US2008300189A1PendingUtilityA1
Pharmaceutical compositions and methods for restoring beta-cell mass and function
Est. expiryDec 30, 2024(expired)· nominal 20-yr term from priority
Inventors:Jerry L. Nadler
A61K 38/2278A61K 38/26A61K 38/38A61K 31/522A61K 31/519A61P 37/00A61K 45/06
66
PatentIndex Score
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Claims
Abstract
Pharmaceutical compositions and methods for using are provided for restoring β-cell mass and function in a mammal in need thereof. The pharmaceutical compositions have a biological response modifier and a β-cell growth factor in admixture with a pharmaceutically acceptable carrier, adjuvant or vehicle.
Claims
exact text as granted — not AI-modified1 . A pharmaceutical composition for administration in a mammal, comprising a biological response modifier and a β-cell growth or differentiating factor in admixture with a pharmaceutically acceptable carrier, adjuvant or vehicle, wherein the pharmaceutical composition restores β-cell mass and function in a mammal in need thereof.
2 . The pharmaceutical composition of claim 1 , wherein the biological response modifier is an immunomodulator comprising lisofylline, including pharmaceutically acceptable enantiomers, diastereomers, tautomers, salts and solvates thereof.
3 . The pharmaceutical composition of claim 2 , wherein the β-cell growth factor comprises islet neogenesis associated protein (INGAP).
4 . The pharmaceutical composition of claim 1 , wherein the biological response modifier comprises a compound, including resolved enantiomers, diastereomers, tautomers, salts and solvates thereof, having the following formula:
wherein:
X, Y and Z are independently selected from a member of the group consisting of C(R 3 ), N, N(R 3 ) and S;
R 1 is selected from a member of the group consisting of hydrogen, methyl, C (5-9) alkyl, C (5-9) alkenyl, C (5-9) alkynyl, C (5-9) hydroxyalkyl, C (3-8) alkoxyl, C (5-9) alkoxyalkyl, the R 1 being optionally substituted;
R 2 and R 3 are independently selected from a member of the group consisting of hydrogen, halo, oxo, C (1-20) alkyl, C (1-20) hydroxyalkyl, C (1-20) thioalkyl, C (1-20) alkylamino, C (1-20) alkylaminoalkyl, C (1-20) aminoalkyl, C (1-20) aminoalkoxyalkenyl, C (1-20) aminoalkoxyalkynyl, C (1-20) diaminoalkyl, C (1-20) triaminoalkyl, C (1-20) tetraminoalkyl, C (5-15) aminotrialkoxyamino, C (1-20) alkylamido, C (1-20) alkylamidoalkyl, C (1-20) amidoalkyl, C (1-20) acetamidoalkyl, C (1-20) alkenyl, C (1-20) alkynyl, C (3-8) alkoxyl, C (1-11) alkoxyalkyl, and C (1-20) dialkoxyalkyl.
5 . The pharmaceutical composition of claim 4 , wherein R 1 is substituted with a member of the group consisting of N—OH, acylamino, cyano group, sulfo, sulfonyl, sulfinyl, sulfhydryl (mercapto), sulfeno, sulfanilyl, sulfamyl, sulfamino, and phosphino, phosphinyl, phospho, phosphono and —NR a R b , wherein each of R a and R b may be the same or different and each is selected from the group consisting of hydrogen, optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl and heterocyclic group.
6 . The pharmaceutical composition of claim 4 , wherein R 2 and R 3 are selected from the group consisting of methyl, ethyl, oxo, isopropyl, n-propyl, isobutyl, n-butyl, t-butyl, 2-hydroxyethyl, 3-hydroxypropyl, 3-hydroxy-n-butyl, 2-methoxyethyl, 4-methoxy-n-butyl, 5-hydroxyhexyl, 2-bromopropyl, 3-dimethylaminobutyl, 4-chloropentyl, methylamino, aminomethyl, and methylphenyl.
7 . The pharmaceutical composition of claim 4 , wherein each R 2 and R 3 is substituted with one or more members of the group consisting of hydroxyl, methyl, carboxyl, furyl, furfuryl, biotinyl, phenyl, naphthyl, amino group, amido group, carbamoyl group, cyano group, sulfo, sulfonyl, sulfinyl, sulfhydryl, sulfeno, sulfanilyl, sulfamyl, sulfamino, phosphino, phosphinyl, phospho, phosphono, N—OH, —Si(CH 3 ) 3 , C (1-3) alkyl, C (1-3) hydroxyalkyl, C (1-3) thioalkyl, C (1-3) alkylamino, benzyldihydrocinnamoyl group, benzoyldihydrocinnamido group, optionally substituted heterocyclic group and optionally substituted carbocyclic group.
8 . The pharmaceutical composition of claim 4 , wherein the heterocyclic group or carbocyclic group is substituted with one or more members of the group consisting of halo, hydroxyl, nitro, SO 2 NH 2 , C (1-6) alkyl, C (1-6) haloalkyl, C (1-8) alkoxyl, C (1-11) alkoxyalkyl, C (1-6) alkylamino, and C (1-6) aminoalkyl.
9 . The pharmaceutical composition of claim 8 , wherein the heterocyclic group is a member selected from the group consisting of acridinyl, aziridinyl, azocinyl, azepinyl, benzimidazolyl, benzodioxolanyl, benzofuranyl, benzothiophenyl, carbazole, 4a H-carbazole, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, dioxoindolyl, furazanyl, furyl, furfuryl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthalenyl, naphthyridinyl, norbornanyl, norpinanyl, octahydroisoquinolinyl, oxazolidinyl, oxazolyl, oxiranyl, perimidinyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phenyl, phthalazinyl, piperazinyl, piperidinyl, 4-piperidonyl, piperidyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyrenyl, pyridazinyl, pyridinyl, pyridyl, pyridyl, pyrimidinyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolonyl, pyrrolyl, 2H-pyrrolyl, quinazolinyl, 4H-quinolizinyl, quinolinyl, quinoxalinyl, quinuclidinyl, β-carbolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 2H-,6H-1,5,2-dithiazinyl, thianthrenyl, thiazolyl, thienyl, thiophenyl, triazinyl, xanthenyl and xanthinyl.
10 . The pharmaceutical composition of claim 9 , wherein the carbocyclic group is a member selected from the group consisting of adamantyl, anthracenyl, benzamidyl, benzyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.1]hexanyl, bicyclo[2.2.2]octanyl, bicyclo[3.2.0]heptanyl, bicyclo[4.3.0]nonanyl, bicyclo[4.4.0]decanyl, biphenyl, biscyclooctyl, cyclobutyl, cyclobutenyl, cycloheptyl, cycloheptenyl, cyclohexanedionyl, cyclohexenyl, cyclohexyl, cyclooctanyl, cyclopentadienyl, cyclopentanedionyl, cyclopentenyl, cyclopentyl, cyclopropyl, decalinyl, 1,2-diphenylethanyl, indanyl, 1-indanonyl, indenyl, naphthyl, napthlalenyl, phenyl, resorcinolyl, stilbenzyl, tetrahydronaphthyl, tetralinyl, tetralonyl, and tricyclododecanyl.
11 . The pharmaceutical composition of claim 1 , wherein the biological response modifier is
or a pharmaceutically acceptable salt thereof.
12 . The pharmaceutical composition of claim 1 , wherein the biological response modifier is
or a pharmaceutically acceptable salt thereof.
13 . The pharmaceutical composition of claim 1 , or pharmaceutically acceptable salt thereof, wherein the biological response modifier is a member selected from the group consisting of:
14 . The pharmaceutical composition of claim 1 , wherein the biological response modifier is selected from the group consisting of the compounds defined in Table 1.
15 . The pharmaceutical composition of claim 1 , wherein the β-cell growth or differentiating factor comprises a GLP-1 analog selected from the group consisting of: Liraglutide; CJC-1131; Albugon; and LY-548806.
16 . The pharmaceutical composition of claim 1 , wherein the β-cell growth or differentiating factor is a DPP-IV inhibitor selected from the group consisting of: Sitagliptin, Vildagliptin, NVP DPP728, Saxagliptin, P32/98, FE 999011, and PHX1149.
17 . The pharmaceutical composition of claim 1 , wherein the β-cell growth or differentiating factor is a member selected from the group consisting of: gastric inhibitory polypeptide (GIP) and analogs thereof; gastrin; epidermal growth factor 1; islet neogenesis therapy; insulin like growth factor 1 or 2; Parathyroid hormone related peptide (PTHrP); Hepatocyte growth factor; islet neogenesis associated protein (INGAP); NVP-LAQ824; TrichostatinA-0; hydroxamate; suberanihohydroxamic; tetrapeptides, apicidin; trapoxin; CG1521; scriptide; oxamflatin; pyroxamide; propenamides; chlamydocin; diheteropeptin; WF-3136; Cyl-1; Cyl-2; FR 901228; cyclic-hydroxamic-acid-containing peptides; MS-275, CI-994; depudecin, Neurogen 3, PDX-1, and NKX6.1.
18 . A method for restoring β-cell mass and function in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a pharmaceutical composition comprising a biological response modifier and a β-cell growth or differentiating factor in admixture with a pharmaceutically acceptable carrier, adjuvant or vehicle, wherein β-cell mass and function in the mammal are restored after administration of the pharmaceutical composition is withdrawn;
wherein the biological response modifier comprises a compound, including resolved enantiomers, diastereomers, tautomers, salts and solvates thereof, having the following formula:
wherein:
X, Y and Z are independently selected from a member of the group consisting of C(R 3 ), N, N(R 3 ) and S;
R 1 is selected from a member of the group consisting of hydrogen, methyl, C (5-9) alkyl, C (5-9) alkenyl, C (5-9) alkynyl, C (5-9) hydroxyalkyl, C (3-8) alkoxyl, C (5-9) alkoxyalkyl, the R 1 being optionally substituted;
R 2 and R 3 are independently selected from a member of the group consisting of hydrogen, halo, oxo, C (1-20) alkyl, C (1-20) hydroxyalkyl, C (1-20) thioalkyl, C (1-20) alkylamino, C (1-20) alkylaminoalkyl, C (1-20) aminoalkyl, C (1-20) aminoalkoxyalkenyl, C (1-20) aminoalkoxyalkynyl, C (1-20) diaminoalkyl, C (1-20) triaminoalkyl, C (1-20) tetraminoalkyl, C (5-15) aminotrialkoxyamino, C (1-20) alkylamido, C (1-20) alkylamidoalkyl, C (1-20) amidoalkyl, C (1-20) acetamidoalkyl, C (1-20) alkenyl, C (1-20) alkynyl, C (3-8) alkoxyl, C (1-11) alkoxyalkyl, and C (1-20) dialkoxyalkyl; and
wherein the β-cell growth or differentiating factor is a member selected from the group consisting of: Liraglutide; CJC-1131; Albugon; LY-548806; Sitagliptin, Vildagliptin, NVP DPP728, Saxagliptin, P32/98, FE 999011, PHX1149; gastric inhibitory polypeptide (GIP); gastrin; epidermal growth factor 1; islet neogenesis therapy; insulin like growth factor 1; insulin like growth factor 2; Parathyroid hormone related peptide (PTHrP); Hepatocyte growth factor; islet neogenesis associated protein (INGAP); NVP-LAQ824; TrichostatinA-0; hydroxamate; suberoylanilide hydroxamic acid; apicidin; trapoxin; CG1521; scriptide; oxamflatin; pyroxamide; propenamides; chlamydocin; diheteropeptin; WF-3136; Cyl-1; Cyl-2; FR 901228; MS-275, CI-994; depudecin, Neurogen 3, PDX-1, and NKX6.1.
19 . A method for treating Type 1 diabetes, autoimmune diabetes, insulin dependent diabetes mellitus (IDDM) or LADA comprising administering to a mammal in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a biological response modifier and a β-cell growth or differentiating factor in admixture with a pharmaceutically acceptable carrier, adjuvant or vehicle; wherein the biological response modifier comprises a compound, including resolved enantiomers, diastereomers, tautomers, salts and solvates thereof, having the following formula:
wherein:
X, Y and Z are independently selected from a member of the group consisting of C(R 3 ), N, N(R 3 ) and S;
R 1 is selected from a member of the group consisting of hydrogen, methyl, C (5-9) alkyl, C (5-9) alkenyl, C (5-9) alkynyl, C (5-9) hydroxyalkyl, C (3-8) alkoxyl, C (5-9) alkoxyalkyl, the R 1 being optionally substituted;
R 2 and R 3 are independently selected from a member of the group consisting of hydrogen, halo, oxo, C (1-20) alkyl, C (1-20) hydroxyalkyl, C (1-20) thioalkyl, C (1-20) alkylamino, C (1-20) alkylaminoalkyl, C (1-20) aminoalkyl, C (1-20) aminoalkoxyalkenyl, C (1-20) aminoalkoxyalkynyl, C (1-20) diaminoalkyl, C (1-20) triaminoalkyl, C (1-20) tetraminoalkyl, C (5-15) aminotrialkoxyamino, C (1-20) alkylamido, C (1-20) alkylamidoalkyl, C (1-20) amidoalkyl, C (1-20) acetamidoalkyl, C (1-20) alkenyl, C (1-20) alkynyl, C (3-8) alkoxyl, C (1-11) alkoxyalkyl, and C (1-20) dialkoxyalkyl; and
wherein the β-cell growth or differentiating factor is a member selected from the group consisting of: Liraglutide; CJC-1131; Albugon; LY-548806; Sitagliptin, Vildagliptin, NVP DPP728, Saxagliptin, P32/98, FE 999011, PHX1149; gastric inhibitory polypeptide (GIP); gastrin; epidermal growth factor 1; islet neogenesis therapy; insulin like growth factor 1; insulin like growth factor 2; Parathyroid hormone related peptide (PTHrP); Hepatocyte growth factor; islet neogenesis associated protein (INGAP); NVP-LAQ824; TrichostatinA-0; hydroxamate; suberoylanilide hydroxamic acid; apicidin; trapoxin; CG1521; scriptide; oxamflatin; pyroxamide; propenamides; chlamydocin; diheteropeptin; WF-3136; Cyl-1; Cyl-2; FR 901228; MS-275, CI-994; depudecin, Neurogen 3, PDX-1, and NKX6.1.
20 . A means for delivering a therapeutically effective amount of the pharmaceutical composition of claim 1 in a mammal.
21 . The method according to either claim 18 or claim 20 , wherein R 1 is substituted with a member of the group consisting of N—OH, acylamino, cyano group, sulfo, sulfonyl, sulfinyl, sulfhydryl (mercapto), sulfeno, sulfanilyl, sulfamyl, sulfamino, and phosphino, phosphinyl, phospho, phosphono and —NR a R b , wherein each of R a and R b may be the same or different and each is selected from the group consisting of hydrogen, optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl and heterocyclic group.
22 . The method according to either claim 18 , claim 19 or claim 20 , wherein R 2 and R 3 are selected from the group consisting of methyl, ethyl, oxo, isopropyl, n-propyl, isobutyl, n-butyl, t-butyl, 2-hydroxyethyl, 3-hydroxypropyl, 3-hydroxy-n-butyl, 2-methoxyethyl, 4-methoxy-n-butyl, 5-hydroxyhexyl, 2-bromopropyl, 3-dimethylaminobutyl, 4-chloropentyl, methylamino, aminomethyl, and methylphenyl.
23 . The method according to either claim 18 , claim 19 or claim 20 , wherein each R 2 and R 3 is substituted with one or more members of the group consisting of hydroxyl, methyl, carboxyl, furyl, furfuryl, biotinyl, phenyl, naphthyl, amino group, amido group, carbamoyl group, cyano group, sulfo, sulfonyl, sulfinyl, sulfhydryl, sulfeno, sulfanilyl, sulfamyl, sulfamino, phosphino, phosphinyl, phospho, phosphono, N—OH, —Si(CH 3 ) 3 , C (1-3) alkyl, C (1-3) hydroxyalkyl, C (1-3) thioalkyl, C (1-3) alkylamino, benzyldihydrocinnamoyl group, benzoyldihydrocinnamido group, optionally substituted heterocyclic group and optionally substituted carbocyclic group.
24 . The method according to either claim 18 or claim 20 , wherein the heterocyclic group or carbocyclic group is substituted with one or more members of the group consisting of halo, hydroxyl, nitro, SO 2 NH 2 , C (1-6) alkyl, C (1-6) haloalkyl, C (1-8) alkoxyl, C (1-11) alkoxyalkyl, C (1-6) alkylamino, and C (1-6) aminoalkyl.
25 . The method according to claim 24 , wherein the heterocyclic group is a member selected from the group consisting of acridinyl, aziridinyl, azocinyl, azepinyl, benzimidazolyl, benzodioxolanyl, benzofuranyl, benzothiophenyl, carbazole, 4a H-carbazole, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, dioxoindolyl, furazanyl, furyl, furfuryl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthalenyl, naphthyridinyl, norbornanyl, norpinanyl, octahydroisoquinolinyl, oxazolidinyl, oxazolyl, oxiranyl, perimidinyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phenyl, phthalazinyl, piperazinyl, piperidinyl, 4-piperidonyl, piperidyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyrenyl, pyridazinyl, pyridinyl, pyridyl, pyridyl, pyrimidinyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolonyl, pyrrolyl, 2H-pyrrolyl, quinazolinyl, 4H-quinolizinyl, quinolinyl, quinoxalinyl, quinuclidinyl, β-carbolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 2H-,6H-1,5,2-dithiazinyl, thianthrenyl, thiazolyl, thienyl, thiophenyl, triazinyl, xanthenyl and xanthinyl.
26 . The method according to claim 25 , wherein the carbocyclic group is a member selected from the group consisting of adamantyl, anthracenyl, benzamidyl, benzyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.1]hexanyl, bicyclo[2.2.2]octanyl, bicyclo[3.2.0]heptanyl, bicyclo[4.3.0]nonanyl, bicyclo[4.4.0]decanyl, biphenyl, biscyclooctyl, cyclobutyl, cyclobutenyl, cycloheptyl, cycloheptenyl, cyclohexanedionyl, cyclohexenyl, cyclohexyl, cyclooctanyl, cyclopentadienyl, cyclopentanedionyl, cyclopentenyl, cyclopentyl, cyclopropyl, decalinyl, 1,2-diphenylethanyl, indanyl, 1-indanonyl, indenyl, naphthyl, napthlalenyl, phenyl, resorcinolyl, stilbenzyl, tetrahydronaphthyl, tetralinyl, tetralonyl, and tricyclododecanyl.
27 . The method according to either claim 18 or claim 20 , wherein the biological response modifier is
or a pharmaceutically acceptable salt thereof.
28 . The method according to either claim 18 or claim 20 , wherein the biological response modifier is
or a pharmaceutically acceptable salt thereof.
29 . The method according to either claim 18 or claim 20 , or pharmaceutically acceptable salt thereof, wherein the biological response modifier is a member selected from the group consisting of:
30 . The method according to either claim 18 , claim 19 or claim 20 , wherein the biological response modifier is a compound of Formula II:
wherein R 4 , R 5 , and R 6 are each selected as shown in the following Table:
TABLE 1
R 4
R 5
R 6
Me
H
Me
H
Me
H
Me
H
Me
H
Me
H
Me
H
Me
H
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CH 2 OEt
Me
CH 2 OEt
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CH 2 OEt
Me
CH 2 OEt
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CH 2 OEt
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CH 2 OEt
Me
CH 2 OEt
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CH 2 OEt
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CH 2 OEt
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CH 2 OEt
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CH 2 OEt
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CH 2 OEt
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CH 2 OEt
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CH 2 OEt
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CH 2 OEt
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CH 2 OEt
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CH 2 OEt
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CH 2 OEt
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CH 2 OEt
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CH 2 OEt
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CH 2 OEt
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CH 2 OEt
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CH 2 OEt
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CH 2 OEt
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CH 2 OEt
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CH 2 OEt
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CH 2 OEt
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CH 2 OEt
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CH 2 OEt
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CH 2 OEt
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CH 2 OEt
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CH 2 OEt
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CH 2 OEt
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CH 2 OEt
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CH 2 OEt
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CH 2 OEt
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CH 2 OEt
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CH 2 OEt
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CH 2 OEt
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CH 2 OEt
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CH 2 OEt
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CH 2 OEt
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CH 2 OEt
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CH 2 OEt
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CH 2 OEt
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CH 2 OEt
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CH 2 OEt
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CH 2 OEt
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CH 2 OEt
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CH 2 OEt
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CH 2 OEt
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CH 2 OEt
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CH 2 OEt
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CH 2 OEt
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CH 2 OEt
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CH 2 OEt
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CH 2 OEt
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CH 2 OEt
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CH 2 OEt
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CH 2 OEt
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CH 2 OEt
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CH 2 OEt
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CH 2 OEt
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CH 2 OEt
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CH 2 OEt
Me
CH 2 OEt
Me
CH 2 OEt
Me
CH 2 OEt
Me
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31 . The method according to either claim 18 or claim 20 , wherein the β-cell growth or differentiating factor is a member selected from the group consisting of: Liraglutide; CJC-1131; Albugon; and LY-548806.
32 . The method according to either claim 18 or claim 20 , wherein the β-cell growth or differentiating factor is a member selected from the group consisting of: Sitagliptin, Vildagliptin, NVP DPP728, Saxagliptin, P32/98, FE 999011, and PHX1149.
33 . The method according to either claim 18 or claim 20 , wherein the β-cell growth or differentiating factor is a member selected from the group consisting of: gastric inhibitory polypeptide (GIP); gastrin; epidermal growth factor 1; islet neogenesis therapy; insulin like growth factor 1 or 2; Parathyroid hormone related peptide (PTHrP); Hepatocyte growth factor; islet neogenesis associated protein (INGAP); NVP-LAQ824; TrichostatinA-0; hydroxamate; suberoylanilide hydroxamic acid; apicidin; trapoxin; CG1521; scriptide; oxamflatin; pyroxamide; propenamides; chlamydocin; diheteropeptin; WF-3136; Cyl-1; Cyl-2; FR 901228; MS-275, CI-994; depudecin, Neurogen 3, PDX-1, and NKX6.1.
34 . The method according to either claim 18 or claim 20 , wherein the biological response modifier is lisofylline.
35 . The method according to claim 34 , wherein the β-cell growth factor is islet neogenesis associated protein (INGAP).Join the waitlist — get patent alerts
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