CN101272789A - Melanocortin receptor-specific piperazine compounds with diamine groups - Google Patents

Melanocortin receptor-specific piperazine compounds with diamine groups Download PDF

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CN101272789A
CN101272789A CNA2006800353810A CN200680035381A CN101272789A CN 101272789 A CN101272789 A CN 101272789A CN A2006800353810 A CNA2006800353810 A CN A2006800353810A CN 200680035381 A CN200680035381 A CN 200680035381A CN 101272789 A CN101272789 A CN 101272789A
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propyl
naphthalen
piperazin
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舒比·D·夏尔多
施亦群
凯文·伯里斯
吴志骏
帕皮雷蒂·普尔马
亚蒂·雷迪·博努加
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Abstract

Melanocortin receptor-specific compounds with diamine groups of the general formula (I) and pharmaceutically acceptable salts thereof, where W is a diamine heteroatom unit with at least one cationic center, hydrogen bond donor or hydrogen bond acceptor, J, Q, L1, L2, L3, R1a, R1b, R2a, R2b and X are as defined in the specification, and the carbon atom marked with an asterisk can have any stereochemical configuration. Compounds disclosed herein bind to one or more melanocortin receptors and may be an agonist, a partial agonist, an antagonist, an inverse agonist or an antagonist of an inverse agonist as to one or more melanocortin receptors, and may be employed for treatment of one or more melanocortin receptor-associated conditions or disorders, including specifically treatment of obesity and related conditions.

Description

Melanocortin receptor-specific piperazine and ketone-piperazine compounds
Background
Field of the invention (technical field):
the present invention relates to tetrasubstituted piperazine compounds that bind to one or more melanocortin receptors and are agonists, antagonists, mixed agonist-antagonists, inverse agonists or antagonists of inverse agonists for one or more melanocortin receptors, and their use for the treatment of metabolic, immune, infection-related and other melanocortin receptor-mediated diseases, including the treatment of obesity and related energy homeostasis diseases and conditions.
Background art:
a family of melanocortin receptor types and subtypes have been identified, including the melanocortin-1 receptor (MC1-R) expressed on normal human melanocytes and melanoma cells, the melanocortin-2 receptor for ACTH (adrenocorticotropic hormone) expressed in adrenal cells (MC2-R), the melanocortin-3 and melanocortin-4 receptors (MC3-R and MC4-R) expressed primarily in hypothalamic, midbrain and brain stem cells, and the melanocortin-5 receptor (MC5-R) expressed in widely distributed tissues.
In general, compounds specific for MC1-R are believed to be useful in the treatment of melanoma. Compounds specific for MC3-R or MC4-R are believed to be useful for modulating energy homeostasis, including as medicaments for reducing food intake and body weight gain, as weight gain adjuncts for the treatment of anorexia, for the treatment of obesity, and for other food intake and metabolism-related purposes. Compounds specific to MC3-R and MC4-R may also be used as agents for the treatment of sexual dysfunction, including male erectile dysfunction and female sexual dysfunction. Other melanocortin receptor-specific compounds, such as MCR-1 agonists, can be used as tanning agents (tanning agents) to increase melanin production in the skin, acting as chemoprotectants against the harmful effects of UV solar radiation. Compounds specific for MCR-1 and MCR-3 may also be used to modulate inflammatory processes.
There is a significant need for compounds with high specificity for individual melanocortin receptors, as well as compounds that are agonists or antagonists for specific melanocortin receptors. High affinity compounds to the melanocortin receptor may also be used as agonists or antagonists to study different physiological responses associated with the melanocortin receptor. In addition, melanocortin receptors have effects on the activities of various cytokines, and compounds having high affinity for melanocortin receptors can also be used to modulate cytokine activity.
There are known piperazine and piperidine compounds, such as those disclosed in WO 02/070511 (Bristol-Myers Squibb Company), WO 02/059095 (lei Lillyand Company), and WO 00/74679 (Merck & co., Inc.) claiming specificity for melanocortins or related receptors. However, in general, such compounds have up to two functional substituents, have relatively poor affinity and specificity, and are not suitable for use as pharmaceutical compounds. There is a significant need for compounds that have high specificity for individual receptors, such as melanocortin and other receptors, as well as for compounds that are agonists or antagonists of such receptors. High affinity compounds for these receptors as agonists or antagonists may be used to study different physiological responses associated with the receptors. Thus, there is a need for compounds that are more selective, including higher affinity and specificity, and in particular for compounds having at least three or four biologically active substituents. The present invention meets this need.
WO 02/085925, "melanocortin receptor Ligands," by Proctor & Gamble discloses ketopiperazine structures and methods of synthesizing the same, but does not disclose piperazine structures, piperazine structures having four or more substituents, methods of synthesizing piperazine structures having four or more substituents, or methods of synthesizing optically pure structures, and does not disclose structures having a single substituent that is a single D-Phe or D-Nal residue, or a derivative or homolog thereof, optionally having an amine-terminating (capping) group.
Commonly owned U.S. patent application serial No. 10/837,519, publication No. US2004/0224957a1, discloses piperazine compounds having specificity for one or more melanocortin receptors, but does not disclose piperazine or ketopiperazine compounds having four substituents, where one substituent comprises a heteroatom unit having at least one cationic center, hydrogen bond donor or hydrogen bond acceptor, and the remaining three substituents each comprise a ring structure.
With respect to certain objects, methods, synthetic schemes, entities, applications, definitions, schemes and other disclosures, the present application is directed to U.S. patent application Ser. No. 10/762,079, filed 21/2004 under the name "piperazine melanocortin-Specific compounds" and International application No. PCT/US02/25574, filed 12/2002 under the name "Peptidomimetics of bioactive Metal peptides" (International publication No. WO 03/013571), each of the foregoing specifications being incorporated herein by reference as if fully set forth herein.
There remains a significant need for compounds specific for MC4-R for use in the treatment of disorders associated with the regulation of energy homeostasis, including use as agents for reducing food intake and weight gain, for treating obesity, and for other food intake and metabolism-related purposes.
Summary of The Invention
In one aspect of the invention, there is provided a compound having structural formula I:
Figure A20068003538100191
or an enantiomer, stereoisomer or diastereoisomer thereof, or a pharmaceutically acceptable salt thereof.
Wherein
J is a ring structure selected from the group consisting of: substituted or unsubstituted aromatic carbocyclic ring, substituted or unsubstituted non-aromatic carbocyclic ring, substituted or unsubstituted aromatic fused carbo-heterocyclic group wherein the rings are joined by a bond, -CH2-or-O-linked two substituted or unsubstituted aromatic carbocyclic rings, and a substituted or unsubstituted aromatic fused heterobicyclic group, wherein in each case the rings comprise 5 or 6 ring atoms;
w is a heteroatom unit having at least one cationic center, hydrogen bond donor or hydrogen bond acceptor, wherein at least one heteroatom is nitrogen or oxygen;
q is an aromatic carbocyclic ring selected from the group consisting of: phenyl, substituted phenyl, naphthyl and substituted naphthyl;
L1is a bond or a linker unit comprising 1 to 8 backbone atoms selected from the group consisting of carbon, sulfur, oxygen or nitrogen;
L2is a bond or- (CH)2)z-；
L3Is a bond or linker unit comprising 1 to 9 moieties selected from the group consisting of carbon,a main chain atom of the group consisting of sulfur, oxygen or nitrogen;
to R1a，R1b，R2aAnd R2bThe selection is made such that:
R2aand R2bOne of them is
Figure A20068003538100201
And R is2aAnd R2bThe remainder being hydrogen and R1aAnd R1bEach is hydrogen, R1aAnd R1bTogether form ═ O, or R1aAnd R1bOne of them being C1-C6Aliphatic linear or branched and R1aAnd R2bThe remaining one is hydrogen and the other is,
or R2aAnd R2bEach of which is hydrogen, and is,
and R is1aAnd R1bOne of them is
Figure A20068003538100202
And R is1aAnd R1bThe remaining one is hydrogen;
x is CH2C ═ O or C ═ S:
z is a subscript value of 1 to 6; and
y is a subscript value of 0 to 5;
the carbon atom marked with an asterisk therein can have any stereochemical configuration. In the compounds of structure I, J may be
Which is unsubstituted or substituted by one or more ring substituents. If substituted, J may be substituted with one or more ring substituents independently selected from the group consisting of: hydroxy, halogen, sulfonamide, alkyl, -O-alkyl, aryl, and-O-aryl.
In the compounds of structure I, Q may be
Wherein R is3a，R3bAnd R3cAre optional ring substituents and, when one or more are present, are the same or different and are independently a hydroxyl, halogen, alkyl, -O-alkyl, aryl or-O-aryl group. In one aspect, R3a，R3bOr R3cAt least one of is-CH3or-O-CH3. In another aspect, R3a，R3bOr R3cAt least one of (A) is-Cl or-CF3。
In the compounds of structure I, -L3-Q and-L1-J may be the same, wherein Q and J are aromatic carbocyclic rings selected from the group consisting of phenyl, substituted phenyl, naphthyl and substituted naphthyl.
The group W in the compounds of structure I may include amines, amides, alcohols, carboxylic acids, ethers, esters, guanidines, or ureas, more than one of the foregoing, or a combination of the foregoing. Thus, W may have the following structure:
wherein R is4Is that
NH，
O，
CH2Provided that R is5Including the N or the O, and the N or the O,
C6H5provided that R is5Including the N or the O, and the N or the O,
N(CH2)zin which N (CH)2)zAnd R5Together form a ring,
N((CH2)y-CH3)，
NH-C(＝O)，
NH-C(＝O)-NH，
C(＝O)，
C(＝O)-NH，
c (═ O) -O, or
O-C(＝O)；
R5Is that
NH2，
OH，
CH3Provided that R is4Including the N or the O, and the N or the O,
NH-(CH2)zin which NH- (CH)2)zAnd R4Together form a ring,
NH-(CH2)y-CH3，
N(-(CH2)y-CH3)2，
NH-(CH2)z-NH2，
NH-(CH2)z-NH-(CH2)y-CH3，
NH-(CH2)z-N-((CH2)y-CH3)2，
N(-(CH2)y-CH3)-C(＝NH)-NH2，
N(-(CH2)y-CH3)-C(＝N((CH2)y-CH3))-NH2，
NH-C(＝NH)-NH2，
NH-C(＝N((CH2)y-CH3))-NH2，
N(-(CH2)y-CH3)-(CH2)z-NH(CH2)y-CH3，
N(-(CH2)y-CH3)-(CH2)z-N((CH2)y-CH3)2，
N(-(CH2)y-CH3)-C(＝N((CH2)y-CH3))-NH(CH2)y-CH3，
NH-C(＝N((CH2)y-CH3))-NH-(CH2)y-CH3，
N(-(CH2)y-CH3)-C(＝NH)-NH(CH2)y-CH3，
NH-C(＝N((CH2)y-CH3))-N((CH2)y-CH3)2，
N(-(CH2)y-CH3)-C(＝NH)-N((CH2)y-CH3)2，
NH-C(＝O)-(CH2)y-NH2，
O-(CH2)y-CH3，
SO2-NH2，
SO2-NH-(CH2)y-CH3，
SO2-N(-(CH2)y-CH3)2，
SO2-(CH2)y-CH3，
Figure A20068003538100231
wherein one or more of positions 1 to 5 is a heteroatom selected from N for position 1, S, O or NH for positions 2 to 5,
Figure A20068003538100232
wherein none, one or two of positions 1 to 5 are heteroatoms, said heteroatoms being for position 1, and for binding R if said position does not comprise C6The position of (A) is selected from N, otherwise from S, O or NH,
Figure A20068003538100233
wherein at least one bond between adjacent ring atoms is a double bond, one or more of positions 1 to 5 is a heteroatom selected from N for position 1 and any double bond position, further positions 2 to 5, said heteroatom selected from S, O or NH, with the proviso that no more than one position is S or O,
Figure A20068003538100241
wherein at least one bond between adjacent ring atoms is a double bond and one or more of positions 1 to 5 is optionally a heteroatom that binds R for position 1 if that position does not include C6And any double bond position is selected from N, further selected from S, O or NH for positions 2 to 5, provided that no more than one position is S or O,
Figure A20068003538100242
wherein at least one bond between adjacent ring atoms is a double bond, the oxo (oxo) is bound to a ring carbon, and the remaining one or more of positions 1 to 5 are optionally heteroatoms selected from N for position 1 and any double bond position, and additionally from S, O or NH for positions 2 to 5, with the proviso that no more than one position is S or O,
Figure A20068003538100243
wherein at least one bond between adjacent ring atoms is a double bond, oxo is bound to a ring carbon, one or more of positions 1 to 5 is optionally a heteroatom for position 1, R if said position does not include C6The position to which it is bound and any double bond position being selected from N, and further for positions 2 to 5 the heteroatom being selected from S, O or NH, with the proviso that no more than one position is S or O,
Figure A20068003538100244
wherein one or more of positions 1 to 6 is a heteroatom selected from N for position 1And is selected from S, O or NH for positions 2 to 6,
Figure A20068003538100245
wherein none, one or two of positions 1 to 6 are heteroatoms, said heteroatom being for position 1, and R is bound if said position does not comprise C6The position of (A) is selected from N, otherwise from S, O or NH,
wherein at least one bond between adjacent ring atoms is a double bond and one or more of positions 1 to 6 is a heteroatom selected from N for position 1 and any double bond position, further selected from S, O or NH for positions 2 to 6, provided that no more than two positions are S or O,
Figure A20068003538100252
wherein at least one bond between adjacent ring atoms is a double bond and one or more of positions 1 to 6 is optionally a heteroatom that binds R for position 1 if that position does not include C6And any double bond position is selected from N, and further for positions 2 to 6 the heteroatom is selected from S, O or NH, with the proviso that no more than two positions are S or O,
Figure A20068003538100253
wherein at least one bond between adjacent ring atoms is a double bond, the oxo group is bound to a ring carbon, and the remaining one or more of positions 1 to 6 are optionally a heteroatom selected from N for position 1 and N for any double bond position, further selected from S, O or NH for positions 2 to 6The member is S or O in not more than 2 positions, or
Figure A20068003538100254
Wherein at least one bond between adjacent ring atoms is a double bond, the oxo group is bound to a ring carbon, and one or more of positions 1 to 6 is optionally a heteroatom that binds R for position 1 if that position does not include C6And any double bond position is selected from N, further selected from S, O or NH for positions 2 to 6, provided that no more than two positions are S or O;
R8is hydroxy, (CH)2)y-CH3，(CH2)y-NH2，NH-(CH2)y-CH3Or N (- (CH)2)y-CH3)2；
t is a subscript value of 0 to 5;
z is a subscript value of 1 to 6; and
y is independently in each occurrence a subscript value of 0 to 5;
with the proviso that any NH or NH in the foregoing2May be substituted with N-Prg or NH-Prg, respectively, wherein each Prg is independently an amine protecting group. In the foregoing description, the ring structure comprises one circle in the ring, it being understood that the ring structure may comprise only one double bond, or may comprise more than one double bond, in particular the use of a circle does not imply that all possible double bonds are present. Each Prg may be independently acetyl, adamantyloxy, benzoyl, benzyl, benzyloxycarbonyl, tert-butoxycarbonyl, mesitylene-2-sulfonyl, 4-methoxy-2, 3-6-trimethyl-benzenesulfonyl, 2, 2,4, 6, 7-pentamethyldihydrobenzofuran-5-sulfonyl, 2, 2, 5, 7, 8-pentamethylbenzodihydropyran-6-sulfonyl, 9-fluorenylmethyloxycarbonyl, or tosyl.
In another aspect, the compound of structure I has the formula:
wherein:
R7is H or ═ O;
R8is hydrogen or N (R)9aR9b)；
R9aAnd R9bEach independently is hydrogen, acetyl, methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, isobutyl, benzyl, benzoyl, hexanoyl, propionyl, butyryl, pentanoyl, heptanoyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclobutylmethyl, cyclohexyl, cyclohexylmethyl, or polyethylene glycol;
v is independently in each case a subscript value of 0 to 2; and
y is independently in each occurrence a subscript value of 0 to 5;
wherein if R is8Instead of hydrogen, the adjacent carbon atom marked with an asterisk may have any stereochemical configuration. If R is9aOr R9bIs a polyethylene glycol having a molecular weight of between 100 and 50,000.
In one aspect of the compounds of structure I, R2aAnd R2bOne of them is
Figure A20068003538100271
R2aAnd R2bThe remaining one and R1aAnd R1bBoth are hydrogen.
The present invention also provides compounds having structural formula II:
Figure A20068003538100272
or an enantiomer, stereoisomer or diastereoisomer thereof, or a pharmaceutically acceptable salt thereof,
wherein,
each J is independently a ring structure selected from the group consisting of: a substituted or unsubstituted aromatic carbocyclic ring, a substituted or unsubstituted non-aromatic carbocyclic ring, a substituted or unsubstituted aromatic fused carbo-heterocyclic group wherein the rings are joined by a bond, -CH2Two substituted or unsubstituted aromatic carbocyclic rings, and substituted or unsubstituted aromatic fused heterobicyclic groups, which are linked by-O-, wherein the rings in each case comprise 5 or 6 ring atoms;
w is a heteroatom unit having at least one cationic center, hydrogen bond donor or hydrogen bond acceptor, wherein at least one heteroatom is nitrogen or oxygen;
L1is a bond or a linker unit comprising 1 to 8 backbone atoms selected from the group consisting of carbon, sulfur, oxygen or nitrogen;
L2is a bond or- (CH)2)z-；
L3Is a bond or a linker unit comprising 1 to 8 backbone atoms selected from the group consisting of carbon, sulfur, oxygen or nitrogen;
to R1a，R1b，R2aAnd R2bIs selected so that
R2aAnd R2bOne of them is
Figure A20068003538100281
And R is2aAnd R2bThe remainder being hydrogen and R1aAnd R1bEach is hydrogen, R1aAnd R1bTogether form ═ O, or R1aAnd R1bOne of them being C1-C6Aliphatic linear or branched and R1aAnd R2bThe remaining one is hydrogen and the other is,
or R2aAnd R2bEach of which is hydrogen, and is,
R1aand R1bOne of them is
Figure A20068003538100282
And R is1aAnd R1bThe remaining one is hydrogen;
x is CH2C ═ O or C ═ S;
z is a subscript value of 1 to 6; and
y is a subscript value of 0 to 5;
the carbon atom marked with an asterisk therein can have any stereochemical configuration. In the compounds of structure II, each J may independently be
Figure A20068003538100283
Figure A20068003538100291
Which is unsubstituted or substituted with one or more ring substituents independently selected from the group consisting of: hydroxy, halogen, sulfonamide, alkyl, -O-alkyl, aryl, and-O-aryl. In a particular aspect of the compound of structure II, -L3-J and-L1-J are identical.
The invention also provides pharmaceutical compositions comprising a compound of structure I or structure II and a pharmaceutically acceptable carrier. The pharmaceutical composition may be used to affect melanocortin receptor function in a human or non-human mammal. The pharmaceutical compositions may also be used to treat diseases that respond to altered melanocortin receptor function in a human or non-human mammal by administering a pharmaceutically effective amount of the pharmaceutical composition to the human or non-human mammal. The disease may be selected from the group consisting of: male sexual dysfunction, female sexual dysfunction, eating disorders, above-normal body weight (above-optimal body weight), obesity, below-optimal body weight (below-optimal body weight) and cachexia.
The present invention also provides compounds that are agonists of melanocortin receptors including one or more of MC1-R, MC3-R, MC4-R, or MC 5-R. The compounds are alternatively antagonists of melanocortin receptors including one or more of MC1-R, MC3-R, MC4-R, or MC 5-R. The compounds are alternatively inverse agonists of melanocortin receptors including one or more of MC1-R, MC3-R, MC4-R, or MC 5-R. The compounds are alternatively antagonists of inverse agonists of melanocortin receptors including one or more of MC1-R, MC3-R, MC4-R, or MC 5-R.
The invention also includes a method of altering a disease or condition associated with the activity of a melanocortin receptor comprising administering to a patient a pharmaceutically effective amount of a compound of the invention. In one embodiment, the disease or disorder is a dietary disease such as cachexia. In another embodiment, the disease or disorder is obesity and associated impairment of energy homeostasis. In another embodiment, the disease or condition is sexual dysfunction such as erectile dysfunction or female sexual dysfunction.
It is an object of the present invention to provide conformationally constrained and optically pure isomers of tetra-substituted piperazines wherein the pendant group substituents are amino acid moieties, amino acid side chain moieties or derivatives thereof such that the resulting cyclic compounds biologically mimic the relevant inverted peptide structure.
It is another object of the present invention to provide a method for synthesizing an optically pure tetra-substituted piperazine compound.
It is another object of the present invention to provide piperazine compounds having four pendant groups consisting of any moiety other than H, O, S, or halogen.
It is another object of the present invention to provide piperazine core compounds wherein a pendant group is provided which is or includes an amino acid side chain moiety.
It is another object of the present invention to provide tetrasubstituted piperazine compounds, wherein the compounds are specific for one or more melanocortin receptors.
It is another object of the present invention to provide a method for synthesizing the tetra-substituted piperazine compounds of the present invention.
Additional objects, advantages and novel features of the invention, as well as additional scope of applicability thereof, will be set forth in part in the detailed description which follows and in part will become apparent to those skilled in the art upon examination of the following or may be learned from practice of the invention.
Detailed Description
Disclosed herein are piperazine and ketopiperazine rings that can employ four qualifiers, wherein each qualifier is a separate pendant group covalently attached to a given ring atom, and wherein at least three qualifiers comprise a ring structure. The rings in the ring structure of each delimiter or side group may be heterocyclic or carbocyclic, and at least two such rings are aromatic. By applying four qualifiers, the inventors further found that the chirality and steric structure of the ring is generally fixed in the desired structure, thereby more closely mimicking the desired pharmacophore, and that the qualifiers are located within the most relevant chemical space.
The present application includes ketopiperazines as well as piperazine compounds. Thus, the following compounds are included in the present invention as examples:
Figure A20068003538100311
wherein L is1，L2，L3J, W, Q and y are as defined in the summary of the invention.
The invention also includes compounds that are penta-substituted piperazine or ketopiperazine compounds where the fifth substituent is C1-C6Aliphatic straight or branched chains. The following are representative examples of this class, it being understood that the methyl group shown may be any C1-C6Aliphatic linear or branched chains:
Figure A20068003538100321
wherein L here1，L2，L3J, W, Q and y are also as defined in the summary of the invention.
The present invention thus discloses the use of tetra-and penta-substituted piperazine and keto-piperazine templates for drug design, wherein four substituents are provided, at least three of which comprise a ring structure. The present invention further relates to enantiomerically pure compounds, preferably prepared by the synthetic routes disclosed herein and modifications thereof. One class of piperazine rings are conformationally dynamic 6-membered ring structures. A variety of conformational states may exist, often referred to as chair, boat, twist chair or twist boat conformations. Due to this dynamic of structural states, the positioning of the delimiters on the loops plays an important role in stabilizing the loops in a single conformational state, which, if chosen appropriately, facilitates the preparation of molecules that are more selective for their receptors. For example, the 1, 3 axial placement of two bulky qualifiers generally results in unfavorable steric interactions between the two groups and thus makes the chair conformation energetically less stable. Therefore, a chair conformation is not preferred, resulting in a twisted chair or boat conformation. The twisted chair or boat conformation results in a specific stereochemical arrangement of the qualifiers, which is specifically related to the interaction of the desired receptor. Therefore, the conformation resulting from the 1, 3 axial placement of the two qualifiers can yield a structure that is more selective for the receptor subtype.
In another embodiment, the invention features piperazine and ketopiperazine compounds specific for G-protein coupled receptor systems including, but not limited to, melanotropin or melanocortin receptors (MC1-R, MC3-R, MC4-R and MC 5-R).
In another embodiment, the present invention provides novel routes and methods for synthesizing piperazine and ketopiperazine compounds.
Before further describing the present invention, certain terms are defined herein.
"amino acids" and "amino acids" are used herein and are used in the specification and claims, including known naturally occurring protein amino acids, which are referred to by both their common three-letter abbreviations and their single letter abbreviations. See generallySynthetic Peptides: a User's Guide (synthetic peptide: user guide)GA Grant, edit, w.h.freeman&Co., new york, 1992, the teachings of which are incorporated herein by reference, including the contents and tables given on pages 11-24. As noted above, the term "amino acid" also includes stereoisomers and modified forms of naturally occurring protein amino acids, non-protein amino acids, post-translationally modified amino acids, enzymatically synthesized amino acids, derivatized amino acids, constructs or structures designed to mimic amino acids, and the like. Modified and unusual amino acids are generally disclosed in the aboveSynthetic Peptides: a User's Guide (synthetic peptide: User Guide)Hruby VJ, Al-obeidi F and Kazmierski W: biochem J (journal of biochemistry) 268: 249-262, 1990; and Toniolo C: int J Peptide Protein Res (journal of international Peptide Protein research) 35: 287-300, 1990, respectively; and the teachings of these are incorporated herein by reference.
The term "amino acid side chain moiety" as used herein includes any side chain of any amino acid, as the term "amino acid" is defined herein, including any derivative of an amino acid side chain moiety, as the term "derivative" is defined herein. Thus, the present application includes side chain moieties found in naturally occurring amino acids. Also included are side chain moieties of modified naturally occurring amino acids, such as glycosylated amino acids. It also includes side chain moieties in stereoisomers and modified forms of naturally occurring protein amino acids, non-protein amino acids, post-translationally modified amino acids, enzymatically synthesized amino acids, derivatized amino acids, constructs or structures designed to mimic amino acids, and the like. For example, the side chain portion of any amino acid disclosed herein is included in the definition of amino acid side chain portion.
"derivatives" of an amino acid side chain moiety include any modification or variation of any amino acid side chain moiety, including modifications of naturally occurring amino acid side chain moieties. For example, derivatives of amino acid side chain moieties include linear or branched, cyclic or acyclic, substituted or unsubstituted, and saturated or unsaturated alkyl, aryl, or aralkyl moieties.
Conventional amino acid residue abbreviations haveManual of Patent external Procedure Examination method manualChapter 2400, 8 th edition. Therefore, "Nle" means norleucine, "Asp" means aspartic acid, "His" means histidine, "D-Phe" means D-phenylalanine, "Arg" means arginine, "Trp" means tryptophan, "Lys" means lysine, "Gly" means glycine, "Pro" means proline, "Tyr" means tyrosine, "Ser" means serine, and the like.
In the specification and claims, the term "homologue" includes, but is not limited to, (a) a D-amino acid residue or side chain that replaces the side chain of an L-amino acid residue, (b) a post-translationally modified residue or side chain that replaces that residue or side chain, (c) a non-peptide or other modified amino acid residue or side chain based on another such residue or side chain, such as phenylglycine, homophenylalanine, ring-substituted halogenated and alkylated or arylated phenylalanine, diaminopropionic acid, diaminobutyric acid, ornithine, homoarginine of lysine and arginine residues, and the like for phenylalanine residues, and (D) any amino acid residue or side chain, which is encoded or otherwise, or a construct or structure that mimics an amino acid residue or side chain, which has at least a similarly charged side chain (neutral, positive or negative), preferably has a similar hydrophobicity or hydrophilicity, and preferably have side chains that are similar in saturated aliphatic side chains, functionalized aliphatic side chains, aromatic side chains, or heteroaromatic side chains.
The term "olefin" includes unsaturated hydrocarbons containing one or more carbon-carbon double bonds. Examples of such olefinic groups include ethylene, propylene, and the like.
The term "alkenyl group" includes a straight-chain monovalent hydrocarbon group of 2 to 6 carbon atoms or a branched-chain monovalent hydrocarbon group of 3 to 6 carbon atoms containing at least one double bond, and examples thereof include a vinyl group, a 2-propenyl group and the like.
As used herein, "alkyl" includes those alkyl groups in either a straight or branched configuration. Examples of the alkyl group include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl, and the like.
The term "alkynyl" includes a straight-chain monovalent hydrocarbon group of 2 to 6 carbon atoms or a branched-chain monovalent hydrocarbon group of 3 to 6 carbon atoms containing at least one triple bond, and examples thereof include ethynyl, propynyl, butynyl, and the like.
The term "aryl" includes monocyclic or bicyclic aromatic hydrocarbon groups of 6 to 12 ring atoms, and is optionally independently substituted with one or more substituents selected from: alkyl, haloalkyl, cycloalkyl, alkoxy, alkylthio, halogen, nitro, acyl, cyano, amino, mono-substituted amino, di-substituted amino, hydroxy, carboxy, or alkoxycarbonyl. Examples of aryl groups include phenyl, biphenyl, naphthyl, 1-naphthyl, and 2-naphthyl, derivatives thereof, and the like.
The term "aralkyl" includes the group-RaRbWherein R isaIs alkylene (divalent alkyl) and RbIs an aryl group as defined above. Examples of aralkyl groups include benzyl, phenylethyl, 3- (3-chlorophenyl) -2-methylpentyl, and the like.
The term "aliphatic" includes compounds having a hydrocarbon chain, such as, for example, alkanes, alkenes, alkynes, and derivatives thereof.
The term "acyl" includes the group RCO-, where R is an organic group. An example is acetyl CH3CO-。
A group or aliphatic moiety is "acylated" when an alkyl or substituted alkyl group as defined above is bonded via one or more carbonyl groups [ - (C ═ O) - ].
"ω amino derivatives" include aliphatic moieties having a terminal amino group. Examples of omega amino derivatives include aminoheptanoyl and the amino acid side chain moieties of ornithine and lysine.
The term "heteroaryl" includes mono-and bicyclic aromatic rings containing 1-4 heteroatoms selected from nitrogen, oxygen and sulfur. The 5-or 6-membered heteroaryl group is a monocyclic heteroaromatic ring, and examples thereof include thiazole, oxazole, thiophene, furan, pyrrole, imidazole, isoxazole, pyrazole, triazole, thiadiazole, tetrazole, oxadiazole, pyridine, pyridazine, pyrimidine, pyrazine and the like. Bicyclic heteroaromatic rings include, but are not limited to, benzothiadiazole, indole, benzothiophene, benzofuran, benzimidazole, benzisoxazole, benzothiazole, quinoline, benzotriazole, benzoxazole, isoquinoline, purine, furopyridine, and thienopyridine.
"amide" includes compounds having a trivalent nitrogen (-CO. NH) attached to a carbonyl group2) For example, formamide, acetamide, propionamide, and the like.
"imine" includes compounds containing an imino group (-CO.NH.CO-).
"amine" includes compounds containing ammoniaRadical (-NH)2) The compound of (1).
"nitrile" includes compounds that are derivatives of carboxylic acids and contain a (-CN) group attached to an organic group.
Amino acid side chain moieties are "hydrogen bonded" when the side chain includes a hydrogen bond donor and/or a hydrogen bond acceptor.
"amine end capping group" includes any end group attached via a terminal amine, including but not limited to any omega amino derivative, acyl group, or terminal aryl or aralkyl group, including groups such as C1-C6Straight or branched chains such as methyl, dimethyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl or hexyl, groups such as allyl, cyclopropanemethyl, hexanoyl, heptanoyl, acetyl, propionyl, butyryl, phenylacetyl, cyclohexylacetyl, naphthylacetyl, cinnamoyl, phenyl, benzyl, benzoyl, 12-Ado, 7' -aminoheptanoyl, 6-Ahx, Amc or 8-Aoc, or molecules such as polyethylene glycol having a molecular weight of from 100 to 50,000.
In pharmaceutical compositions, the term "composition" is intended to encompass a product comprising the active ingredient and the inert components which make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the components, or from dissociation of one or more of the components, or from other types of reactions or interactions of one or more of the components. Thus, the pharmaceutical compositions of the present invention include any composition made by mixing a compound of the present invention with one or more pharmaceutically acceptable carriers, and/or other excipients, and optionally one or more other pharmaceutically active ingredients and agents.
Various chemicals and compounds are used in the present invention, and the following abbreviations have the meanings given:
boc tert-butoxycarbonyl
Cbz benzyloxycarbonyl
DCM dichloromethane
DIAD azodicarboxylic acid diisopropyl ester
DMF N, N-dimethylformamide
DMSO dimethyl sulfoxide
EDC N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride
EtOAc ethyl acetate
Fmoc 9-fluorenylmethoxycarbonyl
HEPES 4- (2-hydroxyethyl) 1-piperazineethanesulfonic acid
HOAt 1-hydroxy-7-azabenzotriazole
IBCF isobutyl chloroformate
LAH lithium aluminum hydride
NMM N-methylmorpholine
Pd/C palladium on carbon
TBTU 2- (1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium (uronium) tetrafluoro-chloride
Borate salt
TEA Triethylamine
TFA trifluoroacetic acid
THF tetrahydrofuran
TPP triphenylphosphine
As used herein, a "tetra-substituted piperazine" is a piperazine compound or derivative thereof in which groups other than H, and preferably including amino acid residues or amino acid side chain moieties, are attached to each ring N member, and further in which groups other than H, O, S or halogen, preferably including amino acid side chain moieties, are attached to both ring C members.
"sexual dysfunction" refers to any condition that inhibits or impairs normal sexual function, including sexual intercourse. The term is not limited to physiological conditions and includes pathological conditions or sensory impairments without formal pathology or disease diagnosis. Sexual dysfunction includes erectile dysfunction in male mammals and female sexual dysfunction in female mammals.
An "erectile dysfunction" is a disorder in which a male mammal is unable to achieve a functional erection, ejaculation, or both. Erectile dysfunction is a synonym for impotence and may include sufficient rigidity to fail or sustain an erection to intercourse. Symptoms of erectile dysfunction include failure to achieve or maintain an erection, failure to ejaculate, premature ejaculation, or failure to achieve orgasm, which may occur alone or in combination. The increase in erectile dysfunction is often age-related and may be caused by physiological diseases or side effects of drug therapy.
"female sexual dysfunction" is a disease that includes sexual arousal disorder. The term "sexual arousal disorder" includes persistent or recurrent lubrication-swelling reactions that fail to achieve or maintain sexual arousal until sexual activity is complete. Sexual dysfunction in females may also include inhibited orgasm and dyspareunia, which refers to pain or difficulty in intercourse. Female sexual dysfunction includes, but is not limited to, various types of diseases, conditions and disorders, including hypoactive sexual desire disorder, anorgasmia, sexual arousal disorder, dyspareunia, and vaginismus. Hypoactive sexual disorders include those in which sexual thoughts and desire to continue or repeatedly diminish or lack sexual activity, causing severe distress or personal difficulties. Hypoactive sexual dysfunction may be associated with distress or inadequacy in long-standing relationships, depression, stress, dependence on alcohol or neuroactive drugs, side effects of prescribed drugs, or hormonal deficiencies. Lack of sexual pleasure includes diminished or diminished pleasure in sexual activity. Anhedonia can be caused by depression, drugs or interpersonal factors. Sexual arousal disorder may be caused by estrogen deprivation, disease or treatment with diuretics, antihistamines, antidepressants, or antihypertensives. Dyspareunia and vaginismus are painful sexual disorders characterized by pain resulting from penetration and may be caused by, for example, medications to reduce lubrication, endometriosis, pelvic inflammatory disease, inflammatory bowel disease or urinary tract problems.
By a melanocortin receptor "agonist" is meant an endogenous or pharmaceutical substance or compound, including a compound of the invention, that can interact with and elicit the pharmacological response characteristic of a melanocortin receptor. By "antagonist" of a melanocortin receptor is meant a drug or compound, including compounds of the present invention, which antagonizes the melanocortin receptor-associated response normally induced by a melanocortin receptor agonist.
By "binding affinity" is meant the ability of a compound or drug to bind to its biological target.
The chemical nomenclature and the block diagrams used herein use and rely on, for example, the chemical nomenclature characteristics used by ChemDraw program (available from cambridge software Corp.) or ISIS Draw (MDL information system, Inc.). In particular, the compound name is derived from the structure using the auto-naming (autonom) program as used by ChemDraw Ultra or ISIS Draw.
The compounds disclosed herein may be used for medical use and in animal feeding or veterinary applications. Typically, the product is for use on humans, but may be used on other mammals as well. The term "patient" is intended to mean a mammalian individual, and is used as such throughout the specification and claims. The main application of the invention relates to human patients, but the invention may be used in laboratories, farms, zoos, wildlife, pets, sports or other animals.
The melanocortin receptor-specific compounds of the present invention, which are specific for MC1-R, are useful as chemoprotectants against the tumorigenic activity of human skin caused by sunlight, such as UV radiation. The MC1-R agonist compounds of the invention may be used to stimulate epidermal melanocytes to produce melanin and convert phenomelanoidins (pheomelanin) to eumelanoidins. Eumelanin is a dark brown or black pigmentation that is considered more photoprotective than pheomelanin, which is a yellow or red pigmentation. Melanogenesis is thought to be involved in stimulating MC1-R in epidermal melanocytes, thereby mediating the stimulatory effects of tyrosinase within these pigment cells, inducing the conversion of tyrosine to dopa, and subsequently to eumelanin by dopaquinone. Tanning caused by direct exposure to the sun is believed to be caused by the same pathway, by local production of melanotropic peptides from the intraepidermal POMC gene. Stimulating melanogenesis and converting phenolic melanoidins to melanoidins may therefore be a form of chemoprotection required to block solar or UV-induced neoplastic activity in the skin. Therefore, the potent, high affinity and high selectivity MC1-R agonist compounds of the invention can be used as therapeutic chemoprotectants against harmful sunlight or UV exposure that causes tumor activity in skin melanocytes.
In another embodiment, compounds of the invention, including but not limited to compounds that are MC4-R agonists, partial agonists or functional inactivations, may be used as therapeutic agents to alter energy metabolism and eating behavior, including the treatment of morbid obesity and related disorders. In addition to being useful in treating patients clinically diagnosed with obesity, the compounds of the present invention may be useful as weight loss aids for persons with excessive body weight. The compounds of the present invention, including but not limited to MC4-R antagonists, may be useful as therapeutic agents for eating disorders, such as anorexia and cachexia, due to malnutrition and wasting as a result of the disease. In addition to being useful for treating patients diagnosed with anorexia and cachexia, the compounds of the present invention may be useful in people with substandard body weight, particularly patients in need of additional muscle gain.
In another embodiment, the compounds of the present invention may be used as therapeutic agents for the treatment of sexual dysfunction, including the treatment of male erectile dysfunction and female sexual dysfunction.
In another embodiment, the compounds of the invention may be used as therapeutic agents for the treatment of inflammation, including in particular MC1-R, MC3-R and MC5-R agonists.
In another embodiment of the invention, compounds of the invention specific for MC5-R may be used as agents that reduce sebum production, and thus may be effective in the treatment of acne and related diseases. The compounds for such use may conveniently be formulated for topical administration, for example by means of a gel, lotion, cream or other topical formulation.
In another embodiment, the compounds of the invention may be used for the treatment of drug or alcohol dependence, depression, anxiety and related conditions and indications.
The compounds may be formulated by any method as is known in the art, including but not limited to tablets, capsules, caplets, suspensions, powders, lyophilizates, and aerosol/aerosolizable formulations, and may be mixed and formulated with buffers, binders, stabilizers, antioxidants, and other agents known in the art. The compounds may be administered by any systemic or partial systemic means as known to those skilled in the art, including, but not limited to, intravenous injection, subcutaneous injection, transmucosal administration, oral administration, transdermal administration, dermal patch, aerosol, and the like.
The invention further provides a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable carrier. The compounds of the present invention may thus be formulated or synthesized as a pharmaceutical composition containing at least one compound of the present invention in combination with one or more pharmaceutically acceptable carriers comprising excipients such as diluents, carriers and the like, and additives such as stabilizers, preservatives, solubilizers, buffers and the like, as desired. Formulation excipients may include polyvinylpyrrolidone, gelatin, hydroxycellulose, acacia, polyethylene glycol, mannitol, sodium chloride or sodium citrate. For injectable or other liquid administration formulations, water containing at least one or more buffering components is suitable, and stabilizers, preservatives and solubilizers may also be employed. For solid dosage formulations, various thickening, bulking and carrier additives may be used, such as any of the starches, sugars, fatty acids, and the like. For topical formulations, any of a variety of creams, ointments, gels, lotions and the like may be employed. For most pharmaceutical formulations, the inactive ingredients should constitute a large proportion of the formulation by weight or volume. For pharmaceutical formulations, any of a variety of metered, sustained or timed release formulations are also contemplated and additives may be employed such that the dosage may be formulated to effectively deliver the compounds of the present invention over a period of time.
The compounds of the present invention may be in the form of any pharmaceutically acceptable salt. Acid addition salts of the compounds of the present invention are prepared in a suitable solvent from the compound and an excess of an acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, maleic acid, succinic acid or methanesulfonic acid. The acetate salt form is particularly suitable. When a compound of the invention contains an acidic moiety, suitable pharmaceutically acceptable salts may include alkali metal salts, such as sodium or potassium salts, or alkaline earth metal salts, such as calcium or magnesium salts.
The compounds and pharmaceutical compositions of the present invention may be administered by injection, which may be intravenous, subcutaneous, intramuscular, intraperitoneal or by any other means known in the art. In general, any route of administration that allows entry of the compounds of the invention through the epidermal layer of cells may be employed. Modes of administration may include transmucosal, buccal, oral, transdermal, inhalation, nasal, and the like. A therapeutic dose is an amount sufficient to produce the desired therapeutic effect administered by any of the above-described means or any other means.
One advantageous route of administration is nasal administration, such as by liquid spray, gel or powder. In one route of administration, the aqueous solution is applied, preferably by a dosing device. By "nasal administration" is meant any intranasal administration form of any of the compounds and pharmaceutical compositions of the present invention. Thus, in one embodiment, the compounds and pharmaceutical compositions of the present invention comprise aqueous solutions, such as solutions comprising saline, citrate or other common excipients or preservatives, formulated for intranasal administration. In another embodiment, the compounds and pharmaceutical compositions of the present invention comprise dry or powdered formulations, which are formulated for intranasal administration. Formulations for nasal administration may take a variety of forms, such as for administration in nasal drops, nasal sprays, gels, ointments, creams, powders or suspensions. A variety of dispensers and delivery vehicles are known in the art, including single dose ampoules, metered dose devices, nebulizers, pumps, nasal pads, nasal sponges, nasal capsules, and the like.
The pharmaceutical composition may be in solid, semi-solid or liquid form. For solid forms, the compound and other ingredients may be mixed together by blending, tumble mixing, lyophilization, solvent evaporation, co-grinding, spray drying, and/or other techniques known in the art. Semisolid pharmaceutical compositions suitable for intranasal administration may take the form of aqueous or oil-based gels or ointments. For example, the compound and other ingredients may be mixed together with microspheres of starch, gelatin, collagen, dextran, polylactide, polyglycolide, or other similar substances that form a hydrophilic gel. In one embodiment, the microspheres may be internally loaded or coated with a compound that forms a gel upon administration that adheres to the nasal mucosa. In another embodiment, the formulation is a liquid, which is understood to include, for example, aqueous solutions, aqueous suspensions, oil solutions, oil suspensions or emulsions depending on the physicochemical properties of the compound and the other ingredients.
For liquid formulations, excipients necessary or desired for formulation, stability and/or bioavailability may be included in the pharmaceutical composition. Exemplary excipients include sugars (such as glucose, sorbitol, mannitol, or sucrose), absorption enhancers (such as chitosan), thickening and stability enhancers (such as cellulose, polyvinylpyrrolidone, starch, and the like), buffers, preservatives, and/or acids and/or bases to adjust pH. In one embodiment, an absorption-promoting ingredient is included in the pharmaceutical composition. Exemplary absorption-promoting ingredients include surfactant acids such as cholic acid, glycocholic acid, taurocholic acid and other cholic acid derivatives, chitosan and cyclodextrins.
The pharmaceutical composition may also include optional ingredients such as humectants, preservatives and the like. Humectants or humectants can be used to reduce water loss in the pharmaceutical composition and optionally wet the nasal mucosa. Exemplary humectants include hygroscopic substances such as glycerin, propylene glycol, polyethylene glycol, polysaccharides, and the like. Preservatives may be used to prevent or limit the growth of bacteria and other microorganisms. One such preservative that may be used is benzalkonium chloride such as 0.05% benzalkonium chloride. Other preservatives include, for example, benzyl alcohol, methyl paraben, propyl paraben, butyl paraben, chlorobutanol, phenylethyl alcohol, phenylmercuric acetate, and the like.
The pharmaceutical composition may also include rheology modifiers, such as to modify the viscosity of the pharmaceutical composition. Exemplary rheology modifiers include polymers (polyers) and the like, such as sodium carboxymethylcellulose, alginic acid, carageenan, carbomer, galactomannan, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyethylene glycol, polyvinyl alcohol, polyvinyl pyrrolidone, sodium carboxymethyl chitin, sodium carboxymethyl dextran, sodium carboxymethyl starch, xanthan gum, and combinations of the foregoing. These agents may also be used as bioadhesives to extend the residence time of the compounds of the invention on the nasal mucosa.
Depending on the formulation and route of administration, aqueous solutions of the compounds or pharmaceutical compositions of the present invention may be suitably buffered with saline, acetate, phosphate, citrate, acetate or other buffering agents at any physiologically acceptable pH, typically from about pH 4 to about pH 8. Combinations of buffers may also be used, such as phosphate buffered saline, saline and acetate buffers, and the like. In the case of brine, a 0.9% brine solution may be used. In the case of acetate, phosphate, citrate, acetate, etc., a 50mM solution may be used.
In another route of administration, the compounds and pharmaceutical compositions of the present invention may be administered directly into the lungs. Intrapulmonary administration may be carried out by means of a metered dose inhaler, a device that allows self-administration of metered doses of the compounds and pharmaceutical compositions of the present invention by the patient when the patient inhales. Dry powder inhalation and nebulized aerosols can be used. Thus, compounds and pharmaceutical compositions of the present invention that can exist in dry and particulate form are possible and contemplated. In one embodiment, the particles are between about 0.5 and 6.0 μm, such that the particles have sufficient mass to be located on the surface of the lungs and not be exhaled, but are small enough that they do not remain on the surface of the respiratory tract until they reach the lungs. Any of a number of different techniques may be used to prepare the dry powder microparticles, including but not limited to, micro-milling, spray drying and flash-freeze aerosol followed by lyophilization. With regard to microparticles, the constructs may be deposited in the deep lung, thereby providing rapid and efficient adsorption into the bloodstream. Furthermore, with such methods, no penetration enhancer is required, as is sometimes necessary for transdermal, nasal or oral mucosal delivery routes. Any of a variety of inhalers can be used, including propellant-based aerosols, nebulizers, single dose dry powder inhalers, and multi-dose dry powder inhalers. Common devices in use today include metered dose inhalers for delivering drugs to treat asthma, chronic obstructive pulmonary disease, and the like. Preferred devices include dry powder inhalers designed to form a cloud or aerosol of fine powder having a total particle size of less than about 6.0 μm.
The size of the microparticles, including the average size distribution, can be controlled by the method of preparation. For micro-milling, the size of the milling head cutter, the speed of the rotor, the time of treatment, etc. control the size of the micro-particles. For spray drying, the microparticle size is controlled by nozzle size, flow rate, dryer heat, and the like. For preparation by rapid freezing of the aerosol followed by lyophilization, the microparticle size is controlled by nozzle size, flow rate, concentration of the aerosolized solution, and the like. These parameters and others can be used to control microparticle size.
The compounds and pharmaceutical compositions of the present invention may be formulated for administration by injection, such as deep intramuscular injection, e.g., of a time-release injectable formulation in the buttocks or deltoid muscle. In one embodiment, the compounds or pharmaceutical compositions of the invention are formulated with PEG, such as poly (ethylene glycol) 3350 and optionally one or more additional excipients and preservatives, including but not limited to excipients such as salts, polysorbate 80, sodium hydroxide or hydrochloric acid to adjust the pH, and the like. In another embodiment, the compounds or pharmaceutical compositions of the present invention are formulated with a poly (orthoester), which may be an autocatalytic poly (orthoester) having any varying percentage of lactic acid in the polymer backbone, and optionally one or more additional excipients. In one embodiment, a poly (D, L-lactide-co-glycolide) polymer (PLGA polymer), preferably a PLGA polymer with hydrophilic end groups, such as PLGA RG502H from briegger bergham (Boehringer inger Ingelheim, Inc.), is used. The formulations may be prepared, for example, by combining the compounds of the invention in a suitable solvent, such as methanol, with a solution of PLGA in dichloromethane in a reactor under suitable mixing conditions, and adding thereto a solution of the continuous phase of polyvinyl alcohol. Generally, any of a number of injectable and biodegradable polymers, preferably also adhesive polymers, may be used in the time-release injectable formulations. The teachings of U.S. Pat. Nos. 4,938,763, 6,432,438, and 6,673,767, and the biodegradable polymers and formulation methods disclosed therein, are incorporated herein by reference. The formulation may be such that injections need to be made on a weekly, monthly or other periodic basis, depending on the concentration and amount of the construct, the rate of biodegradation of the polymer, and other factors known to those skilled in the art.
In general, the actual amount of a compound of the invention administered to a patient will vary within a fairly wide range depending upon the mode of administration, the formulation used and the desired response. A therapeutic dose is an amount administered by any of the above means or any other means known in the art sufficient to produce the desired therapeutic effect. One of ordinary skill in the art can readily determine such means as pharmacokinetic studies, plasma half-life studies, dose-expansion studies, and the like. A pharmaceutically effective amount therefore includes an amount of a compound or pharmaceutical composition of the invention sufficient to elicit the desired therapeutic effect.
Typically, the compounds of the invention are highly active, with dose responses as low as 0.01 μ g/kg, typically with an optimal or peak dose response between about 0.01 μ g/kg and 25 μ g/kg, depending on the particular compound and route of administration. For example, the compound may be administered at 0.01, 0.05, 0.1, 0.5, 1, 5, 10, 50, 100 or 500 μ g/kg body weight, depending on the particular compound selected, the desired therapeutic response, the route of administration, the formulation and other factors known to those skilled in the art. Routine dose response studies and other pharmacological means can be used to determine the optimal dose for a given compound, a given formulation, and a given route of administration to achieve a desired effect.
Combination therapy and weight regulation it is also possible and contemplated to use the compounds of the present invention in combination with other drugs or agents for the treatment of various weight and diet related disorders. The compounds of the invention may be used in combination with any other agent or drug which has previously been used as a dietary aid, or which reduces food intake and/or body weight. The compounds of the invention may also be used in combination with any other agent or drug previously used to increase food intake and/or body weight.
The drug moiety that reduces energy intake includes a variety of agents, called anorexics, which are used as adjuncts to behavioral therapy in weight reduction regimens. Classes of anorexic drugs include, but are not limited to, noradrenergic and 5-hydroxytryptamine-capable drugs. Noradrenergic medications can be as described for medications that generally maintain the anorexia effect of amphetamines, but have less stimulatory activity. In addition to phenylpropanolamine, norepinephrine generally acts through centrally mediated pathways in the hypothalamus, which can cause anorexia. Phenylpropanolamine, a racemic mixture of norephedrine esters, causes the release of norepinephrine throughout the body and stimulates hypothalamic adrenoreceptors to reduce appetite.
Suitable noradrenergic agents include, but are not limited to, bupropion, such as TENUATETM(1-propanone, 2- (diethylamino) -1-phenyl-, hydrochloride), commercially available from Merrell; chlorfenamidoindole (or 5- (p-chlorophenyl) -2, 5-dihydro-3H-imidazo [2, 1-a)]Isoindol-5-ols), such as SANOREXTMCommercially available from Novartis or MAZANORTMCommercially available from hui pharmaceutical factory, usa (Wyeth ayersst); phenylpropanolamine (or benzyl alcohol, α - (1-aminoethyl) -, hydrochloride); phentermine (or phenol, 3- [ [4, 5-dihydro-1H-imidazol-2-yl)]Ethyl radical](4-methylphenyl) amino), monohydrochloride salts), e.g. ADIPEX-PTMCommercially available from Simon (Lemmon), FASTINGTMCommercially available from Smith-Kline Beecham and IonaminTMCommercially available from Medeva; benzotrozine (or (2S, 3S) -3, 4-dimethyl-2-phenylmorpholine L- (+) -tartrate (1: 1)), such as METRATMCommercially available from Forest (Forest), PLAGINETMCommercially available from the hui pharmaceutical factory, usa (wyeth ayersst); PRELU-2, commercially available from Boehringer Invighland (Boehringer Ingelheim), and STATOBEXTMCommercially available from limmon (Lemmon); tartaric acid of a phenamine, e.g. THEPHORINTM(2, 3, 4, 9-tetrahydro-2-methyl-9-phenyl-1H-indenol [2, 1-c)]Pyridine L- (+) -tartrate (1: 1)), commercially available from Hoffmann-LaRoche; methamphetamine, e.g. desoxyynTMTablets ((S) - -N (α) -dimethylphenylethylamine hydrochloride), commercially available from jabott (Abbott); and phendimetrazine tartrate, e.g. BONTRILTMSustained release capsules (-3, 4-dimethyl-2-phenylmorpholine tartrate), commercially available from Amarin.
Suitable 5-hydroxytryptamine agents include, but are not limited to sibutramine (sibutramine), such as MERIDIATMCapsules (racemic mixture of (+) and (-) enantiomers of cyclobutanemethylamine, 1- (4-chlorophenyl) -N, N-dimethyl- (. alpha.) - (2-methylpropyl) -, hydrochloride, monohydrate), commercially available from Kono (Knell), fenfluramine, e.g., PondiminTM(phenethylamine, N-ethyl- α -methyl-3- (trifluoromethyl) -, hydrochloride salt, commercially available from robins (Robbins); dexfenfluramine, e.g. ReduxTM(Phenylethanamine, N-ethyl-alpha-methyl)-3- (trifluoromethyl) -, hydrochloride, commercially available from Interneuron (Interneuron). Fenfluramine and dexfenfluramine stimulate the release of 5-hydroxytryptamine and inhibit its reuptake. Sibutramine inhibits reuptake of 5-hydroxytryptamine, norepinephrine, and dopamine, but does not stimulate secretion of 5-hydroxytryptamine.
Other 5-hydroxytryptamine-capable drugs used in the practice of the present invention include, but are not limited to, certain appetite (auoretic) gene 5HT1a inhibitors (brain, 5-hydroxytryptamine) such as carbidopa and benserazide, disclosed in U.S. patent No. 6,207,699, which is incorporated herein by reference; and certain neurokinin 1 receptor antagonists and selective 5-hydroxytryptamine reuptake inhibitors including fluoxetine, fluvoxamine, paroxetine, sertraline and other effective compounds disclosed in U.S. patent No. 6,162,805, which is incorporated herein by reference. Other potential agents that may be used include, for example, 5HT2c agonists.
Other useful compounds for reducing energy intake include, but are not limited to, certain aryl substituted cyclobutyl alkylamines disclosed in U.S. Pat. No. 6,127,424, which is incorporated herein by reference; certain trifluoromethylthiophenylethylamine derivatives disclosed in U.S. patent No. 4,148,923, which is incorporated herein by reference; certain compounds disclosed in U.S. patent No. 6,207,699, which is incorporated herein by reference; certain kainite or AMPA receptor antagonists disclosed in U.S. patent No. 6,191,117, which is incorporated herein by reference; certain neuropeptide receptor subtypes 5, disclosed in U.S. patent No. 6,140,354, which is incorporated herein by reference; and certain alpha-blockers disclosed in U.S. patent No. 4,239,763, which is incorporated herein by reference.
In addition, several peptides and hormones regulate feeding behavior. For example, cholecystokinin and 5-hydroxytryptamine play a role in reducing appetite and food intake. Leptin, a hormone produced by adipocytes, controls food intake and energy expenditure. In obese people who lose weight without drugs, the loss of weight is associated with a decrease in circulating levels of leptin, suggesting a role in weight homeostasis. Obese patients with high leptin levels are thought to have down-regulation of leptin receptors secondary to peripheral leptin resistance. Non-limiting examples of effective compounds that affect feeding behavior include certain leptin-lipolytic stimulation receptors disclosed in WO 01/21647, which is incorporated herein by reference; certain phosphodiesterase inhibitors disclosed in WO 01/35970, which is incorporated herein by reference; certain compounds having the nucleotide sequence of the mahogany (mahogany) gene disclosed in WO 00/05373, which is incorporated herein by reference; and certain sapogenin compounds disclosed in U.S. patent 4,680,289, which is incorporated herein by reference.
Other effective compounds include certain gamma Peroxisome Proliferator Activated Receptor (PPAR) agonists disclosed in WO 01/30343 and U.S. Pat. No. 6,033,656, which are incorporated herein by reference; and certain polypeptides, such as the fibroblast growth factor-10 polypeptide disclosed in WO 01/18210, which is incorporated herein by reference.
In addition, monoamine oxidase inhibitors that reduce energy intake or increase energy expenditure are suitable for the practice of the present invention. Suitable, non-limiting examples of monoamine oxidase inhibitors include befloxatone, moclobemide, bromofamine, phenothiazine, ethiprole, befol, toloxatone (toloxatone), pirlindole, amifostine, sercloemine, bazaloline, lazabemide, melacetamide, caroxazone and certain other compounds disclosed in WO 01/12176, which are incorporated herein by reference.
Certain compounds that increase lipid metabolism are also suitable for use in the practice of the present invention. Such compounds include, but are not limited to, the evodiamine compounds disclosed in U.S. patent No. 6,214,831, which is incorporated herein by reference.
Nutritional sequestering agents and digestion inhibitors are another strategy in the treatment of obesity by interfering with the breakdown, digestion, or absorption of dietary fat in the gastrointestinal tract. Gastric and pancreatic lipases assist in the digestion of food triglycerides by making them free fatty acids which are then absorbed into the small intestine. Inhibition of these enzymesCan inhibit the digestion of food triglyceride. Non-limiting examples include lipase inhibitors, orlistat, such as XENICAL, commercially available from Roche LaboratoriesTMCapsule ((S) -2-formylamino-4-methyl-pentanoic acid (S) -1- [ [ (2S, 3S) -3-hexyl-4-oxo-2-oxetanyl)]Methyl radical]-dodecyl esters) and certain benzoxazinones as described in WO 00/40247, which is incorporated herein by reference.
Agents that increase energy expenditure are also referred to as heat generating drugs. Non-limiting examples of suitable thermogenic drugs include xanthines, such as caffeine and theophylline, selective beta-3-adrenergic agonists, such as certain compounds disclosed in U.S. patent No. 4,626,549, which is incorporated herein by reference, and alpha-2-adrenergic and growth hormone compounds, such as those described in U.S. patent nos. 4,937,267 and 5,120,713, which are incorporated herein by reference.
In general, the total dosage of the above-mentioned obesity controlling agents or drugs, when used in combination with the compounds of the present invention, may range from 0.1 to 3,000 mg/day, preferably from about 1 to 1,000 mg/day and more preferably from about 1 to 200 mg/day, once a day or 2 to 4 divided doses. However, the precise dose may be determined by a clinician and will depend on such factors as the efficacy of the compound being administered, the age, weight, condition and response of the patient.
Agents or drugs for increasing food intake and/or body weight include appetite stimulants such as megestrol acetate (megastrol acetate), adrenocortical hormones such as prednisolone and dexamethasone, cyproheptadine, 5-hydroxytryptamine drugs such as fenfluramine, neuropeptide Y, and androgen antagonists such as flutamide, nilutamide, and zanoteron.
Test and animal models
Selected compounds were tested in assays to determine binding and functional status, and in animal models of feeding behavior described below. The following tests and animal models were used and were varied as described in the examples.
Using [ I125]Competitive inhibition assay of NDP-alpha-MSH competitive inhibition binding assays were performed using membrane homogenates prepared from HEK-293 cells expressing recombinant hMC4-R, hMC3-R, or hMC5-R and B-16 mouse melanoma cells (including endogenous MC 1-R). In some cases, HEK-293 cells expressing recombinant hMC1-R were used. In the examples below, all MC3-R, MC4-R and MC5-R values are for human recombinant receptors. The MC1-R values were for B-16 mouse melanoma cells, except for the title "hMC 1-R", in which case the values were for human recombinant MC 1-R. The assay was performed in a 96-well GF/B Millipore (Millipore) multi-screen filter plate (MAFB NOB10) pre-coated with 0.5% bovine serum albumin (fraction V). In buffer, membrane homogenates were mixed with 0.2nM (for hMC4-R)0.4nM (for MC3-R and MC5-R) or 0.1nM (for mouse B16MC1-R or hMC1-R) [ I125]NDP-alpha-MSH (PerkinElmer) and increasing concentrations of test compounds were incubated together, the buffer comprising 25mM HEPES buffer (pH 7.5) with 100mM NaCl, 2mM CaCl2，2mM MgCl20.3mM 1, 10-phenanthroline, and 0.2% bovine serum albumin. After incubation at 37 ℃ for 60 minutes, the test mixture was filtered and the membrane was washed 3 times with ice-cold buffer. The filters were dried and their bound radioactivity was counted in a gamma counter. By in the presence of 1. mu.M NDP-alpha-MSH, on [ I125]Inhibition of NDP-alpha-MSH binding measures non-specific binding. The maximum specific binding (100%) was defined as the difference in radioactivity (cpm) bound to the cell membrane in the absence and presence of 1 μ M NDP-. alpha. -MSH. The radioactivity (cpm) obtained in the presence of test compound was normalized to 100% specific binding to determine [ I125]Percent inhibition of NDP- α -MSH binding. Each assay was performed in triplicate and the actual average was described, with results less than 0% reported as 0%. Using Graph-Pad
Figure A20068003538100471
The curve fitting software determines the Ki values for the test compounds.
Using [ I125]Of AgRP (83-132)Competitive binding assay use of Membrane homogenates isolated from cells expressing hMC4-R [ I125]Competitive binding studies of AgRP (83-132). The assay was performed in a 96-well GF/B Millipore (Millipore) multi-screen filter plate (MAFB NOB10) pre-coated with 0.5% bovine serum albumin (fraction V). The test mixture contained 25mM HEPES buffer (pH 7.5) with 100mM NaCl, 2mM CaCl2，2mM MgCl20.3mM 1, 10-phenanthroline, and 0.5% bovine serum albumin, membrane homogenate, radioligand [ I125]AgRP (83-132) (perkin elmer), concentration increasing compound, total volume 200 μ Ι _. Binding was measured at a radioligand concentration of 0.2 nM. After incubation for 1 hour at 37 ℃, the reaction mixture was filtered and washed with test buffer, which contained 500mM NaCl. The dried discs were removed from the plate and counted on a gamma counter. The total radioligand binding was no more than 10% of the amount added to the reaction mixture. Using Graph-Pad
Figure A20068003538100481
The curve fitting software determines the Ki values for the test compounds.
Assay of intracellular cAMP accumulation as a measure of the ability of a test compound to provoke a functional response in MC4-R expressing HEK-293 cells. Confluent HEK-293 cells expressing recombinant hMC4-R were detached from the culture plates by incubation in enzyme-free cell dissociation buffer. The dispersed cells were suspended in Earle's balanced salt solution containing 10mM HEPES (pH 7.5), 1mM MgCl21mM glutamine, 0.5% albumin and 0.3mM 3-isobutyl-1-methyl-xanthine (IBMX), a phosphodiesterase inhibitor. The cells were plated at 0.5x105The density of cells/well was seeded in 96-well plates and pre-incubated for 30 minutes. Cells were exposed to test compounds dissolved in DMSO (final DMSO concentration 1%) at a concentration range of 0.05-5000nM in a total test volume of 200 μ L for 1 hour at 37 ℃. NDP- α -MSH was used as a reference agonist. At the end of the incubation period, the time of incubation,cells were disrupted by addition of 50 μ L lysis buffer (cAMP EIA kit, amoxicillin (Amersham)), followed by vigorous pipetting. The level of cAMP in the lysate was determined using the cAMP EIA kit (amoxicillin (Amersham)). By using Graph-Pad
Figure A20068003538100482
The software performs nonlinear regression analysis for data analysis. The test compounds were compared to the maximum efficacy obtained with the reference melanocortin agonist NDP- α MSH.
Food intake changes of selected compounds were evaluated. Male C57BL/6 mice were obtained from Jackson laboratories (Bar Harbor, ME). Animals were individually housed in conventional perspex cages and maintained under a controlled light cycle of 12 hours on/12 hours off. Water and pellet (Harlan Teklad 201818% protein rodent diet) were provided ad libitum. Mice were dosed IP (by intraperitoneal injection) 24 hours after fasting or with vehicle or selected compound (0.1-3mg/kg, and IN some cases up to 10mg/kg) IN (by intranasal administration). All animals were dosed once daily (or up to 4 consecutive days) at the beginning of the "off light" period. Changes in food intake weight were measured relative to vehicle-administered control animals at 4 and 20 hour post-dose periods.
Mass values were determined using a Waters MicroMass ZQ instrument using the positive mode. The measured value of mass is compared to the calculated value and expressed as mass plus 1(M +1 or M + H).
Proton NMR data were obtained using a Bruker 300MHz spectrometer. The spectrum is obtained after dissolving the compound in a suitable deuterated solvent such as chloroform, DMSO or methanol.
Synthesis method of the invention
One general strategy involves the development of linear intermediates using chiral building blocks such as amino acid derivatives. The linear intermediates can be cyclized using a Mitsunobo reaction strategy, or by spontaneous cyclization of reactive groups, such as the reaction between amine and ester or amine and aldehyde functional groups. In these cyclization reactions, the driving force of intramolecular reaction to intermolecular reaction is a thermodynamically favorable reaction to form a 6-membered ring structure. In many cases, the methods incorporate conditions that do not involve reversal or racemization of chiral centers. In cases where a small proportion of racemates is observed, such as in the use of alpha-aminoaldehydes at certain positions, the desired chiral product is readily purified by methods known in the art, such as flash chromatography on silica gel columns.
Preferably, the group comprising the Q ring is prepared by using an aldehyde derivative of a D-amino acid. By using α -aminoaldehydes, the resulting groups have the general structure, in the most basic form:
Figure A20068003538100491
as an example, if an aldehyde derivative of D-Phe is used in the synthesis, a compound is obtained in which r is 1 and Q is phenyl. However, it can be readily observed that any D-amino acid can be used as the aldehyde derivative and that an improvement over-NH can also be observed2Any amine capping group may replace one or both hydrogen atoms. In the synthesis, preferably using N-protected D-amino acid aldehyde, wherein the N-protective group is usually Boc or Fmoc. Because of the inherent instability of α -aminoaldehydes in solution, these compounds are preferably synthesized immediately prior to use. Two methods were used for the synthesis.
In the first method, TBTU (1 equivalent) (here and anywhere else herein "equivalent" is an abbreviation for one and more equivalents, as the context requires) and NMM (1 equivalent) are added to an N-protected amino acid (e.g., with a Boc-or Fmoc group) in dichloromethane. The mixture was stirred for half an hour and N, O-dimethylhydroxylamine hydrochloride (1 equivalent) and NMM (1 equivalent) were added. The reaction was allowed to proceed overnight. The solvent was removed and EtOAc was added. The organic phase was washed with aqueous sodium bicarbonate, brine and dried over sodium sulfate. After evaporation of the solvent and drying under vacuum, the residue was dissolved in THF at-78 ℃ under nitrogen. To this solution LAH (1M in THF, 1.5 equiv) was added slowly. The solution was stirred for another half hour. The reaction was diluted with ether and quenched with aqueous potassium hydrogen sulfate. The organic phase was washed with 1N HCl, water, brine and dried over sodium sulfate. After removal of the solvent, the aldehyde was used immediately for the next reaction without purification.
In the second method, borane-THF (1M, 1.2 equivalents) is added slowly to an N-protected amino acid (e.g., with a Boc-or Fmoc group) in THF at 0 ℃. The temperature was raised to room temperature and the solution was stirred for 2 hours. The reaction was quenched with 1N HCl and the solvent was evaporated. The crude product was purified on a silica gel column to give a purified N-protected amino alcohol. The alcohol was dissolved in anhydrous dichloromethane and Dess-Martin periodinane (1.1 equiv) was added. The solution was stirred for 1 hour and the reaction was diluted with ether. The organic phase was washed with saturated sodium bicarbonate with 10% sodium thiosulfate, followed by water, followed by brine, and dried over sodium sulfate. After removal of the solvent, the crude product was used immediately in the next reaction without further purification.
In the synthesis method used, any of the aforementioned methods may be used for using the D-amino acid aldehyde.
Generally, the synthetic methods used are modifications of those described in the aforementioned applications, including specifically patent application Ser. No. 10/837,519, but using an amino acid aldehyde, and in most cases a D-amino acid aldehyde.
Route 1
In Fmoc-NHCH2(R2) R in-COOH2Is in structure IPosition R2aOr R2bThe group of (1). Thus R2Can be cyclohexane, methyl-cyclohexane, ethyl-cyclohexane, propyl-cyclohexane, benzene, toluene, ethyl-benzene, propyl-benzene, etc., including the specific general structure
Figure A20068003538100512
Or
Figure A20068003538100521
Wherein y is a value of 0 to 5.
To Fmoc-NHCH2(R2) A solution of-COOH (1-1) in DCM was added TBTU (1.05 eq) and NMM (1.05 eq) and the mixture was stirred at rt for 1 h. To this mixture was added N, O-dimethylhydroxylamine HCl salt (1.1 equiv) and NMM (1.1 equiv). The reaction was continued at room temperature overnight. The solvent was removed and the residue partitioned between EtOAc and water. The organic layer was washed with water, 1N HCl, saturated sodium bicarbonate, brine and dried over sodium sulfate. The solvent was removed and the crude compound 1-2 was used in the next reaction.
LAH (1.2 equiv.) is slowly added to a solution of compound 1-2 in anhydrous THF at-78 deg.C under nitrogen. After the addition was complete, the reaction mixture was stirred at-78 ℃ for one hour. The reaction was quenched by addition of aqueous potassium hydrogen sulfate. The mixture was diluted with EtOAc and the solid was removed and the solvent was evaporated. The residue was dissolved in EtOAc and the organic layer was washed with 1N HCl, water and dried over sodium sulfate. The solvent was removed and the crude product 1-3 was used in the next reaction.
To a suspension of H-Om (Boc) -OMe HCl salt in THF was added TEA (1 eq). The mixture was stirred under nitrogen for 30 minutes. To this mixture was added 1-3 in THF, followed by addition
Figure A20068003538100522
And (3) a molecular sieve. The mixture was stirred at room temperature for 2 hours, and sodium triacetoxyborohydride (1.5) was addedEquivalent weight). The reaction was continued at room temperature overnight. The solid was removed by celite pad, the solvent was removed and the residue was partitioned between EtOAc and water. The organic layer was collected and dried over sodium sulfate. After removal of the solvent, the products 1-4 were obtained as crude compounds and used in the next reaction without further purification.
Compounds 1-4 were dissolved in 30% diethylamine in EtOAc. The reaction was left overnight at room temperature. The solvent was removed and the residue was purified on a silica gel column to give purified products 1-5.
Dissolve compound 1-5 in DCM and add TEA (1.5 eq). To this solution was added benzyl chloroformate (1.2 equiv.) at 0 ℃. The reaction mixture was stirred at room temperature overnight. The solvent was removed from the reaction mixture and the residue was purified on silica gel column to give compounds 1-6.
borane-THF (6 equivalents) was added slowly to a solution of compounds 1-6 in THF at 0 deg.C. The reaction was continued at room temperature overnight. The reaction was quenched by the addition of water, followed by removal of the solvent. The residue was stirred in sodium hydroxide in methanol (10 eq) for 24 h, and then EtOAc and water were added. The organic layer was washed with water and brine and dried over sodium sulfate. After removal of the solvent, the residue was purified on a silica gel column to give purified products 1-7.
Formation of Compounds 1-8:
method A: a solution of J-carboxylic acid (1.5eq) HOAt (1.5eq) and EDC (1.5eq) in N, N-dimethylformamide was stirred at 0 ℃ for 30 minutes. To this solution was added compounds 1-7. The reaction was continued at room temperature overnight. The solvent was removed and the residue was purified by flash chromatography to give compounds 1-8.
Method B: to a solution of compounds 1-7 and TEA (3 equiv.) in THF at 0 deg.C was added J-carbonyl chloride (1.5 equiv.). The reaction was continued at room temperature overnight. The solvent was removed and the residue was purified by silica gel column to give compounds 1-8.
Compounds 1-8 were treated with a solution of TFA/DCM (v: v ═ 3: 1) for 1 hour. The solvent was removed and the residue was dissolved in acetonitrile. The solution was basified by adding TEA. The solvent was removed and the residue redissolved in acetonitrile. To this solution were added TEA (1 equivalent) and N, N' -bis (tert-butoxycarbonyl) -1H-pyrazole-1-carboxamidine (1.2 equivalents), and the resulting mixture was stirred at room temperature overnight. After removal of the solvent, the residue was purified on a silica gel column to give the products 1-9.
Compounds 1-9 were dissolved in ethanol and stirred under one atmosphere of hydrogen in the presence of catalytic amounts of Pd/C (10%). The reaction was continued at room temperature overnight. The catalyst was removed by filtration. The solvent was removed to give the crude product. The crude product was dissolved in THF and reacted with Q-aldehyde (Q-L) from Q-COOH3-) in a manner to form with said compounds 1-4. Purification through a silica gel column afforded the Boc-protected compound, which was treated with TFA/DCM (50: 50) for one hour. After evaporation of the solvent, the final compounds 1-10 were purified by HPLC.
Route 2
In Fmoc-NHCH2(R2) R in-COOH (2-1)2Is in position R of structure I2aOr R2bThe group of (1). Thus, R2May be cyclohexane, methyl-cyclohexane, ethyl-cyclohexane, propyl-cyclohexane, benzene, toluene, ethyl-benzene, propyl-benzene (benezene), and the like, including the specific general structures
Figure A20068003538100542
Wherein y is a value from 0 to 5.
To Fmoc-NHCH2(R2) TBTU (1.05 equiv.) was added as a solution of-COOH (2-1) in DCM) And NMM (1.05 eq). The mixture was stirred at room temperature for one hour. To this mixture was added N, O-dimethylhydroxylamine HCl salt (1.1 equiv) and NMM (1.1 equiv). The reaction was continued at room temperature overnight. The solvent is removed. The residue was partitioned between EtOAc and water. The organic layer was washed with water, 1N HCl, saturated sodium bicarbonate, brine and dried over sodium sulfate. The solvent was removed and the crude compound 2-2 was used in the next reaction.
LAH (1.2 equiv.) was added slowly to a solution of compound 2-2 in anhydrous THF at-78 deg.C under nitrogen. After the addition was complete, the reaction mixture was stirred at-78 ℃ for one hour. The reaction was quenched by addition of aqueous potassium hydrogen sulfate. The mixture was diluted with EtOAc and the solid was removed. The solvent was evaporated and the residue was dissolved in EtOAc, the organic layer was washed with 1N HCl, water and dried over sodium sulfate. The solvent was removed and the crude product 2-3 was used in the next reaction.
To a suspension of H-Orn (Boc) -OMe HCl salt in THF was added TEA (1 eq). The mixture was stirred under nitrogen for 30 minutes. To this mixture, 2-3 in THF was added, followed by
Figure A20068003538100551
And (3) a molecular sieve. The mixture was stirred at room temperature for 2 hours, followed by the addition of sodium triacetoxyborohydride (1.5 equivalents). The reaction was continued at room temperature overnight. The solid was removed through a pad of celite. The solvent was removed and the residue partitioned between EtOAc and water. The organic layer was collected and dried over sodium sulfate. After removal of the solvent, the product 2-4 was obtained as crude compound, which was used in the next reaction without further purification.
Compounds 2-4 were dissolved in 30% diethylamine in EtOAc. The reaction was left overnight at room temperature. The solvent was removed and the residue was purified on a silica gel column to give purified products 2-5.
Dissolve compound 2-5 in DCM and add TEA (1.5 eq). To this solution was added benzyl chloroformate (1.2 equiv.) at 0 ℃. The reaction mixture was stirred at room temperature overnight. The solvent was removed from the reaction mixture and the residue was purified on silica gel column to give compounds 2-6.
borane-THF (6 equivalents) was added slowly to a solution of compound 2-6 in THF at 0 deg.C. The reaction was continued at room temperature overnight. The reaction was quenched by the addition of water, followed by removal of the solvent. The residue was stirred in sodium hydroxide (10 equivalents) in methanol for 24 hours. And then EtOAc and water were added. The organic layer was washed with water, brine and dried over sodium sulfate. After removal of the solvent, the residue was purified on a silica gel column to give purified products 2-7.
Formation of Compounds 2-8:
method A: a solution of J-carboxylic acid (1.5eq) HOAt (1.5eq) and EDC (1.5eq) in N, N-dimethylformamide was stirred at 0 ℃ for 30 minutes. To this solution was added compounds 2-7. The reaction was continued at room temperature overnight. The solvent was removed and the residue was purified by flash chromatography to afford compounds 2-8.
Method B: to a solution of compounds 2-7 and TEA (3 equiv.) in THF was added J-carbonyl chloride (1.5 equiv.) at 0 deg.C. The reaction was continued at room temperature overnight. The solvent was removed and the residue was purified by silica gel column to give compounds 2-8.
Compounds 2-8 were treated with a solution of TFA/DCM (v: v ═ 3: 1) for 1 hour. The solvent was removed and the residue was dissolved in acetonitrile. The solution was basified by adding TEA. The solvent was removed and the residue was redissolved in acetonitrile. To this solution were added TEA (1 eq) and N, N' -bis (tert-butoxycarbonyl) -1H-pyrazole-1-carboxamidine (1.2 eq). And the mixture was stirred at room temperature overnight. After removal of the solvent, the residue was purified on a silica gel column to give the product 2-9.
Compounds 2-9 were dissolved in ethanol and stirred under one atmosphere of hydrogen in the presence of catalytic amounts of Pd/C (10%). The reaction was continued at room temperature overnight and the catalyst was removed by filtration. The solvent was removed to give the crude product. This crude product was dissolved in THF and reacted with Q-COOH in a manner similar to the formation of compounds 2-8 (method A). Purification through a silica gel column afforded the Boc-protected compound, which was treated with TFA/DCM (50: 50) for one hour. After evaporation of the solvent, the final compounds 2-10 were purified by HPLC.
Route 3
Figure A20068003538100581
A mixture of Cbz-Glu (OtBu) -OH, TBTU (1.1 equiv.) and NMM (1.5 equiv.) in 100mL of DCM was stirred at room temperature under nitrogen for 30 min. Adding NH in the form of a hydrochloride to said solution2-CH(R2) COOMe (1.05 equiv.) and NMM (1.13 eq). The mixture was stirred at room temperature overnight. The solvent was removed and the residue was dissolved in 250mL EtOAc. The organic solvent was washed with water, 1N HCl, saturated aqueous sodium bicarbonate solution and dried over sodium sulfate. After removal of the solvent, the product (3-1) was used for the next step reaction without further purification.
Compound 3-1 was dissolved in EtOAc. It was treated with hydrogen at room temperature in the presence of Pd/C for three days at 1 atmosphere. The reaction mixture was filtered through a celite pad, followed by washing with methanol. The solvent was removed and the product 3-2 was used for the next reaction without purification.
Compound 3-2 was dissolved in dmf the solution was heated at 90 ℃ for three days. The solvent was removed and the residue was dissolved in DCM, which was washed with 1N HCl. The organic layer was separated and dried over sodium sulfate. After removal of the solvent, the product 3-3 was obtained.
A suspension of compound 3-3 in THF was stirred at 0 deg.C. LAH (4.6 equivalents) was added to the suspension. The mixture was stirred at 0 ℃ for 25 minutes, at room temperature for 4 hours, then refluxed under nitrogen overnight. The reaction was quenched by the addition of water, 15% sodium hydroxide and water at 0 ℃. The mixture was stirred at room temperature for an additional 30 minutes. The solid was removed by filtration and washed with diethyl ether. The solvent was removed and dried under vacuum to give crude compound 3-4.
Compound 3-4 was dissolved in THF. To this solution was added benzyl chloroformate (2.5 equivalents), followed by water and sodium bicarbonate (6 equivalents) such that the ratio of THF to water was 2: 1. The mixture was stirred at room temperature overnight. To the mixture was added EtOAc and water. The organic layer was washed with water and dried over sodium sulfate. The solvent was removed and the residue was dissolved in methanol and 1N sodium hydroxide (3 equivalents). The reaction was carried out at room temperature for three days. The solvent was removed and the resulting residue was dissolved in EtOAc. The organic phase was washed with 1N HCl, water, aqueous sodium bicarbonate solution and dried over sodium sulfate. The solvent was removed and the residue was purified on silica gel column to give the product 3-5.
Compound 3-5 was dissolved in DCM. To this solution Dess-Martin periodinane (1.1 equiv) was added. The reaction was continued at room temperature for 1.5 hours. Diethyl ether was added to dilute the mixture and the reaction was quenched by addition of a solution of sodium thiosulfate in saturated sodium bicarbonate. The organic layer was washed with the same solution and dried over sodium sulfate. After removal of the solvent, the crude product 3-6 was used for the next reaction without further purification.
To a solution of compound 3-6 and N-Boc-ethylenediamine (1.05 eq.) in THF was added molecular sieves. The mixture was stirred at room temperature for 3 hours. To the mixture was added sodium triacetoxyborohydride (1.5 equivalents). The reaction mixture was stirred at room temperature overnight and the solids were removed by filtration. After removal of the solvent, the residue was partitioned between EtOAc and water, the organic layer was separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over sodium sulfate. After removal of the solvent, the residue was dissolved in THF and water (v: v ═ 2: 1). To this solution was added di-tert-butyl dicarbonate (1.2 equivalents) and sodium bicarbonate (5 equivalents). The mixture was stirred at room temperature overnight. EtOAc was added and the organic layer was washed with water and dried over sodium sulfate. After removal of the solvent, the residue was purified on silica gel column to give the product 3-7.
Compounds 3-7 were dissolved in ethanol and treated with hydrogen in the presence of catalytic amounts of Pd/C at atmospheric pressure. The reaction was carried out at room temperature overnight. The solid was filtered and washed several times with ethanol. The solvent was removed to give the product 3-8.
To a solution of Q-COOH (4 equiv.) in DMF was added HOAT (4 equiv.) and EDC (4 equiv.) at 0 deg.C. After stirring the mixture for 30 minutes, compounds 3-8 were added to the mixture. The reaction was continued at room temperature overnight. The solvent was removed and the residue was purified on silica gel column to give the product 3-9.
Compounds 3-9 were treated with TFA at room temperature for three hours. After removal of the solvent, the residue was purified by HPLC to give compounds 3-10.
Route 4
Figure A20068003538100621
Fmoc-Lys (Trt) -OH was partially dissolved in DCM. To this mixture was added TBTU (1.1 eq) and NMM (1.5 eq). After stirring the mixture at room temperature for 45 minutes under nitrogen, NH was added2-CH(R2) -COOMe (i.e. H-D-Leu-ome. hcl) (1.05 equivalents) and NMM (1.1 equivalents). The reaction was allowed to proceed overnight at room temperature.
The solvent was evaporated and the residue partitioned between EtOAc and water. The organic layer was passed through 1N HCl, saturated NaHCO3Washed with water and dried over sodium sulfate. After removal of the solvent, the product 1.1 was obtained and used for the next reaction without further purification.
Compound 4-1 was dissolved in 30% Et in EtOAc2And (4) NH. The solution was stirred at room temperature for 2 hours. The solvent is removed. The crude product 4-2 was used for the next reaction without further purification.
Compound 4-2 was partially dissolved in anhydrous DMF. The mixture was heated at 90 ℃ for three days under nitrogen. The reaction was terminated and DMF was removed under vacuum. The crude product was purified on a silica gel column eluted with EtOAc/heptane (1: 1), DCM followed by MeOH/DCM (9: 1). After evaporation of the solvent, the final product 4-3 was collected.
Compound 4-3 was suspended in THF under nitrogen at 0 ℃. LAH (3.5 equivalents) was added dropwise to the suspension. The suspension became a clear solution after the addition of LAH was complete. The reaction was stirred at room temperature for 45 minutes and refluxed overnight. The reaction mixture was quenched by the sequential addition of water, 15% NaOH and water at 0 ℃. The mixture was stirred at room temperature for 20 minutes. The solid was removed by filtration and washed with diethyl ether, and the diethyl ether was evaporated to give crude product 4-4.
Compound 4-4 was dissolved in THF. To this solution was added benzyl chloroformate (3 equivalents), followed by water and sodium bicarbonate (5 equivalents). The reaction mixture was stirred at room temperature for 3 hours. To the mixture was added water and EtOAc. The organic layer was separated and washed with water until the aqueous layer reached a neutral pH. The organic layer was dried over sodium sulfate. The solvent was evaporated and the residue was purified on a silica gel column eluted with EtOAc/heptane (1: 4) to afford product 4-5.
Compound 4-5 was dissolved in 5% TFA/1% TIS/DCM solution and the mixture was stirred for 1 hour. The reaction mixture was diluted with DCM. The organic phase was washed with saturated sodium bicarbonate, water, brine and dried over sodium sulfate. After evaporation of the solvent, the crude product 4-6 was used for the next reaction.
Compounds 4-6 were dissolved in DCM. Pyridine (10 equivalents) was added slowly to the solution at 0 ℃, followed by 2-nitrobenzenesulfonyl chloride (2 equivalents). The temperature was raised to room temperature and stirred overnight. The solvent is removed. The residue was dissolved in EtOAc, washed with 1N HCl, water, brine and dried over sodium sulfate. After removal of the solvent, the residue was purified on a silica gel column eluted with 25% EtOAc in heptane. After removal of the solvent, compounds 4-7 were obtained.
Compound 4-7, TPP (3 equivalents) and N-Boc-2-hydroxy-ethylamine (3 equivalents) were dissolved in anhydrous toluene. To this solution was added DIAD (3 equivalents) in toluene at 0 ℃. After 30 minutes, the temperature was raised to room temperature and the solution was stirred overnight. The solvent was removed and the residue was purified on a silica gel column eluted with 50% EtOAc in heptane. After removal of the solvent, compounds 4-8 were obtained.
Compounds 4-8 were dissolved in anhydrous acetonitrile. To this solution was added potassium carbonate (6 equiv.) and 4-mercaptophenol (4.5 equiv.). The mixture was stirred at room temperature overnight. The solvent was removed and the residue was partitioned with EtOAc and water. The organic layer was separated, washed with water, brine and dried over sodium sulfate. The crude compounds 4-9 were used for the next reaction.
Compounds 4-9 were dissolved in THF/water (2/1). Subsequently, sodium bicarbonate (5 equivalents) and di-tert-butyl carbonate (2 equivalents) were added to the solution. The mixture was stirred at room temperature overnight. After removal of THF, EtOAc was added to extract the product. The organic layer was washed with 1N HCl, water, brine and dried over sodium sulfate. The solvent was removed and the residue was purified on a silica gel column eluted with 25% EtOAc in heptane. After removal of the solvent, the product was obtained 4-10.
Compounds 4-10 were treated with catalytic amounts of palladium on carbon in ethanol overnight at room temperature under hydrogen (one atmosphere). After filtration through a celite pad, the solvent was removed. The crude product was dried under vacuum and used for the next reaction without further purification.
Q-COOH (i.e., Boc-D-2-naphthylalanine) (4 equivalents), EDC (4 equivalents) and HOAt (4 equivalents) were dissolved in DMF. The mixture was stirred at 0 ℃ for 30 minutes. To this solution, one portion of compound 4-10 was added. The reaction was carried out at room temperature overnight. The solvent was removed and the residue was purified on silica gel column to give the product 4-11.
Compound 4-11 was treated with TFA at room temperature for 3 hours. After removal of the solvent, the residue was purified by HPLC to give the product 4-12.
Representative Compounds of the invention
Example 1N- {3- [ (2S, 5R) -1- ((R) -2-amino-3-naphthalen-2-yl-propionyl) -5-benzyl-4- (2-naphthalen-2-yl-acetyl) -piperazin-2-yl]-propyl } -guanidine
The following compounds were synthesized by the procedure of scheme 2, using 2-naphthylacetic acid as J-COOH and D-Phe as NHCH2(R2) -COOH, and Boc-D-2' -naphthylalanine as Q-COOH. After purification, the test was performed as described above and the results are given. The mass analysis was 641(M + H).
Figure A20068003538100651
Inhibition at 1. mu.M (NDP-. alpha. -MSH)
MC1-R MC3-R MC4-R MC5-R
4％ 57％ 100％ 84％
Ki(nM)(NDP-α-MSH)
MC1-R MC3-R MC4-R MC5-R
＞1000 250 3 171
Ki(nM) (AgRP)
MC3-R MC4-R
＞1000 ND
In the cAMP assay used to determine functionality in MC4-R expressing cell lines, the maximum effect observed for the compound was 87% of the maximum obtained for NDP- α -MSH.
In the mouse model IP feeding study, there was an 8% and 23% reduction in food intake observed over a 20 hour period at the 3 and 10mg/kg dose levels, respectively. IN the mouse model IN feeding study, there was a 15% reduction IN food intake observed over a 20 hour period at the 3mg/kg dose level.
Example 2N- {3- [ (2S, 5R) -5-benzyl-1- ((R) -2-dimethylamino-3-naphthalen-2-yl-propionyl) -4- (2-naphthalen-2-yl-acetyl) -piperazin-2-yl]-propyl } -guanidine
The following compounds were synthesized by the procedure of scheme 2, using 2-naphthylacetic acid as J-COOH and D-Phe as NHCH2(R2) -COOH, and Fmoc-D-2' -naphthylalanine as Q-COOH. Methylation of amines was performed by dissolving compounds 2-9 in ethanol and stirring under one atmosphere of hydrogen in the presence of catalytic amounts of Pd/C (10%). The reaction was continued at room temperature overnight and the catalyst was removed by filtration. The solvent was removed to give the crude product. This crude product was dissolved in THF and reacted with Q-COOH in the manner described for the formation of compounds 2-8 (method A). Purification through silica gel column gave Fmoc-and Boc-protected compounds. Fmoc was removed with 30% diethylamine in EtOAc for 2 hours. Removing the solvent and removing the residueThe residue was dissolved in dichloroethane. To this solution was added formaldehyde (37% aq. solution, 10 equivalents). After stirring for 10 min, sodium triacetoxyborohydride (5 equivalents) was added. Next, the mixture was stirred at room temperature overnight. The reaction was washed with water, brine and dried over sodium sulfate. After removal of the solvent, the product was treated with TFA/DCM (50: 50) for 1 hour and purified by HPLC to afford the purified compound. After purification, the compounds were tested as described above and the results were displayed. The mass analysis was 669.3(M + H).
Figure A20068003538100661
Inhibition at 1. mu.M (NDP-. alpha. -MSH)
MC1-R MC3-R MC4-R MC5-R
17 58 97 54
Ki(nM)(NDP-α-MSH)
MC1-R MC3-R MC4-R MC5-R
＞1000 590 26 678
Ki(nM) (AgRP)
MC3-R MC4-R
＞1000 49
In the cAMP assay used to determine the functionality of the MC4-R expressing cell line, the maximal effect observed for the compound was 90% of the maximum obtained for NDP- α -MSH.
Example 3N- {3- [ (2S, 5R) -5-benzyl-1- (4' -chloro-diphenyl-2-carbonyl) -4- (2-naphthalen-2-yl-acetyl) -piperazin-2-yl]-propyl } -guanidine
Will be described as followsThe compound was synthesized by the procedure of scheme 2, using 2-naphthylacetic acid as J-COOH, D-Phe-OH as NHCH2(R2) -COOH, and 4' -chloro-biphenyl-2-carboxylic acid as Q-COOH. After purification, the compounds were tested as described above and the results were displayed. Mass analysis was 658.2(M + H).
Inhibition at 1. mu.M (NDP-. alpha. -MSH)
MC1-R MC3-R MC4-R MC5-R
32 21 88 4
Ki(nM)(NDP-α-MSH)
MC1-R MC3-R MC4-R MC5-R
317 ＞1000 32 910
Ki(nM) (AgRP)
MC3-R MC4-R
＞1000 180
In the cAMP assay used to determine functionality in MC4-R expressing cell lines, the maximum effect observed for the compound was 106% of the maximum obtained for NDP-. alpha. -MSH
Example 4N- {3- [ (2S, 5R) -5-benzyl-1- (4' -chloro-biphenyl-3-carbonyl) -4- (2-naphthalen-2-yl-acetyl) -piperazin-2-yl]-propyl } -guanidine
The following compounds were synthesized by the procedure of scheme 2, using 2-naphthylacetic acid as J-COOH, D-Phe-OH as NHCH2(R2) -COOH, and 4' -chloro-biphenyl-3-carboxylic acid as Q-COOH. After purification, compounds were tested as described above and the results shown. The mass analysis was 658.3(M + H).
Figure A20068003538100681
Inhibition at 1. mu.M (NDP-. alpha. -MSH)
MC1-R MC3-R MC4-R MC5-R
37 23 88 18
Ki(nM)(NDP-α-MSH)
MC1-R MC3-R MC4-R MC5-R
338 ＞500 30 ＞1000
Ki(nM) (AgRP)
MC3-R MC4-R
＞1000 152
In the cAMP assay used to determine functionality in MC4-R expressing cell lines, the maximal effect observed for the compound was 98% of the maximum obtained for NDP- α -MSH.
Example 5N- {3- [ (2S, 5R) -5-benzyl-1- (4' -chloro-biphenyl-4-carbonyl) -4- (2-naphthalen-2-yl-acetyl) -piperazin-2-yl]-propyl } -guanidine
The following compounds were synthesized by the procedure of scheme 2, using 2-naphthylacetic acid as J-COOH and D-Phe as NHCH2(R2) -COOH, and 4' -chloro-biphenyl-4-carboxylic acid. After purification, the compounds were tested as described above and the results were displayed. Mass analysis was 658.2(M + H).
Figure A20068003538100691
Example 6N- {3- [ (2S, 5R) -5-benzyl-1- [2- (4' -chloro-biphenyl-2-yl) -acetyl]-4- (2-naphthalen-2-yl-acetyl) -piperazin-2-yl]-propyl } -guanidine
The following compounds were synthesized by the procedure of scheme 2, using 2-naphthylacetic acid as J-COOH, D-Phe-OH as NHCH2(R2) -COOH, and (4' -chloro-biphenyl-2-yl) -acetic acid as Q-COOH. After purification, the compounds were tested as described above and the results were displayed. The mass analysis was 672.2(M + H).
Figure A20068003538100692
Example 7N- {3- [ (2S, 5R) -5-benzyl-1- (2 ', 4' -dichloro-biphenyl-2-carbonyl) -4- (2-naphthalen-2-yl-acetyl) -piperazin-2-yl]-propyl } -guanidine
The following compounds were synthesized by the procedure of scheme 2, using 2-naphthylacetic acid as J-COOH, D-Phe-OH as NHCH2(R2) -COOH, and 2 ', 4' -dichloro-biphenyl-2-carboxylic acid as Q-COOH. After purification, the compounds were tested as described above and the results were displayed. The mass analysis was 692.3(M + H).
Figure A20068003538100701
Inhibition at 1. mu.M (NDP-. alpha. -MSH)
MC1-R MC3-R MC4-R MC5-R
0 19 90 34
Ki(nM)(NDP-α-MSH)
MC1-R MC3-R MC4-R MC5-R
＞1000 ＞1000 54 ＞1000
Ki(nM) (AgRP)
MC3-R MC4-R
＞1000 76
In the cAMP assay used to determine functionality in MC4-R expressing cell lines, the maximal effect observed for the compound was 99% of the maximal value observed for NDP- α -MSH.
Example 8N- {3- [ (2S, 5R) -5-benzyl-1- (3 ', 4' -dichloro-biphenyl-2-carbonyl) -4- (2-naphthalen-2-yl-acetyl) -piperazin-2-yl]-propyl } -guanidine
The following compounds were synthesized by the procedure of scheme 2, using 2-naphthylacetic acid as J-COOH, D-Phe-OH as NHCH2(R2) -COOH, and 3 ', 4' -dichloro-biphenyl-2-carboxylic acid as Q-COOH. After purification, the compounds were tested as described above and the results were displayed. The mass analysis was 692.3(M + H).
Figure A20068003538100711
Inhibition at 1. mu.M (NDP-. alpha. -MSH)
MC1-R MC3-R MC4-R MC5-R
3 24 94 46
Ki(nM)(NDP-α-MSH)
MC1-R MC3-R MC4-R MC5-R
＞1000 432 23 684
Ki(nM) (AgRP)
MC3-R MC4-R
＞1000 34
In the cAMP assay used to determine functionality in MC4-R expressing cell lines, the maximal effect observed for the compound was 78% of the maximum obtained for NDP- α -MSH.
Example 9N- {3- [ (2S, 5R) -5-benzyl-1- (3 ', 5' -dichloro-biphenyl-2-carbonyl) -4- (2-naphthalen-2-yl-acetyl) -piperazin-2-yl]-propyl } -guanidine
The following compounds were synthesized by the procedure of scheme 2, using 2-naphthylacetic acid as J-COOH, D-Phe-OH as NHCH2(R2) -COOH, and 3 ', 5' -dichloro-biphenyl-2-carboxylic acid as Q-COOH. After purification, the compounds were tested as described above and the results were displayed. The mass analysis was 692.3(M + H).
Figure A20068003538100721
Inhibition at 1. mu.M (NDP-. alpha. -MSH)
MC1-R MC3-R MC4-R MC5-R
17 22 88 29
Ki(nM)(NDP-α-MSH)
MC1-R MC3-R MC4-R MC5-R
＞1000 ＞1000 84 960
Ki(nM) (AgRP)
MC3-R MC4-R
＞1000 132
In the cAMP assay used to test functionality in MC4-R expressing cell lines, the maximum effect observed for the compound was 86% of the maximum observed for NDP- α -MSH.
Example 10N- {3- [ (2S, 5R) -1- ((R) -2-amino-3-naphthalen-2-yl-propyl) -5-benzyl-4- (2-naphthalen-2-yl-acetyl) -piperazin-2-yl]-propyl } -guanidine
The following compounds were synthesized by the procedure of scheme 1, using 2-naphthylacetic acid as J-COOH, D-Phe-OH as NHCH2(R2) -COOH, and Boc-D-2' -naphthylalanine carboxylic acid as Q-COOH. After purification, the compounds were tested as described above and the results were displayed. The mass analysis was 627.5(M + H).
Figure A20068003538100731
Inhibition at 1. mu.M (NDP-. alpha. -MSH)
MC1-R MC3-R MC4-R MC5-R
22 49 92 87
Ki(nM)(NDP-α-MSH)
MC1-R MC3-R MC4-R MC5-R
＞1000 ＞1000 61 178
Ki(nM) (AgRP)
MC3-R MC4-R
＞1000 90
In the cAMP assay used to determine functionality with respect to MC4-R, the compounds were determined not to show any response at a concentration of 1. mu.M.
In the mouse model IP feeding study, there were 9% and 31% reductions in food intake observed over a 20 hour period at the 3 and 10mg/kg dose levels, respectively.
Example 11N- {3- [ (2S, 5R) -5-benzyl-1- (2 ', 4' -dichloro-biphenyl-3-carbonyl) -4- (2-naphthalen-2-yl-acetyl) -piperazin-2-yl]-propyl } -guanidine
The following compounds were synthesized by the procedure of scheme 1, using 2-naphthylacetic acid as J-COOH, D-Phe-OH as NHCH2(R2) -COOH, and 2 ', 4' -dichloro-biphenyl-3-carboxylic acid as Q-COOH, except that the guanidine Boc group was not removed in steps 2-9. After purification, the compounds were tested as described above and the results were displayed. Mass analysis was 892(M + H).
Example 12N- {3- [ (2S, 5R) -5-benzyl-1- (2 ', 4' -dichloro-biphenyl-3-carbonyl) -4- (2-naphthalen-2-yl-acetyl) -piperazin-2-yl]-propyl } -guanidine
The following compounds were synthesized by the procedure of scheme 2, using 2-naphthylacetic acid as J-COOH, D-Phe-OH as NHCH2(R2) -COOH, and 2 ', 4' -dichloro-biphenyl-3-carboxylic acid as Q-COOH. After purification, the compounds were tested as described above and the results were displayed. The mass analysis was 692.3(M + H).
Example 13N- {3- [ (2S, 5R) -5-benzyl-1- (3 ', 4' -dichloro-biphenyl-3-carbonyl) -4- (2-naphthalen-2-yl-acetyl) -piperazin-2-yl]-propyl } -guanidine
Passing the following compounds throughThe procedure of scheme 2, using 2-naphthylacetic acid as J-COOH and D-Phe-OH as NHCH2(R2) -COOH, and 3 ', 4' -dichloro-biphenyl-3-carboxylic acid as Q-COOH. After purification, the compounds were tested as described above and the results were displayed. The mass analysis was 692.3(M + H).
Figure A20068003538100751
Example 14N- {3- [ (2S, 5R) -5-benzyl-1- (3 ', 5' -dichloro-biphenyl-3-carbonyl) -4- (2-naphthalen-2-yl-acetyl) -piperazin-2-yl]-propyl } -guanidine
The following compounds were synthesized by the procedure of scheme 2, using 2-naphthylacetic acid as J-COOH, D-Phe-OH as NHCH2(R2) -COOH, and 3 ', 5' -dichloro-biphenyl-3-carboxylic acid as Q-COOH. After purification, the compounds were tested as described above and the results were displayed. The mass analysis was 692.6(M + H).
Example 15N- {3- [ (2S, 5R) -5-benzyl-1- (3-iodo-benzoyl) -4- (2-naphthalen-2-yl-acetyl) -piperazin-2-yl]-propyl } -guanidine
The following compounds were synthesized by the procedure of scheme 2, using 2-naphthylacetic acid as J-COOH, D-Phe-OH as NHCH2(R2) -COOH, and 3-iodo-phenyl-carboxylic acid as Q-COOH. After purification, the compounds were tested as described above and the results were displayed. The mass analysis was 674.2(M + H).
Figure A20068003538100761
Example 16N- {3- [ (2S, 5R) -5-benzyl-1- (2 ', 4' -dichloro-biphenyl-3-ylmethyl) -4- (2-naphthalen-2-yl-acetyl) -piperazin-2-yl]-propyl } -guanidine
The following compounds were synthesized by the procedure of scheme 1, using 2-naphthylacetic acid as J-COOH, D-Phe-OH as NHCH2(R2) -COOH, and 2 ', 4' -dichloro-biphenyl-3-carboxylic acid as Q-COOH. After purification, the compounds were tested as described above and the results were displayed. The mass analysis was 678.6(M + H).
Figure A20068003538100762
Inhibition at 1. mu.M (NDP-. alpha. -MSH)
MC1-R MC3-R MC4-R MC5-R
22％ 40％ 37％ 8％
Example 17N- {3- [ (2S, 5R) -5-benzyl-1- (4' -chloro-biphenyl-2-ylmethyl) -4- (2-naphthalen-2-yl-acetyl) -piperazin-2-yl]-propyl } -guanidine
The following compounds were synthesized by the procedure of scheme 1, using 2-naphthylacetic acid as J-COOH, D-Phe-OH as NHCH2(R2) -COOH, and 4' -chloro-biphenyl-2-carboxylic acid as Q-COOH. After purification, the compounds were tested as described above and the results were displayed. The mass analysis was 644.6(M + H).
Figure A20068003538100771
Inhibition at 1. mu.M (NDP-. alpha. -MSH)
MC1-R MC3-R MC4-R MC5-R
18％ 37％ 46％ 24％
Example 18N- {3- [ (2S, 5R) -5-benzyl-1- (4' -chloro-biphenyl-3-ylmethyl) -4- (2-naphthalen-2-yl-acetyl) -piperazin-2-yl]-propyl } -guanidine
The following compounds were synthesized by the procedure of scheme 1, using 2-naphthylacetic acid as J-COOH, D-Phe-OH as NHCH2(R2) -COOH, and 4' -chloro-biphenyl-3-carboxylic acid as Q-COOH. After purification, the compounds were tested as described above and the results were displayed. The mass analysis was 644.6(M + H).
Inhibition at 1. mu.M (NDP-. alpha. -MSH)
MC1-R MC3-R MC4-R MC5-R
21％ 35％ 46％ 26％
Example 19N- {3- [ (2S, 5R) -5-benzyl-1-biphenyl-2-ylmethyl-4- (2-naphthalen-2-yl-acetyl) -piperazin-2-yl]-propyl } -guanidine
The following compounds were synthesized by the procedure of scheme 2, using 2-naphthylacetic acid as J-COOH, D-Phe-OH as NHCH2(R2) -COOH, and biphenyl-2-carboxylic acid as Q-COOH. After purification, the compounds were tested as described above and the results were displayed. The mass analysis was 610.5(M + H).
Figure A20068003538100781
Inhibition at 1. mu.M (NDP-. alpha. -MSH)
MC1-R MC3-R MC4-R MC5-R
0％ 50％ 57％ 58％
Example 20N- {3- [ (2S, 5R) -1- [ (R) -2-amino-3- (2, 4-dimethyl-phenyl) -propyl]-5-benzyl-4- (2-naphthalen-2-yl-acetyl) -piperazin-2-yl]-propyl } -guanidine
The following compounds were synthesized by the procedure of scheme 1, using 2-naphthylacetic acid as J-COOH, Fmoc-D-Phe-OH as NHCH2(R2) -COOH, and Boc-D-2, 4-dimethyl-D-Phe-OH as Q-COOH. After purification, the compounds were tested as described above and the results were displayed. The mass analysis was 605(M + H).
Figure A20068003538100791
Inhibition at 1. mu.M (NDP-. alpha. -MSH)
MC1-R MC3-R MC4-R MC5-R
0％ 79％ 96％ 94％
Ki(nM)(NDP-α-MSH)
MC1-R MC3-R MC4-R MC5-R
＞1000 78 9 115
Ki(nM) (AgRP)
MC3-R MC4-R
876 19
In a cAMP assay to determine functionality, the assay shows no response for MC4-R at a concentration of 1. mu.M.
In the mouse model IP feeding study, there was a maximum 14% and 38% reduction in food intake observed over a 20 hour period at 1 and 10mg/kg dose levels, respectively.
Example 21N- {3- [ (2S, 5S) -1- ((R) -2-amino-3-naphthalen-2-yl-propionyl) -5-benzyl-4- (2-naphthalen-2-yl-acetyl) -piperazin-2-yl]-propyl } -guanidine
The following compounds were synthesized by the procedure of scheme 2, using 2-naphthylacetic acid as J-COOH, D-Phe-OH as NHCH2(R2) -COOH, and Boc-D-2' -naphthylalanine as Q-COOH. After purification, the compounds were tested as described above and the results were displayed. The mass analysis was 641(M + H).
Figure A20068003538100801
Inhibition at 1. mu.M (NDP-. alpha. -MSH)
MC1-R MC3-R MC4-R MC5-R
59 78 87 83
Ki(nM)(NDP-α-MSH)
MC1-R MC3-R MC4-R MC5-R
190 162 134 291
In the cAMP assay used to determine functionality in MC4-R expressing cell lines, the maximum effect observed for the compound was 40% of the maximum observed for NDP- α -MSH.
Example 22N- {3- [ (2R, 5R) -1- ((R) -2-amino-3-naphthalen-2-yl-propionyl) -5-benzyl-4- (2-naphthalen-2-yl-acetyl) -piperazin-2-yl]-propyl } -guanidine
The following compounds were synthesized by the procedure of scheme 2, using 2-naphthylacetic acid as J-COOH, D-Phe-OH as NHCH2(R2) -COOH, and Boc-D-2' -naphthylAlanine as Q-COOH, where D-Om (Boc) -OMe was used in steps 2-4. After purification, the compounds were tested as described above and the results were displayed. The mass analysis was 641.3(M + H).
Figure A20068003538100802
Inhibition at 1. mu.M (NDP-. alpha. -MSH)
MC1-R MC3-R MC4-R MC5-R
19 39 80 44
Ki(nM)(NDP-α-MSH)
MC1-R MC3-R MC4-R MC5-R
＞1000 300 121 493
Example 23N- {3- [ (2S, 5R) -1- [ (R) -2-amino-3- (2, 4-dimethyl-phenyl) -propyl]-5-cyclohexylmethyl-4- (2-naphthalen-2-yl-acetyl) -piperazin-2-yl]-propyl } -guanidine
The following compounds were synthesized by the procedure of scheme 1, using 2-naphthylacetic acid as J-COOH and Fmoc-D-Cha-OH as Fmoc-NHCH2(R2) -COOH, and Boc-D-2, 4-dimethyl-phenylalanine as Q-COOH. After purification, the compounds were tested as described above and the results were displayed. The mass analysis was 610.8(M + H).
Figure A20068003538100811
Inhibition at 1. mu.M (NDP-. alpha. -MSH)
MC1-R MC3-R MC4-R MC5-R
12％ 15％ 90％ 28％
Ki(nM)(NDP-α-MSH)
MC1-R MC3-R MC4-R MC5-R
＞1000 494 89 269
Ki(nM) (AgRP)
MC3-R MC4-R
＞1000 89
In the cAMP assay used to determine functionality with MC4-R, the determination of the compound at a concentration of 1 μ M did not show any response.
Example 24N- {3- [ (2S, 5R) -1- [ (R) -2-amino-3- (2, 4-dichloro-phenyl) -propyl]-5-cyclohexylmethyl-4- (2-naphthalen-2-yl-acetyl) -piperazin-2-yl]-propyl } -guanidine
The following compounds were synthesized by the procedure of scheme 1, using 2-naphthylacetic acid as J-COOH and Fmoc-D-Cha-OH as Fmoc-NHCH2(R2) -COOH, and Boc-D-2, 4-dichloro-phenylalanine as Q-COOH. After purification, the compounds were tested as described above and the results were displayed. The mass analysis was 650.6(M + H).
Figure A20068003538100821
Inhibition at 1. mu.M (NDP-. alpha. -MSH)
MC1-R MC3-R MC4-R MC5-R
14％ 27％ 90％ 42％
Ki(nM)(NDP-α-MSH)
MC1-R MC3-R MC4-R MC5-R
＞1000 411 100 325
Ki(nM) (AgRP)
MC3-R MC4-R
＞1000 74
In the cAMP assay used to test functionality in MC4-R expressing cell lines, the maximal effect observed for the compound was 22% of the maximum obtained for NDP- α -MSH.
In the mouse model IP feeding study, there was an 11% reduction in food intake observed over a 20 hour period at the 1mg/kg dose level.
Example 25N- {3- [ (2S, 5R) -5-cyclohexylmethyl-1- [ (R) -3- (2, 4-dichloro-phenyl) -2-dimethylamino-propyl]-4- (2-naphthalen-2-yl-acetyl) -piperazin-2-yl]-propyl } -guanidine
The following compounds were synthesized by the procedure of scheme 1, using 2-naphthylacetic acid as J-COOH and Fmoc-D-Cha-OH as Fmoc-NHCH2(R2) -COOH, and Fmoc-D-2, 4-dichloro-phenylalanine as Q-COOH. Methylation of amines was performed by dissolving compounds 1-9 in ethanol and stirring under one atmosphere of hydrogen in the presence of catalytic amounts of Pd/C (10%). The reaction was continued at room temperature overnight and the catalyst was removed by filtration. The solvent was removed to give the crude product. This crude product was dissolved in THF and reacted with Q-aldehyde derived from Q-COOH in the manner described for the formation of compounds 1-4. Purification through silica gel column gave Fmoc-and Boc-protected compounds. Fmoc was removed with 30% diethylamine in EtOAc for 2 hours. The solvent was removed and the residue was dissolved in dichloroethane. To this solution was added formaldehyde (37% water (aq.) solution, 10 equivalents). After stirring for 10 min, sodium triacetoxyborohydride (5 equivalents) was added. Next, the mixture was stirred at room temperature overnight. The reaction was washed with water, brine and dried over sodium sulfate. After removal of the solvent, the product was treated with TFA/DCM (50: 50) for 1 hour and purified by HPLC to afford the purified compound. After the purification, the mixture is subjected to a purification treatment,compounds were tested as described above and the results were displayed. The mass analysis was 678.7(M + H).
Figure A20068003538100841
Inhibition at 1. mu.M (NDP-. alpha. -MSH)
MC1-R MC3-R MC4-R MC5-R
67％ 75％ 98％ 91％
Ki(nM)(NDP-α-MSH)
MC1-R MC3-R MC4-R MC5-R
146 198 10 143
Ki(nM) (AgRP)
MC3-R MC4-R
241 13
In the cAMP assay for determining functionality, the determination of the compound at a concentration of 1 μ M did not show any response.
In the mouse model IP feeding study, a 3% reduction in food intake was observed at 20 hours at the 3mg/kg dose level.
Example 26(R) -2-amino-1- { (2R, 5S) -4- [ (R) -2-amino-3- (2, 4-dimethyl-phenyl) -propionyl]-5- [3- (2-amino-ethylamino) -propyl]-2-cyclohexylmethyl-piperazin-1-yl } -3- (2, 4-dimethyl-phenyl) -propan-1-one
The following compounds were synthesized by the procedure of scheme 3, using Boc-2, 4-dimethyl-phenylalanine as Q-COOH and D-cyclohexylalanine as NH2CH(R2) -COOMe. After purification, compounds were tested as described above and the results shown. The mass analysis was 632.8(M + H).
Inhibition at 1. mu.M (NDP-. alpha. -MSH)
hMC1-R MC3-R MC4-R MC5-R
35 22 83 43
Ki(nM)(NDP-α-MSH)
MC1-R MC3-R MC4-R MC5-R
ND ND 81 ND
Example 27(R) -2-amino-1- { (2R, 5S) -4- [ (R) -2-amino-3- (2, 4-dichloro-phenyl) -propionyl]-5- [3- (2-amino-ethylamino) -propyl]-2-cyclohexylmethyl-piperazin-1-yl } -3- (2, 4-dichloro-phenyl) -propan-1-one
The following compounds were synthesized by the procedure of scheme 3, using Boc-2, 4-dichloro-phenylalanine as Q-COOH and D-cyclohexylalanine as NH2CH(R2) -COOMe. After purification, the compounds were tested as described above and the results were displayed. The mass analysis was 712.6(M + H).
Figure A20068003538100852
Inhibition at 1. mu.M (NDP-. alpha. -MSH)
hMC1-R MC3-R MC4-R MC5-R
27％ 36％ 83％ 31％
Ki(nM)(NDP-α-MSH)
MC1-R MC3-R MC4-R MC5-R
ND ND 74 ND
Example 28(R) -2-amino-1- [ (2R, 5S) -5- [3- (2-amino-ethylamino) -propyl]-4- ((R) -2-amino-3-naphthalen-2-yl-propionyl) -2-cyclohexylmethyl-piperazin-1-yl]-3-naphthalen-2-yl-propan-1-one
The following compounds were synthesized by the procedure of scheme 3, using Boc-D-2' -naphthylalanine as Q-COOH and D-cyclohexylalanine as NH2CH(R2) -COOMe. After purification, the compounds were tested as described above and the results were displayed. The mass analysis was 676.6(M + H).
Figure A20068003538100861
Ki(nM)(NDP-α-MSH)
hMC1-R MC3-R MC4-R MC5-R
22 36 81 30
Ki(nM)(NDP-α-MSH)
MC1-R MC3-R MC4-R MC5-R
ND ND 99 ND
Example 29(R) -2-amino-1- [ (2S, 5R) -2- [4- (2-amino-ethylamino) -butyl]-4- ((R) -2-amino-3-naphthalen-2-yl-propionyl) -5-cyclohexylmethyl-piperazin-1-yl]-3-naphthalen-2-yl-propan-1-one
The following compounds were synthesized by the procedure of scheme 4, using Boc-D-2' -naphthylalanine as Q-COOH and D-cyclohexylalanine as NH2CH(R2) -COOMe. After purification, compounds were tested as described aboveAnd displaying the result. The mass analysis was 691.3(M + H).
Figure A20068003538100871
Ki(nM)(NDP-α-MSH)
hMC1-R MC3-R MC4-R MC5-R
153 435 20 103
IN the mouse model IN feeding study, there was a 14% and 18% reduction IN food intake observed at 20 hours, at 0.1 and 0.3mg/kg dose levels, respectively.
Example 30(R) -2-amino-1- { (2S, 5R) -4- [ (R) -2-amino-3- (2, 4-dichloro-phenyl) -propionyl]-2- [4- (2-amino-ethylamino) -butyl]-5-cyclohexylmethyl-piperazin-1-yl } -3- (2, 4-dichloro-phenyl) -propan-1-one
The following compounds were synthesized by the procedure of scheme 4, using Boc-2, 4-dichloro-phenylalanine as Q-COOH and D-cyclohexylalanine as NH2CH(R2) -COOMe. After purification, the compounds were tested as described above and the results were displayed. The mass analysis was 727(M + H).
Figure A20068003538100881
Ki(nM)(NDP-α-MSH)
hMC1-R MC3-R MC4-R MC5-R
270 443 17 139
Similar success can be achieved by repeating the preceding examples by replacing those used in the preceding examples with the generically or specifically described reactants and/or synthesis conditions of this invention.
While the invention has been described in detail with particular reference to these preferred embodiments, other embodiments can achieve the same results. Variations and modifications of the present invention will be obvious to those skilled in the art and it is intended to cover all such modifications and equivalents. All references, patent applications, patents, and publications cited above and corresponding applications are hereby incorporated by reference in their entirety.

Claims (24)

1. A compound having the structural formula I:
or an enantiomer, stereoisomer or diastereoisomer thereof, or a pharmaceutically acceptable salt thereof.
Wherein
J is a ring structure selected from the group consisting of: substituted or unsubstituted aromatic carbocyclic ring, substituted or notSubstituted non-aromatic carbocyclic ring, substituted or unsubstituted aromatic fused carbo-heterocyclic ring group wherein the rings are joined by a bond, -CH2-or-O-linked two substituted or unsubstituted aromatic carbocyclic rings, and a substituted or unsubstituted aromatic fused heterobicyclic group, wherein in each case the rings comprise 5 or 6 ring atoms;
w is a heteroatom unit having at least one cationic center, hydrogen bond donor or hydrogen bond acceptor, wherein at least one heteroatom is nitrogen or oxygen;
q is an aromatic carbocyclic ring selected from the group consisting of: phenyl, substituted phenyl, naphthyl and substituted naphthyl;
L1is a bond or a linker unit comprising 1 to 8 backbone atoms selected from the group consisting of carbon, sulfur, oxygen or nitrogen;
L2is a bond or- (CH)2)z-；
L3Is a bond or a linker unit comprising 1 to 9 backbone atoms selected from the group consisting of carbon, sulfur, oxygen or nitrogen;
to R1a，R1b，R2aAnd R2bThe selection is made such that:
R2aand R2bOne of them is
Figure A20068003538100022
And R is2aAnd R2bThe remainder of (A) is hydrogen and R1aAnd R1bEach of which is hydrogen, R1aAnd R1bTogether form ═ O, or R1aAnd R1bOne of them being C1-C6Aliphatic linear or branched and R1aAnd R2bThe remaining one of (a) is hydrogen,
or R2aAnd R2bEach of which is hydrogen, and is,
and R is1aAnd R1bOne of them is
Figure A20068003538100031
And R is1aAnd R1bThe remaining one is hydrogen;
x is CH2C ═ O or C ═ S:
z is a subscript value of 1 to 6; and
y is a subscript value of 0 to 5;
the carbon atom marked with an asterisk therein can have any stereochemical configuration.
2. The compound of claim 1, wherein J is
Figure A20068003538100032
Figure A20068003538100041
Unsubstituted or substituted with one or more ring substituents.
3. The compound of claim 2, wherein J is substituted with one or more ring substituents independently selected from the group consisting of: hydroxy, halogen, sulfonamide, alkyl, -O-alkyl, aryl, and-O-aryl.
4. The compound of claim 1 wherein Q is
Figure A20068003538100042
And wherein R3a，R3bAnd R3cIs an optional ring substituent and, when one or more are present, is the same or different and is independently hydroxy, halogen, alkyl, -O-alkyl, aryl or-O-arylA group.
5. The compound of claim 4, wherein R3a，R3bOr R3cAt least one of which is-CH3or-O-CH3。
6. The compound of claim 4, wherein R3a，R3bOr R3cAt least one of which is-Cl or-CF3。
7. The compound of claim 1, wherein-L3-Q and-L1-J is the same, wherein Q and J are aromatic carbocyclic rings selected from the group consisting of phenyl, substituted phenyl, naphthyl and substituted naphthyl.
8. The compound of claim 1, wherein W comprises an amine, amide, alcohol, carboxylic acid, ether, ester, guanidine, or urea, more than one of the foregoing, or a combination of the foregoing.
9. The compound of claim 1 wherein W is
Figure A20068003538100043
R4Is that
NH，
O，
CH2Provided that R is5Including the N or the O, and the N or the O,
C6H5provided that R is5Including the N or the O, and the N or the O,
N(CH2)zin which N (CH)2)zAnd R5Together form a ring,
N((CH2)y-CH3)，
NH-C(＝O)，
NH-C(＝O)-NH，
C(＝O)，
C(＝O)-NH，
c (═ O) -O, or
O-C(＝O)；
R5Is that
NH2，
OH，
CH3Provided that R is4Including the N or the O, and the N or the O,
NH-(CH2)zin which NH- (CH)2)zAnd R4Together form a ring,
NH-(CH2)y-CH3，
N(-(CH2)y-CH3)2，
NH-(CH2)z-NH2，
NH-(CH2)z-NH-(CH2)y-CH3，
NH-(CH2)z-N-((CH2)y-CH3)2，
N(-(CH2)y-CH3)-C(＝NH)-NH2，
N(-(CH2)y-CH3)-C(＝N((CH2)y-CH3))-NH2，
NH-C(＝NH)-NH2，
NH-C(＝N((CH2)y-CH3))-NH2，
N(-(CH2)y-CH3)-(CH2)z-NH(CH2)y-CH3，
N(-(CH2)y-CH3)-(CH2)z-N((CH2)y-CH3)2，
N(-(CH2)y-CH3)-C(＝N((CH2)y-CH3))-NH(CH2)y-CH3，
NH-C(＝N((CH2)y-CH3))-NH-(CH2)y-CH3，
N(-(CH2)y-CH3)-C(＝NH)-NH(CH2)y-CH3，
NH-C(＝N((CH2)y-CH3))-N((CH2)y-CH3)2，
N(-(CH2)y-CH3)-C(＝NH)-N((CH2)y-CH3)2，
NH-C(＝O)-(CH2)y-NH2，
O-(CH2)y-CH3，
SO2-NH2，
SO2-NH-(CH2)y-CH3，
SO2-N(-(CH2)y-CH3)2，
SO2-(CH2)y-CH3，
Figure A20068003538100061
wherein one or more of positions 1 to 5 are heteroatoms selected from N for position 1, S, O or NH for positions 2 to 5,
Figure A20068003538100062
wherein none, one or two of positions 1 to 5 are heteroatoms which are opposite to position 1, and R is bound if said position does not comprise C6The position of (A) is selected from N, otherwise from S, O or NH,
Figure A20068003538100063
wherein at least one bond between adjacent ring atoms is a double bond, one or more of positions 1 to 5 is a heteroatom selected from N for position 1 and any double bond position, additionally para2 to 5 said heteroatom is selected from S, O or NH, with the proviso that no more than one position is S or O,
Figure A20068003538100064
wherein at least one bond between adjacent ring atoms is a double bond and one or more of positions 1 to 5 is optionally a heteroatom that binds R for position 1 if that position does not include C6And any double bond position is selected from N, further selected from S, O or NH for positions 2 to 5, provided that no more than one position is S or O,
Figure A20068003538100071
wherein at least one bond between adjacent ring atoms is a double bond, the oxo (oxo) is bound to a ring carbon, and the remaining one or more of positions 1 to 5 is optionally a heteroatom selected from N for position 1 and any double bond position, further selected from S, O or NH for positions 2 to 5, with the proviso that no more than one position is S or O,
Figure A20068003538100072
wherein at least one bond between adjacent ring atoms is a double bond, oxo is bound to a ring carbon, one or more of positions 1 to 5 is optionally a heteroatom to position 1, bound R if said position does not include C6And any double bond position is selected from N, further for positions 2 to 5, the heteroatom is selected from S, O or NH, with the proviso that no more than one position is S or O,
Figure A20068003538100073
wherein one or more of positions 1 to 6 is a heteroatom selected from N for position 1 and S, O or NH for positions 2 to 6,
Figure A20068003538100074
wherein none, one or two of positions 1 to 6 are heteroatoms which are a heteroatom for position 1 and which binds R if said position does not comprise C6The position of (A) is selected from N, otherwise from S, O or NH,
Figure A20068003538100075
wherein at least one bond between adjacent ring atoms is a double bond and one or more of positions 1 to 6 is a heteroatom selected from N for position 1 and any double bond position, further selected from S, O or NH for positions 2 to 6, provided that no more than two positions are S or O,
Figure A20068003538100076
wherein at least one bond between adjacent ring atoms is a double bond and one or more of positions 1 to 6 is optionally a heteroatom that binds R for position 1 if that position does not include C6And any double bond position is selected from N, and further for positions 2 to 6 the heteroatom is selected from S, O or NH, with the proviso that no more than two positions are S or O,
Figure A20068003538100081
wherein at least one bond between adjacent ring atoms is a double bond, the oxo group is bound to a ring carbon, and the remaining one or more of positions 1 to 6 are optionally heteroatoms selected from N for position 1 and any double bond position, and S, O or NH for positions 2 to 6, with the proviso that no more than 2 positions are S or O, or
Figure A20068003538100082
Wherein at least one bond between adjacent ring atoms is a double bond, the oxo group is bound to a ring carbon, and one or more of positions 1 to 6 is optionally a heteroatom that binds R for position 1 if that position does not include C6And any double bond position is selected from N, further selected from S, O or NH for positions 2 to 6, provided that no more than two positions are S or O;
R8is hydroxy, (CH)2)y-CH3，(CH2)y-NH2，NH-(CH2)y-CH3Or N (- (CH)2)y-CH3)2；
t is a subscript value of 0 to 5;
z is a subscript value of 1 to 6; and
y is independently in each occurrence a subscript value of 0 to 5;
with the proviso that any NH or NH in the foregoing2May be substituted with N-Prg or NH-Prg, respectively, wherein each Prg is independently an amine protecting group.
10. The compound of claim 9, wherein each Prg is independently acetyl, adamantyloxy, benzoyl, benzyl, benzyloxycarbonyl, tert-butoxycarbonyl, mesitylene-2-sulfonyl, 4-methoxy-2, 3-6-trimethyl-benzenesulfonyl, 2, 2,4, 6, 7-pentamethyldihydrobenzofuran-5-sulfonyl, 2, 2, 5, 7, 8-pentamethylbenzodihydropyran-6-sulfonyl, 9-fluorenylmethyloxycarbonyl, or tosyl.
11. The compound of claim 1, having the formula:
Figure A20068003538100091
wherein:
R7is H or ═ O;
R8is hydrogen or N (R9aR9b)；
R9aAnd R9bEach independently is hydrogen, acetyl, methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, isobutyl, benzyl, benzoyl, hexanoyl, propionyl, butyryl, pentanoyl, heptanoyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclobutylmethyl, cyclohexyl, cyclohexylmethyl, or polyethylene glycol;
v is independently in each case a subscript value of 0 to 2; and
y is independently in each occurrence a subscript value of 0 to 5;
wherein if R is8Instead of hydrogen, the adjacent carbon atom marked with an asterisk may have any stereochemical configuration.
12. The compound of claim 11, wherein said polyethylene glycol has a molecular formula molecular weight between 100 and 50,000.
13. The compound of claim 1, wherein R2aAnd R2bOne is that
Figure A20068003538100101
And R is2aAnd R2bThe remaining of (C) and R1aAnd R1bBoth are hydrogen.
14. The compound of claim 1, wherein W comprises a monoamine.
15. The compound of claim 1, wherein W comprises N alone and O alone.
16. The compound of claim 1, wherein W comprises-NH-C (═ NH) -NH2。
17. The compound of claim 1, wherein said compound is
N- {3- [ (2S, 5R) -1- ((R) -2-amino-3-naphthalen-2-yl-propionyl) -5-benzyl-4- (2-naphthalen-2-yl-acetyl) -piperazin-2-yl ] -propyl } -guanidine;
n- {3- [ (2S, 5R) -5-benzyl-1- ((R) -2-dimethylamino-3-naphthalen-2-yl-propionyl) -4- (2-naphthalen-2-yl-acetyl) -piperazin-2-yl ] -propyl } -guanidine;
n- {3- [ (2S, 5R) -5-benzyl-1- (4' -chloro-biphenyl-2-carbonyl) -4- (2-naphthalen-2-yl-acetyl) -piperazin-2-yl ] -propyl } -guanidine;
n- {3- [ (2S, 5R) -5-benzyl-1- (4' -chloro-biphenyl-3-carbonyl) -4- (2-naphthalen-2-yl-acetyl) -piperazin-2-yl ] -propyl } -guanidine;
n- {3- [ (2S, 5R) -5-benzyl-1- (4' -chloro-biphenyl-4-carbonyl) -4- (2-naphthalen-2-yl-acetyl) -piperazin-2-yl ] -propyl } -guanidine;
n- {3- [ (2S, 5R) -5-benzyl-1- [2- (4' -chloro-biphenyl-2-yl) -acetyl ] -4- (2-naphthalen-2-yl-acetyl) -piperazin-2-yl ] -propyl } -guanidine;
n- {3- [ (2S, 5R) -5-benzyl-1- (2 ', 4' -dichloro-biphenyl-2-carbonyl) -4- (2-naphthalen-2-yl-acetyl) -piperazin-2-yl ] -propyl } -guanidine;
n- {3- [ (2S, 5R) -5-benzyl-1- (3 ', 4' -dichloro-biphenyl-2-carbonyl) -4- (2-naphthalen-2-yl-acetyl) -piperazin-2-yl ] -propyl } -guanidine;
n- {3- [ (2S, 5R) -5-benzyl-1- (3 ', 5' -dichloro-biphenyl-2-carbonyl) -4- (2-naphthalen-2-yl-acetyl) -piperazin-2-yl ] -propyl } -guanidine;
n- {3- [ (2S, 5R) -1- ((R) -2-amino-3-naphthalen-2-yl-propyl) -5-benzyl-4- (2-naphthalen-2-yl-acetyl) -piperazin-2-yl ] -propyl } -guanidine;
n- {3- [ (2S, 5R) -5-benzyl-1- (2 ', 4' -dichloro-biphenyl-3-carbonyl) -4- (2-naphthalen-2-yl-acetyl) -piperazin-2-yl ] -propyl } -guanidine;
n- {3- [ (2S, 5R) -5-benzyl-1- (2 ', 4' -dichloro-biphenyl-3-carbonyl) -4- (2-naphthalen-2-yl-acetyl) -piperazin-2-yl ] -propyl } -guanidine;
n- {3- [ (2S, 5R) -5-benzyl-1- (3 ', 4' -dichloro-biphenyl-3-carbonyl) -4- (2-naphthalen-2-yl-acetyl) -piperazin-2-yl ] -propyl } -guanidine;
n- {3- [ (2S, 5R) -5-benzyl-1- (3 ', 5' -dichloro-biphenyl-3-carbonyl) -4- (2-naphthalen-2-yl-acetyl) -piperazin-2-yl ] -propyl } -guanidine;
n- {3- [ (2S, 5R) -5-benzyl-1- (3-iodo-benzoyl) -4- (2-naphthalen-2-yl-acetyl) -piperazin-2-yl ] -propyl } -guanidine;
n- {3- [ (2S, 5R) -5-benzyl-1- (2 ', 4' -dichloro-biphenyl-3-ylmethyl) -4- (2-naphthalen-2-yl-acetyl) -piperazin-2-yl ] -propyl } -guanidine;
n- {3- [ (2S, 5R) -5-benzyl-1- (4' -chloro-biphenyl-2-ylmethyl) -4- (2-naphthalen-2-yl-acetyl) -piperazin-2-yl ] -propyl } -guanidine;
n- {3- [ (2S, 5R) -5-benzyl-1- (4' -chloro-biphenyl-3-ylmethyl) -4- (2-naphthalen-2-yl-acetyl) -piperazin-2-yl ] -propyl } -guanidine;
n- {3- [ (2S, 5R) -5-benzyl-1-biphenyl-2-ylmethyl-4- (2-naphthalen-2-yl-acetyl) -piperazin-2-yl ] -propyl } -guanidine;
n- {3- [ (2S, 5R) -1- [ (R) -2-amino-3- (2, 4-dimethyl-phenyl) -propyl ] -5-benzyl-4- (2-naphthalen-2-yl-acetyl) -piperazin-2-yl ] -propyl } -guanidine;
n- {3- [ (2S, 5S) -1- ((R) -2-amino-3-naphthalen-2-yl-propionyl) -5-benzyl-4- (2-naphthalen-2-yl-acetyl) -piperazin-2-yl ] -propyl } -guanidine;
n- {3- [ (2R, 5R) -1- ((R) -2-amino-3-naphthalen-2-yl-propionyl) -5-benzyl-4- (2-naphthalen-2-yl-acetyl) -piperazin-2-yl ] -propyl } -guanidine;
n- {3- [ (2S, 5R) -1- [ (R) -2-amino-3- (2, 4-dimethyl-phenyl) -propyl ] -5-cyclohexylmethyl-4- (2-naphthalen-2-yl-acetyl) -piperazin-2-yl ] -propyl } -guanidine;
n- {3- [ (2S, 5R) -1- [ (R) -2-amino-3- (2, 4-dichloro-phenyl) -propyl ] -5-cyclohexylmethyl-4- (2-naphthalen-2-yl-acetyl) -piperazin-2-yl ] -propyl } -guanidine;
n- {3- [ (2S, 5R) -5-cyclohexylmethyl-1- [ (R) -3- (2, 4-dichloro-phenyl) -2-dimethylamino-propyl ] -4- (2-naphthalen-2-yl-acetyl) -piperazin-2-yl ] -propyl } -guanidine;
(R) -2-amino-1- { (2R, 5S) -4- [ (R) -2-amino-3- (2, 4-dimethyl-phenyl) -propionyl ] -5- [3- (2-amino-ethylamino) -propyl ] -2-cyclohexylmethyl-piperazin-1-yl } -3- (2, 4-dimethyl-phenyl) -propan-1-one;
(R) -2-amino-1- { (2R, 5S) -4- [ (R) -2-amino-3- (2, 4-dichloro-phenyl) -propionyl ] -5- [3- (2-amino-ethylamino) -propyl ] -2-cyclohexylmethyl-piperazin-1-yl } -3- (2, 4-dichloro-phenyl) -propan-1-one;
(R) -2-amino-1- [ (2R, 5S) -5- [3- (2-amino-ethylamino) -propyl ] -4- ((R) -2-amino-3-naphthalen-2-yl-propionyl) -2-cyclohexylmethyl-piperazin-1-yl ] -3-naphthalen-2-yl-propan-1-one;
(R) -2-amino-1- [ (2S, 5R) -2- [4- (2-amino-ethylamino) -butyl ] -4- ((R) -2-amino-3-naphthalen-2-yl-propionyl) -5-cyclohexylmethyl-piperazin-1-yl ] -3-naphthalen-2-yl-propan-1-one; or
(R) -2-amino-1- { (2S, 5R) -4- [ (R) -2-amino-3- (2, 4-dichloro-phenyl) -propionyl ] -2- [4- (2-amino-ethylamino) -butyl ] -5-cyclohexylmethyl-piperazin-1-yl } -3- (2, 4-dichloro-phenyl) -propan-1-one, or a pharmaceutically acceptable salt thereof.
18. A compound having the following structural formula II:
or an enantiomer, stereoisomer or diastereoisomer thereof, or a pharmaceutically acceptable salt thereof.
Wherein,
each J is independently a ring structure selected from the group consisting of: substituted or unsubstituted aromatic carbocyclic ring, substituted or unsubstituted non-aromatic carbocyclic ring, substituted or unsubstituted aromatic fused carbo-heterocyclic group wherein the rings are joined by a bond, -CH2-or-O-linked two substituted or unsubstituted aromatic carbocyclic rings, and a substituted or unsubstituted aromatic fused heterobicyclic group, wherein in each case the rings comprise 5 or 6 ring atoms;
w is a heteroatom unit having at least one cationic center, hydrogen bond donor or hydrogen bond acceptor, wherein at least one heteroatom is nitrogen or oxygen;
L1is a bond or a linker unit comprising 1 to 8 backbone atoms selected from the group consisting of carbon, sulfur, oxygen or nitrogen;
L2is a bond or- (CH)2)z-；
L3Is a bond or a linker unit comprising 1 to 8 backbone atoms selected from the group consisting of carbon, sulfur, oxygen or nitrogen;
to R1a，R1b，R2aAnd R2bIs selected so that
R2aAnd R2bOne is that
Figure A20068003538100131
And R is2aAnd R2bThe remainder of (A) is hydrogen and R1aAnd R1bEach is hydrogen, R1aAnd R1bTogether form ═ O, or R1aAnd R1bOne of them being C1-C6Aliphatic linear or branched and R1aAnd R2bThe remaining one of (a) is hydrogen,
or R2aAnd R2bEach of which is hydrogen, and is,
R1aand R1bIs one of
Figure A20068003538100132
And R is1aAnd
R1bthe remaining one of (a) is hydrogen;
x is CH2C ═ O or C ═ S;
z is a subscript value of 1 to 6; and
y is a subscript value of 0 to 5;
the carbon atom marked with an asterisk therein can have any stereochemical configuration.
19. The compound of claim 18, wherein each J is independently
Figure A20068003538100141
Which is unsubstituted or substituted by one or more ring substituents.
20. The compound of claim 19, wherein J is substituted with one or more ring substituents independently selected from the group consisting of: hydroxy, halogen, sulfonamide, alkyl, -O-alkyl, aryl, and-O-aryl.
21. The compound of claim 18, wherein-L3-J and-L1-J are identical.
22. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
23. Compounds of Structure I
Figure A20068003538100151
Or an enantiomer, stereoisomer or diastereoisomer thereof, or a pharmaceutically-acceptable salt thereof, for use in the manufacture of a medicament for the treatment of a condition responsive to a change in melanocortin receptor function in a human or non-human mammal, wherein
J is a ring structure selected from the group consisting of: substituted or unsubstituted aromatic carbocyclic ring, substituted or unsubstituted non-aromatic carbocyclic ring, substituted or unsubstituted aromatic fused carbo-heterocyclic group wherein the rings are joined by a bond, -CH2-or-O-linked two substituted or unsubstituted aromatic carbocyclic rings, and a substituted or unsubstituted aromatic fused heterobicyclic group, wherein in each case the rings comprise 5 or 6 ring atoms;
w is a heteroatom unit having at least one cationic center, hydrogen bond donor or hydrogen bond acceptor, wherein at least one heteroatom is nitrogen or oxygen;
q is an aromatic carbocyclic ring selected from the group consisting of: phenyl, substituted phenyl, naphthyl and substituted naphthyl;
L1is a bond or comprises 1 to 8A linker unit of a backbone atom selected from the group consisting of carbon, sulfur, oxygen or nitrogen;
L2is a bond or- (CH)2)z-；
L3Is a bond or a linker unit comprising 1 to 8 backbone atoms selected from the group consisting of carbon, sulfur, oxygen or nitrogen;
to R1a，R1b，R2aAnd R2bIs selected so that
R2aAnd R2bOne of them is
Figure A20068003538100152
And R is2aAnd R2bThe remainder of (A) is hydrogen, and R1aAnd R1bEach is hydrogen, R1aAnd R1bTogether form ═ O, or R1aAnd R1bOne is C1-C6Aliphatic linear or branched and R1aAnd R2bThe remaining one is hydrogen and the remaining one is hydrogen,
or R2aAnd R2bEach of which is hydrogen, and is,
R1aand R1bOne of which is
Figure A20068003538100161
Or
Figure A20068003538100162
And R is1aAnd R1bThe remaining one is hydrogen;
x is CH2C ═ O or C ═ S;
z is a subscript value of 1 to 6; and
y is a subscript value of 0 to 5;
the carbon atom marked with an asterisk therein can have any stereochemical configuration.
24. The use of claim 23, wherein the condition responsive to changes in melanocortin receptor function is selected from the group consisting of: male sexual dysfunction, female sexual dysfunction, eating disorders, excess body weight, obesity, substandard body weight and cachexia.
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