WO2002006245A1 - Selective melanin concentrating hormone-1 (mch1) receptor antagonists and uses thereof - Google Patents

Selective melanin concentrating hormone-1 (mch1) receptor antagonists and uses thereof Download PDF

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Publication number: WO2002006245A1
Authority: WO; WIPO (PCT)
Prior art keywords: branched; straight chained; compound; cycloalkyl; alkyl
Prior art date: 2000-07-05

Application number

PCT/US2001/021286

Other languages

English (en)

French (fr)

Inventor

Bharat Lagu

John Wetzel

Mohammad R. Marzabadi

John E. Deleon

Charles Gluchowski

Stewart Noble

Dhanapalan Nagarathnam

George Chiu

Original Assignee

Synaptic Pharmarceutical Corporation

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

2000-07-05

Filing date

2001-07-05

Publication date

2002-01-24

2001-07-05 Application filed by Synaptic Pharmarceutical Corporation filed Critical Synaptic Pharmarceutical Corporation

2001-07-05 Priority to AU73192/01A priority Critical patent/AU783403B2/en

2001-07-05 Priority to EP01952440A priority patent/EP1299362A4/de

2001-07-05 Priority to JP2002512149A priority patent/JP2004504303A/ja

2001-07-05 Priority to CA002384041A priority patent/CA2384041A1/en

2002-01-24 Publication of WO2002006245A1 publication Critical patent/WO2002006245A1/en

2006-01-06 Priority to AU2006200052A priority patent/AU2006200052A1/en

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- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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- C07C233/79—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a ring other than a six-membered aromatic ring
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- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Definitions

MCH Melanin-concentrating hormone
MCH has been reported to participate in a variety of processes including feeding, water balance, energy metabolism, general arousal/attention state, memory and cognitive functions, and psychiatric disorders (for reviews, see Baker, 1991; Baker, 1994; Nahon, 1994; Knigge et al., 1996) . Its role in feeding or body weight regulation is supported by a recent Nature publication (Qu et al., 1996) demonstrating that MCH is overexpressed in the hypothalamus of ob/ob mice compared with o /+ mice, and that fasting further increased MCH mRNA in both obese and normal mice during fasting. MCH also stimulated feeding in normal rats when injected into the lateral ventricles
MCH mRNA levels
the ligand retained biological activity and exhibited specific binding to a variety of cell lines including mouse melanoma (B16-F1, G4F, and G4F-7), PC12, and COS cells.
mouse melanoma B16-F1, G4F, and G4F-7
PC12 PC12
COS cells C12 cells
the K D O.ll ⁇ nM
MCH methylcellulose
lateral hypothalamus a brain area implicated in the regulation of thirst and hunger
orexins A and B which are potent orexigenic agents, have been shown to have very similar localization to MCH in the lateral hypothalamus (Sakurai et al . , 1998).
MCH mRNA levels in this brain region are increased in rats after 24 hours of food-deprivation (Herve and Fellman, 1997); after insulin injection, a significant increase in the abundance and staining intensity of MCH immunoreactive perikarya and fibres was observed concurrent with a significant increase in the level of MCH mRNA (Ba jaoui-Bouhaddi et al . , 1994) . Consistent with the ability of MCH to stimulate feeding in rats (Rossi et al . , 1997) is the observation that MCH mRNA levels are upregulated in the hypothalami of obese ob/ob mice (Qu et al .
MCH appears to act as a functional antagonist of the melanocortin system in its effects on food intake and on hormone secretion within the HPA (hypothalamopituitary/adrenal axis) (Ludwig et al . , 1998) .
the MCH cell group occupies a rather constant location in those areas of the lateral hypothalamus and subthalamus where they lie and may be a part of some of the so-called "extrapyramidal" motor circuits. These involve substantial striato- and pallidofugal pathways involving the thalamus and cerebral cortex, hypothalamic areas, and reciprocal connections to subthalamic nucleus, substantia nigra, and mid-brain centers (Bittencourt et al . , 1992) . In their location, the MCH cell group may offer a bridge or mechanism for expressing hypothalamic visceral activity with appropriate and coordinated motor activity. Clinically it may be of some value 'to consider the involvement of this MCH system in movement disorders, such as Parkinson' s disease and Huntingdon' s Chorea in which extrapyramidal circuits are known to be involved.
MCH may regulate reproductive functions in male and female rats .
MCH transcripts and MCH peptide were found within germ cells in testes of adult rats, suggesting that MCH may participate in stem cell renewal and/or differentiation of early spermatocytes (Hervieu et al . , 1996).
MCH injected directly into the medial preoptic area (MPOA) or ventromedial nucleus (VMN) stimulated sexual activity in female rats (Gonzalez et al . , 1996) .
MCH stimulated luteinizing hormone
anti-MCH antiserum inhibited LH release
the zona incerta which contains a large population of MCH cell bodies, has previously been identified as a regulatory site for the pre-ovulatory LH surge (MacKenzie et al . , 1984).
MCH has been reported to influence release of pituitary hormones including ACTH and oxytocin.
MCH analogues may also be useful in treating epilepsy.
MCH has also been observed to affect behavioral correlates of cognitive functions .
MCH treatment hastened extinction of the passive avoidance response in rats (McBride et al . , 1994), raising the possibility that MCH receptor antagonists may be beneficial for memory storage and/or retention.
a possible role for MCH in the modulation or perception of pain is supported by the dense innervation of the periaqueductal grey (PAG) by MCH-positive fibers.
MCH may participate in the regulation of fluid intake. ICV infusion of MCH in conscious sheep produced diuretic, natriuretic, and kaliuretic changes in response to increased plasma volume (Parkes, 1996) . Together with anatomical data reporting the presence of MCH in fluid regulatory areas of the brain, the results indicate that MCH may be an important peptide involved in the central control of fluid homeostasis in mammals .
the term "antagonist” refers to a compound which binds to, and decreases the activity of, a receptor in the presence of an agonist.
activation may be measured using any appropriate second messenger system which is coupled to the receptor in a cell or tissue in which the receptor is expressed.
second messenger systems are adenylate cyclase, intracellular calcium mobilization, ion channel activation, guanylate cyclase and inositol phospholipid hydrolysis.
agonist refers to a compound which binds to, and increases activity of, a receptor as compared with the activity of the receptor in the absence of any agonist.
the synthesis of novel compounds which bind selectively to the cloned human melanin-concentrating hormone-1 (MCHl) receptor, compared to other cloned G-protein coupled receptors, and inhibit the activation of the cloned receptors as measured in in vi tro assays is disclosed.
MCHl melanin-concentrating hormone-1
the compounds of the present invention may also be used to treat abnormal conditions such as feeding disorders (obesity, bulimia and bulimia nervosa) , sexual/reproductive disorders, depression, anxiety, depression and anxiety, epileptic seizure, hypertension, cerebral hemorrhage, congestive heart failure, sleep disturbances, or any condition in which antagonism of an MCHl receptor may be beneficial.
feeding disorders ovalbumina, bulimia and bulimia nervosa
sexual/reproductive disorders depression, anxiety, depression and anxiety
epileptic seizure hypertension
cerebral hemorrhage congestive heart failure
sleep disturbances or any condition in which antagonism of an MCHl receptor may be beneficial.
the compounds of the present invention may be used to reduce the body mass of a subject.
This invention provides a compound having the structure
each of Y ⁇ , Y 2 , Y 3 , Y 4 and Y 5 is independently -H; straight chained or branched C ⁇ C- ? alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -F, -CI, -Br, or -I; -N0 2 ; -N 3 ; -CN; -OR 3 , -OCOR 3 , -COR 3 , -CON(R 3 ) 2 , or -COOR 3 ; or any two of Y ⁇ / Y 2 , Y 3 , Y 4 and Y 5 present on adjacent carbon atoms can constitute a ethylenedioxy group;
each X is independently S; 0; or NR 3 ; wherein R x is -H; -N0 2 ; -CN; straight chained or branched C- L -C- 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R 3 ) 2 ; -OR 3 ; -(CH 2 ) p OR 3 ; -COR 3 ; -C0 2 R 3 ; -CON(R 3 ) 2 ; or -C0 2 (CH 2 ) n V;
R 2 is -H; straight • chained or branched C 1 -C 7 alkyl, hydroxyalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; C 3 -C 10 cycloalkyl-C 1 -C 10 -alkyl, C 3 -C 10 cycloalkyl-C 1 -C 10 -monofluoroalkyl or C 3 -C 10 cycloalkyl-C ⁇ - C i0 -polyfluoroalkyl; -CN; -CH 2 XR 3 , -CH 2 X (CH 2 ) p NHR 3 , -(CH 2 ) n NHR 3
each R 3 is independently -H; straight chained or branched C 1 -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C alkenyl or alkynyl; C 3 - C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
R 4 is (i)
dashed line represents a single bond or a double bond
each R is independently -H; -F; straight chained or branched C x ⁇ C- ⁇ alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; -N(R 3 ) 2 ; -N0 2 ; -CN; -C0 2 R 3 ; -OR 3 ; or -CON(R 3 ) 2 ;
each V is independently aryl or heteroaryl, optionally substituted with one or more F; CI; Br; I; COR 3 ; C0 2 R 3 ; -CON(R 3 ) 2 ; CN; -N0 2 ; -N(R 3 ) 2 ; -OR 3 ; -SR 3 ; (CH 2 ) q OR 3 ; (CH 2 ) q SR 3 ; straight chained or branched C 1 -C 7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C 2 -C 7 alkenyl, C 2 -C 7 alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; wherein each R 5 is -H; -N0 2 ; -N 3 ;
R 6 is -H; straight chained or branched C x -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R 3 ) 2 ; -OR 3 ; -(CH 2 ) p OR 3 ; -COR 3 ; -C0 2 R 3 ;
-CON(R 3 ) 2 aryl or heteroaryl, optionally substituted with one or more F; CI; Br; I; COR 3 ; C0 2 R 3 ; -CON(R 3 ) 2 ; CN; -N0 2 ; -N(R 3 ) 2 ; -0R 3 ; -SR 3 ; (CH 2 ) q OR 3 ; (CH 2 ) q SR 3 ; straight chained or branched C ] _-C 7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C 2 -C 7 alkenyl, C 2 -C 7 alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
R 7 is H; F; CI; Br; I; -N0 2 ; -N 3 ; -CN; straight chained or branched C ] _-C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R 3 ) 2 ; -OR 3 ; -(CH 2 ) p OR 3 ; -C0R 3 ; -C0 2 R 3 ; or -C0N ( R 3 ) 2 ;
R 8 is independently straight chained or branched C 1 -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
Z is naphthyl, quinolinyl, isoquinolinyl, quinazolinyl, phthalazinyl, quinoxalinyl, indolyl, benzo [b] furanyl, or benzo [b] thiophenyl; wherein the naphthyl, quinolinyl, isoquinolinyl, quinazolinyl, phthalazinyl, quinoxalinyl, indolyl, benzo [b] furanyl, or benzo [b] thiophenyl may be substituted with one or more F; CI; Br; I; C0R 3 ; C0 2 R 3 ; -C0N(R 3 ) 2 ; CN; -N0 2 ; -N(R 3 ) 2 ; -0R 3 ; -SR 3 ; (CH 2 ) g OR 3 ; (CH 2 ) q SR 3 ; straight chained or branched C
each m is independently an integer from 0 to 3 inclusive;
n is independently an integer from 0 to 5 inclusive;
each p is independently an integer from 1 to 7 inclusive;
q is an integer from 1 to 3 inclusive
r is an integer from 0 to 3 inclusive; wherein t is an integer from 2 to 6 inclusive;
This invention further provides a compound having the structure :
each R is independently -H; -F; straight chained or branched C x -C ⁇ j alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; -N(R 3 ) 2 ; -N0 2 ; -CN; -SR 3 ; -C0 2 R 3 ; or
each R x is independently -H; straight chained or branched C 1 -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 - C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -(CH 2 ) 0R 3 ; -C0R 3 ; -C0 2 R 3 ; or -C0N(R 3 ) 2 ;
each R 2 is -H; -N0 2 ; -N 3 ; -CN; straight chained or branched C -C ⁇ alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 - C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R 3 ) 2 ; -0R 3 ; -(CH 2 ) p OR 3 ; -C0R 3 ; -C0 2 R 3 ; or -C0N(R 3 ) 2 ; or aryl or heteroaryl, optionally substituted with one or more F; CI; Br; I; COR 3 ; C0 2 R 3 ; -CON(R 3 ) 2 ; CN; -N0 2 ; -N(R 3 )
each R 3 is independently -H; straight chained or branched C; ⁇ _-C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 - C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
M is aryl or heteroaryl, optionally substituted with one or more F; CI; Br; I; C0R 3 ; C0 2 R 3 ; -C0N(R 3 ) 2 ; CN; -N0 2 ; -N(R 3 ) 2 ; -OR 3 ; ⁇ SR 3 ; (CH 2 ) q 0R 3 ; (CH 2 ) q SR 3 ; straight chained or branched C 1 -C 7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C 2 -C 7 alkenyl, C 2 -C 7 alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
X is (CH 2 ) n , 0, S or NR 3 ;
aryl or heteroaryl optionally substituted with one or more F; CI; Br; I; COR 3 ; C0 2 R 3 ; -CON(R 3 ) 2 ; CN; -N0 2 ; -N(R 3 ) 2 ; -0R 3 ; -SR 3 ; (CH 2 ) q 0R 3 ; (CH 2 ) q SR 3 ; straight chained or branched C ⁇ C- ; alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C 2 -C 7 alkenyl, C 2 -C alkynyl; C 3 -C 7 cycloalkyl;
m is an integer from 0 to 4 inclusive;
n is an integer from 0 to 6 inclusive
p is an integer from 1 to 4 inclusive
q is an integer from 1 to 3 inclusive
This invention also provides a compound having the structure :
each R is independently -H; -F; straight chained or branched C ⁇ C- ? alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; -N(R 3 ) 2 ; -N0 2 ; -CN; -C0 2 R 3 ; -0R 3 ; or -C0N(R 3 ) 2 ;
each R x is independently -H; F; Cl; Br; I; -N0 2 ; -N 3 ; -CN; straight chained or branched C ⁇ C- alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R 3 ) 2 ; -0R 3 ; -(CH 2 ) p 0R 3 ; -C0R 3 ; -C0 2 R 3 ; -CON(R 3 ) 2 ; aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more F; CI; Br; I; COR 3 ; C0 2 R 3 ; -CON(R 3 ) 2 ;
C 1 -C 7 alkyl monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C 2 -C 7 alkenyl, C 2 -C 7 alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
each R 3 is independently -H; straight chained or branched C 1 -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 - C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
R 5 is -H; -N0 2 ; -N 3 ; -CN; straight chained or branched C x -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 - C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R 3 ) 2 ; -OR 3 ; -(CH 2 ) p OR 3 ; -C0R 3 ; -C0 2 R 3 ; -CON(R 3 ) 2 ; aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more F; CI; Br; I; COR 3 ; C0 2 R 3 ; -CON(R 3 ) 2 ; CN; -N0 2 ;
V is H; aryl or heteroaryl, optionally substituted with one or more F; CI; Br; I; COR 3 ; C0 2 R 3 ; -CON(R 3 ) 2 ; CN; -N0 2 ; -N(R 3 ) 2 ; -OR 3 ; -SR 3 ; (CH 2 ) q OR 3 ; (CH 2 ) q SR 3 ; straight chained or branched C ⁇ C-y alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C 2 -C 7 alkenyl, C 2 -C 7 alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
aryl or heteroaryl optionally substituted with one or more F; CI ; Br; I; COR 3 ; C0 2 R 3 ; -CON(R 3 ) 2 ; CN; -N0 2 ; -N(R 3 ) 2 ; -OR 3 ; -SR 3 ; (CH 2 ) q OR 3 ; (CH 2 ) q SR 3 ; straight chained or branched C ⁇ -C ⁇ alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C 2 -C 7 alkenyl, C 2 -C 7 alkynyl; C 3 -C 7 cycloalkyl;
each m is independently an integer from 0 to 3 inclusive;
n is an integer from 0 to 2 inclusive;
t is an integer from 2 to 6 inclusive
each of Y ⁇ r Y 2 , Y 3 , Y and Y 5 is independently -H; straight chained or branched C ] _-C alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C alkenyl or alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -F, -CI, -Br, or -I;
any two of Y , Y 2 , Y 3 , Y 4 and Y 5 present on adjacent carbon atoms can constitute a methylenedioxy group;
each X is independently S; 0; or NR 3 ;
R x is -H; -N0 2 ; -CN; straight chained or branched C ⁇ -C alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R 3 ) 2 ; -OR 3 ; -(CH 2 ) p OR 3 ; -COR 3 ; -C0 2 R 3 ; -CON(R 3 ) 2 ; or C0 2 (CH 2 ) n V;
R 2 is -H; straight chained or branched C ] _-C 7 alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; C 3 -C 10 cycloalkyl-C 1 -C 10 -alkyl, C 3 -C 10 cycloalkyl-Cx-Cx Q -monofluoroalkyl or C 3 -C 10 cycloalkyl-C 1 - C 10 -polyfluoroalkyl; -CN; -CH 2 XR 3 , -CH 2 X (CH 2 ) p NHR 3 , -(CH 2 ) n
each R 3 is independently -H; straight chained or branched C 1 -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 - C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
each R is independently -H; -F; straight chained or branched C ] _-C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; -N(R 3 ) 2 ; -N0 2 ; -CN; -C0 2 R 3 ; -OR 3 ; or -CN(R 3 ) 2 ;
B is N or CY 4 ;
each D is independently C(R 3 ) 2 ; 0; S; NR 3 ; CO; or CS; wherein each ⁇ is independently aryl or heteroaryl, optionally substituted with one or more F; CI; Br; I; COR 3 ; C0 2 R 3 ; -CON(R 3 ) 2 ; CN; -N0 2 ; -N(R 3 ) 2 ; -OR 3 ; -SR 3 ; (CH 2 ) q OR 3 ; (CH 2 ) q SR 3 ; straight chained or branched C ⁇ C- y alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C 2 -C 7 alkenyl, C 2 -C 7 alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or
V is C(R 5 ) 2 ; CR 5 R 6 ; NR 5 or NR 6 ;
W is CR 5 ; CR 6 or N;
Z is S; 0; C(R 3 ) 2 ; or NR 3 ;
each R 5 is -H; -N0 ; -N 3 ; -CN; straight chained or branched C x -C ⁇ alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 - C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R 3 ) 2 ; -OR 3 ; -(CH 2 ) p OR 3 ; -COR 3 ; -C0 2 R 3 ; or -CON(R 3 ) 2 ; -XC0R 8 ; or aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more F; CI; Br; I; COR 3 ; C0 2 R 3 ; -CON(R 3 ) 2 ;
each R 6 is independently -H; straight chained or branched C x -C 7 alkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R 3 ) 2 ; -0R 3 ; -(CH 2 ) p OR 3 ; -C0R 3 ; -C0 2 R 3 ; or -CON(R 3 ) 2 ;
R 7 is -H; aryl or heteroaryl, optionally substituted with one or more F; CI; Br; I; COR 3 ; C0 2 R 3 ; -CON(R 3 ) 2 ; CN; -N0 2 ; -N(R 3 ) 2 ; -OR 3 ; -SR 3 ; (CH 2 ) q OR 3 ; (CH 2 ) q SR 3 ; -XCOR 8 ; straight chained or branched C ] _-C 7 alkyl, monofluoroalkyl, polyfluoroalkyl, or aminoalkyl; straight chained or branched C 2 -C alkenyl, C 2 -C 7 alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
R 8 is -H; straight chained or branched C ] _-C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R 3 ) 2 ; -OR 3 ; -(CH 2 ) p OR 3 ; -COR 3 ; -C0 2 R 3 ; or -CON(R 3 ) 2 ; aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; COR 3 ; C0 2 R 3 ; -CON(R 3 ) 2 ; CN; -N0 2 ; -N(R 3 ) 2 ; -OR 3 ; -SR 3 ; (CH 2 ) )
b is 1 or 2;
d is an integer from 0 to 2 inclusive;
each m is independently an integer from 0 to 3 inclusive;
n is independently an integer from 0 to 5 constitu ive ;
each p is independently an integer from 1 to 7 inclusive;
q is an integer from 1 to 3 inclusive
t is an integer from 2 to 6 ' inclusive;
each of Y , Y 2 , Y 3 , Y and Y 5 is independently -H; straight chained or branched C ⁇ ⁇ -C-y alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -F, -Cl, -Br, or -I;
any two of Y ⁇ r Y 2 , Y 3 , Y 4 and Y 5 present on adjacent carbon atoms can constitute a methylenedioxy group;
each X is independently S; 0; or NR 3 ; wherein R- L is -H; -N0 2 ; -CN; straight chained or branched C ⁇ -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R 3 ) 2 ; -OR 3 ; -(CH 2 ) p OR 3 ; -COR 3 ; -C0 2 R 3 ; -C0N(R 3 ) 2 ; or C0 2 (CH 2 ) n V;
R 2 is -H; straight chained or branched C ⁇ -C- 7 alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; C 3 -C 10 cycloalkyl-C 1 -C 10 -alkyl, C 3 -C 10 cycloalkyl-C 1 -C 10 -monofluoroalkyl or C 3 -C 10 cycloalkyl-C ] ⁇ - C 10 -polyfluoroalkyl; -CN; -CH 2 XR 3 , -CH 2 X (CH 2 ) p NHR 3 , -(CH 2 ) n
each R 3 is independently -H; straight chained or branched C -C ⁇ alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 - C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
each R is independently -H; -F; straight chained or branched C 1 -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; -N(R 3 ) 2 ; -N0 2 ; -CN; -C0 2 R 3 ; -OR 3 ; or -CN(R 3 ) 2 ;
B is N or CY 4 ;
each D is independently C(R 3 ) 2 ; 0; S; NR 3 ; CO; or CS; wherein each U is independently aryl or heteroaryl, optionally substituted with one or more F; CI; Br; I; COR 3 ; C0 2 R 3 ; -CON(R 3 ) 2 ; CN; -N0 2 ; -N(R 3 ) 2 ; -OR 3 ; -SR 3 ; (CH 2 ) q OR 3 ; (CH 2 ) q SR 3 ; straight chained or branched C; L -C 7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C 2 -C 7 alkenyl, C 2 -C alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycl
V is C(R 5 ) 2 ; CR 5 R 6 ; NR 5 or NR 6 ;
W is CR 5 ; CR 5 or N;
Z is S; 0; C(R 3 ) 2 ; or NR 3 ;
each R 5 is -H; -N0 2 ; -N 3 ; -CN; straight chained or branched C ⁇ ⁇ -C-y alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 - C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R 3 ) 2 ; -0R 3 ; -(CH 2 ) p 0R 3 ; -COR 3 ; -C0 2 R 3 ; or -CON(R 3 ) 2 ; -XC0R 8 ; or aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more F; CI; Br; I; COR 3 ; C0 2 R 3 ; -CON(R 3
each R 6 is independently -H; straight chained or branched C 1 -C 7 alkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R 3 ) 2 ; -0R 3 ; -(CH 2 ) p OR 3 ; -COR 3 ; -C0 2 R 3 ; or -CON(R 3 ) 2 ;
R 7 is -H; aryl or heteroaryl, optionally substituted with one or more F; CI; Br; I; C0R 3 ; C0 2 R 3 ; -CON(R 3 ) 2 ; CN; -N0 2 ; -N(R 3 ) 2 ; -0R 3 ; -SR 3 ; (CH 2 ) q 0R 3 ; (CH 2 ) q SR 3 ; -XC0R 8 ; straight chained or branched C ⁇ C ⁇ y alkyl, monofluoroalkyl, polyfluoroalkyl, or aminoalkyl; straight chained or branched C 2 -C 7 alkenyl, C 2 -C 7 alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
R 8 is -H; straight chained or branched Ci-C-y alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R 3 ) 2 ; -0R 3 ; -(CH 2 ) p OR 3 ; -COR 3 ; -C0 2 R 3 ; or -C0N(R 3 ) 2 ; aryl or heteroaryl, optionally substituted with one or more F; CI; Br; I; C0R 3 ; C0 2 R 3 ; -CON(R 3 ) 2 ; CN; -N0 2 ; -N(R 3 ) 2 ; -OR 3 ; -SR 3 ; (CH 2 )
b is 1 or 2;
d is an integer from 0 to 2 inclusive;
each m is independently an integer from 0 to 3 inclusive;
n is independently an integer from 0 to 5 inclusive ;
each p is independently an integer from 1 to 7 inclusive;
q is an integer from 1 to 3 inclusive
t is an integer from 2 to 6 inclusive
the present invention provides a method of treating a subject suffering from depression and/or anxiety which comprises administering to the subject a compound of the aforementioned formula in an amount effective to treat the subject's depression and/or anxiety.
This invention also provides a method of modifying feeding behavior of a subject which comprises administering to the subject an amounr. of a compound effective to decrease the consumption of food by the subject wherein the compound is selected from the group consisting of:
This invention further provides a method of treating a feeding disorder in a subject which comprises administering to the subject an amount of a compound of the invention effective to decrease the consumption of food by the subject.
This invention also provides a pharmaceutical composition
a pharmaceutical composition comprising a therapeutically effective amount of the compound of the invention and a pharmaceutically acceptable carrier.
This invention further provides a pharmaceutical composition made by combining a therapeutically effective amount of the compound of this invention and a pharmaceutically acceptable carrier.
This invention further provides a process for making a pharmaceutical composition comprising combining a therapeutically effective amount of the compound of the invention and a pharmaceutically acceptable carrier.
This invention provides a compound having the structure
each of Y x , Y 2 , Y 3 , Y 4 and Y 5 is independently -H; straight chained or branched C ⁇ C- alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -F, -CI, -Br, or -I; -N0 2 ; -N 3 ; -CN; -OR 3 , -OCOR 3 , -C0R 3 , -CON(R 3 ) 2 , or -COOR 3 ; or any two of Y x , Y 2 ,
Y 3 , Y 4 and Y 5 present on adjacent carbon atoms can constitute a methylenedioxy group
each X is independently S; 0; or NR 3 ;
R x is -H; -N0 2 ; -CN; straight chained or branched Ci-C- alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R 3 ) 2 ; -OR 3 ; -(CH 2 ) p 0R 3 ; -COR 3 ; -C0 2 R 3 ; -CON(R 3 ) 2 ; or -C0 2 (CH 2 ) n V;
R 2 is -H; straight chained or branched C 1 -C 7 alkyl, hydroxyalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; C 3 -C 10 cycloalkyl-C 1 -C 10 -alkyl, C 3 -C 10 cycloalkyl-C 1 -C 10 -monofluoroalkyl or C 3 -C 10 cycloalkyl-C L - C 10 -polyfluoroalkyl; -CN; -CH 2 XR 3 , -CH 2 X (CH 2 ) p NHR 3 , -(CH 2 ) n NHR 3 , -(
each R 3 is independently -H; straight chained or branched C j ⁇ -C- alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 - C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
dashed line represents a single bond or a double bond
each R is independently -H; -F; straight chained or branched C x -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; -N(R 3 ) 2 ; -N0 2 ; -CN; -C0 2 R 3 ; -0R 3 ; or -CON(R 3 ) 2 ;
each V is independently aryl or heteroaryl, optionally substituted with one or more F; CI; Br; I; COR 3 ; C0 2 R 3 ; -CON(R 3 ) 2 ; CN; -N0 2 ; -N(R 3 ) 2 ; -OR 3 ; -SR 3 ; (CH 2 ) q OR 3 ; (CH 2 ) q SR 3 ; straight chained or branched C- L -C 7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C 2 -C 7 alkenyl, C 2 -C 7 alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
each R 5 is -H; -N0 2 ; -N 3 ; -CN; straight chained or branched C ⁇ C- alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 - C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R 3 ) 2 ; -0R 3 ; -(CH 2 ) p 0R 3 ; -COR 3 ; -C0 2 R 3 ; -CON(R 3 ) 2 ; aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more F; CI; Br; I; C0R 3 ; C0 2 R 3 ; -CON(R 3 ) 2 ; CN; -N0 2 ;
R 6 is -H; straight chained or branched C x -C ⁇ alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R 3 ) 2 ; -0R 3 ; -(CH 2 ) p OR 3 ; -COR 3 ; -C0 2 R 3 ;
-CON(R 3 ) 2 aryl or heteroaryl, optionally substituted with one or more F; CI; Br; I; C0R 3 ; C0 2 R 3 ; -CON(R 3 ) 2 ; CN; -N0 2 ; -N(R 3 ) 2 ; -OR 3 ; -SR 3 ; (CH 2 ) q 0R 3 ; (CH 2 ) q SR 3 ; straight chained or branched C ⁇ C-y alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C 2 -C 7 alkenyl, C 2 -C 7 alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
R 7 is H; F; CI; Br; I; -N0 2 ; -N 3 ; -CN; straight chained or branched C x -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R 3 ) 2 ; -0R 3 ; -(CH 2 ) p 0R 3 ; -COR 3 ; -C0 2 R 3 ; or -CON(R 3 ) 2 ;
R 8 is independently straight chained or branched C- L -C- 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
Z is naphthyl, quinolinyl, isoquinolinyl, quinazolinyl, phthalazinyl, quinoxalinyl, indolyl, benzo [b] furanyl, or benzo [b] thiophenyl; wherein the naphthyl, quinolinyl, isoquinolinyl, quinazolinyl, phthalazinyl, quinoxalinyl, indolyl, benzo [b] furanyl, or benzo [b] thiophenyl may be substituted with one or more F; CI; Br; I; COR 3 ; C0 2 R 3 ; -CON(R 3 ) 2 ; CN; -N0 2 ; -N(R 3 ) 2 ; -0R 3 ; -SR 3 ; (CH 2 ) q OR 3 ; (CH 2 ) q SR 3 ; straight chained or branched C 1 -
n is independently an integer from 0 to 5 inclusive;
each p is independently an integer from 1 to 7 inclusive; wherein q is an integer from 1 to 3 inclusive;
r is an integer from 0 to 3 inclusive;
t is an integer from 2 to 6 inclusive
the compounds of this invention comprise the (+) enantiomer. In another embodiment, the compounds comprise the (-) enantiomer.
the compound has the structure:
the compound has the structure:
the compound has the structure:
the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
the compound has the structure:
the compound has the structure
the compound has the structure:
A is
the compound has the structure :
the compound has the structure:
the compound has the structure
the compound has the structure :
the compound has the structure :
the compound has the structure
the compound has the structure :
the compound has the structure
A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
the compound has the structure
the compound has the structure:
the compound has the structure :
the compound has the structure:
A is
the compound has the structure
the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
the compound is ( - ) -1, 2 , 3 , 6-tetra-hydro-l- ⁇ n- [4- (3 , -acet-amido) -phenyl- piperidin-1-yl] ropyl ⁇ carboxamido-4-methoxymethyl-6- (3,4- difluoro-phenyl) -2-oxopyrimidine-5-carboxylic acid methyl ester.
the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N
the compound has the structure
each R is independently -H; -F; straight chained or branched C 1 -C 7 alkyl, monofluoroalkyl or j polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; -N(R 3 ) 2 ; -N0 2 ; -CN; -SR 3 ; -C0 2 R 3 ; or
each R x is independently -H; straight cha'ined or branched C--C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C alkenyl or alkynyl; C 3 - C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -(CH 2 ) p OR 3 ; -COR 3 ; -C0 2 R 3 ; or -CON(R 3 ) 2 ;
each R 2 is -H; -N0 2 ; -N 3 ; -CN; straight chained or branched C j ⁇ -C-y alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 - C cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R 3 ) 2 ; -0R 3 ; -(CH 2 ) p OR 3 ; -COR 3 ; -C0 2 R 3 ; or -CON(R 3 ) 2 ; or aryl or heteroaryl, optionally substituted with one or more F; CI; Br; I; COR 3 ; C0 2 R 3 ; -CON(R 3 ) 2 ; CN; -N0 2 ; -N(R 3 )
each R 3 is independently -H; straight chained or branched C x -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 - C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
M is aryl or heteroaryl, optionally substituted with one or more F; CI; Br; I; C0R 3 ; C0 2 R 3 ; -CON(R 3 ) 2 ; CN; -N0 2 ; -N(R 3 ) 2 ; -OR 3 ; -SR 3 ; (CH 2 ) q OR 3 ; (CH 2 ) q SR 3 ; straight chained or branched C 1 -C alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C 2 -C 7 alkenyl, C 2 -C 7 alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
X is (CH 2 ) n , O, S or NR 3 ;
aryl or heteroaryl optionally substituted with one or more F; Cl; Br; I; COR 3 ; C0 2 R 3 ; -CON(R 3 ) 2 ; CN; -N0 2 ; -N(R 3 ) 2 ; -OR 3 ; -SR 3 ; (CH 2 ) q OR 3 ; (CH 2 ) q SR 3 ; straight chained or branched C;L-C 7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C 2 -C 7 alkenyl, C 2 -C 7 alkynyl; C 3 -C 7 cycloalkyl;
n is an integer from 0 to 6 inclusive
p is an integer from 1 to 4 inclusive
q is an integer from 1 to 3 inclusive
the compounds of this invention comprise the (+) enantiomer. In another embodiment, the compounds comprise the (-) enantiomer.
the compound has the structure:
W is phenyl optionally substituted with one or more F; Cl; Br; I; C0R 3 ; C0 2 R 3 ; -CON(R 3 ) 2 ; CN; -N0 2 ; -N(R 3 ) 2 ; -OR 3 ; -SR 3 ; (CH 2 ) q OR 3 ; or (CH 2 ) q SR 3 .
the compound has the structure
the compound has the structure
each R is independently -H; -F; straight chained or branched C 1 -C alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; -N(R 3 ) 2 ; -N0 2 ; -CN; -C0 2 R 3 ; -OR 3 ; or -CON(R 3 ) 2 ;
each R x is independently -H; F; Cl; Br; I; -N0 2 ; -N 3 ; -CN; straight chained or branched C 1 -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R 3 ) 2 ; -0R 3 ; -(CH 2 ) p OR 3 ; -COR 3 ; -C0 2 R 3 ; -CON(R 3 ) 2 ; aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more F; Cl; Br; I; COR 3 ; C0 2 R 3 ; -CON(R 3 ) 2 ; CN
each R 3 is independently -H; straight chained or branched C 1 -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 - C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
R 5 is -H; -N0 2 ; -N 3 ; -CN; straight chained or branched C ] _-C 7 alkyl, monofluoroalkyl or polyfluoroalkyl ; straight chained or branched C 2 -C alkenyl or alkynyl; C 3 - C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R 3 ) 2 ; -OR 3 ; -(CH 2 ) p OR 3 ; -C0R 3 ; -C0 2 R 3 ; -C0N(R 3 ) 2 ; aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more F; Cl; Br; I; C0R 3 ; C0 2 R 3 ; -C0N(R 3 ) 2 ; CN; -N
V is H; aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; COR 3 ; C0 2 R 3 ; -CON(R 3 ) 2 ; CN; -N0 2 ; -N(R 3 ) 2 ; -OR 3 ; -SR 3 ; (CH 2 ) q OR 3 ;
(CH 2 ) q SR 3 straight chained or branched C- L -C-y alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C 2 -C 7 alkenyl, C -C 7 alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
aryl or heteroaryl optionally substituted with one or more F; Cl; Br; I; COR 3 ; C0 2 R 3 ; -CON(R 3 ) 2 ; CN; -N0 2 ; -N(R 3 ) 2 ; -OR 3 ; -SR 3 ; (CH 2 ) q OR 3 ; (CH 2 ) q SR 3 ; straight chained or branched C x -C 7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C 2 -C 7 alkenyl, C 2 -C 7 alkynyl; C 3 -C 7 cycloalkyl;
each m is independently an integer from 0 to 3 inclusive;
n is an integer from 0 to 2 inclusive;
p is an integer from 1 to 7 inclusive
q is an integer from 1 to 3 inclusive
t is an integer from 2 to 6 inclusive
the compounds of this invention comprise the (+) enantiomer. In another embodiment, the compounds comprise the (-) enantiomer.
the compound has the structure :
the compound has the structure
W is phenyl optionally substituted with one or more F; Cl; Br; I; COR 3 ; C0 2 R 3 ; -CON(R 3 ) 2 ; CN; -N0 2 ; -N(R 3 ) 2 ; -OR 3 ; -SR 3 ; (CH 2 ) q OR 3 ; (CH 2 ) q SR 3 ; or straight chained or branched C 1 -C 7 alkyl groups .
the compound has the structure
aryl includes phenyl and naphthyl and the term “heteroaryl” is used to include five and six membered unsaturated rings that may contain one or more heteroatoms such as oxygen, sulfur, and nitrogen.
heteroaryl groups include, but are not limited to, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl.
heteroaryl is used to include fused bicyclic ring systems that may contain one or more heteroatoms such as oxygen, sulfur and nitrogen.
heteroaryl groups include, but are not limited to, indolizinyl, indolyl, isoindolyl, benzo [b] furanyl, benzo [b] thiophenyl , indazolyl, benzimidazolyl , benzthiazolyl , purinyl, imidazo [2 , 1-jb] thiazolyl, quinolinyl, isoquinolinyl, quinolizinyl, and 2,1,3- benzothiazolyl .
the salts include but are not limited to the acids and bases listed herein.
the salts include, but are not limited to the following inorganic acids: hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and boric acid.
the salts include, but are not limited to the following organic acids: acetic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, maleic acid, citric acid, methanesulfonic acid, benzoic acid, glycolic acid, lactic acid and mandelic acid.
the salts include, but are not limited to the inorganic base, ammonia.
the salts include, but are not limited to the following organic bases: methylamine, ethylamine, propylamine, dimethylamine, diethylamine, trimethylamine, triethylamine, ethylenediamine, hydroxyethyla ine, morpholine, piperazine and guanidine .
This invention further provides for the hydrates and polymorphs of all of the compounds described herein .
the present invention includes within its scope prodrugs of the compounds of the invention.
prodrugs will be functional derivatives of the compounds of the invention which are readily convertible in vivo into the required compound.
the term "administering" shall emcompass the treatment of the various conditions described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient.
Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985.
the present invention further includes metabolites of the compounds of the present invention.
Metabolites include active species produced upon introduction of compounds of this invention into the biological milieu.
This invention further provides a pharmaceutical composition comprising a therapeutically effective amount of the compound of the invention and a pharmaceutically acceptable carrier.
the amount of the compound is an amount from about 0.01 mg to about 800 mg .
the amount of the compound is an amount from about 0.01 mg to about 500 mg .
the amount of the compound is an amount from about 0.01 mg to about 250 mg .
the amount of the compound is an amount from about 0.1 mg to about 60 mg .
the amount of the co pound is an amount from about 1 mg to about 20 mg .
the carrier is a liquid and the composition is a solution.
the carrier is a solid and the composition is a tablet.
the carrier is a gel and the composition is a suppository.
This invention provides a pharmaceutical composition made by combining a therapeutically effective amount of the compound of this invention and a pharmaceutically acceptable carrier.
This invention provides a process for making a pharmaceutical composition comprising combining a therapeutically effective amount of the compound of this invention and a pharmaceutically acceptable carrier.
the "pharmaceutically acceptable carrier” is any physiological carrier known to those of ordinary skill in the art useful in formulating pharmaceutical compositions .
the pharmaceutical carrier may be a liquid and the pharmaceutical composition would be in the form of a solution.
the pharmaceutically acceptable carrier is a solid and the composition is in the form of a powder or tablet.
the pharmaceutical carrier is a gel and the composition is in the form of a suppository or cream.
the compound may be formulated as a part of a pharmaceutically acceptable transdermal patch.
a solid carrier can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents; it can also be an encapsulating material.
the carrier is a finely divided solid which is in admixture with the finely divided active ingredient.
the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain up to 99% of the active ingredient.
Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins .
Liquid carriers are used in preparing solutions, suspensions, emulsions, syrups, elixirs and pressurized compositions.
the active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats.
the liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators .
suitable examples of liquid carriers for oral and parenteral administration include water (partially containing additives as above, e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution) , alcohols (including monohydric alcohols and polyhydric alcohols, e.g. glycols) and their derivatives, and oils
the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate.
Sterile liquid carriers are useful in sterile liquid form compositions for parenteral administration.
the liquid carrier for pressurized compositions can be halogenated hydrocarbon or other pharmaceutically acceptable propellent .
Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by for example, intramuscular, intrathecal, epidural, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously.
the compounds may be prepared as a sterile solid composition which may be dissolved or suspended at the time of administration using sterile water, saline, or other appropriate sterile injectable medium.
Carriers are intended to include necessary and inert binders, suspending agents, lubricants, flavorants, sweeteners, preservatives, dyes, and coatings.
the compound can be administered orally in the form of a sterile solution or suspension containing other solutes or suspending agents (for example, enough saline or glucose to make the solution isotonic), bile salts, acacia, gelatin, sorbitan monoleate, polysorbate 80 (oleate esters of sorbitol and its anhydrides copolymerized with ethylene oxide) and the like.
solutes or suspending agents for example, enough saline or glucose to make the solution isotonic
bile salts for example, enough saline or glucose to make the solution isotonic
acacia gelatin
sorbitan monoleate sorbitan monoleate
polysorbate 80 oleate esters of sorbitol and its anhydrides copolymerized with ethylene oxide
compositions suitable for oral administration include solid forms, such as pills, capsules, granules, tablets, and powders, and liquid forms, such as solutions, syrups, elixirs, and suspensions.
forms useful for parenteral administration include sterile solutions, emulsions, and suspensions.
the present invention also provides a method of modifying feeding behavior of a subject which comprises administering to the subject an amount of a compound effective to decrease the consumption of food by the subject wherein the compound has the structure:
each of Y X l Y 2 , Y 3 , Y 4 and Y 5 is independently -H; straight chained or branched C;-C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C alkenyl or alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -F, -Cl, -Br, or -I; -N0 2 ; -N 3 ; -CN; -OR 3 , -OCOR 3 , -COR 3 , -CON(R 3 ) 2 , or -COOR 3 ; or any two of Y ⁇ r Y 2 , Y 3 , Y 4 and Y 5 present on adjacent carbon atoms can constitute a methylenedioxy group;
each X is independently S; 0; or NR 3 ;
R x is -H; -N0 2 ; -CN; straight chained or branched Ci-C-; alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R 3 ) 2 ; -OR 3 ; -(CH 2 ) p OR 3 ; -COR 3 ; -C0 2 R 3 ; -CON(R 3 ) 2 ; or C0 2 (CH 2 ) n V;
R 2 is -H; straight chained or branched C 1 -C 7 alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; C 3 -C 10 cycloalkyl-C; L -C 10 -alkyl, C 3 -C 10 cycloalkyl-C; L -C 10 -monofluoroalkyl or C 3 -C 10 cycloalkyl-C ; - C 10 -polyfluoroalkyl; -CN; -CH 2 XR 3 , -CH 2 X (CH 2 ) p NHR 3 , -(CH 2 )
each R 3 is independently -H; straight chained or branched C ; -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 - C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
each R is independently -H; -F; straight chained or branched C ⁇ -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; -N(R 3 ) 2 ; -N0 2 ; -CN; -C0 2 R 3 ; -0R 3 ; or -CN(R 3 ) 2 ;
B is N or CY ;
each D is independently C(R 3 ) 2 ; 0; S; NR 3 ; CO; or CS;
each ⁇ is independently aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; COR 3 ; C0 2 R 3 ; -CON(R 3 ) 2 ; CN; -N0 2 ; -N(R 3 ) 2 ; -OR 3 ; -SR 3 ; (CH 2 ) q 0R 3 ; (CH 2 ) q SR 3 ; straight chained or branched C- L -C 7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C 2 -C 7 alkenyl, C 2 -C 7 alkynyl; C 3 -C cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
V is C(R 5 ) 2 ; CR 5 R 6 ; NR 5 or NR 6 ;
Z is S; 0; C(R 3 ) 2 ; or NR 3 ;
each R 5 is -H; -N0 2 ; -N 3 ; -CN; straight chained or branched C ⁇ C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 - C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R 3 ) 2 ; -0R 3 ; -(CH 2 ) p OR 3 ; -C0R 3 ; -C0 2 R 3 ; or -C0N(R 3 ) 2 ; -XC0R 8 ; or aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more F; Cl; Br; I; C0R 3 ; C0 2 R 3 ; -C0N(R 3 )
each R 6 is independently -H; straight chained or branched C j ⁇ -C-y alkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R 3 ) 2 ; -OR 3 ; -(CH 2 ) p OR 3 ; -COR 3 ; -C0 2 R 3 ; or -CON(R 3 ) 2 ;
R is -H; aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; COR 3 ; C0 2 R 3 ;
R 8 is -H; straight chained or branched C x -C alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R 3 ) 2 ; -OR 3 ; -(CH 2 ) p OR 3 ; -COR 3 ; -C0 2 R 3 ; or -CON(R 3 ) 2 ; aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; COR 3 ; C0 2 R 3 ; -CON(R 3 ) 2 ; CN; -N0 2 ; -N(R 3 ) 2 ; -OR 3 ; -SR 3 ; (CH 2 ) q OR
b is 1 or 2;
d is an integer from 0 to 2 inclusive;
each m is independently an integer from 0 to 3 inclusive;
n is independently an integer from 0 to 5 inclusive;
each p is independently an integer from 1 to 7 inclusive;
q is an integer from 1 to 3 inclusive
t is an integer from 2 to 6 inclusive
the compound has the structure
the compound has the structure
the compound has the structure
At least one R 5 group is an aryl or heteroaryl group optionally substituted with one or more F; Cl; Br; I; -N0 2 ; -N(R 3 ) 2 ; -OR 3 ; -XCOR 8 ; or straight chained or branched C- L -C 7 alkyl.
A is :
the compound is selected from the group consisting of:
the compound has the structure
the compound has the structure
A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
R 7 is phenyl, optionally substituted with one or more F; Cl; Br; I; COR 3 ; C0 2 R 3 ; -CON(R 3 ) 2 ; CN; -N0 2 ; -N(R 3 ) 2 ; -OR 3 ; -SR 3 ; (CH 2 ) q OR 3 ; (CH 2 ) q SR 3 ; -XCOR 3 ; or straight chained or branched C- L -C 7 alkyl.
the compound has the structure
the compound has the structure
the compound has the structure
A is
the compound is selected from the group consisting of
the compound has the structure
the compound has the structure
A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
the compound has the structure
the compound has the structure
the compound has the structure
the compound has the structure
the compound has the structure
the compound has the structure
each of Y x , Y 2 , Y 3 ,. Y 4 and Y 5 is independently -H; straight chained or branched C J ⁇ -C- J alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -F, -Cl, -Br, or -I;
any two of Y x , Y 2 , Y 3 , Y 4 and Y 5 present on adjacent carbon atoms can constitute a methylenedioxy group;
each X is independently S; 0; or NR 3 ; wherein R x is -H; -N0 2 ; -CN; straight chained or branched Ci L -C- alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R 3 ) 2 ; ⁇ OR 3 ; -(CH 2 ) p OR 3 ; -COR 3 ; -C0 2 R 3 ; -CON(R 3 ) 2 ; or C0 2 (CH 2 ) n V;
R 2 is -H; straight chained or branched C- L -C 7 alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or .alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; C 3 -C 10 cycloalkyl-C 1 -C 10 -alkyl, C 3 -C 10 cycloalkyl-C 1 -C 10 -monofluoroalkyl or C 3 -C 10 cycloalkyl-Ci- C 10 -polyfluoroalkyl; -CN; -CH 2 XR 3 , -CH 2 X (CH 2 ) p NHR 3 , -(CH 2 ) n
each R 3 is independently -H; straight chained or branched C;-C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 - C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
each R is independently -H; -F; straight chained or branched C; L -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; -N(R 3 ) 2 ; -N0 2 ; -CN; -C0 2 R 3 ; -OR 3 ; or -CN(R 3 ) 2 ;
B is N or CY ;
each D is independently C(R 3 ) 2 ; 0; S; NR 3 ; CO; or CS;
each U is independently aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; COR 3 ; C0 2 R 3 ; -CON(R 3 ) 2 ; CN; -N0 2 ; -N(R 3 ) 2 ; -0R 3 ; -SR 3 ; (CH 2 ) q OR 3 ; (CH 2 ) q SR 3 ; straight chained or branched C; L -C 7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C 2 -C 7 alkenyl, C 2 -C 7 alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
V is C(R 5 ) 2 ; CR 5 R 6 ; NR 5 or NR 6 ;
W is CR 5 ; CR 6 or N;
Z is S; 0; C(R 3 ) 2 ; or NR 3 ;
each R 5 is -H; -N0 2 ; -N 3 ; -CN; straight chained or branched C ⁇ C-y alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 - C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R 3 ) 2 ; -0R 3 ; -(CH 2 ) p OR 3 ; -COR 3 ; -C0 2 R 3 ; or -CON(R 3 ) 2 ; -XCOR 8 ; or aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more F; Cl; Br; I; C0R 3 ; C0 2 R 3 ; -CON(R 3 ) 2 ; CN
each R 6 is independently -H; straight chained or branched C 1 -C 7 alkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
R 7 is -H; aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; COR 3 ; C0 2 R 3 ;
R 8 is -H; straight chained or branched L -C-; alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R 3 ) 2 ; -OR 3 ; -(CH 2 ) p OR 3 ; -COR 3 ; -C0 2 R 3 ; or -CON(R 3 ) 2 ; aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; COR 3 ; C0 2 R 3 ; -CON(R 3 ) 2 ; CN; -N0 2 ; -N(R 3 ) 2 ; -OR 3 ; -SR 3 ; (CH 2 ) q OR
b is 1 or 2;
d is an integer from 0 to 2 inclusive;
each m is independently an integer from 0 to 3 inclusive;
n is independently an integer from 0 to 5 inclusive;
each p is independently an integer from 1 to 7 inclusive;
q is an integer from 1 to 3 inclusive
t is an integer from 2 to 6 inclusive
the present invention provides a method of treating a subject suffering from depression and/or anxiety which comprises administering to the subject a compound of the aforementioned formula in an amount effective to treat the subject's depression and/or anxiety.
This invention also provides a method of modifying feeding behavior of a subject which comprises administering to the subject an amount of a compound effective to decrease the consumption of food by the subject wherein the compound is selected from the group consisting of:
This invention further provides a method of modifying feeding behavior of a subject which comprises administering to the subject an amount of a compound of the present invention effective to decrease the consumption of food by the subject.
This invention also provides a method of treating a feeding disorder in a subject which comprises administering to the subject an amount of a compound of the present invention effective to decrease the consumption of food by the subject.
the feeding disorder is bulimia, obesity or bulimia nervosa.
the subject is a vertebrate, a mammal , a human or a canine .
the compound is administered in combination with food.
a "therapeutically effective amount" is any amount of a compound which, when administered to a subject suffering from a disease against which the compounds are effective, causes reduction, remission, or regression of the disease.
Optimal dosages to be administered may be determined by those skilled in the art, and will vary with the particular compound in use, the strength of the preparation, the mode of administration, and the advancement of the disease condition. Additional factors depending on the particular subject being treated will result in a need to adjust dosages, including subject age, weight, gender, diet, and time of administration.
compositions which need not be pharmaceutical as that term is understood in the art.
Such compositions comprise a compound in accordance with the subject invention in an amount effective to antagonize an MCHl receptor and a suitable carrier.
the invention provides a method of agonizing and/or antagonizing an MCHl receptor which comprises contacting the receptor, e.g. in vitro or in in vivo, with an amount of a compound of this invention effective to agonize and/or antagonize the receptor.
PYRIMIDINE To a stirring solution of 5- (benzyloxycarbonyl) -1, 6-dihydro-2- methoxy-4-ethyl-6- (3 , 4-difluorophenyl) pyrimidine (17.0 g, 44.0 mmol) and 4-dimethylaminopyridine (7.00 g, 57.3 mmol) in CH 2 C1 2 (200 mL) was added 4-nitrophenyl chloroformate as a powder (11.5 g, 57.1 mmol) at room temperature. The reaction mixture was stirred for 12 h and then the solvent was removed in vacuo .
the organic layer was dried over Na 2 S0 4 , filtered and solvent was removed in vacuo.
the resulting mixture of diastereomers was separated by column chromatography (petroleum ether/ether, 9/1 to 4/1) .
the first major product to elute was (+) -5- (benzyloxycarbonyl) -4-ethyl- 1, 6-dihydro-l- ⁇ N- [1- phenyl) -ethyl] ⁇ carboxamido-2- methoxy-6- (3, -difluorophenyl) pyrimidine .
5-METHYLBENZFUROXAN 4-Methyl-2-nitroaniline (100 g, 0.650 mol) was suspended in saturated methanolic sodium hydroxide solution (1.50 L) . This suspension was cooled (5 °C) and aqueous sodium hypochlorite until the red color disappeared. The resulting fluffy yellow precipitate was filtered, washed with cold water and recrystallized from ethanol, giving 5-methylbenzfuroxan (88.2 g, 89 % yield) as a pale yellow solid: H NMR d 2.39 (s, 3 H) , 6.90-7.40 (br m. 3 H) .
5-METHYLBENZOFURAZAN To 5-Methylbenzfuroxan (88.2 g, 0.590 mol) in refluxing EtOH (75 mL) was added dropwise P(OEt) 3 (150 mL) . Heating was continued at reflux temperature for 1 h. The solvent was removed in vacuo and the residue was shaken with water (200 mL) and allowed to stand overnight at (0-5 °C) . The resulting brown solid was filtered, washed with water.
5-DIBROMOMETHYLBENZOFURAZAN An anhydrous solution of 5-methylbenzofurazan (70.0 g, 0.520 mol), N-bromosuccinamide (325 g) , and benzoyl peroxide (0.50 g) in carbon tetrachloride (1.5 L) was heated at reflux temperature with stirring for 30 h. The reaction mixture was washed with water (2 X 500 mL) , dried (NaS0 4 ) , and the solvent was removed in vacuo .
6- (3, 4-DIFLUOROPHENYL) -1,2,3, 6-TETRAHYDRO-2-OXO-5-METHOXY CARBON-YL-4-METHYL-l- ( 4-NITROPHENOXY) CARBONYLPYRIMIDINE : Aqueous 6 N hydrochloric acid (10 mL) was added to a stirring solution of 6- (3, 4-difluorophenyl) -1, 6- dihydro- 2-methoxy-5-methoxycarbonyl- 4-methyl-1-
reaction mixture was cooled to -78 °C and tert- butyl 4-oxo-l-piperidinecarboxylate (40.0 mmol) in THF (40 mL) was added dropwise to the reaction mixture and stirred for 30 minutes.
Tf 2 NPh (15.0 g, 42.0 mmol) in THF (40 mL) was added dropwise to the reaction mixture and the mixture was stirred at 0 °C overnight.
the reaction mixture was concentrated in vacuo, re-dissolved in hexanes/EtOAc (9/1), passed through a plug of alumina and washed with hexanes/EtOAc (9/1) .
TERT-BUTYL 4-[3-(ACETYLAMINO)PHENYL]-l,2,3, 6- TETRAHYDRO-1- PYRIDINECARBOXYLATE A mixture of saturated of aqueous Na 2 C0 3 solution (25 mL) , tert-butyl 4- ⁇ [ (trifluoromethyl) sulfonyl] oxy ⁇ - 1,2,3,6- tetrahydro-1-pyridine-carboxylate (20 mmol) , 3-acet- amidophenylboronic acid (30 mmol) and tetrakis- triphenylphosphine palladium (0) (1.15 g) and dimethoxyethane (40 mL) was heated at reflux temperature overnight.
PIPERIDINECARBOXYLATE A mixture tert-butyl 4- [3- (acetylamino) phenyl] -1,2,3, 6-tetra-hydro-l- pyridinecarboxylate (710 mg) and 5% Pd/C (100 mg) in EtOH (10 mL) was hydrogenated (balloon technique) at room temperature overnight. The reaction mixture was passed through a pad of Celite 545 and the pad of Celite was washed with ethanol. The combined ethanol extracts were concentrated and chromatograghed, giving the desired product (660 mg) . : H NMR ⁇ 7.80 (s, 1 H) , 7.41-7.20 (m, 3
1-BENZYL-4-METHYL-4-PHENYLPIPERIDINE l-Benzyl-4-methyl- piperidin-4-ol (4.81 g, 23.4 mmol) was added to a suspension of A1C1 3 (15.62 g, 117 mmol) in benzene (100 mL) at room temperature under argon. The mixture was stirred at reflux for 24 hours, then cooled and poured cautiously into ice water (100 g of ice, 50 mL of water) . The aqueous phase was adjusted to pH 11-12 by addition of 6 N aqueous NaOH at 0 °C, and extracted with EtOAc (3 x 100 mL) .
the aqueous phase was adjusted to pH 11 by addition of 1 N aqueous NaOH.
the organic phase was separated, dried over magnesium sulfate and concentrated.
the residual oil was purified by flash chromatography (CHCl 3 /MeOH/2 N NH 3 in MeOH 100/4/0 to 100/20/10), giving l-benzyl-4- methyl-4- phenylpiperidine (1.20 g) and 1.10 g (51%, 82% based on consumed starting material) of 4-methyl-4-phenylpiperidine :
the solvent was evaporated from the filtrate and residue was dried under vacuum for 4 h.
the crude product was dissolved in 50 mL of chloroform, stirred for 1 h, and filtered. The white solid was washed with additional chloroform (20 mL) , the solvent was evaporated from the combined filtrates to leave the crude product as an oil .
the oil was purified by column chromatography (dichloromethane / methanol / 2 M ammonia in methanol, 10/3/1), giving the desired product (2.70 g, 93%).
TETRAHYDRO-1-PYRIDINECARBOXYLATE n-Butyl lithium (17.6 mL, 44.2 mmol, 2.5 M in hexanes) was added to a solution of diisopropyl amine (96.2 mL,
1,2, 3, 6-TETRAHYDRO-4- (3-NITROPHENYL) PYRIDINE Into a stirred solution of 5.00 -g (16.0 mmol) of tert-butyl 1,2,3, 6-tetrahydro-4- (3-nitrophenyl) pyridine-1- carboxylate in 100 ml of 1,4-dioxane at 0°C was bubbled HCl gas for 10 minutes. The reaction mixture was allowed to warm to room temperature and the bubbling of the HCl gas was continued for an additional 1 hour. The solvent was removed in vacuo, the residue was dissolved in 50 mL of water and was neutralized by the addition of KOH pellets.
TERT-BUTYL 3- (4- (3-NITROPHENYL) -3 , 6-DIHYDRO-l (2H) - PYRIDINYL) PROPYLCARBAMATE : A mixture of 2.80 g (14.0 mmol) of 1, 2, 3, 6-tetrahydro-4- (3-nitrophenyl) pyridine, 3.60 g (15.0 mmol) of tert-butyl N-(3- bromopropyl) carbamate, 11.6 g (84.0 mmol) of K 2 C0 3 , 14.6 mL (84.0 mmol) of diisopropylethylamine and 0.78 g (2.00 mmol) of tetrabutylammonium iodide in 250 mL of 1,4- dioxane was heated at reflux temperature for 14 hours.
TETRAHYDRO-5-PYRIMIDINECARBOXYLATE A mixture of 3.02 g (6.33 mmol) 5-methyl 1- ( 4-nitrophenyl) (6S)-6-(3,4- difluorophenyl) -4- (methoxymethyl) -2-oxo-3, 6-dihydro- 1, 5 ( 2H) -pyrimidinedicarboxylate, 1.50 g (5.80 mmol) of 3- (4- (3-nitrophenyl) -3, 6-dihydro-l (2H) -pyridinyl) -1- propanamine, 7.94 g (75.5 mmol) of K 2 C0 3 and 1.00 L of methanol in 200 mL dichloromethane (under argon) was stirred at room temperature for 1 hour.
the reaction mixture was filtered and concentrated in vacuo .
the residue was dissolved in 100 L of ethyl acetate and washed 3 X 50 mL of 5% aqueous NaOH solution, the organic layer was dried (MgS0 4 ) and concentrated in vacuo .
the residue was dissolved in 100 mL of anhydrous ethanol containing 0.50 g 10% Pd/C and the reaction mixture was stirred under a hydrogen balloon for 24 hours.
the reaction mixture was passed through a column of Celite 545 filtering agent, washed with ethanol, the filtrate was dried (MgS0 4 ) and concentrated in vacuo .
reaction mixture was flushed with Argon three times, then the reaction mixture was heated to 100 °C for 3 hrs. After cooling to room 'temperature, the reaction mixture was diluted with methylene chloride (30 mL) and water (30 mL) and the organic layer was separated. The aqueous layer was extracted with methylene chloride (3x20 mL) and the combined organic extracts were washed with sat NH 4 C1 (20 mL) and brine (20 mL) , dried over MgS0 4 and concentrated under reduced pressure.
4- (4-Nitrophenyl) -1,2,3, 6 tetrahydropyridine was prepared by a similar procedure to that used for the preparation of 2-methyl-W- [3- ( 4- piperidinyl) phenyl] propanamide using HCl gas and tert- Butyl 4- (4-Nitrophenyl) -3, 6-dihydro-l ⁇ 2H) - pyridinecarboxylate (130 mg) in dioxane (5.0 mL) at room temperature. The reaction mixture was concentrated in va cuo to give the crude product (69.8 mg) that used in the next reaction without further purification.
BENZYL 6- (3 , 4-DIFLUOROPHENYL) -4-ETHYL-2-METHOXY-1 , 6- DIHYDRO-5-PYRIMIDINECARBOXYLATE.
(+) -BENZYL 6- (3, 4-DIFLUOROPHENYL) -4-ETHYL-2-METHOXY-1, 6- DIHYDRO-5-PYRIMIDINECARBOXYLATE.
(+) -benzyl 6- (3, 4-difluorophenyl) -4-ethyl-2-methoxy- 1- ( ⁇ [ (li?) -1-phenylethyl] amino ⁇ carbonyl) -1, 6-dihydro-5- pyrimidinecarboxylate (17.1 mmol, 9.35 g) in CH 2 C1 2 was added 1, 8-diazabicyclo [5, 4 , 0] -undec-7-ene (17.1 mmol, 2.56 mL) and stirring was continued for 16 h at room temperature.
(+) -benzyl 6- (3, 4- difluorophenyl) -4-ethyl-2-methoxy-l, 6-dihydro-5- pyrimidinecarboxylate 6. 4 g, 16.0 mmol
pyridine 1.5 mL
4-nitrophenyl chloroformate (3.41 g, 19.2 mmol) at room temperature.
PYRIMIDINEDICARBOXYLATE Into a well-stirred solution of 6- (3, 4-Difluorophenyl) -1, 6-dihydro-2-methoxy-5- methoxycarbonyl-4-methyl-l- [ (4- nitrophenyloxy) carbonyl] pyrimidine (1.5 mmol, 0.66 g) in 5 L of chloroform was added a solution of bromine (1.5 mmol, 0.09 mL) in 3 mL of chloroform at 0 °C and the solution was allowed to attain room temperature over 1.5 h. The solvent was removed in vacuo and the residue was again dissolved in CHC1 3 (20 mL) and washed with brine.
TERT-BUTYL N-(4-[ ( 1-NAPHTHYLCARBONYL) AMINO] - CYCLOHEXYLMETHYL) -CARBAMATE A mixture of 1-naphthoic acid (1.00 mmol, 0.172 g) , DMAP (2.00 mmol, 0.250 g) and ECD (0.383 g, 2.00 mmol) in dry dichloromethane (20 mL) was stirred at room temperature for 0.5 h followed by the addition of tert-butyl (4-amino) cyclohexyl) ethylcarbamate amine (1.09 mmol, 0.250 g) .
4-ACETYL-l- (3-AMINOPROPYL) -4-PHENYLPIPERIDINE A solution of 4-Acetyl-4-phenylpiperidine (7, 1.53 g, 7.50 mmol), 3-bromo-propylamine hydrobromide (1.64 g, 7.50 mmol) and potassium carbonate (1.24 g, 9.00 mmol) was stirred in refluxing 1,4-dioxane (50 mL) for 12 h. After removal of dioxane, water (50 mL) was added and the pH was adjusted to 11-12 by addition of 1 N aqueous NaOH. The mixture was extracted with CH 2 C1 2 (100 L + 3 x 50 mL) .
the reaction mixture was stirred at room temperature for 12 h.
the reaction mixture was quenched with aqueous 6 N HCl .
the reaction mixture was concentrated to a small volume, partitioned between dichloromethane and water (100 mL each) , the mixture was adjusted to pH 8 by addition of Na 2 C0 3 , the layers were separated, and the aqueous layer was extracted with dichloromethane (3 x 30 mL) .
the combined organic extracts were dried (Na 2 S0 4 ) and the product was chromatographed, giving the desired product.
the HCl salt was prepared by the addition of 1 N HCl in ether to a solution of the product in CH 2 C1 2 .
Example 8 6- (BENZOFURAZAN-5-YL) -1,2,3, 6-TETRAHYDRO-5-METHOXYCARBONY L-4- METHYL-2-OXO-l- ⁇ N- [3- (4-PHENYLPIPERIDIN-l-YL) PROPYL] ⁇ CARBOXAMIDO-PYRIMIDINE: A solution of 6- (benzofurazan- 5-yl) -1, 6-dihydro-2- methoxy-5-methoxycarbonyl- 4 -methyl-1- ⁇ N- [3- (4-phenylpiperidin-l- yl) propyl] ⁇ carboxamidopyrimidine in MeOH was treated with 6 N HCl at 0 °C .
Example 9 4- (3-METHOXY) -PHENYL PIPERIDINE: HCl salt; mp 150-154 °C; l R NMR52.04 (s, br, 2H) , 2.25 (s, br, 2H) , 2.80 (s, br, IH) , 3.09 (s, br, 2H) , 3.66 (s, 2H) , 3.78 (s, 3H) , 6.79 (s, br, 3H) , 7.23 (s, IH) , 9.41 (s, br, IH) .
the compound of Example 10 may also be prepared via hydrogenation of the compoun of example 2 (H 2 balloon method, methanol, Pd/C, overnight) .
a synthetic path analogous to the latter route (Scheme 11) was used in the preparation of the tritiated analog, which in turn, was used as a radioligand in the MCH pharmacological assays.
3- (4-PHENYLPIPERIDIN-l-YL) PROPYLAMINE A solution of BH 3 in THF (1.0 M, 83.0 mL, 83.0 mmol, 3.5 eq) was added to a stirring solution of 3- (4-phenylpiperidin-l-yl) - propionitrile (5.10 g, 24.0 mmol) in anhydrous THF (20 mL) under argon at room temperature. The mixture was heated at reflux temperature for 4.5 hours and then cooled to room temperature. Aqueous 6 N HCl (130 mL) was added and stirring was continued for 2 hours at 50-70 °C .
the mixture was basified to pH 9 by addition of aqueous 6 N NaOH and extracted with EtOAc (100 mL) and CH 2 C1 2 (3 x 100 L) .
the combined organic extracts were dried over magnesium sulfate and concentrated.
the residue was dissolved in CH 2 C1 2 (20 mL) and treated with HCl in ether (1.0 M, 50 mL) .
the solvents were removed, ether (250 mL) was added, the mixture was filtered, and the filter cake was washed with ether. Water ⁇ 60 mL) was added to the resulting white solid, 1 N NaOH was added until pH 10-11 was reached, and then the aqueous phase was extracted with CH 2 C1 2 (3 X 50 mL) .
the combined extracts were dried over magnesium sulfate and the solvents were evaporated, giving the desired product (4.50 g, 87%) .
6-(3,4-DIFLOUROPHENYL) -1,2,3, 6-TETRAHYDRO-5-METHOXYCARBON YL-4- METHYL-2-OXO-l- ⁇ N-[3- (4-PHENYLPIPERIDIN-l-YL) PROPYL] ⁇ CARBOXAMIDO-PYRIMIDINE: A solution of 6- (3, 4- difluorophenyl) -1, 6-dihydro- 2-methoxy-5-methoxy carbonyl-4-methyl-l- ⁇ N- [3- (4-phenyl-piperidin- 1-yl) propyl] ⁇ carboxamidopyrimidine (100 mg, 0.185 mmol, mp 43-45 °C) in MeOH (5 mL) was treated with aqueous 6 N HCl (1.5 mL) at 0 °C .
HYDROBROMIDE A solution. of 2 , 4 ' -dipyridyl (25.0 g, 160 mmol) and 3-bromopropyl-amine hydrobromide (35.0 g, 160 mmol) in DMF (60 mL) was heated at 90-95 °C for 10 h.
3-AMINOPROPYL-4- (2-PYRIDYL) PIPERIDINE A suspension of 3- (3 ' , 6 ' -dihydro-2 ' -H- [2, 4 ' ' ] bipyridinyl-1 ' -yl) -propylamin e (3.48 g crude, 15.9 mmol) and Pearlman's catalyst (1.0 g) in MeOH (40 mL) was hydrogenated under 120 psi for 10 h, after which the reaction mixture was filtered through a pad of Celite and the solvent was removed.
the HCl salt was prepared by treatment of a solution of the free base in ether with 1 N HCl in ether.
the white powder was dried under reduced pressure: 1 H NMR ⁇ 2.05-2.20 (m, 4H) , 2.77-2.88 (m, 2H) , 3.00-3.20 ( , 4H) , 3.35-3.47 (m, 2H) , 3.47 (s, 3H) , 3.64-3.70 (m, 2H) , 3.71 (s, 3H) , 4.05 (br t, IH) , 4.67 (s, 2H) , 6.59 (s, IH) , 7.05-7.20 (m, 3H) , 7.79 (t, IH) , 8.00 (d, IH) , 8.43 (dt, IH) , 8.96 (br t, IH, NH) , 12.4 (br s, IH) . m.p. 188-191
PROPYLAMINE N- ( tert-utoxycarbonyl) -3-bromopropylamine (0.772 g, 3.27 mmol) and potassium carbonate (0.904 g, 6.54 mmol) were added to a stirring solution of the amine (0.566 g, 3.27 mmol) in dioxane ( 20 mL) and the reaction mixture was heated at reflux temperature for 24 h. The reaction mixture was cooled to room temperature, concentrated and partitioned between chloroform (40 mL) and water (5 mL) .
Trifluoroacetic acid (1 ml) was added to 1-tert- butoxycarbonyl-3- (4-spiro [isobenzo-furan-1 (3H) , 4 ' - piperidine] ) propylamine ( 0.180 g, 0.52 mmol) in dichloromethane (5 ml) and the resulting solution was stirred at room temperature for 1 hour. The solution was concentrated, neutralized with 10% KOH solution and extracted into dichloromethane (25 ml) . The organic layer was dried over sodium sulfate, filtered and concentrated, giving propylamine (0.156 g, 100%) which was used in the subsequent step without further purification .
reaction mixture was stirred for another 1 h after addition of 2 mL of 6N HCl.
the combined organic extracts were dried over sodium sulfate, filtered and concentrated.
Example 22 (+) -1,2, 3, 6-TETRAHYDRO-l- (N- [4- (BENZO-4' ,5' (H) FURAN) PIPER IDIN-1- YL] PROPYL ⁇ CARBOXAMIDO-4-ETHYL- 6- (3, 4- DIFLUOROPHENYL) -2-OXO- PYRIMIDINE-5-CARBOXAMIDE HYDROCHLORIDE: DMAP • ECD (0.250 mmol, 0.050 g) was added to a stirred mixture of (+) -1, 2, 3, 6-tetra-hydro-l- ⁇ N- [4- (benzo-4 ' , 5 ' (h) furan) piperidin-1-yl] propyl ⁇ carbox- amido-4-ethyl-6- (3, 4-difluorophenyl) -2-oxo-pyrimidine-5-c arboxyl-ic acid hydrochloride (0.100 mmol, 0.055 g
Example 23 (1) -1,2,3, 6-TETRAHYDRO-l- ⁇ N-[4- ( 3 , 4-DIHYDRO-2-OXOSPIRO- NAPHTHALENE-1 (2H) ) -PIPERIDINE-1-YL] PROPYL ⁇ CARBOXAMIDO-5- METHOXYCARBONYL-2- 0X0-6- ( 3 , 4-BENZOFURAZAN) -4- METHYLPYRIMIDINE HYDROCHLORIDE
Step B 1- (3-AMINOPROPYL) SPIRO [ISOCHROMAN-3 , 4 ' PIPERIDIN] -1-ONE : To 1- (3-tert-Butoxycarbonylaminopropyl) spiro [isochroman-3, 4 ' -piperidin] -1-one (0.144 g, 0.375 mmol) in 5 mL of dichloromethane, 1 mL of trifluoroacetic acid , was added and the solution stirred at room temperature for 1 h. The solution was concentrated, neutralized with 10 % KOH solution and extracted into 25 mL of dichloromethane. The organic layer was dried over sodium sulfate, filtered and concentrated, giving 0.110 g (100%) of the product which was used as such for the subsequent step.
reaction mixture was stirred for another 1 h after addition of 2 mL of 6N HCl.
the organic layer was dried over sodium sulfate, filtered and concentrated.
reaction mixture was stirred for another 1 h after addition of 2 mL of 6N HCl.
the organic layer was dried over sodium sulfate, filtered and concentrated.
Example 42 The product was obtained according to the method described for methyl (4S) -4- (3, 4-difluorophenyl) -3- ( ⁇ [3- (4- ⁇ 3- [ (3, 3-dimethylbutanoyl) amino] phenyl ⁇ -l- piperidinyl) propyl] mino ⁇ carbonyl) -6- (methoxymethyl ) -2- oxo-1, 2,3, 4-tetrahydro-5-pyrimidinecarboxylate .

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AU783403B2 (en)	2005-10-20
EP1299362A1 (de)	2003-04-09
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AU7319201A (en)	2002-01-30
CA2384041A1 (en)	2002-01-24

Publication	Publication Date	Title
AU783403B2 (en)	2005-10-20	Selective melanin concentrating hormone-1 (MCH1) receptor antagonists and uses thereof
US6720324B2 (en)	2004-04-13	Selective melanin concentrating hormone-1 (MCH1) receptor antagonists and uses thereof
AU727972B2 (en)	2001-01-04	Dihydropyrimidines and uses thereof
US6245773B1 (en)	2001-06-12	5-(heterocyclic alkyl)-6-aryl-dihydropyrimidines
US6248747B1 (en)	2001-06-19	5-(heterocyclic alkyl)-6-aryl-dihydropyrimidines
EP1246847A2 (de)	2002-10-09	FüR EINEN HUMANEN MELANIN-KONZENTRIERENDEN REZEPTOR (MCH1) KODIERENDE DNS UND DEREN VERWENDUNGEN
EP1318811B1 (de)	2006-08-30	Cyclopentylmodulatoren der chemokin-rezeptor-aktivität
EP1531816B1 (de)	2009-01-21	Spirozyklische piperidine als mch1-antagonisten und ihre verwendungen
JP4870163B2 (ja)	2012-02-08	Ｍｃｈ受容体アンタゴニストとしてのインダン誘導体
JP2003525928A (ja)	2003-09-02	新規ｃｃｒ５モジュレーター：ベンズイミダゾール類またはベンズトリアゾール類
US7105544B2 (en)	2006-09-12	Substituted alkyl amido piperidines
WO2004064774A2 (en)	2004-08-05	Dna encoding a human melanin concentrating hormone receptor (mch1) and uses thereof
US7473698B2 (en)	2009-01-06	Secondary amino anilinic piperidines as MCH1 antagonists and uses thereof
AU2006200052A1 (en)	2006-02-02	Selective melanin concentrating hormone-1 (MCH1) receptor antagonists and uses thereof
EP1139972A1 (de)	2001-10-10	Dihydropyrimidine und deren verwendungen
JP2006525274A (ja)	2006-11-09	新規なピペリジン誘導体

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