarboxylic acid];

(ii.) 7-[3-(4-acetyl-2-ethyl-5-hydroxyphenoxy)propoxy]-3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid;

(iii.) 2,4-dichloro-6-(N-(trifluoromethanesulfonyl))sulfamoylphenyl 3,5-dichloro-2-hydroxybenzenesulfonate;

(iv.) 7-[(4-acetyl-3-hydroxy-2-propylphenyl)methoxy]4-oxo-8-propyl4H-1-benzopyran-2-carboxylic acid;

(v.) 7-[3-(4-acetyl-3-methoxy-2-propylphenoxy)propoxy]-3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid;

(vi.) 3,4-dihydro-8-propyl-7-[[3-[2-ethyl-5-hydroxy-4-(1H-pyrazol-3-yl)phenoxy]propyl]oxy]-2H-1-benzopyran-2-carboxylic acid;

(vii.) 3,4-dihydro-8-propyl-7-[[3-[2-ethyl-5-hydroxy-4-ethoxyphenoxy]propyl]oxy]-2H-1-benzopyran-2-carboxylic acid;

(viii.) 3-[4-[7-carboxy-9-oxo-3-[3-[2-ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy]propoxy]-9H-xanthene]]propanoic acid;

(ix.) 8-propyl-7-(quinol-2′

-ylmethoxy)-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid;

(x.) 7-(naphth-2′

-ylmethoxy)-8-propyl-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid;

(xi.) N-(trifluoromethanesulfonyl)-3,5-dinitro-4-(N′

,N′

-dipropylamino)benzenesulfonamide;

(xii.) 8-propyl-7-[3-[4-(4-fluorophenyl)-2-ethyl-5-hydroxyphenoxy]propoxy]-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid;

(xiii.) 3,4-dihydro-7-[[6-(4-methoxyphenyl)hexenyl]oxy]-8-propyl-2H-1-benzopyran-2-carboxylic acid; and

(xiv.) 8,8′

-[Carbonylbis[imino-3,1-phenylenecarbonylimino(4-methyl-3,1-phenylene)carbonylimino]]bis-1,3,5-naphthalenetrisulfonic acid.

13. A method according to claim 6 wherein V₁ is selected from the group consisting of:

benzene, pyridine, pyridazine, pyrimidine, pyrazine and triazine.

14. A method according to claim 6 wherein V₂ is selected from the group consisting of:

cyclopenta-1,3-diene, pyrrole, furan, thiophene, oxazole, isoxazole, pyrazole, imidazole, thiazole, isothiazole and triazole, optionally substituted with up to 4 R₁ groups.

15. A method according to claim 6 wherein W₂ is selected from the group consisting of:

naphthalene, quinoline, isoquinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, indole, benzothiophene, benzofuran, benzimidazole, indazole, benzoxazole, benzisooxazole, benzthiazole, benzisothiazole, purine, indoline and isoindoline.

16. A method according to claim 6 wherein R₂ and R′

₂ are joined to form cyclic structures selected from the group consisting of;

pyrrolidine, piperidine, hexahydro-1H-azepine, morpholine and piperazine.

17. A method according to claim 6 wherein Y₁ is selected from the group consisting of:

croman, isochroman, benzofuran, cromene, 1,2,3,4-tetrahydronaphthalene, 1,4-dihydronaphthalene, indan, indene, benzopiperidine, indoline, isoindoline, quinoline, isoquinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline pteridine, coumarin and 2,3-dihydrocoumarin.

18. A method according to claim 6 wherein Y₂ is selected from the group consisting of:

9H-xanthone, 9H-xanthene, phenoxathiin, phenoxathiin-10-oxide, phenoxathiin-10-dioxide, acridine, phenazine, phenothiazine, phenoxazine, phenothiazine-5-oxide, phenothiazine-5-dioxide, thiathrene-5-dioxide, thiathrene-5-oxide, carbazole, dibenzo[b,d]furan and dibenzo[b,d]thiophene.

11. A method for identifying a non-peptidyl compound possessing ionic and hydrophobic chemical moieties spatially located so as to mimic particular ionic and hydrophobic amino acid residues of insulin and which binds to the insulin binding site of the insulin receptor, said method comprising the steps of:

(1) comparing the three dimensional structure of the non-peptidyl compound with a three dimensional pharmacophore of an active site of insulin; and

(2) selecting a non-peptidyl compound with ionic and hydrophobic chemical moieties spatially located so as to mimic said site.

12. A method for determining whether a non-peptidyl compound identified according to the method of claim 11 is an agonist or an antagonist, said method comprising the step of:

exposing the compound to an insulin or insulin like receptor and measuring the change in biological activity following exposure of the compound to the receptor.

19. A method for treating a patient suffering from one or more insulin related ailments selected from the group consisting of hypoglycemia, insulinomas, insulin and hypoglycemic drug overdose, gastric dumping syndrome and congenital hyperinsulinism, which method comprises the step-of:

administering to a patient in need thereof a therapeutically effective amount of a non-peptidyl compound which possesses one or more ionic and hydrophobic chemical moieties spatially located so as to mimic the spatial location of at least an ionic or a hydrophobic amino acid residue of insulin and which binds to the insulin binding site of the insulin receptor, wherein said compound is an insulin antagonist.

20. A method according to claim 19, wherein the ionic amino acid residue is selected from the group consisting of:

A21 Asn, B21 Glu and A17 Glu.

21. A method according to claim 19, wherein the ionic and hydrophobic amino acid residue(s) is(are) selected from the group consisting of:

A21 Asn, B21 Glu, A17 Glu, B24 Phe, B25 Phe, A19 Tyr, B12 Val, B16 Tyr, A2 Ile, A3 Val and A1 Gly.

22. A method according to claim 19, wherein at least one amino acid is selected from the group consisting of:

A17 Glu, B21 Glu and A21 Asn; and

at least one amino acid is selected from the group consisting of;

B24 Phe, B25 Phe, A19 Tyr, B12 Val and B16 Tyr.

23. A method according to claim 19, wherein the non-peptidyl compound possesses ionic and hydrophobic chemical moieties spatially located so as to mimic ionic and hydrophobic residues associated with at least one of the following groups of amino acid residues:

(i.) A21 Asn, B21 Glu, A17 Glu, B24 Phe, B25 Phe;

(ii.) A21 Asn, B21 Glu, B24 Phe, B25 Phe;

(iii.) A21 Asn, B21 Glu, B24 Phe, B25 Phe, A1 Gly, A2 Ile, A3 Val;

(iv.) A21 Asn, B21 Glu, A17 Glu, A19 Tyr, A1 Gly, A2 Ile, A3 Val;

(v.) A21 Asn, B21 Glu, A17 Glu, B12 Val, A1 Gly, A2 Ile, A3 Val;

(vi.) A21 Asn, B21 Glu, B12 Val, A1 Gly, A2 Ile, A3 Val;

(vii.) A21 Asn, B21 Glu, A17 Glu, B16 Tyr, A1 Gly, A2 Ile, A3 Val;

(viii.) A21 Asn, B21 Glu, A17 Glu, A19 Tyr, B12 Val, B16 Tyr;

(ix.) A21 Asn, B21 Glu, A19 Tyr, B12 Val, B16 Tyr;

(x.) A21 Asn, B21 Glu, A17 Glu, B24 Phe, B25 Phe, A19 Tyr, B12 Val, B16 Tyr;

(xi.) A21 Asn, B21 Glu, B24 Phe, B25 Phe, A19 Tyr, B12 Val, B16 Tyr;

(xii.) A21 Asn, B21 Glu, B24 Phe, B25 Phe, B12 Val, B16 Tyr;

(xiii.) A21 Asn, B21 Glu, A17 Glu, B24 Phe, B25 Phe, A19 Tyr;

(xiv.) A21 Asn, B21 Glu, B24 Phe, B25 Phe, A19 Tyr;

(xv.) A21 Asn, A17 Glu, B24 Phe, B25 Phe, A19 Tyr;

(xvi.) B21 Glu, A17 Glu, B24 Phe, B25 Phe, A19 Tyr;

(xvii.) A21 Asn, B21 Glu, A17 Glu, B24 Phe, B25 Phe, B12 Val;

(xviii.) A21 Asn, B21 Glu, B24 Phe, B25 Phe, B12 Val;

(xix.) A21 Asn, A17 Glu, B24 Phe, B25 Phe, B12 Val;

(xx.) B21 Glu, A17 Glu, B24 Phe, B25 Phe, B12 Val;

(xxi.) A21 Asn, B21 Glu, A17 Glu, B24 Phe, B25 Phe, B16 Tyr;

(xxii.) A21 Asn, B21 Glu, B24 Phe, B25 Phe, B16 Tyr;

(xxiii.) A21 Asn, A17 Glu, B24 Phe, B25 Phe, B16 Tyr;

(xxiv.) B21 Glu, A17 Glu, B24 Phe, B25 Phe, B16 Tyr;

(xxv.) A21 Asn, B21 Glu, A17 Glu, B24 Phe, A19 Tyr, B12 Val, B16 Tyr;

(xxvi.) A21 Asn, B21 Glu, B24 Phe, A19 Tyr, B12 Val, B16 Tyr;

(xxvii.) A21 Asn, A17 Glu, B24 Phe, A19 Tyr, B12 Val, B16 Tyr;

(xxviii.) B21 Glu, A17 Glu, B24 Phe, A19 Tyr, B12 Val, B16 Tyr;

(xxix.) A21 Asn, B21 Glu, A17 Glu, B25 Phe, A19 Tyr, B12 Val, B16 Tyr;

(xxx.) A21 Asn, B21 Glu, B25 Phe, A19 Tyr, B12 Val, B16 Tyr;

(xxxi.) A21 Asn, A17 Glu, B25 Phe, A19 Tyr, B12 Val, B16 Tyr; and

(xxxii.) B21 Glu, A17 Glu, B25 Phe, A19 Tyr, B12 Val.

24. A method according to claim 19, wherein the non-peptidyl compound has the following formula:

AXYXZ_n 

 

(formula

     1)

where A is W or VXW;

V is V₁ or V₂;

V is substituted with up to two X groups;

V₁ is a phenyl or 6 membered heteroaromatic ring, optionally substituted with up to 5 R₁ groups;

V₂ is a 5 member ring system which may incorporate up to 4 hetero atoms which may be independently a nitrogen atom, a nitrogen atom optionally substituted with R₂, oxygen or sulfur, the ring system being optionally substituted with up to 4 R₁ groups;

W is W₁ or W₂ or W₃;

W is substituted with up to two X groups;

W₁ is V₁;

W₂ is a fused bicyclic ring system comprising rings of 5 or 6 atoms, which may incorporate up to 4 hetero atoms, which may be independently a nitrogen atom, a nitrogen atom optionally substituted with R₂, oxygen or sulfur, the system being optionally substituted with up to seven R₁ groups;

W₃ is —

N(R₂)R′

₂;

R₁ is independently H, OH, alkyl, alkenyl, alkynyl, alkoxy, alkanol, hydroxyalkoxy, haloalkyl, haloalkoxy, halogen, SH, thioalkyl, cyano (—

CN), N(R₂)R′

₂, phenyl, phenyl optionally substituted with up to five alkyl groups of 1 to 3 carbon atoms or up to five halogen atoms, benzyl, phenethyl, nitro, —

COR₃, —

R₅COR₃, —

R₅SOR₃, —

R₅SO₂R₃, —

SO₂N(R₂)R′

₂ or azido;

R₂ and R′

₂ are independently H, alkyl of 1 to 6 carbon atoms, alkenyl of 3 to 6 carbon atoms, alkynyl of 3 to 6 carbons, hydroxyalkyl of 2 to 6 carbons, alkoxy of 2 to 6 carbons, haloalkyl, haloalkenyl, haloalkoxy, benzyl, benzyl optionally substituted with up to four R₁ groups, phenylethyl, phenylethyl optionally substituted with up to four R₁ groups, arylalkyl, and where R₂ and R′

₂ can also be joined to form cyclic structures;

R₃ is independently H, OH, alkyl, alkenyl, alkynyl, alkoxy, alkanol, hydroxyalkoxy, —

R₄N(R₂)R′

₂, mesyl, triflouromesyl, —

NHSO₂CH₃ or —

NHSO₂CF₃;

R₄ is independently a bond, alkyl, alkenyl or alkynyl;

X is independently, a bond, —

R₄N(R₂)R₄—

, —

R₄N═

NR₄—

, —

R₄N(R₂)—

N(R₂)R₄—

, —

R₄OR₄, —

R₄SR₄—

, —

R₅—

, —

R₅O—

, —

R₅S—

, —

R₅N(R₂)—

, —

SO—

, sulfonyl (—

SO₂—

), —

CO—

, —

CONH—

, —

NHCONH—

, —

NHCO—

, —

CONHCO—

, —

CON(R₂)—

, —

R₅COR₅—

, —

R₅COR₅N(R₂)R₅—

, —

N(R₂)CO—

or —

R₄N(R₂)R₄COR₄—

;

R₅ is independently alkyl, alkenyl, alkynyl, alkoxy, alkanol, hydroxyalkoxy;

Y is either Y₁, Y₂ or Y₃;

Y is substituted with at least two, but optionally up to four X linking groups;

Y₁ is a fused bicyclic ring system comprising rings of 5 or 6 atoms which may incorporate up to 4 hetero atoms, which may be independently a nitrogen atom, a nitrogen atom optionally substituted with R₂, oxygen or sulfur, the ring system optionally independently incorporating a sulfoxide (SO), sulfone (SO₂) or carbonyl (CO) group and optionally up to seven R₁ groups;

Y₂ is a 6;

6;

6 or a 6;

5;

6 fused tricyclic system which may incorporate up to 4 hetero atoms which may be independently a nitrogen atom, a nitrogen atom optionally substituted with R₂, oxygen or sulfur, the ring system optionally independently incorporating a sulfoxide (SO), sulfone (SO₂) or carbonyl (CO) group, and the ring system being substituted with at least two, but optionally up to four X linking groups and optionally up to seven R₁ groups;

Y₃ is V₁;

Z is independently —

R₆COOH, —

R₆SO₃H, —

R₆NO₂, —

R₆SO₂H, —

R₆SO₂NHR₂;

—

R₇SO₂NHCOR₄—

N-trifluoromesylsulfonamidate, —

OH, -2-yl-hydroxyethanoic acid (—

CH(OH)COOH), -3-yl-2-hydroxypropanoic acid (—

CH₂CH(OH)COOH)-2-yl-2-hydroxypropanoic acid (—

CH(CH₃)(OH)COOH), -3-yl-2,3-dihydroxypropanoic acid (—

CH(OH)CH(OH)COOH), -2-yl-2,3-dihydroxypropanoic acid (—

C(CH₂(OH))(OH)COOH), -3-yl-2-hydroxypropan-3-one-1-oic acid (—

COCH(OH)COOH, 2-yl-2-hydroxypropandioic acid (—

C(COOH)(OH)COOH), -2-yl-propandioic acid (—

C(COOH)(H)COOH), -4-yl-2-hydroxybutan-4-one-1-oic acid (—

COCH₂CH(OH)COOH, 2-yl-2-hydroxybutan-1,4-dioic acid (—

C(OH)(COOH)CH₂COOH), 3-yl-2-hydroxybutan-1,4-dioic acid (—

CH(CH(OH)COOH)COOH), 5-yl-tetrazole,

R₆ is independently a bond, alkyl, alkenyl, alkynyl, alkoxy, —

CO(CH₂)_n—

, where n is an integer between 0 and 4, alkanoic, alkenoic or alkynoic;

with the exception that where W₁ is an optionally substituted phenyl then Y₃ cannot be an optionally substituted phenyl.

25. A method according to claim 24, wherein the non-peptidyl compound is a dimer or heterodimer wherein the compounds are joined through a X linking group by way of their V or W groups.

26. A method according to claim 24, wherein when V is V₁ or V₂, then:

V₁ is selected from the group consisting of, benzene, pyridine, pyridazine, pyrimidine, pyrazine and triazine and is optionally substituted with up to 5 R₁ groups; and

V₂ is selected from the group consisting of, cyclopenta-1,3-diene, pyrrole, furan, thiophene, oxazole, isoxazole, pyrazole, imidazole, thiazole, isothiazole and triazole and is optionally substituted with up to 4 R₁ groups;

and W is W₂ then

W₂ is selected from the group consisting of naphthalene, quinoline, isoquinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, indole, benzothiophene, benzofuran, benzimidazole, indazole, benzoxazole, benzisooxazole, benzthiazole, benzisothiazole, purine, indoline and isoindoline and is optionally substituted with up to seven R₁ groups; and

Y is either Y₁ or Y₂ then

Y₁ is selected from the group consisting of croman, isochroman, benzofuran, cromene, 1,2,3,4-tetrahydronaphthalene, 1,4-dihydronaphthalene, indan, indene, benzopiperidine, indoline, isoindoline, quinoline, isoquinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline or pteridine, coumarin and 2,3-dihydrocoumarin and is optionally substituted with up to seven R₁ groups; and

Y₂ is selected from the group consisting of 9H-xanthone, 9H-xanthene, phenoxathiin, phenoxathiin-10-oxide, phenoxathiin-10-dioxide, acridine, phenazine, phenothiazine, phenoxazine, phenothiazine-5-oxide, phenothiazine-5-dioxide, thiathrene-5-dioxide, thiathrene-5-oxide, carbazole, dibenzo[b,d]furan and dibenzo[b,d]thiophene and is optionally substituted with up to seven R₁ groups.

27. A method according to claim 24, wherein when A is VXW then:

V is phenyl or pyrazole, optionally substituted with up to 5 R₁ groups;

and when A is W or VXW then W is W₁, W₂ or W₃ wherein W₁ is phenyl optionally substituted with up to 5 R₁ groups;

W₂ is naphthalene or quinoline optionally substituted with up to seven R₁ groups wherein R₁ is independently H, OH, methyl, ethyl, propyl, nitro, methoxy, ethoxy, 2-hydroxyethoxy, chloro, fluoro or acetyl;

W₃ is —

N(R₂)R₂ wherein R₂ is propyl;

X is independently, a bond, methoxy (—

OCH₂—

), oxypropoxy (—

O(CH₂)₃O—

), hexenyloxy (—

O(CH₂)₄CH═

CH—

), sulfonyloxy (—

SO₂—

), methyl (—

CH₂—

), amidyl (—

CONH—

) or —

NHCONH—

; and

Y is either Y₁ or Y₂ then

Y₁ is croman, 4-H-chromen-4-one or napthalene optionally substituted with up to seven R₁ groups wherein R₁ is independently H, OH, methyl, ethyl, propyl, nitro, methoxy, ethoxy, 2-hydroxyethoxy, chloro, fluoro or acetyl;

Y₂ is 9H-xanthone optionally substituted with up to seven R₁ groups wherein R₁ is independently H, OH, methyl, ethyl, propyl, nitro, methoxy, ethoxy, 2-hydroxyethoxy, chloro, fluoro or acetyl;

Y₃ is phenyl optionally substituted with up to 5 R₁ groups wherein R₁ is independently H, OH, methyl, ethyl, propyl, nitro, methoxy, ethoxy, 2-hydroxyethoxy, chloro, fluoro or acetyl; and

Z is independently —

R₆COOH, —

R₆SO₃H or —

N-trifluoromesylsulfonamidate wherein R₆ is independently a bond or propyl.

28. A method according to claim 24, wherein the non-peptidyl compound is selected from the following group of compounds:

(i.) 4,4′

-Methylenebis[3-hydroxy-2-naphthalenecarboxylic acid];

(ii.) 7-[3-(4-acetyl-2-ethyl-5-hydroxyphenoxy)propoxy]-3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid;

(iii.) 2,4-dichloro-6-(N-(trifluoromethanesulfonyl))sulfamoylphenyl 3,5-dichloro-2-hydroxybenzenesulfonate;

(iv.) 7-[(4-acetyl-3-hydroxy-2-propylphenyl)methoxy]-4-oxo-8-propyl4H-1-benzopyran-2-carboxylic acid;

(v.) 7-[3-(4-acetyl-3-methoxy-2-propylphenoxy)propoxy]-3,4dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid;

(vi.) 3,4-dihydro-8-propyl-7-[[3-[2-ethyl-5-hydroxy-4-(1H-pyrazol-3-yl)phenoxy]propyl]oxy]-2H-1-benzopyran-2-carboxylic acid;

(vii.) 3,4-dihydro-8-propyl-7-[[3-[2-ethyl-5-hydroxy-4-ethoxyphenoxy]propyl]oxy]-2H-1-benzopyran-2-carboxylic acid;

(viii.) 3-[4-[7-carboxy-9-oxo-3-[3-[2-ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy]propoxy]-9H-xanthene]]propanoic acid;

(ix.) 8-propyl-7-(quinol-2′

-ylmethoxy)-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid;

(x.) 7-(naphth-2′

-ylmethoxy)-8-propyl-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid;

(xi.) N-(trifluoromethanesulfonyl)-3,5-dinitro-4-(N′

,N′

-dipropylamino)benzenesulfonamide;

(xii.) 8-propyl-7-[3-[4-(4-fluorophenyl)-2-ethyl-5-hydroxyphenoxy]propoxy]-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid; and

(xiii.) 3,4-dihydro-7-[[6-(4-methoxyphenyl)hexenyl]oxy]-8-propyl-2H-1-benzopyran-2-carboxylic acid.

29. A method according to claim 24 wherein V₁ is selected from the group consisting of:

benzene, pyridine, pyridazine, pyrimidine, pyrazine and triazine.

30. A method according to claim 24 wherein V₂ is selected from the group consisting of:

cyclopenta-1,3-diene, pyrrole, furan, thiophene, oxazole, isoxazole, pyrazole, imidazole, thiazole, isothiazole and triazole, optionally substituted with up to 4 R₁ groups.

31. A method according to claim 24 wherein W₂ is selected from the group consisting of:

naphthalene, quinoline, isoquinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, indole, benzothiophene, benzofuran, benzimidazole, indazole, benzoxazole, benzisooxazole, benzthiazole, benzisothiazole, purine, indoline and isoindoline.

32. A method according to claim 24 wherein R₂ and R′

₂ are joined to form cyclic structures selected from the group consisting of;

pyrrolidine, piperidine, hexahydro-1H-azepine, morpholine and piperazine.

33. A method according to claim 24 wherein Y₁ is selected from the group consisting of:

croman, isochroman, benzofuran, cromene, 1,2,3,4-tetrahydronaphthalene, 1,4-dihydronaphthalene, indan, indene, benzopiperidine, indoline, isoindoline, quinoline, isoquinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline or pteridine, coumarin and 2,3-dihydrocoumarin.

34. A method according to claim 24 wherein Y₂ is selected from the group consisting of:

9H-xanthone, 9H-xanthene, phenoxathiin, phenoxathiin-10-oxide, phenoxathiin-10-dioxide, acridine, phenazine, phenothiazine, phenoxazine, phenothiazine-5-oxide, phenothiazine-5-dioxide, thiathrene-5-dioxide, thiathrene-5-oxide, carbazolc, dibenzo[b,d]furan and dibenzo[b,d]thiophene.