US 6,552,168 B1Granted

Gamma-ketoacid tetrapeptides as inhibitors of caspase-3

AssigneeMerck Frosst Canada, Inc.

InventorsErich L. Grimm, Johanne Renaud, Renee Aspiotis, Christopher I. Bayly, Robert Zamboni, Shawn Black

Life of this patent

Estimating the term…

Abstract

The invention encompasses the novel class of compounds represented by formula I, which are caspase-3 inhibitors. The invention also encompasses certain pharmaceutical compositions for treatment of caspase-3 mediated diseases comprising compounds of formula I.

Claims26

Dependent claims

A compound of formula I

or a salt thereof, wherein:
R is selected from the group consisting of:
(a) H and
(b) C(O)R1;
R1 is selected from the group consisting of:
(a) hydrogen,
(b) C1-6alkoxy,
(c) NR6R7,
(d) benzyloxy or mono- or disubstituted benzyloxy, wherein the substituent is selected from the group consisting of:
(1) methyl,
(2) halogen,
(3) methoxy and
(4) cyano,
(e) C1-6alkyl or substituted C1-6alkyl, wherein the substituent is selected from the group consisting of:
(1) hydroxy,
(2) halo,
(3) C1-3alkoxy,
(4) C1-3alkylthio.
(5) phenyl C1-3alkoxy,
(6) phenyl C1-3alkylthio,
(7) phenylcarboxy and
(8) carboxy,
(f) aryl or arylC1-6alkyl wherein the aryl group is selected from the group consisting of:
(1) phenyl,
(2) naphthyl.
(3) pyridyl,
(4) furyl.
(5) thienyl,
(6) thiazolyl,
(7) isothiazolyl,
(8) imidazolyl,
(9) benzimidazolyl,
(10) pyrazinyl,
(11) pyrimidyl,
(12) quinolyl,
(13) isoquinolyl,
(14) benzofuryl,
(15) benzothienyl,
(16) pyrazolyl,
(17) indolyl,
(18) purinyl,
(19) isoxazolyl and
(20) oxazolyl, and
(g) mono and di-substituted aryl as defined above in items (1) to (20) of (f), wherein the substituents are independently selected from:
(1) halo,
(2) amino,
(3) nitro,
(4) hydroxy,
(5) cyano,
(6) carboxy,
(7) formyl,
(8) amino carbonyl,
(9) C1-6alkyl,
(10) C1-6fluoroalkyl,
(11) C1-6alkylcarbonyl
(12) C1-6alkoxycarbonyl,
(13) C1-6alkoxy,
(14) C1-6alkylthio,
(15) C1-6alkylsulfonyl and
(16) deuterio;
R2 is selected from the group consisting of:
(a) CH2CO2H,
(b) CH2CO2C1-4alkyl,
(c) CH2SC1-4alkyl and
(d) CH2S(O)2C1-4alkyl;
R3 is selected from the group consisting of:
(a) H,
(b) CH3,
(c) CH(CH3)2,
(d) CH2CH(CH3)2,
(e) CH2Ph,
(f) CH2PHOH,
(g) CH2OH,
(h) CH2SH,
(i) CH2CH2SCH3,
(j) CH(CH3)CH2CH3,
(k) CH(CH3)OH,
(l) CH2COOH,
(m) CH2CH2 COOH,
(n) CH2CH2CH2NHCNH(NH2),
(o) CH2CH2CH2CH2NH2,
(p) CH2C(O)NH2,
(q) CH2CH2C(O)NH2,
(r) CH2CH2CO2C1-4alkyl,
(s) CH2CH2S(O)2C1-4alkyl,
or R3 and X3 together form a saturated monocyclic ring having the following structure:
R4 is selected from the group consisting of:
(a) H,
(b) CH3,
(c) CH(CH3)2,
(d) CH2CH(CH3)2,
(e) CH2Ph
(t) CH2PhOH,
(g) CH2OH,
(h) CH2SH
(i) CH2CH2SCH3,
(j) CH(CH3)CH2CH3,
(k) CH(CH3)OH,
(l) CH2COOH,
(m) CH2CH2COOH,
(n) CH2CH2CH2NHCNH(NH2),
(o) CH2CH2CH2CH2NH2,
(p) CH2C(O)NH2,
(q) CH2CH2C(O)NH2,
or R4 and X4 together form a saturated monocyclic ring having the following structure:
R5 is selected from the group consisting of:
(a) C1-6alkyl,
(b) arylC1-8alkyl wherein the aryl is selected from the group consisting of:
(1) phenyl,
(2) naphthyl,
(3) pyridyl,
(4) furyl,
(5) thienyl,
(6) thiazolyl,
(7) isothiazolyl,
(8) imidazolyl,
(9) benzimidazolyl,
(10) pyrazinyl,
(11) pyrimidyl,
(12) quinolyl,
(13) isoquinolyl,
(14) benzofuryl,
(15) benzothienyl,
(16) pyrazolyl,
(17) indolyl,
(18) purinyl,
(19) isoxazolyl,
(20) oxazolyl and
(21) coumarinyl, and
the aryl may be optionally mono- or di-substituted with a substituent independently selected from:
(1) halo,
(2) amino,
(3) nitro,
(4) hydroxy,
(5) cyano,
(6) carboxy,
(7) formyl,
(8) amino carbonyl,
(9) C1-6alkyl,
(10) C1-6fluoroalkyl,
(11) C1-6alkylcarbonyl,
(12) C1-6alkoxycarbonyl,
(13) C1-6alkoxy,
(14) C1-6alkylthio and
(15) C1-6alkylsulfonyl;
R6 and R7 are independently selected from the group consisting of:
(a) C1-4alkyl,
(b) C1-4fluoroalkyl and
(c) benzyl or mono- or disubstituted benzyl wherein the substituent is selected from the group consisting of:
(1) methyl,
(2) halogen,
(3) methoxy and
(4) cyano,
or R6 and R7 may be joined to form a pyrrolidine, piperidine, morpholine, thiamorpholine or N—R8 substituted piperazine wherein R8 is H or C1-3alkyl;
and
X2, X3 and X4 are independently H, or
X3 and R3, or X4 and R4 may together form a saturated monocyclic ring having the following structure:

154 more elements

A compound of formula I

or a salt thereof, wherein:
R is selected from the group consisting of:
(a) H and
(b) C(O)R1;
R1 is selected from the group consisting of:
(a) hydrogen,
(b) C1-6alkoxy,
(c) NR6R7,
(d) benzyloxy or mono- or disubstituted benzyloxy, wherein the substituent is selected from the group consisting of:
(1) methyl,
(2) halogen,
(3) methoxy and
(4) cyano,
(e) C1-6alkyl or substituted C1-6alkyl, wherein the substituent is selected from the group consisting of:
(1) hydroxy,
(2) halo,
(3) C1-3alkoxy,
(4) C1-3alkylthio,
(5) phenyl C1-3alkoxy,
(6) phenyl C1-3alkylthio,
(7) phenylcarboxy and
(8) carboxy,
(f) aryl or arylC1-6alkyl wherein the aryl group is selected from the group consisting of:
(1) phenyl,
(2) naphthyl,
(3) pyridyl,
(4) furyl,
(5) thienyl,
(6) thiazolyl,
(7) isothiazolyl,
(8) imidazolyl,
(9) benzimidazolyl,
(10) pyrazinyl,
(11) pyrimidyl,
(12) quinolyl,
(13) isoquinolyl,
(14) benzofuryl,
(15) benzothienyl,
(16) pyrazolyl,
(17) indolyl,
(18) purinyl,
(19) isoxazolyl and
(20) oxazolyl, and
(g) mono and di-substituted aryl as defined above in items (1) to (20) of (f), wherein the substituents are independently selected from:
(1) halo,
(2) amino,
(3) nitro,
(4) hydroxy,
(5) cyano,
(6) carboxy,
(7) formyl,
(8) amino carbonyl,
(9) C1-6alkyl,
(10) C1-6fluoroalkyl,
(11) C1-6alkylcarbonyl,
(12) C1-6alkoxycarbonyl,
(13) C1-6alkoxy,
(14) C 1-6alkylthio,
(15) C1-6alkylsulfonyl and
(16) deuterio;
R2 is selected from the group consisting of:
(a) H,
(b) CH3,
(c) CH(CH3)2,
(d) CH2CH(CH3)2,
(e) CH2Ph,
(f) CH2OH,
(g) CH2SH,
(h) CH2CH2SCH3,
(i) CH(CH3)CH2CH3,
(j) CH(CH3)OH,
(k) CH2COOH,
(l) CH2CH2COOH,
(m) CH2CH2CH2NHCNH(NH2),
(n) CH2CH2CH2CH2NH2,
(o) CH2C(O)NH2,
(p) CH2CH2C(O)NH2,
(q) CH2CO2C1-4alkyl,
(r) CH2SC1-4alkyl,
(s) CH2S(O)2C1-4alkyl,
or R2 and X2 together form a saturated monocyclic ring having the following structure:
R3 is selected from the group consisting of:
(a) CH3,
(b) CH2CH2CO2H,
(c) CH2CH2CO2C1-4alkyl and
(d) CH2CH2S(O)2C1-4alkyl;
R4 is selected from the group consisting of:
(a) H,
(b) CH3,
(c) CH(CH3)2,
(d) CH2CH(CH3)2,
(e) CH2Ph,
(f) CH2PhOH,
(g) CH2OH,
(h) CH2SH,
(i) CH2CH2SCH3,
(j) CH(CH3)CH2CH3,
(k) CH(CH3)OH,
(l) CH2COOH,
(m) CH2CH2COOH,
(n) CH2CH2CH2NHCNH(NH2),
(o) CH2CH2CH2CH2NH2,
(p) CH2C(O)NH2,
(q) CH2CH2C(O)NH2,
or R4 and X4 together form a saturated monocyclic ring having the following structure:
R5 is selected from the group consisting of:
(a) C1-6alkyl,
(b) arylC1-8alkyl wherein the aryl is selected from the group consisting of:
(1) phenyl,
(2) naphthyl,
(3) pyridyl,
(4) furyl,
(5) thienyl,
(6) thiazolyl,
(7) isothiazolyl,
(8) imidazolyl,
(9) benzimidazolyl,
(10) pyrazinyl,
(11) pyrimidyl,
(12) quinolyl,
(13) isoquinolyl,
(14) benzofuryl,
(15) benzothienyl,
(16) pyrazolyl,
(17) indolyl,
(18) purinyl,
(19) isoxazolyl,
(20) oxazolyl and
(21) coumarinyl, and
the aryl may be optionally mono- or di-substituted with a substituent independently selected from:
(1) halo,
(2) amino,
(3) nitro,
(4) hydroxy,
(5) cyano,
(6) carboxy,
(7) formyl,
(8) amino carbonyl,
(9) C1-6alkyl,
(10) C1-6fluoroalkyl,
(11) C1-6alkylcarbonyl,
(12) C1-6alkoxycarbonyl,
(13) C1-6alkoxy,
(14) C1-6alkylthio and
(15) C1-6alkylsulfonyl;
R6 and R7 are independently selected from the group consisting of:
(a) C1-4alkyl,
(b) C1-4fluoroalkyl and
(c) benzyl or mono- or disubstituted benzyl wherein the substituent is selected from the group consisting of:
(1) methyl,
(2) halogen,
(3) methoxy and
(4) cyano,
or R6 and R7 may be joined to form a pyrrolidine, piperidine, morpholine, thiamorpholine or N—R8 substituted piperazine wherein R8 is H or C1-3alkyl;
and
X2, X3 and X4 are independently H, or
X2 and R2, or X4 and R4 may together form a saturated monocyclic ring having the following structure:

154 more elements

A compound of formula I

or a salt thereof, wherein:
R is selected from the group consisting of:
(a) H and
(b) C(O)R1;
R1 is selected from the group consisting of:
(a) hydrogen,
(b) C1-6alkoxy,
(c) NR6R7,
(d) benzyloxy or mono- or disubstituted benzyloxy, wherein the substituent is selected from the group consisting of:
(1) methyl,
(2) halogen,
(3) methoxy and
(4) cyano,
(e) C1-6alkyl or substituted C1-6alkyl, wherein the substituent is selected from the group consisting of:
(1) hydroxy,
(2) halo,
(3) C1-3alkoxy,
(4) C1-3alkylthio,
(5) phenyl C1-3alkoxy,
(6) phenyl C1-3alkylthio,
(7) phenylcarboxy and
(8) carboxy,
(f) aryl or arylC1-6alkyl wherein the aryl group is selected from the group consisting of:
(1) phenyl,
(2) naphthyl,
(3) pyridyl,
(4) furyl,
(5) thienyl,
(6) thiazolyl,
(7) isothiazolyl,
(8) imidazolyl,
(9) benzimidazolyl,
(10) pyrazinyl,
(11) pyrimidyl,
(12) quinolyl,
(13) isoquinolyl,
(14) benzofuryl,
(15) benzothienyl,
(16) pyrazolyl,
(17) indolyl,
(18) purinyl,
(19) isoxazolyl and
(20) oxazolyl, and
(g) mono and di-substituted aryl as defined above in items (1) to (20) of (f), wherein the substituents are independently selected from:
(1) halo,
(2) amino,
(3) nitro,
(4) hydroxy,
(5) cyano,
(6) carboxy,
(7) formyl,
(8) amino carbonyl,
(9) C1-6alkyl,
(10) C1-6fluoroalkyl,
(11) C1-6alkylcarbonyl,
(12) C1-6alkoxycarbonyl,
(13) C1-6alkoxy,
(14) C1-6alkylthio,
(15) C1-6alkylsulfonyl and
(16) deuterio;
R2 is selected from the group consisting of:
(a) H,
(b) CH3,
(c) CH(CH3)2,
(d) CH2CH(CH3)2,
(e) CH2Ph,
(f) CH2OH,
(g) CH2SH,
(h) CH2CH2SCH3,
(i) CH(CH3)CH2CH3,
(j) CH(CH3)OH,
(k) CH2COOH,
(l) CH2CH2COOH,
(m) CH2CH2CH2NHCNH(NH2),
(n) CH2CH2CH2CH2NH2,
(o) CH2C(O)NH2,
(p) CH2CH2C(O)NH2,
(q) CH2CO2C1-4alkyl,
(r) CH2SC1-4alkyl,
(s) CH2S(O)2C1-4alkyl,
or R2 and X2 together form a saturated monocyclic ring having the following structure:
R3 is selected from the group consisting of:
(a) H,
(b) CH3,
(c) CH(CH3)2,
(d) CH2CH(CH3)2,
(e) CH2Ph,
(f) CH2PhOH,
(g) CH2OH,
(h) CH2SH,
(i) CH2CH2SCH3,
(j) CH(CH3)CH2CH3,
(k) CH(CH3)OH,
(l) CH2COOH,
(m) CH2CH2COOH,
(n) CH2CH2CH2NHCNH(NH2),
(o) CH2CH2CH2CH2NH2,
(p) CH2C(O)NH2,
(q) CH2CH2C(O)NH2,
(r) CH2CH2CO2C1-4alkyl,
(s) CH2CH2S(O)2C1-4alkyl,
or R3 and X3 together form a saturated monocyclic ring having the following structure:
R4 is isopropyl;
R5 is selected from the group consisting of:
(a) C1-6alkyl,
(b) arylC1-8alkyl wherein the aryl is selected from the group consisting of:
(1) phenyl,
(2) naphthyl,
(3) pyridyl,
(4) furyl,
(5) thienyl,
(6) thiazolyl,
(7) isothiazolyl,
(8) imidazolyl,
(9) benzimidazolyl,
(10) pyrazinyl,
(11) pyrimidyl,
(12) quinolyl,
(13) isoquinolyl,
(14) benzofuryl,
(15) benzothienyl,
(16) pyrazolyl,
(17) indolyl,
(18) purinyl,
(19) isoxazolyl,
(20) oxazolyl and
(21) coumarinyl and
(c) aryl as defined above in items (1) to (21) of (b), wherein the aryl portions may be optionally mono- or di-substituted with a substituent independently selected from:
(1) halo,
(2) amino,
(3) nitro,
(4) hydroxy,
(5) cyano,
(6) carboxy,
(7) formyl,
(8) amino carbonyl,
(9) C1-6alkyl,
(10) C1-6fluoroalkyl,
(11) C1-6alkylcarbonyl,
(12) C1-6alkoxycarbonyl,
(13) C1-6alkoxy,
(14) C1-6alkylthio and
(15) C1-6alkylsulfonyl;
R6 and R7 are independently selected from the group consisting of:
(a) C1-4alkyl,
(b) C1-4fluoroalkyl and
(c) benzyl or mono- or disubstituted benzyl wherein the substituent is selected from the group consisting of:
(1) methyl,
(2) halogen,
(3) methoxy and
(4) cyano,
or R6 and R7 may be joined to form a pyrrolidine, piperidine, morpholine, thiamorpholine or N—R8 substituted piperazine wherein R8 is H or C1-3alkyl;
and
X2, X3 and X4 are independently H, or
X2 and R2, or X3 and R3 may together form a saturated monocyclic ring having the following structure:

152 more elements

A compound selected from the following group:

(a) (3S)-3-((2S )-2-[((2S)-2-[(2S)-2-(Acetylamino)-3-carboxypropanoyl]amino-4-carboxybutanoyl)amino]-3-methylbutanoylamino)-4-oxo-7-phenylheptanoic acid (SEQ ID NO 1);
(b) (4S)-4-[(2S)-2-(Acetylamino)-3-carboxypropanoyl]amino-5-[(1S)-1-([(1S)-1-(carboxymethyl)-2-oxopropyl]aminocarbonyl)-2-methylpropyl]amino-5-oxopentanoic acid (SEQ ID NO 2);
(c) (3S)-3-((2S)-2-[((2S)-2-[(2S)-2-(Acetylamino)-3-carboxypropanoyl]amino-4-carboxybutanoyl)amino]-3-methylbutanoylamino)-4-oxo-9-phenylnonanoic acid (SEQ ID NO 3);
(d) (3S)-3-((2S)-2-[((2S)-2-[(2S)-2-(Acetylamino)-3-carboxypropanoyl]amino-4-carboxybutanoyl)amino]-3-methylbutanoylamino)-4-oxoheptanoic acid (SEQ ID NO 5);
(e) (3S)-3-((2S)-2-[((2S)-2-[(2S)-2-(Acetylamino)-3-carboxypropanoyl]amino-4-carboxybutanoyl)amino]-3-methylbutanoylamino)-4-oxo-6-phenylhexanoic acid (SEQ ID NO 6);
(f) (3S)-3-((2S)-2-[((2S)-2-[(2S)-2-(Acetylamino)-3-carboxypropanoyl]amino-4-carboxybutanoyl)amino]-3-methylbutanoylamino)-4-oxo-8-phenyloctanoic acid (SEQ ID NO 7);
(g) (3S)-3-((2S)-2-[((2S)-2-[(2S)-2-(Acetylamino)-3-carboxypropanoyl]amino-4-carboxybutanoyl)amino]-3-methylbutanoylamino)-4-oxo-5-phenylpentanoic acid (SEQ ID NO 8);
(h) (3S)-3-((2S)-2-[((2S)-2-[(2S)-2-(Acetylamino)-3-carboxypropanoyl]amino-4-carboxybutanoyl)amino]-3-methylbutanoylamino)-7-(4-methoxyphenyl)-4-oxoheptanoic acid (SEQ ID NO 9);
(i) (3S)-3-((2S)-2-[((2S)-2-[(2S)-2-(Acetylamino)-3-carboxypropanoyl]amino-4-carboxybutanoyl)amino]-3-methylbutanoylamino)-7-(1-naphthyl)-4-oxoheptanoic acid (SEQ ID NO 10);
(j) (3S)-3-((2S)-2-[((2S)-2-[(2S)-2-(Acetylamino)-3-carboxypropanoyl]aminopropanoyl)amino]-3-methylbutanoylamino)-4-oxo-7-phenylheptanoic acid (SEQ ID NO 12);
(k) (3S)-3-((2S)-2-[((2S)-2-[(2S)-2-(Acetylamino)-3-carboxypropanoyl]aminopropanoyl)amino]-3-methylbutanoylamino)-4-oxo-9-phenylnonanoic acid (SEQ ID NO 13);
(l) (3S)-3-[((2S)-2-[(2S)-2-((2S)-3-Carboxy-2-[(3,5-dibromobenzoyl)amino]propanoylamino)propanoyl]amino-3-methylbutanoyl)amino]-4-oxo-7-phenylheptanoic acid (SEQ ID NO 14);
(m) (3S)-3-[((2S)-2-[(2S)-2-((2S)-3-Carboxy-2-[(3,5-dideuteriobenzoyl)amino]propanoylamino)propanoyl]amino-3-methylbutanoyl)amino]-4-oxo-7-phenylheptanoic-acid (SEQ ID NO 15);
(n) (3S)-3-((2S)-2-[((2S)-2-[(2S)-2-Amino-4-methoxy-4-oxobutanoyl]aminopropanoyl)amino]-3-methylbutanoylamino)-4-oxo-7-phenylheptanoic acid (SEQ ID NO 16);
(o) (3S)-3-((2S)-2-[((2S)-2-[(2S)-2-(Acetylamino)-4-methoxy-4-oxobutanoyl]aminopropanoyl)amino]-3-methylbutanoylamino)-4-oxo-7-phenylheptanoic acid (SEQ ID NO 26);
(p) (3S)-3-((2S)-2-[((2S)-2-[(2S)-2-(Acetylamino)-3-carboxypropanoyl]aminopropanoyl)amino]-3-methylbutanoylamino)-7-(1-naphthyl)-4-oxoheptanoic acid (SEQ ID NO 17);
(q) (3S)-3-[((2S)-2-[(2S)-2-((2S)-3-Carboxy-2-[(4-iodobenzoyl)amino]propanoylamino)propanoyl]amino-3-methylbutanoyl)amino]-4-oxo-7-phenylheptanoic acid (SEQ ID NO 18);
(r) (3S)-3-[((2S)-2-[(2S)-2-[(2S)-2-(Acetylamino)-3-carboxypropanoyl]amino-4-(methylsulfonyl)butanoyl]amino-3-methylbutanoyl)amino]-4-oxo-7-phenylheptanoic acid (SEQ ID NO 19);
(s) (3S)-3-((2S)-2-[((2S)-2-[(2R)-2-(Acetylamino)-3-(methylsulfanyl)propanoyl]aminopropanoyl)amino]-3-methylbutanoylamino)-4-oxo-7-phenylheptanoic acid (SEQ ID NO 20);
(t) (3S)-3-((2S)-2-[((2S)-2-[(2R)-2-(Acetylamino)-3-(methylsulfonyl)propanoyl]aminopropanoyl)amino]-3-methylbutanoylamino)-4-oxo-7-phenylheptanoic acid (SEQ ID NO 21);
(u) (3S)-3-((2S)-2-[((2S)-2-[(2R)-2-(Acetylamino)-3-(methylsulfanyl)propanoyl]aminopropanoyl)amino]-3-methylbutanoylamino)-7-(1-naphthyl)-4-oxoheptanoic acid (SEQ ID NO 22);
and
(v) (3S)-3-((2S)-2-[((2S)-2-[(2R)-2-(Acetylamino)-3-(methylsulfonyl)propanoyl]aminopropanoyl)amino]-3-methylbutanoylamino)-7-(1-naphthyl)-4-oxoheptanoic acid (SEQ ID NO 23).

20 more elements

Dependencies are inferred from the claim text.

Facts

Application: 09/453,201Filed 2 Dec 1999 · us provisional application
Priority: 2 Dec 1998
Granted: 22 Apr 2003
Term ends: Not estimatedThe source records don’t support an estimate.

Classification15 codes

C07K 5/0202
Containing at least one abnormal peptide link: containing the structure -NH-X-X-C-, X being an optionally substituted carbon atom or a heteroatom,…
A61P 3/10
For glucose homeostasis: for hyperglycaemia, e.g. antidiabetics
A61P 9/10
Drugs for disorders of the cardiovascular system: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary…
A61P 17/14
Drugs for dermatological disorders: for baldness or alopecia

Family

Application60/110,567Us provisional application · filed 2 Dec 1998
US 6,552,168 B1This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

A compound of formula I

or a salt thereof, wherein:
R is selected from the group consisting of:
(a) H and
(b) C(O)R1;
R1 is selected from the group consisting of:
(a) hydrogen,
(b) C1-6alkoxy,
(c) NR6R7,
(d) benzyloxy or mono- or disubstituted benzyloxy, wherein the substituent is selected from the group consisting of:
(1) methyl,
(2) halogen,
(3) methoxy and
(4) cyano,
(e) C1-6alkyl or substituted C1-6alkyl, wherein the substituent is selected from the group consisting of:
(1) hydroxy,
(2) halo,
(3) C1-3alkoxy,
(4) C1-3alkylthio.
(5) phenyl C1-3alkoxy,
(6) phenyl C1-3alkylthio,
(7) phenylcarboxy and
(8) carboxy,
(f) aryl or arylC1-6alkyl wherein the aryl group is selected from the group consisting of:
(1) phenyl,
(2) naphthyl.
(3) pyridyl,
(4) furyl.
(5) thienyl,
(6) thiazolyl,
(7) isothiazolyl,
(8) imidazolyl,
(9) benzimidazolyl,
(10) pyrazinyl,
(11) pyrimidyl,
(12) quinolyl,
(13) isoquinolyl,
(14) benzofuryl,
(15) benzothienyl,
(16) pyrazolyl,
(17) indolyl,
(18) purinyl,
(19) isoxazolyl and
(20) oxazolyl, and
(g) mono and di-substituted aryl as defined above in items (1) to (20) of (f), wherein the substituents are independently selected from:
(1) halo,
(2) amino,
(3) nitro,
(4) hydroxy,
(5) cyano,
(6) carboxy,
(7) formyl,
(8) amino carbonyl,
(9) C1-6alkyl,
(10) C1-6fluoroalkyl,
(11) C1-6alkylcarbonyl
(12) C1-6alkoxycarbonyl,
(13) C1-6alkoxy,
(14) C1-6alkylthio,
(15) C1-6alkylsulfonyl and
(16) deuterio;
R2 is selected from the group consisting of:
(a) CH2CO2H,
(b) CH2CO2C1-4alkyl,
(c) CH2SC1-4alkyl and
(d) CH2S(O)2C1-4alkyl;
R3 is selected from the group consisting of:
(a) H,
(b) CH3,
(c) CH(CH3)2,
(d) CH2CH(CH3)2,
(e) CH2Ph,
(f) CH2PHOH,
(g) CH2OH,
(h) CH2SH,
(i) CH2CH2SCH3,
(j) CH(CH3)CH2CH3,
(k) CH(CH3)OH,
(l) CH2COOH,
(m) CH2CH2 COOH,
(n) CH2CH2CH2NHCNH(NH2),
(o) CH2CH2CH2CH2NH2,
(p) CH2C(O)NH2,
(q) CH2CH2C(O)NH2,
(r) CH2CH2CO2C1-4alkyl,
(s) CH2CH2S(O)2C1-4alkyl,
or R3 and X3 together form a saturated monocyclic ring having the following structure:
R4 is selected from the group consisting of:
(a) H,
(b) CH3,
(c) CH(CH3)2,
(d) CH2CH(CH3)2,
(e) CH2Ph
(t) CH2PhOH,
(g) CH2OH,
(h) CH2SH
(i) CH2CH2SCH3,
(j) CH(CH3)CH2CH3,
(k) CH(CH3)OH,
(l) CH2COOH,
(m) CH2CH2COOH,
(n) CH2CH2CH2NHCNH(NH2),
(o) CH2CH2CH2CH2NH2,
(p) CH2C(O)NH2,
(q) CH2CH2C(O)NH2,
or R4 and X4 together form a saturated monocyclic ring having the following structure:
R5 is selected from the group consisting of:
(a) C1-6alkyl,
(b) arylC1-8alkyl wherein the aryl is selected from the group consisting of:
(1) phenyl,
(2) naphthyl,
(3) pyridyl,
(4) furyl,
(5) thienyl,
(6) thiazolyl,
(7) isothiazolyl,
(8) imidazolyl,
(9) benzimidazolyl,
(10) pyrazinyl,
(11) pyrimidyl,
(12) quinolyl,
(13) isoquinolyl,
(14) benzofuryl,
(15) benzothienyl,
(16) pyrazolyl,
(17) indolyl,
(18) purinyl,
(19) isoxazolyl,
(20) oxazolyl and
(21) coumarinyl, and
the aryl may be optionally mono- or di-substituted with a substituent independently selected from:
(1) halo,
(2) amino,
(3) nitro,
(4) hydroxy,
(5) cyano,
(6) carboxy,
(7) formyl,
(8) amino carbonyl,
(9) C1-6alkyl,
(10) C1-6fluoroalkyl,
(11) C1-6alkylcarbonyl,
(12) C1-6alkoxycarbonyl,
(13) C1-6alkoxy,
(14) C1-6alkylthio and
(15) C1-6alkylsulfonyl;
R6 and R7 are independently selected from the group consisting of:
(a) C1-4alkyl,
(b) C1-4fluoroalkyl and
(c) benzyl or mono- or disubstituted benzyl wherein the substituent is selected from the group consisting of:
(1) methyl,
(2) halogen,
(3) methoxy and
(4) cyano,
or R6 and R7 may be joined to form a pyrrolidine, piperidine, morpholine, thiamorpholine or N—R8 substituted piperazine wherein R8 is H or C1-3alkyl;
and
X2, X3 and X4 are independently H, or
X3 and R3, or X4 and R4 may together form a saturated monocyclic ring having the following structure:

154 more elements

Facts

Application

09/453,201Filed 2 Dec 1999 · us provisional application

Priority

2 Dec 1998

Granted

22 Apr 2003

Term ends

Not estimatedThe source records don’t support an estimate.

Classification15 codes

C07K 5/0202
Containing at least one abnormal peptide link: containing the structure -NH-X-X-C-, X being an optionally substituted carbon atom or a heteroatom,…
A61P 3/10
For glucose homeostasis: for hyperglycaemia, e.g. antidiabetics
A61P 9/10
Drugs for disorders of the cardiovascular system: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary…
A61P 17/14
Drugs for dermatological disorders: for baldness or alopecia