U.S. patent application number 10/797458 was filed with the patent office on 2004-09-02 for novel ppar-gamma agonists as agents for the treatment of type ii diabetes.
Invention is credited to Cavallaro, Cullen, Kolb, Hartmuth C., Kolla, Laxma Reddy, McGeehan, Gerard, Shi, Zhi-Cai.
Application Number | 20040171656 10/797458 |
Document ID | / |
Family ID | 31998955 |
Filed Date | 2004-09-02 |
United States Patent
Application |
20040171656 |
Kind Code |
A1 |
Kolb, Hartmuth C. ; et
al. |
September 2, 2004 |
Novel PPAR-gamma agonists as agents for the treatment of type II
diabetes
Abstract
Disclosed are compounds of the formula: 1 or the
pharmaceutically acceptable non-toxic salts thereof wherein: Z is
aryl or heteroaryl; n and m are 0, 1 or 2; A is a carboxylic acid
or ester; or A is 2 where D, F and G are hydrogen, (un)substituted
amino, (un)substituted alkoxy, methylene or an (un)substituted
sulfide; X is N, O, CH.sub.2, S, SO or SO.sub.2; R.sub.4 is oxo,
hydrogen, hydroxy, lower alkyl, lower alkoxy, cycloalkyl, keto,
acyl, or sulfonyl; Y is hydrogen, (un)substituted amino,
(un)substituted alkoxy, methylene, an (un)substituted sulfide,
(un)substituted sulfonyl or an (un)substituted sulfoxide; and
R.sub.5, R.sub.6 and R.sub.8 are hydrogen, lower alkyl, lower
alkoxy, cycloalkyl, keto, acyl, or sulfonyl; or R.sub.5 and R.sub.6
together form a ring. These [N-(substituted)carbamoylaryl- and
heteroaryl aminopropanoic and butanoic acid compounds are highly
selective agonists for the PPAR-.gamma. receptor or prodrugs of
agonists for the PPAR-.gamma. receptor. Thus these compounds are
useful in the treatment of Type II diabetes (NIDDM).
Inventors: |
Kolb, Hartmuth C.; (East
Windsor, NJ) ; McGeehan, Gerard; (Chester Springs,
PA) ; Shi, Zhi-Cai; (North Brunswick, NJ) ;
Kolla, Laxma Reddy; (North Brunswick, NJ) ;
Cavallaro, Cullen; (Allentown, NJ) |
Correspondence
Address: |
McDonnell Boehnen Hulbert & Berghoff
31st Floor
300 South Wacker Drive
Chicago
IL
60606
US
|
Family ID: |
31998955 |
Appl. No.: |
10/797458 |
Filed: |
March 10, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10797458 |
Mar 10, 2004 |
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09552477 |
Apr 18, 2000 |
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6713514 |
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60130011 |
Apr 19, 1999 |
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60175528 |
Jan 11, 2000 |
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Current U.S.
Class: |
514/357 ;
514/408; 514/567; 546/335; 548/571; 562/430; 562/442 |
Current CPC
Class: |
C07C 2601/08 20170501;
C07C 323/42 20130101; C07C 2601/14 20170501; C07C 237/30 20130101;
C07C 237/38 20130101 |
Class at
Publication: |
514/357 ;
514/408; 514/567; 546/335; 548/571; 562/442; 562/430 |
International
Class: |
C07D 213/55; A61K
031/44; A61K 031/40 |
Claims
What is claimed is:
1. A compound of the formula: 16or the pharmaceutically acceptable
non-toxic salts thereof wherein: Z is a 5 or 6 membered aryl or
heteroaryl ring optionally substituted with up to three groups
selected from lower alkyl, halogen or lower alkoxy; n and m
independently represent 0, 1 or 2; A is C0.sub.2R.sub.9; or A is
17D, F and G are the same or different and represent hydrogen,
NR.sub.1R.sub.12, OR.sub.1, CH.sub.2R.sub.1 or SR.sub.1; R.sub.1
and R.sub.12 are the same or different and represent hydrogen,
lower alkyl, R.sub.10C.dbd.O, R.sub.10SO.sub.2, or cycloalkyl
optionally substituted with one, two, three or four groups
independently selected from halogen, trifluoromethyl,
trifluoromethoxy, cyano, nitro, carboxyl, alkoxycarboxy,
alkylcarboxy, hydroxy, lower alkyl, lower alkoxy, amino, or mono or
dialkylamino where each alkyl portion is lower alkyl, or aryl,
heteroaryl, arylalkyl, or heteroarylalkyl, where the ring portion
of each is optionally substituted with one, two, three or four
groups independently selected from halogen, trifluoromethyl,
trifluoromethoxy, cyano, nitro, carboxyl, alkoxycarboxy,
alkylcarboxy, hydroxy, lower alkyl, lower alkoxy, amino, or mono or
dialkylamino where each alkyl portion is lower alkyl; R.sub.10 is
hydrogen or lower alkyl, or aryl, heteroaryl, arylalkyl or
heteroarylalkyl, where the ring portion of each is optionally
substituted with one, two or three groups independently selected
from halogen, trifluoromethyl, trifluoromethoxy, cyano, nitro,
carboxyl, alkoxycarboxy, alkylcarboxy, hydroxy, lower alkyl, lower
alkoxy, amino, or mono or dialkylamino where each alkyl portion is
lower alkyl; R.sub.9 is H or lower alkyl; X is N, O, CH.sub.2, S,
SO or SO.sub.2; R.sub.4 is O, hydrogen, hydroxy, lower alkyl, lower
alkoxy, cycloalkyl, R.sub.10C.dbd.O or R.sub.10SO.sub.2; Y is
hydrogen, NR.sub.1R.sub.12, OR.sub.1, CH.sub.2R.sub.1, SR.sub.1,
SOR.sub.1 or SO.sub.2R.sub.1; and R.sub.5, R.sub.6 and R.sub.8, are
the same or different and represent hydrogen, lower alkyl,
R.sub.10C.dbd.O, R.sub.10SO.sub.2, or cycloalkyl optionally
substituted with one, two, three or four groups independently
selected from halogen, trifluoromethyl, trifluoromethoxy, cyano,
nitro, carboxyl, alkoxycarboxy, alkylcarboxy, hydroxy, lower alkyl,
lower alkoxy, amino, or mono or dialkylamino where each alkyl
portion is lower alkyl, or aryl, heteroaryl, arylalkyl, or
heteroarylalkyl, where the ring portion of each is optionally
substituted with one, two, three or four groups independently
selected from halogen, trifluoromethyl, trifluoromethoxy, cyano,
nitro, carboxyl, alkoxycarboxy, alkylcarboxy, hydroxy, lower alkyl,
lower alkoxy, amino, or mono or dialkylamino where each alkyl
portion is lower alkyl; or R.sub.5 and R.sub.6 together with the
carbon atom to which they are attached form a 5, 6, or 7 membered
carbocyclic ring up to two of which members are optionally hetero
atoms selected from oxygen, sulfur and nitrogen.
2. A compound of the formula: 18or the pharmaceutically acceptable
non-toxic salts thereof wherein: n and m independently represent 0,
1 or 2; A is CO.sub.2R.sub.9; or A is 19D, F and G are the same or
different and represent hydrogen, NR.sub.1R.sub.12, OR.sub.1,
CH.sub.2R.sub.1 or SR.sub.1; R.sub.1 and R.sub.12 are the same or
different and represent hydrogen, lower alkyl, R.sub.10C.dbd.O,
R.sub.10SO.sub.2, or cycloalkyl optionally substituted with one,
two, three or four groups independently selected from halogen,
trifluoromethyl, trifluoromethoxy, cyano, nitro, carboxyl,
alkoxycarboxy, alkylcarboxy, hydroxy, lower alkyl, lower alkoxy,
amino, or mono or dialkylamino where each alkyl portion is lower
alkyl, or aryl, heteroaryl, arylalkyl, or heteroarylalkyl, where
the ring portion of each is optionally substituted with one, two,
three or four groups independently selected from halogen,
trifluoromethyl, trifluoromethoxy, cyano, nitro, carboxyl,
alkoxycarboxy, alkylcarboxy, hydroxy, lower alkyl, lower alkoxy,
amino, or mono or dialkylamino where each alkyl portion is lower
alkyl; R.sub.10 is hydrogen or lower alkyl, or aryl, heteroaryl,
arylalkyl or heteroarylalkyl, where the ring portion of each is
optionally substituted with one, two or three groups independently
selected from halogen, trifluoromethyl, trifluoromethoxy, cyano,
nitro, carboxyl, alkoxycarboxy, alkylcarboxy, hydroxy, lower alkyl,
lower alkoxy, amino, or mono or dialkylamino where each alkyl
portion is lower alkyl; R.sub.9 is H or lower alkyl; X is N, O,
CH.sub.2, S, SO or SO.sub.2; R.sub.4 is O, hydrogen, hydroxy, lower
alkyl, lower alkoxy, cycloalkyl, R.sub.10C.dbd.O or
R.sub.10SO.sub.2; Y is hydrogen, NR.sub.1R.sub.12, OR.sub.1,
CH.sub.2R.sub.1, SR.sub.1, SOR.sub.1 or SO.sub.2R.sub.1; and
R.sub.5, R.sub.6 and R.sub.8, are the same or different and
represent hydrogen, lower alkyl, R.sub.10C.dbd.O, R.sub.10SO.sub.2,
or cycloalkyl optionally substituted with one, two, three or four
groups independently selected from halogen, trifluoromethyl,
trifluoromethoxy, cyano, nitro, carboxyl, alkoxycarboxy,
alkylcarboxy, hydroxy, lower alkyl, lower alkoxy, amino, or mono or
dialkylamino where each alkyl portion is lower alkyl, or aryl,
heteroaryl, arylalkyl, or heteroarylalkyl, where the ring portion
of each is optionally substituted with one, two, three or four
groups independently selected from halogen, trifluoromethyl,
trifluoromethoxy, cyano, nitro, carboxyl, alkoxycarboxy,
alkylcarboxy, hydroxy, lower alkyl, lower alkoxy, amino, or mono or
dialkylamino where each alkyl portion is lower alkyl; or R.sub.5
and R.sub.6 together with the carbon atom to which they are
attached form a 5, 6, or 7 membered carbocyclic ring up to two of
which members are optionally hetero atoms selected from oxygen,
sulfur and nitrogen.
3. A compound according to claim 1 which is
(2S)-2-[benzylamino]-3-{4-[N-(- 3-phenylpropyl)carbamoyl]phenyl}
propanoic acid; (2S)-3-{4-[N-methyl-N(2-p-
henylthiocyclopentyl)carbamoyl]phenyl}-2-[benzylamino]propanoic
acid;
(2S)-2-{[(4-methoxyphenyl)methyl]amino}-3-{4-[N-(3-phenylpropyl)
carbamoyl]phenyl}propanoic acid;
(2S)-3-{4-[N-methyl-N-(2-phenylthiocyclo-
pentyl)carbamoyl]phenyl}-2-({[4-(trifluoromethoxy)phenyl]methyl}amino)prop-
anoic acid;
(2S)-2-{[(4-fluorophenyl)methyl]amino}-3-{4-[N-methyl-N-(2-phe-
nylthiocyclopentyl)carbamoyl]phenyl}propanoic acid;
(2S)-3-{4-[N-methyl-N-(2-phenoxycyclopentyl)carbamoyl]phenyl}-2-[benzylam-
ino]propanoic acid;
(2S)-3-{4-[N-methyl-N-(2-phenylthiocyclohexyl)carbamoy-
l]phenyl}-2-({[4-(trifluoromethoxy)phenyl]methyl}amino)propanoic
acid; and (2S)-2-{ [(4-fluorophenyl)methyl]
amino}-3-{4-[N-methyl-N-(2-phenylthiocy-
clohexyl)carbamoyl]phenyl}propanoic acid.
4. A pharmaceutical composition comprising a compound according to
claim 1 and a pharmaceutically acceptable carrier.
5. A method of treating Type II diabetes in a mammal comprising
administering to said mammal a compound according to claim 1.
Description
BACKGROUND OF THE INVENTION
[0001] This application claims the benefit of U.S. Provisional
Application No. 60/130,011, filed Apr. 19, 1999 and U.S.
Provisional Application No. 60/175,528, filed Jan. 11, 2000.
[0002] 1. Field of the Invention
[0003] This invention relates to certain 1,4-disubstituted phenyl
derivatives that act as agonists to the PPAR-.gamma. receptor. This
invention also relates to pharmaceutical compositions comprising
such compounds. It further relates to the use of such compounds in
treating Type II diabetes, or NIDDM. The interaction of certain
1,4-disubstituted phenyl derivatives of the invention with the
nuclear receptor PPAR-.gamma. is described. This interaction
results in the pharmacological activities of these compounds.
[0004] 2. Description of the Related Art
[0005] Type II diabetes, or non-insulin-dependent diabetes mellitus
(NIDDM), is a common metabolic disorder which has no effective
treatment. NIDDM occurs predominantly in adults and involves a
subnormal or inadequate amount of circulating endogenous insulin.
The two defects associated with NIDDM are tissue insensitivity to
insulin and impaired pancreatic B-cell response to glucose. Both of
these defects are further aggravated by increased hyperglycemia,
and therefore many therapeutic maneuvers seek to reduce this
condition.
[0006] The currently marketed oral agents for Type II diabetes fall
into several classes (i) sulphonylureas (ii) biguanides, or (iii)
thiazolidinedione (TZD) derivatives such as the recently approved
insulin sensitizer Rezulin.TM., an agonist of the PPAR-.gamma.
receptor. The sulfonyureas are an older class of drug which suffer
serious drawbacks such as profound hypoglycemia and cardiovascular
disease. At least three mechanisms of sulfonylurea action have been
proposed: (1) release of insulin from B-cells, (2) reduction of
serum glucagon levels, and (3) an extrapancreatic effect to
potentiate the action of insulin on its targets. Examples of
sulfonylureas are tolbutamide, tolazimide, acetohexamide,
chloropropamide and second generation hyperglycemic agents such as
glyburide, glipizide and glimepiride.
[0007] Biguanides, such as metformin, have also been around since
the mid-1950s and are generally considered as anti-hyperglycemic
agents with marginal effects on insulin responsiveness. Currently
proposed mechanisms of action for biguanides include (1) direct
stimulation of glycolysis in tissues, with increased glucose
removal from blood; (2) reduced hepatic gluconeogenesis; (3)
slowing of glucose absorption from the gastrointestinal tract; and
(4) reduction of plasma glucagon levels. While biguanides do not
cause hyperglycemia, there is a clear need for more effective drugs
that provide glycemic control and promote insulin
responsiveness.
[0008] TZD derivatives are a new class of oral antidiabetic drugs
in which the primary mechanism appears to be increased target
tissue sensitivity to insulin. Specifically, the TZD involves
binding to nuclear receptors (PPAR) that regulate the transcription
of a number of insulin responsive genes critical for the control of
glucose and lipid metabolism. This type of drug potentiates the
action of insulin to increase glucose uptake and glucose oxidation
in both muscle and adipose tissue, while reducing hepatic glucose
output as well as lipid synthesis in muscle and fat cells. TZDs
such as troglitazone (Rezulin.TM.), ciglitazone, englitazone,
rosiglitazone and pioglitazone are said to reduce hyperglycemia,
hyperinsulinemia and hypertriglyceridemia in animal models.
[0009] The recently marketed TZD, Rezulin.TM., while effective, has
a number of post-marketing safety problems including induction of
liver enzymes (e.g. P450 3A4) and hepatotoxicity with significantly
associated lethality. A newer TZD, rosiglitazone, suffers a poor
pharmacokinetic profile in humans, which could limit its
effectiveness in a larger population. Therefore, there is a clear
need for more effective novel structures of PPAR-.gamma. agonists
that provide glycemic control and promote insulin
responsiveness.
SUMMARY OF THE INVENTION
[0010] This invention provides novel compounds of Formula I that
interact with the nuclear receptor PPAR-.gamma..
[0011] The invention provides pharmaceutical compositions
comprising the compounds of Formula I. The invention also provides
compounds useful in the treatment of Type II diabetes, or NIDDM.
Accordingly, a broad embodiment of the invention is directed to
compounds of general Formula I: 3
[0012] wherein:
[0013] Z is a 5 or 6 membered aryl or heteroaryl ring optionally
substituted with up to three groups selected from lower alkyl,
halogen or lower alkoxy;
[0014] n and m independently represent 0, 1 or 2;
[0015] A is CO.sub.2R.sub.9; or
[0016] A is 4
[0017] D, F and G are the same or different and represent hydrogen,
NR.sub.1R.sub.12, OR.sub.1, CH.sub.2R.sub.1 or SR.sub.1;
[0018] R.sub.1 and R.sub.12 are the same or different and represent
hydrogen, lower alkyl, R.sub.10C.dbd.O, R.sub.10SO.sub.2, or
[0019] cycloalkyl optionally substituted with one, two, three or
four groups independently selected from halogen, trifluoromethyl,
trifluoromethoxy, cyano, nitro, carboxyl, alkoxycarboxy,
alkylcarboxy, hydroxy, lower alkyl, lower alkoxy, amino, or mono or
dialkylamino where each alkyl portion is lower alkyl, or
[0020] aryl, heteroaryl, arylalkyl, or heteroarylalkyl, where the
ring portion of each is optionally substituted with one, two, three
or four groups independently selected from halogen,
trifluoromethyl, trifluoromethoxy, cyano, nitro, carboxyl,
alkoxycarboxy, alkylcarboxy, hydroxy, lower alkyl, lower alkoxy,
amino, or mono or dialkylamino where each alkyl portion is lower
alkyl;
[0021] R.sub.10 is hydrogen or lower alkyl, or aryl, heteroaryl,
arylalkyl or heteroarylalkyl, where the ring portion of each is
optionally substituted with one, two or three groups independently
selected from halogen, trifluoromethyl, trifluoromethoxy, cyano,
nitro, carboxyl, alkoxycarboxy, alkylcarboxy, hydroxy, lower alkyl,
lower alkoxy, amino, or mono or dialkylamino where each alkyl
portion is lower alkyl;
[0022] R.sub.9 is H or lower alkyl;
[0023] X is N, O, CH.sub.2, S, SO or SO.sub.2;
[0024] R.sub.4 is O, hydrogen, hydroxy, lower alkyl, lower alkoxy,
cycloalkyl, R.sub.10C.dbd.O or R.sub.10SO.sub.2;
[0025] Y is hydrogen, NR.sub.1R.sub.12, OR.sub.1, CH.sub.2R.sub.1,
SR.sub.1, SOR.sub.1 or SO.sub.2R.sub.12; and
[0026] R.sub.5, R.sub.6 and R.sub.8, are the same or different and
represent hydrogen, lower alkyl, R.sub.10C.dbd.O, R.sub.10SO.sub.2,
or
[0027] cycloalkyl optionally substituted with one, two, three or
four groups independently selected from halogen, trifluoromethyl,
trifluoromethoxy, cyano, nitro, carboxyl, alkoxycarboxy,
alkylcarboxy, hydroxy, lower alkyl, lower alkoxy, amino, or mono or
dialkylamino where each alkyl portion is lower alkyl, or
[0028] aryl, heteroaryl, arylalkyl, or heteroarylalkyl, where the
ring portion of each is optionally substituted with one, two, three
or four groups independently selected from halogen,
trifluoromethyl, trifluoromethoxy, cyano, nitro, carboxyl,
alkoxycarboxy, alkylcarboxy, hydroxy, lower alkyl, lower alkoxy,
amino, or mono or dialkylamino where each alkyl portion is lower
alkyl; or
[0029] R.sub.5 and R.sub.6 together with the carbon atom to which
they are attached form a 5, 6, or 7 membered carbocyclic ring up to
two of which members are optionally hetero atoms selected from
oxygen, sulfur and nitrogen.
[0030] These compounds are highly selective agonists for the
PPAR-.gamma. receptor or prodrugs of agonists for the PPAR-.gamma.
receptor. These compounds are therefore useful in the treatment of
Type II diabetes.
DETAILED DESCRIPTION OF THE INVENTION
[0031] The novel compounds encompassed by the instant invention can
be described by the general Formula I set forth above or the
pharmaceutically acceptable non-toxic salts thereof.
[0032] In addition, the present invention also encompasses
compounds of Formula II 5
[0033] wherein n, m, A, D, X, Y, R.sub.4, R.sub.5, R.sub.6 and
R.sub.8 are as defined above for Formula I.
[0034] Preferred compounds of Formula II are where n is 1; m is 0;
A is CO.sub.2R.sub.9; D is NR.sub.1R.sub.12; R.sub.4 is O; X is N;
Y is --S-aryl, --O-aryl or --CH.sub.2-aryl; R.sub.9 is hydrogen or
lower alkyl; R.sub.8 is hydrogen or lower alkyl; R.sub.12 is
hydrogen; and R.sub.1 is a substituted or unsubstituted aryl or
arylalkyl. "" refers to a bond or nothing.
[0035] By "alkyl", "lower alkyl", and "C.sub.1-C.sub.6 alkyl" in
the present invention is meant straight or branched chain alkyl
groups having 1-6 carbon atoms, such as, methyl, ethyl, propyl,
isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl,
isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl.
These groups may be substituted with up to four groups mentioned
below for substituted aryl.
[0036] By "alkoxy", "lower alkoxy", and "C.sub.1-C.sub.6 alkoxy" in
the present invention is meant straight or branched chain alkoxy
groups having 1-6 carbon atoms, such as, for example, methoxy,
ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy,
pentoxy, 2-pentyl, isopentoxy, neopentoxy, hexoxy, 2-hexoxy,
3-hexoxy, and 3-methylpentoxy. These groups may be substituted with
up to four groups mentioned below for substituted aryl.
[0037] By the term "halogen" in the present invention is meant
fluorine, bromine, chlorine, and iodine.
[0038] A "carbocyclic group" or "cycloalkyl" is a nonaromatic
cyclic ring or fused rings having from 3 to 7 ring members.
Examples include cyclopropyl, cyclobutyl, and cycloheptyl. These
rings may be substituted with one or more of the substituent groups
mentioned below for aryl, for example alkyl, halo, amino, hydroxy,
and alkoxy. Typical substituted carbocyclic groups include
2-chlorocyclopropyl, 2,3-diethoxycyclopentyl, and
2,2,4,4-tetrafluorocyclohexyl. The carbocyclic group may contain
one or two heteroatoms selected from oxygen, sulfur, and nitrogen,
and such ring systems may be referred to as "heterocyclyl" or
"heterocyclic". Examples include pyranyl, tetrahydrofuranyl, and
dioxanyl. These heterocyclyl groups may be substituted with up to
four of the substituent groups mentioned for aryl to give groups
such as 3-chloro-2-dioxanyl, and 3,5-dihydroxymorpholino.
[0039] By heteroaryl is meant one or more aromatic ring systems of
5-, 6-, or 7-membered rings containing at least one and up to four
heteroatoms selected from nitrogen, oxygen, or sulfur. Such
heteroaryl groups include, for example, thienyl, furanyl,
thiazolyl, imidazolyl, (is)oxazolyl, pyridyl, pyrimidinyl,
(iso)quinolinyl, napthyridinyl, benzimidazolyl, benzoxazolyl. The
heteroaryl group is optionally substituted with up to four groups
mentioned below for substituted aryl.
[0040] By aryl is meant an aromatic carbocyclic group having a
single ring (e.g., phenyl), multiple rings (e.g., biphenyl), or
multiple condensed rings in which at least one is aromatic, (e.g.,
1,2,3,4-tetrahydronaphthy- l, naphthyl, anthryl, or phenanthryl),
which is optionally mono-, di-, or trisubstituted with, e.g.,
halogen, --OH, --SH, lower alkyl, lower alkoxy, lower alkylthio,
trifluoromethyl, trifluoromethoxy, lower acyloxy, aryl, heteroaryl,
amino, mono- or kialkylamino, and nitro, . A preferred aryl is
phenyl.
[0041] In certain situations, compounds of Formula I and Formula II
may contain one or more asymmetric carbon atoms, so that the
compounds can exist in different stereoisomeric forms. These
compounds can be, for example, racemates or optically active forms.
In these situations, the single enantiomers, i.e., optically active
forms, can be obtained by asymmetric synthesis or by resolution of
the racemates. Resolution of the racemates can be accomplished, for
example, by conventional methods such as crystallization in the
presence of a resolving agent, or chromatography, using, for
example a chiral HPLC colunn.
[0042] Representative compounds of the invention are shown below in
Table 1.
1TABLE 1 6 7 8 9 10 11 12 13
[0043] Representative compounds of the present invention, which are
encompassed by Formula I, include, but are not limited to the
compounds in Table I and their pharmaceutically acceptable salts.
In addition, if the compound of the invention is obtained as an
acid addition salt, the free base can be obtained by basifying a
solution of the acid salt. Conversely, if the product is a free
base, an addition salt, particularly a pharmaceutically acceptable
addition salt, may be produced by dissolving the free base in a
suitable organic solvent and treating the solution with an acid, in
accordance with conventional procedures for preparing acid addition
salts from base compounds.
[0044] Non-toxic pharmaceutically acceptable salts include salts of
acids such as hydrochloric, phosphoric, hydrobromic, sulfuric,
sulfinic, formic, toluenesulfonic, methanesulfonic, nitric,
benzoic, citric, tartaric, maleic, hydriodic, alkanoic such as
acetic, HOO--(CH.sub.2).sub.n--CO.sub.2H where n is 0-4, and the
like. Those skilled in the art will recognize a wide variety of
non-toxic pharmaceutically acceptable addition salts.
[0045] The present invention also encompasses the acylated prodrugs
of the compounds of Formula I. Those skilled in the art will
recognize various synthetic methodologies which may be employed to
prepare non-toxic pharmaceutically acceptable addition salts and
acylated prodrugs of the compounds encompassed by Formula I.
[0046] The compounds of Formula I and their salts are suitable for
the treatment of Type II diabetes, both in human and non-human
animals and domestic pets or companion animals, especially dogs and
cats and farm animals such as sheep, swine and cattle.
[0047] The compounds of general Formula I may be administered
orally, topically, parenterally, by inhalation or spray, or
rectally in unit dosage formulations containing conventional
non-toxic pharmaceutically acceptable carriers, adjuvants, and
vehicles. The term parenteral as used herein includes subcutaneous
injections, intravenous, intramuscular, intrastemal injection or
infusion techniques. In addition there is provided a pharmaceutical
formulation comprising a compound of general Formula I and a
pharmaceutically acceptable carrier. One or more compounds of
general Formula I may be present in association with one or more
non-toxic pharmaceutically acceptable carriers and/or diluents
and/or adjuvants and if desired other active ingredients. The
pharmaceutical compositions containing compounds of general Formula
I may be in a form suitable for oral use, for example, as tablets,
troches, lozenges, aqueous or oily suspensions, dispersible powders
or granules, emulsions, hard or soft capsules, or syrups or
elixirs.
[0048] Compositions intended for oral use may be prepared by any
method known to the art for the manufacture of pharmaceutical
compositions and such compositions may contain one or more agents
selected from the group consisting of sweetening agents, flavoring
agents, coloring agents, and preserving agents in order to provide
pharmaceutically elegant and palatable preparations. Tablets
contain the active ingredient in admixture with non-toxic
pharmaceutically acceptable excipients which are suitable for the
manufacture of tablets. These excipients may be, for example, inert
diluents, such as calcium carbonate, sodium carbonate, lactose,
calcium phosphate or sodium phosphate; granulating and
disintegrating agents, for example, cornstarch or align acid;
binding agents, for example starch, gelatin, or acacia; and
lubricating agents, for example, magnesium stearate, stearic acid,
or talc. The tablets may be uncoated or they may be coated by known
techniques to delay disintegration and absorption in the
gastrointestinal tract and thereby provide a sustained action over
a longer period. For example, a time delay material such as
glyceryl monostearate or glyceryl distaerate may be employed.
[0049] Formulations for oral use may also be presented as hard
gelatin capsules wherein the active ingredient is mixed with an
inert solid diluent, for example, calcium carbonate, calcium
phosphate, or kaolin, or as soft gelatin capsules wherein the
active ingredient is mixed with water or an oil medium, for example
peanut oil, liquid paraffin, or olive oil.
[0050] Aqueous suspensions contain the active materials with
excipients suitable for the manufacture of aqueous suspensions.
Such excipients are suspending agents, for example, sodium
cerboxymethylcellulose, methylcellulose,
hydropropylmethyl-cellulose, sodium alginate, polyvinylpyrrolidone,
gum tragacanth, and gum acacia; dispersing or wetting agents may be
a naturally occurring phosphatide, for example, lecithin, or
condensation products of an alkylene oxide with fatty acids, for
example polyoxyethylene stearate, or condensation products of
ethylene oxide with long chain aliphatic alcohols. for example
heptadecaethyleneoxycetanol, or condensation products of ethylene
oxide with partial esters derived from fatty acids and a hexitol
such as polyoxyethylene sorbitol monooleate, or condensation
products of ethylene oxide with partial esters derived from fatty
acids and hexitol anhydrides, for example polyethylene
sorbitanmonooleate. The aqueous suspensions may also contain one or
more preservatives, for example, ethyl or n-propyl
p-hydroxybenzoate, one or more coloring agents, one or more
flavoring agents, and one or more sweetening agents, such as
sucrose or saccharin.
[0051] Oily suspensions may be formulated by suspending the active
ingredient in a vegetable oil, for example arachis oil, olive oil,
sesame oil, or coconut oil, or in a mineral oil such as liquid
paraffin. The oily suspensions may contain a thickening agent, for
example beeswax, hard paraffin, or cetyl alcohol. Sweetening agents
such as those set forth above, and flavoring agents may be added to
provide palatable oral preparations. These compositions may be
preserved by the addition of an anti-oxidant such as ascorbic
acid.
[0052] Dispersible powders and granules suitable for preparation of
an aqueous suspension by the addition of water provide the active
ingredient in admixture with a dispersing or wetting agent,
suspending agent, and one or more preservatives. Suitable
dispersing or wetting agents and suspending agents are exemplified
by those already mentioned above. Additional excipients, for
example sweetening, flavoring, and coloring agents, may also be
present.
[0053] Pharmaceutical compositions of the invention may also be in
the form of oil-in-water emulsions. The oily phase may be a
vegetable oil, for example olive oil or arachis oil, or a mineral
oil, for example liquid paraffin, or mixtures of these. Suitable
emulsifying agents may be naturally occurring gums, for example gum
acacia or gum tragacanth, naturally occurring phosphatides, for
example soy bean, lecithin, and esters or partial esters derived
from fatty acids and hexitol, anhydrides, for example sorbitan
monoleate, and condensation products of the said partial esters
with ethylene oxide, for example polyoxyethylene sorbitan
momoleate. The emulsions may also contain sweetening and flavoring
agents.
[0054] Syrups and elixirs may be formulated with sweetening agents,
for example glycerol, propylene glycol, sorbitol, or sucrose. Such
formulations may also contain a demulcent, a preservative, and
flavoring and coloring agents. The pharmaceutical compositions may
be in the form of a sterile injectable aqueous or oleaginous
suspension. This suspension may be formulated according to the
known art using those suitable dispersing or wetting agents and
suspending agents which have been mentioned above. The sterile
injectable preparation may also be a sterile injectable solution or
suspension in a non-toxic parentally acceptable diluent or solvent,
for example as a solution in 1,3-butanediol. Among the acceptable
vehicles and solvents that may be employed are water, Ringer's
solution, and isotonic sodium chloride solution. In addition,
sterile, fixed oils are conventionally employed as a solvent or
suspending medium. For this purpose any bland fixed oil may be
employed including synthetic mono or digylcerides. In addition,
fatty acids such as oleic acid find use in the preparation of
injecatables.
[0055] The compounds of general Formula I may also be administered
in the form of suppositories for rectal administration of the drug.
These compositions can be prepared by mixing the drug with a
suitable non-irritating excipient which is solid at ordinary
temperatures but liquid at rectal temperature and will therefore
melt in the rectum to release the drug. Such materials are cocoa
butter and polyethylene glycols.
[0056] Compounds of general Formula I may be administered
parenterally in a sterile medium. The drug, depending on the
vehicle and concentration used, can either be suspended or
dissolved in the vehicle. Advantageously, adjuvants such as local
anesthetics, preservatives, and buffering agents can be dissolved
in the vehicle.
[0057] It will be understood that the specific dose level for any
particular patient will depend upon a variety of factors including
the activity of the specific compound employed, the patient's age,
body weight, general health, sex, and diet, and the time of
administration, route of administration, rate of excretion, drug
combination, and the severity of the particular disease undergoing
therapy.
[0058] For administration to non-human animals, the composition may
also be added to the animal feed or drinking water. It will be
convenient to formulate these animal feed and drinking water
compositions with a mullet-dose of the drug so that the animal
takes in an appropriate quantity of the composition along with its
diet. It will also be convenient to present the composition as a
premix for addition to the feed or drinking water.
[0059] An illustration of the preparation of compounds of the
present invention is given in Scheme I and Scheme II. In Scheme II,
the groups R.sub.5, R.sub.6, R.sub.8 and Y are as defined in
general Formula I; and
[0060] R.sub.3 is hydrogen, lower alkyl, or
[0061] aryl, heteroaryl, arylalkyl, or heteroarylalkyl, where the
ring portion of each is optionally substituted with one, two, three
or four groups independently selected from halogen,
trifluoromethyl, trifluoromethoxy, cyano, nitro, carboxyl,
alkoxycarboxy, alkylcarboxy, hydroxy, lower alkyl, lower alkoxy,
amino, or mono or dialkylamino where each alkyl portion is lower
alkyl, or
[0062] R.sub.3 together with the carbon atom to which it is
attached forms an optionally substituted cycloalkyl. 14 15
[0063] Those having skill in the art will recognize that the
starting materials may be varied and additional steps employed to
produce compounds encompassed by the present invention, as
demonstrated by the following examples.
[0064] The disclosures in this application of all articles and
references, including patents, are incorporated herein by
reference.
[0065] The invention is illustrated further by the following
examples which are not to be construed as limiting the invention in
scope or spirit to the specific procedures described in them.
[0066] The starting materials and various intermediates may be
obtained from commercial sources, prepared from commercially
available organic compounds, or prepared using well known synthetic
methods.
[0067] Representative examples of methods for preparing
intermediates of the invention are set forth below.
EXAMPLE1
1. Loading Scaffold on Wang Resin
[0068] 6.0 g of Wang Resin (0.89 mmol/g, 5.34 mmol) is washed with
DMA (N,N-dimethylacetamide) 3.times.40 ml, DCM (dichloromethane)
3.times.40 ml in the peptide vessel. The resin is then dried over a
vacuum pump for 2 hrs.
[0069] The treated resin is swelled in 70 ml of DCM. 5.83 g of
Fmoc-amino acid (12.38 mmol), 3.8 g of
1-(mesitylene-2-sulfonyl)-3-nitro-1,2,4-triaz- ole (MSNT) (12.8
mmol) and 32 ml of 1-methylimidazole (402 mmol) are added
subsequently. The resultant mixture is shaken on the orbital shaker
(200 rpm) for 3.5 hrs. The resin is drained and washed with DMA
(4.times.50 ml), tetrahydrofuran (THF) (4.times.50ml), DCM
(4.times.50 ml) and dried under vacuum pump overnight.
[0070] 2 ml of DCM and 2 ml of TFA are added to 237 mg of coupled
resin in peptide vessel. The mixture is shaken at room temperature
for 30 min. The resin is filtered off and washed with
DCM/trifluoroacetic acid (TFA)=1/1 (3.times.2 ml), DCM (3.times.5
ml). The filtrates are combined together. Removal of solvents gives
a white solid (70 mg). After the blank of resin is deducted
(.about.6mg), the loading efficiency of coupling reaction between
Fmoc protected amino acid made and Wang resin is 0.573 mmol/g.
2. Deprotection of Fmoc Group
[0071] Dimethylformamide (DMF) (60 ml) and piperidine (40 ml) are
added to Fmoc-(4-allyloxycarbonyl)-L-Tyr-Wang resin (6g, 3.44
mmol). The mixture is shaken (200 rpm) at room temperature for 40
min. The resin is then drained and washed with DMF (3.times.40 ml),
THF (3.times.40 ml), DCM (3.times.40 ml) and dried under high
vacuum pump overnight.
3. Reductive Amination
[0072] The above amine resin is swelled in 60 ml of TMOF, and
benzaldehyde (9.6 ml, 94.4 mmol) is added and the mixture is shaken
for 40 min. The resin is drained and washed with TMOF (2.times.40
ml) to remove excess aldehyde. The resin is re-swelled in 60 ml of
TMOF and sodium cyanoborohydride (5.6 g, 89.2 mmol) is added
followed by 1 ml of acetic acid. The mixture is shaken (200 rpm) at
room temperature overnight. The resin is then drained and washed
with MeOH (3.times.40 ml), DMF(3.times.40 ml), THF (3.times.40 ml),
DCM (3.times.40 ml) and dried under high vacuum pump overnight.
4. Allyl deprotection
[0073] The above resin is swelled in 60 ml of anhydrous THF and 2.1
ml of morpholine (24.2 mmol, 7 eq.) is added followed by 1.2 g of
Pd(PPh.sub.3).sub.4 (30% mol). The mixture is shaken (200 rpm) at
room temperature overnight. The resin is then drained and washed
with HOAc (3.times.40 ml), DMF (3.times.40 ml), THF (3.times.40
ml), DCM (3.times.40 ml) and dried under a high vacuum pump
5. Coupling with 3-phlenyl-1-propylamine
[0074] The above resin is swelled in 70 ml of DMA. HOBt (3.48 g,
25.8 mmol, 7.5 eq.), HBTU (9.78 g, 25.8 mmol, 7.5 eq.), DIEA (8.37
ml, 14 eq.) and 3-phenyl-1-propylamine (4.9 ml, 10 eq.) are added.
The mixture is shaken (200 rpm) at room temperature for 2 days. The
resin is then drained and washed with DMF (4.times.40 ml), THF
(4.times.40 ml) and then DCM (4.times.40 ml) and dried under high
vacuum pump.
6. Cleavage from Resin
[0075] The above resin is swelled in 60 ml of DCM and 40 ml of TFA
is added. The mixture is shaken at room temperature for 30 min. The
resin is drained and the TFA/DCM solution is collected. The resin
is washed with DCM (2.times.30 ml) and all organic solutions are
combined. Removal of solvents gives crude product, which is
purified by column chromatography (SiO.sub.2, CHCl.sub.3/MeOH=10/1
to 4/1) to produce 811 mg of a white solid.
EXAMPLE 2
[0076] The following compounds are prepared essentially as
described in example 1:
[0077] (a)
(2S)-2-[benzylamino]-3-{4-[N-(3-phenylpropyl)carbamoyl]phenyl}p-
ropanoic acid (Compound 1);
[0078] (b)
(2S)-3-{4-[N-methyl-N(2-phenylthiocyclopentyl)carbamoyl]phenyl}-
-2-[benzylamino]propanoic acid (Compound 2);
[0079] (c) (2S)-2- {[(4-methoxyphenyl)methyl]
amino}-3-{4-[N-(3-phenylprop- yl)carbamoyl]phenyl}propanoic acid
(Compound 3);
[0080] (d)
(2S)-3-{4-[N-methyl-N-(2-phenylthiocyclopentyl)carbamoyl]phenyl-
}-2-({[4-(trifluoromethoxy)phenyl]methyl}amino)propanoic acid
(Compound 4);
[0081] (e)
(2S)-2-{[(4-fluorophenyl)methyl]amino}-3-{4-[N-methyl-N-(2-phen-
ylthiocyclopentyl)carbamoyl]phenyl}propanoic acid (Compound 5);
[0082] (f)
(2S)-3-{4-[N-methyl-N-(2-phenoxycyclopentyl)carbamoyl]phenyl}-2-
-[benzylamino]propanoic acid (Compound 6);
[0083] (g)
(2S)-3-{4-[N-methyl-N-(2-phenylthiocyclohexyl)carbamoyl]phenyl}-
-2-({[4-(trifluoromethoxy)phenyl]methyl}amino)propanoic acid
(Compound 7); and
[0084] (h)
(2S)-2-{[(4-fluorophenyl)methyl]amino}-3-{4-[N-methyl-N-(2-phen-
ylthiocyclohexyl)carbamoyl]phenyl}propanoic acid (Compound 8).
EXAMPLE 3
Human Adipocyte Differentiation
[0085] Assays are carried out on primary human subcutaneous
preadipocytes. Preadipocytes are inoculated at high density in
preadipocyte medium (DME/F-10, 1:1, (v/v) containing 10% fetal calf
serum) and maintained overnight for attachment. Drug treatment is
initiated the second day by changing to serum free medium
containing test compounds. The basal medium, which is used as the
negative control, contains DME/F-10, biotin (33 .mu.M),
pantothenate (17 .mu.M), insulin (100 nM), and dexamethasone (1
.mu.M) and BRL 49653 is included as a positive control. The culture
is maintained for 14 days with the compound treatment during the
first five days. At the end of the culture, cells are fixed in 5%
formalin and stained with oil red-O dye. The dye is extracted by
isopropanol and quantitated by measure the optical density at 500
nm. EC50 values found in Table 1 reflect the human adipocyte
differentiation of the compound in presence of insulin and
dexamethasone.
2TABLE 1 Human Adipocyte Differentiation EC50 Inhibition of
Compound EC50 Differentiation Differentiation 1 150 nm >10 .mu.m
2 175 nm >10 .mu.m Rosiglitizone 100 nm >10 .mu.m
EXAMPLE 4
Binding to PPAR-.gamma. Receptor
[0086] Compounds are assayed for their ability to inhibit the
binding of 3H-PPAR-.gamma. ligand to the LBD (ligand binding
domain) of the PPAR-.gamma. receptor. Compounds are tested at 4
concentrations (1 .mu.M to 1 nM) in triplicate. Compounds are
incubated with H3-PPAR ligand (8 nM final concentration) and LBD
(210 ng/assay well) in assay buffer (50mM Tris pH8.0. 50 mM KCL, 2
mM EDTA, 0.3% CHAPS, 0.1 mg/ml BSA, 10 mM DTT) for 2 hours with
gentle shaking. Non-specific binding is measured in the presence of
10 .mu.M excess cold competitor. Bound ligand is separated using
gel filtration plates (Edge Biosystems 31909) and captured on 96
well Wallac MicroBeta plates (1450-5150 by centrifugation for 5
minutes at 2500 rpm. Radioactivity is measured in a Wallac Micro
Beta counter. Table 2 gives the IC50 values of compounds 1 and
2.
3 TABLE 2 Compound IC.sub.50 (.mu.m) 1 1.7 2 3.3
Example 5
Blood Glucose Lowering in Diabetic Rats
[0087] Male Zucker lean rats, 24-28 weeks of age, are fed high fat
chow (AIN-93-M formulation) for two weeks to elevate blood glucose.
At blood glucose concentrations over 160 mg/dl, a three day
pre-study baseline is established by measuring blood glucose daily
(at 0700-0800 hrs) via tail vein blood extraction and measurement
using a glucometer. Animals are segregated into groups of 5 based
on weights and baseline glucose. Compounds are then administered to
the animals at various concentrations (30 mg compound/kg body
weight or 10 mg compound/kg body weight). The drugs were suspended
in 0.5% carboxymethylcellulose (Sigma) in a total gavage volume of
250 .mu.L. Animals are dosed for seven days, once daily in the
morning after blood glucose and weight determination. At the end of
the seven-day period, the animals are euthanized by exsanguination
after isofluorane anesthesia. Table 3 depicts the normalization of
blood glucose in the rats.
4TABLE 3 Normalization of Blood Glucose in Zucker Obese Rats Blood
Glucose (mg/dl .+-. SEM) Treatment Day Vehicle Cmpd. 1 Cmpd. 2 0
129 .+-. 7 133 .+-. 11 133 .+-. 11 1 134 .+-. 15 134 .+-. 11 136
.+-. 5 2 133 .+-. 7 105 .+-. 7 104 .+-. 1 3 129 .+-. 5 105 .+-. 4
100 .+-. 9 4 143 .+-. 3 97 .+-. 16 93 .+-. 6 5 120 .+-. 10 113 .+-.
3 100 .+-. 4 6 127 .+-. 5 105 .+-. 6 101 .+-. 5 7 132 .+-. 6 104
.+-. 8 92 .+-. 6
[0088] The invention and manner and process of making and using it,
are now described in such full, clear, concise and exact terms as
to enable any person skilled in the art to which it pertains, to
make and use the same. It is to be understood that the foregoing
describes preferred embodiments of the present invention and that
modifications may be made therein without departing from the spirit
or scope of the present invention as set forth in the claims. To
particularly point out and distinctly claim the subject matter
regarded as invention, the following claims conclude this
specification.
* * * * *