Source: http://www.google.com/patents/US7754722?ie=ISO-8859-1
Timestamp: 2014-07-13 00:48:30
Document Index: 628770150

Matched Legal Cases: ['Application No. 60', 'art 1', 'art 2', 'art 3', 'art 4', 'art 5', 'art 4']

Patent US7754722 - Piperazine derivatives and methods of use - Google PatentsSearch Images Maps Play YouTube News Gmail Drive More »Sign in<nobr>Advanced Patent Search</nobr>PatentsThe invention provides 2-carboxamide piperazine compounds of formula I, R3.IN\′N�′R2I(0)z-oR4I wherein R′, R2, R3 and R4 are as defined in the claims and methods of treatment and pharmaceutical compositions that utilize or comprise one or more such compounds. Compounds of the invention are useful...http://www.google.com/patents/US7754722?utm_source=gb-gplus-sharePatent US7754722 - Piperazine derivatives and methods of useAdvanced Patent SearchPublication numberUS7754722 B2Publication typeGrantApplication numberUS 10/528,437PCT numberPCT/EP2003/050640Publication dateJul 13, 2010Filing dateSep 19, 2003Priority dateSep 20, 2002Fee statusPaidAlso published asCA2499732A1, EP1542993A1, EP1542993B1, US20060223813, US20100305137, US20130143893, WO2004031182A1Publication number10528437, 528437, PCT/2003/50640, PCT/EP/2003/050640, PCT/EP/2003/50640, PCT/EP/3/050640, PCT/EP/3/50640, PCT/EP2003/050640, PCT/EP2003/50640, PCT/EP2003050640, PCT/EP200350640, PCT/EP3/050640, PCT/EP3/50640, PCT/EP3050640, PCT/EP350640, US 7754722 B2, US 7754722B2, US-B2-7754722, US7754722 B2, US7754722B2InventorsSharad Magar, Andreas Goutopoulos, Yihua Liao, Matthias Schwarz, Russell J. ThomasOriginal AssigneeMerck Serono SaExport CitationBiBTeX, EndNote, RefManPatent Citations (14), Non-Patent Citations (4), Classifications (27), Legal Events (5) External Links: USPTO, USPTO Assignment, EspacenetPiperazine derivatives and methods of useUS 7754722 B2Abstract The invention provides 2-carboxamide piperazine compounds of formula I, R3.IN\′N�′R2I(0)z-oR4I wherein R′, R2, R3 and R4 are as defined in the claims and methods of treatment and pharmaceutical compositions that utilize or comprise one or more such compounds. Compounds of the invention are useful for the treatment of mammalian infertility.
CROSS REFERENCE TO RELATED APPLICATIONS This application is a national stage application of International Application No. PCT/EP2003/050640, filed Sep. 19, 2003, which claims priority to U.S. Provisional Application No. 60/412,308, filed Sep. 20, 2002, each of which is incorporated in its entirety by reference herein.
SUMMARY OF THE INVENTION We have now found that 2-carboxamide piperazine compounds are potent Follicle Stimulating Hormone receptor (FSH) agonists. Compounds of the invention are particularly useful for treatment of infertility in mammals.
DETAILED DESCRIPTION OF THE INVENTION We have now discovered that substituted carboxamide piperazine compounds, including compounds of the above Formulae I, II and III, that are useful for treatment of infertility in mammals, including female and male humans.
�C1-C12-alkyl� refers to monovalent alkyl groups having 1 to 12 carbon atoms. This term is exemplified by groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-t-butyl, n-hexyl and the like. By analogy, �C1-C16-alkyl� refers to monovalent alkyl groups having 1 to 16 carbon atoms, �C1-C8-alkyl� refers to monovalent alkyl groups having 1 to 8 carbon atoms and �C1-C6-alkyl� refers to monovalent alkyl groups having 1 to 6 carbon atoms.
�Aryl� refers to an unsaturated aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring or �monocyclic ring� (e.g., phenyl), multiple condensed rings or �polycyclic ring�, including for example �bi-cyclic� ring (e.g., naphthyl), �tri-cyclic� ring (e.g. 9-carbazolyl) or other linked multiple rings (e.g. bi-phenyl). Preferred aryl include phenyl, naphthyl, anthracenyl, acenaphthyl, phenanthrenyl and the like. The expression �fused aryl� means an aryl that is fused with further cycloalkyl, heterocycloalkyl, aryl or heteroaryl group(s), preferably 1 or 2.
�C1-C12-alkyl aryl� refers to C1-C12-alkyl groups having an aryl substituent, including benzyl, phenethyl and the like. By analogy, �C1-C16-alkyl aryl� refers to C1-C16-alkyl groups having an aryl substituent and �C1-C8-alkyl aryl� refers to C1-C8-alkyl groups having an aryl substituent.
�Heteroaryl� refers to a monocyclic heteroaromatic, or a bicyclic or a tricyclic fused-ring heteroaromatic group. Particular examples of heteroaromatic groups include optionally substituted pyridyl, pyrrolyl, furyl, thienyl, imidazolyl, benzoxazole, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,3,4-triazinyl, 1,2,3-triazinyl, benzofuryl, [2,3-dihydro]benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, isobenzothienyl, indolyl, isoindolyl, 3H-indolyl, benzimidazolyl, imidazo[1,2-a]pyridyl, benzothiazolyl, benzoxa-zolyl, quinolizinyl, quinazolinyl, pthalazinyl, quinoxalinyl, cinnolinyl, napthyridinyl, pyrido[3,4-b]pyridyl, pyrido[3,2-b]pyridyl, pyrido[4,3-b]pyridyl, quinolyl, isoquinolyl, tetrazolyl, 5,6,7,8-tetrahydroquinolyl, 5,6,7,8-tetrahydroisoquinolyl, purinyl, pteridinyl, carbazolyl, xanthenyl or benzoquinolyl.
�C1-C12-alkyl heteroaryl� refers to C1-C12-alkyl groups having a heteroaryl substituent, including 2-furylmethyl, 2-thienylmethyl, 2-(1H-indol-3-yl)ethyl and the like. By analogy, �C1-C16-alkyl heteroaryl� refers to C1-C16-alkyl groups having a heteroaryl substituent and �C1-C8-alkyl heteroaryl� refers to C1-C8-alkyl groups having an heteroaryl substituent.
�C2-C12-alkenyl� refers to alkenyl groups preferably having from 2 to 12 carbon atoms and having at least 1 or 2 sites of alkenyl unsaturation. By analogy, �C2-C16-alkenyl� refers to alkenyl groups preferably having from 2 to 16 carbon atoms and having at least 1 or 2 sites of alkenyl unsaturation Preferable alkenyl groups include ethenyl (�CH═CH2), n-2-propenyl (allyl, �CH2CH═CH2) and the like.
�C2-C12-alkenyl aryl� refers to C2-C12-alkenyl groups having an aryl substituent, including 2-phenylvinyl and the like. By analogy, �C2-C16-alkenyl aryl� refers to C2-C16-alkenyl groups having an aryl substituent
�C2-C12-alkenyl heteroaryl� refers to C2-C12-alkenyl groups having a heteroaryl substituent, including 2-(3-pyridinyl)vinyl and the like. By analogy, �C2-C16-alkenyl heteroaryl� refers to C2-C16-alkenyl groups having a heteroaryl substituent
�C2-C12-alkynyl� refers to alkynyl groups preferably having from 2 to 12 carbon atoms and having at least 1-2 sites of alkynyl unsaturation. By analogy, �C2-C16-alkynyl� refers to alkynyl groups preferably having from 2 to 16 carbon atoms and having at least 1-2 sites of alkynyl unsaturation. Preferred alkynyl groups include ethynyl (�C≡CH), propargyl (�CH2C≡CH), and the like.
�C2-C12-alkynyl aryl� refers to C2-C12-alkynyl groups having an aryl substituent, including phenylethynyl and the like. By analogy, �C2-C16-alkynyl aryl� refers to C2-C16-alkynyl groups having an aryl substituent.
�C2-C12-alkynyl heteroaryl� refers to C2-C12-alkynyl groups having a heteroaryl substituent, including 2-thienylethynyl and the like. By analogy, �C2-C16-alkynyl heteroaryl� refers to C2-C16-alkynyl groups having a heteroaryl substituent
�C3-C8-cycloalkyl� refers to a saturated carbocyclic group of from 3 to 8 carbon atoms having a single ring (e.g., cyclohexyl) or multiple condensed rings (e.g., norbornyl). Preferred cycloalkyl include cyclopentyl, cyclohexyl, norbornyl and the like.
�Heterocycloalkyl� refers to a C3-C8-cycloalkyl group according to the definition above, in which up to 3 carbon atoms are replaced by heteroatoms chosen from the group consisting of O, S, NR, R being defined as hydrogen, C1-6 alkyl, alkoxy and the like. thyl. Preferred heterocycloalkyl include pyrrolidine, piperidine, piperazine, 1-methylpiperazine, morpholine, and the like.
�C1-C12-alkyl cycloalkyl� refers to C1-C12-alkyl groups having a cycloalkyl substituent, including cyclohexylmethyl, cyclopentylpropyl, and the like. By analogy, �C1-C16-alkyl cycloalkyl� refers to C1-C16-alkyl groups having a cycloalkyl substituent
�C1-C12-alkyl heterocycloalkyl� refers to C1-C12-alkyl groups having a heterocycloalkyl substituent, including 2-(1-pyrrolidinyl)ethyl, 4-morpholinylmethyl, (1-methyl-4-piperidinyl)methyl and the like. By analogy, �C1-C16-alkyl heterocycloalkyl� refers to C1-C16-alkyl groups having a heterocycloalkyl substituent
�Carboxy� refers to the group �C(O)OH.
�C1-C12-alkyl carboxy� refers to C1-C12-alkyl groups having a carboxy substituent, including 2-carboxyethyl and the like. By analogy, �C1-C16-alkyl carboxy� refers to C1-C16-alkyl groups having a carboxy substituent
�Acyl� refers to the group �C(O)R where R includes �C1-C12-alkyl�, �C1-C8-alkyl�, �aryl�, �heteroaryl�, �C1-C12-alkyl aryl� or �C1-C12-alkyl heteroaryl�.
�C1-C12-alkyl acyl� refers to C1-C12-alkyl groups having an acyl substituent, including 2-acetylethyl and the like. By analogy, �C1-C16-alkyl acyl� refers to C1-C16-alkyl groups having an acyl substituent
�Aryl acyl� refers to aryl groups having an acyl substituent, including 2-acetylphenyl and the like.
�Heteroaryl acyl� refers to hetereoaryl groups having an acyl substituent, including 2-acetylpyridyl and the like.
�C3-C8-(hetero)cycloalkyl acyl� refers to 3 to 8 membered cycloalkyl or heterocycloalkyl groups having an acyl substituent.
�Acyloxy� refers to the group �OC(O)R where R includes H, �C1-C12-alkyl�, �C2-C12-alkenyl�, �C2-C12-alkynyl�, �C3-C8-cycloalkyl�, �heterocycloalkyl�, �aryl�, �heteroaryl�, �C1-C12-alkyl aryl� or �C1-C12-alkyl heteroaryl�, �C2-C12-alkenyl aryl�, �C2-C12-alkenyl heteroaryl�, �C2-C12-alkynyl aryl�, �C2-C12-alkynylheteroaryl�, �C1-C12-alkyl cycloalkyl�, �C1-C12-alkyl heterocycloalkyl�.
�C1-C12-alkyl acyloxy� refers to C1-C12-alkyl groups having an acyloxy substituent, including 2-(acetyloxy)ethyl and the like. By analogy, �C1-C16-alkyl acyloxy� refers to C1-C16-alkyl groups having an acyloxy substituent
�Alkoxy� refers to the group �O�R where R includes �C1-C12-alkyl�, �C1-C8-alkyl�, �C1-C6-alkyl� or �aryl� or �hetero-aryl� or �C1-C12-alkyl aryl� or �C1-C12-alkyl heteroaryl�. Preferred alkoxy groups include by way of example, methoxy, ethoxy, phenoxy and the like.
�C1-C12-alkyl alkoxy� refers to C1-C12-alkyl groups having an alkoxy substituent, including 2-ethoxyethyl and the like. By analogy, �C1-C16-alkyl alkoxy� refers to C1-C16-alkyl groups having an alkoxy substituent and �C1-C6-alkyl� refers to C1-C6-alkyl groups having an alkoxy substituent
�Alkoxycarbonyl� refers to the group �C(O)OR where R includes H, �C1-C12-alkyl� or �aryl� or �heteroaryl� or �C1-C12-alkyl aryl� or �C1-C12-alkyl heteroaryl�.
�C1-C12-alkyl alkoxycarbonyl� refers to C1-C12-alkyl groups having an alkoxycarbonyl substituent, including 2-(benzyloxycarbonyl)ethyl and the like. By analogy, �C1-C16-alkyl alkoxycarbonyl� refers to C1-C16-alkyl groups having an alkoxycarbonyl substituent
�Aminocarbonyl� refers to the group �C(O)NRR′ where each R, R′ includes independently hydrogen or C1-C12-alkyl or C1-C6-alkyl or aryl or heteroaryl or �C1-C12-alkyl aryl� or �C1-C12-alkyl hetero-aryl�.
�C1-C12-alkyl aminocarbonyl� refers to C1-C12-alkyl groups having an aminocarbonyl substituent, including 2-(dimethylaminocarbonyl)ethyl and the like. By analogy, �C1-C16-alkyl aminocarbonyl� refers to C1-C16-alkyl groups having an aminocarbonyl substituent and �C1-C8-alkyl aminocarbonyl� refers to C1-C8-alkyl groups having an aminocarbonyl substituent, including 2-(dimethylaminocarbonyl)ethyl and the like.
�Acylamino� refers to the group �NRC(O)R′ where each R, R′ is independently hydrogen, �C1-C12-alkyl�, �C2-C12-alkenyl�, �C2-C12-alkynyl�, �C3-C8-cycloalkyl�, �heterocycloalkyl�, �aryl�, �heteroaryl�, �C1-C12-alkyl aryl� or �C1-C12-alkyl heteroaryl�, �C2-C12-alkenyl aryl�, �C2-C12-alkenyl heteroaryl�, �C2-C12-alkynyl aryl�, �C2-C12-alkynylheteroaryl�, �C1-C12-alkyl cycloalkyl�, �C1-C12-alkyl heterocycloalkyl�.
�C1-C12-alkyl acylamino� refers to C1-C12-alkyl groups having an acylamino substituent, including 2-(propionylamino)ethyl and the like. By analogy, �C1-16-alkyl acylamino� refers to C1-C16-alkyl groups having an acylamino substituent
�Ureido� refers to the group �NRC(O)NR′R″ where each R, R′, R″ is independently hydrogen, �C1-C12-alkyl�, �C2-C12-alkenyl�, �C2-C12-alkynyl�, �C3-C8-cycloalkyl�, �heterocycloalkyl�, �aryl�, �heteroaryl�, �C1-C12-alkyl aryl� or �C1-C12-alkyl heteroaryl�, �C2-C12-alkenyl aryl�, �C2-C12-alkenyl heteroaryl�, �C2-C12-alkynyl aryl�, �C2-C12-alkynylheteroaryl�, �C1-C12-alkyl cycloalkyl�, �C1-C12-alkyl heterocycloalkyl�, and where R′ and R″, together with the nitrogen atom to which they are attached, can optionally form a 3-8-membered heterocycloalkyl ring.
�C1-C12-alkyl ureido� refers to C1-C12-alkyl groups having an ureido substituent, including 2-(N′-methylureido)ethyl and the like. By analogy, �C1-C16-alkyl ureido� refers to C1-C16-alkyl groups having an ureido substituent
�Carbamate� refers to the group �NRC(O)OR′ where each R, R′ is independently hydrogen, �C1-C12-alkyl�, �C2-C12-alkenyl�, �C2-C12-alkynyl�, �C3-C8-cycloalkyl�, �heterocycloalkyl�, �aryl�, �heteroaryl�, �C1-C12-alkyl aryl� or �C1-C12-alkyl heteroaryl�, �C2-C12-alkenyl aryl�, �C2-C12-alkenyl heteroaryl�, �C2-C12-alkynyl aryl�, �C2-C12-alkynylheteroaryl�, �C1-C12-alkyl cycloalkyl�, �C1-C12-alkyl heterocycloalkyl�.
�Amino� refers to the group �NRR′ where each R,R′ is independently hydrogen or �C1-C12-alkyl� or �aryl� or �heteroaryl� or �C1-C2-alkyl aryl� or �C1-C12-alkyl heteroaryl�, or �cycloalkyl�, or �heterocycloalkyl�, and where R and R′, together with the nitrogen atom to which they are attached, can optionally form a 3-8-membered heterocycloalkyl ring.
�C1-C12-alkyl amino� refers to C1-C12-alkyl groups having an amino substituent, including 2-(1-pyrrolidinyl)ethyl and the like. By analogy, �C1-C16-alkyl amino� refers to C1-C16-alkyl groups having an amino substituent and �C1-C8-alkyl amino� refers to C1-C8-alkyl groups having an amino substituent
�Ammonium� refers to a positively charged group �N+RR′R″, where each R,R′,R″ is independently �C1-C12-alkyl� or �C1-C12-alkyl aryl� or �C1-C12-alkyl heteroaryl�, or �cycloalkyl�, or �heterocycloalkyl�, and where R and R′, together with the nitrogen atom to which they are attached, can optionally form a 3-8-membered heterocycloalkyl ring.
�C1-C12-alkyl ammonium� refers to C1-C12-alkyl groups having an ammonium substituent, including 2-(1-pyrrolidinyl)ethyl and the like. By analogy, �C1-C16-alkyl ammonium� refers to C1-C16-alkyl groups having an ammonium substituent.
�Sulfonyloxy� refers to a group �OSO2�R wherein R is selected from H, �C1-C12-alkyl�, �C1-C12-alkyl� substituted with halogens, e.g., an �OSO2�CF3 group, �C2-C12-alkenyl�, �C2-C12-alkynyl�, �C3-C8-cycloalkyl�, �heterocycloalkyl�, �aryl�, �heteroaryl�, �C1-C6-alkyl aryl� or �C1-C12-alkyl heteroaryl�, �C2-C12-alkenyl aryl�, �C2-C12-alkenyl heteroaryl�, �C2-C12-alkynyl aryl�, �C2-C12-alkynylheteroaryl�, �C1-C12-alkyl cycloalkyl�, �C1-C12-alkyl heterocycloalkyl�.
�C1-C12-alkyl sulfonyloxy� refers to C1-C12-alkyl groups having a sulfonyloxy substituent, including 2-(methylsulfonyloxy)ethyl and the like. By analogy, �C1-C16-alkyl sulfonyloxy� refers to C1-C16-alkyl groups having a sulfonyloxy substituent
�Sulfonyl� refers to group ��SO2�R� wherein R is selected from H, �aryl�, �heteroaryl�, �C1-C12-alkyl�, �C1-C12-alkyl� substituted with halogens, e.g., an �SO2�CF3 group, �C2-C6-alkenyl�, �C2-C12-alkynyl�, �C3-C8-cycloalkyl�, �heterocycloalkyl�, �aryl�, �heteroaryl�, �C1-C12-alkyl aryl� or �C1-C12-alkyl heteroaryl�, �C2-C12-alkenyl aryl�, �C2-C12-alkenyl heteroaryl�, �C2-C12-alkynyl aryl�, �C2-C12-alkynylheteroaryl�, �C1-C12-alkyl cycloalkyl�, �C1-C12-alkyl heterocycloalkyl�.
�C1-C12-alkyl sulfonyl� refers to C1-C12-alkyl groups having a sulfonyl substituent, including 2-(methylsulfonyl)ethyl and the like. By analogy, �C1-C16-alkyl sulfonyl� refers to C1-C16-alkyl groups having a sulfonyl substituent.
�Sulfinyl� refers to a group ��S(O)�R� wherein R is selected from H, �C1-C12-alkyl�, �C1-C6-alkyl� substituted with halogens, e.g., an �SO�CF3 group, �C2-C12-alkenyl�, �C2-C12-alkynyl�, �C3-C8-cycloalkyl�, �heterocycloalkyl�, �aryl�, �heteroaryl�, �C1-C12-alkyl aryl� or �C1-C12-alkyl heteroaryl�, �C2-C12-alkenyl aryl�, �C2-C12-alkenyl heteroaryl�, �C2-C12-alkynyl aryl�, �C2-C12-alkynylheteroaryl�, �C1-C12-alkyl cycloalkyl�, �C1-C12-alkyl heterocycloalkyl�.
�C1-C12-alkyl sulfinyl� refers to C1-C12-alkyl groups having a sulfinyl substituent, including 2-(methylsulfinyl)ethyl and the like. By analogy, �C1-C16-alkyl sulfinyl� refers to C1-C16-alkyl groups having a sulfinyl substituent.
�Sulfanyl� refers to groups �S�R where R includes H, �C1-C12-alkyl�, �C1-C12-alkyl� substituted with halogens, e.g., a �SO�CF3 group, �C2-C12-alkenyl�, �C2-C12-alkynyl�, �C3-C8-cycloalkyl�, �heterocycloalkyl�, �aryl�, �heteroaryl�, �C1-C12-alkyl aryl� or �C1-C6-alkyl heteroaryl�, �C2-C12-alkenyl aryl�, �C2-C12-alkenyl heteroaryl�, �C2-C12-alkynyl aryl�, �C2-C12-alkynylheteroaryl�, �C1-C12-alkyl cycloalkyl�, �C1-C12-alkyl heterocycloalkyl�. Preferred sulfanyl groups include methylsulfanyl, ethylsulfanyl, and the like.
�C1-C12-alkyl sulfanyl� refers to C1-C12-alkyl groups having a sulfanyl substituent, including 2-(ethylsulfanyl)ethyl and the like. By analogy, �C1-C16-alkyl sulfanyl� refers to C1-C16-alkyl groups having a sulfanyl substituent.
�Sulfonylamino� refers to a group �NRSO2�R′ where each R, R′ includes independently hydrogen, �C1-C12-alkyl�, �C2-C12-alkenyl�, �C2-C12-alkynyl�, �C3-C8-cycloalkyl�, �heterocycloalkyl�, �aryl�, �heteroaryl�, �C1-C12-alkyl aryl� or �C1-C12-alkyl heteroaryl�, �C2-C12-alkenyl aryl�, �C2-C12-alkenyl heteroaryl�, �C2-C12-alkynyl aryl�, �C2-C12-alkynylheteroaryl�, �C1-C12-alkyl cycloalkyl�, �C1-C12-alkyl heterocycloalkyl�.
�C1-C12-alkyl sulfonylamino� refers to C1-C12-alkyl groups having a sulfonylamino substituent, including 2-(ethylsulfonylamino)ethyl and the like. By analogy, �C1-C16-alkyl sulfonylamino� refers to C1-C16-alkyl groups having a sulfonylamino substituent.
�Aminosulfonyl� refers to a group �SO2�NRR′ where each R, R′ includes independently hydrogen, �C1-C12-alkyl�, �C2-C12-alkenyl�, �C2-C12-alkynyl�, �C3-C8-cycloalkyl�, �heterocycloalkyl�, �aryl�, �heteroaryl�, �C1-C12-alkyl aryl� or �C1-C12-alkyl heteroaryl�, �C2-C12-alkenyl aryl�, �C2-C12-alkenyl heteroaryl�, �C2-C12-alkynyl aryl�, �C2-C12-alkynylheteroaryl�, �C1-C12-alkyl cycloalkyl�, �C1-C12-alkyl heterocycloalkyl�.
�C1-C12-alkyl aminosulfonyl� refers to C1-C12-alkyl groups having an aminosulfonyl substituent, including 2-(cyclohexylaminosulfonyl)ethyl and the like. By analogy, �C1-C16-alkyl aminosulfonyl� refers to C1-C16-alkyl groups having an aminosulfonyl substituent.
�Substituted or unsubstituted� or �optionally substituted: Unless otherwise constrained by the definition of the individual substituent, the above set out groups, like �alkyl�, �alkenyl�, �alkynyl�, �aryl� and �heteroaryl� etc. groups can optionally be substituted with from 1 to 5 substituents selected from the group consisting of �C1-C12-alkyl�, �C2-C12-alkenyl�, �C2-C12-alkynyl�, �cycloalkyl�, �heterocycloalkyl�, �C1-C12-alkyl aryl�, �C1-C12-alkyl heteroaryl�, �C1-C12-alkyl cycloalkyl�, �C1-C12-alkyl heterocycloalkyl�, �amino�, �ammonium�, �acyl�, �acyloxy�, �acylamino�, �aminocarbonyl�, �alkoxycarbonyl�, �ureido�, �aryl�, �carbamate�, �heteroaryl�, �sulfinyl�, �sulfonyl�, �alkoxy�, �sulfanyl�, �halogen�, �carboxy�, trihalomethyl, cyano, hydroxy, mercapto, nitro, and the like. Alternatively said substitution could also comprise situations where neighbouring substituents have undergone ring closure, notably when vicinal functional substituents are involved, thus forming, e.g., lactams, lactone, cyclic anhydrides, but also acetals, thioacetals, aminals formed by ring closure for instance in an effort to obtain a protective group.
4-hexyl-1-(thiophene-2-sulfonyl)-piperazine-2-carboxylic acid (1-ethyl-2-pyridinyl-3-yl-1H-benzoimidazole-5-yl)-amide) 4-pentanoyl-1-(thiophene-2-sulfonyl)-piperazine-2-carboxylic acid (9-ethyl-9H-carbazol-3-yl) amide {[3-(9-ethyl-9H-carbazol-3-ylcarbamoyl)-4-(thiophene-2-sulfonyl)-piperazine-1-carbonyl]-amino}acetic acid ethyl ester 4-(thiophene-2-sulfonyl)-piperazine-1,3-dicarboxylic acid 1-ethylamide 3-[(9-ethyl-9H-carbazol-3-yl)amide] 4-(thiophene-2-sulfonyl)-piperazine-1,3-dicarboxylic acid 3-[(9-ethyl-9H-carbazol-3-yl)amide]-1-pentylamide 4-hexyl-1-(thiophene-2-sulfonyl)-piperazine-2-carboxylic acid (9-ethyl-9H-carbazol-3-yl) amide 4-(thiophene-2-sulfonyl)-piperazine-1,3-dicarboxylic acid 3-[(9-ethyl-9H-carbazol-3-yl)-amide]1-{(2-methoxy-ethyl)-amide] 4-(thiophene-2-sulfonyl)-piperazine-1,3-dicarboxyclic acid 1-pentylamide 3-[(3-pyridin-4-yl-phenyl)-amide] 4-(1-methyl-1H-imidazole-4-sulfonyl)-piperazine-1,3-dicarboxylic acid 3-[(9-ethyl-9H-carbazol-3-yl)-amide]1-pentylamide 4-dimethylsulfamoyl-piperazine-1,3-dicarboxylic acid 3-[(9-ethyl-9H-carbazol-3-yl)-amide]1-pentylamide 4-hexyl-1-(thiophene-2-sulfonyl)-piperazine-2-carboxylic acid (1-oxo-2,3,4,9-tetrahydro-1H-beta-carbolin-6-yl)-amide 4-heptyl-1-(thiophene-2-sulfonyl)-piperazine-2-carboxylic acid (1-ethyl-2-pyridin-3-yl-1H-benzoimidazol-5-yl)-amide 4-(thiophene-2-sulfonyl)-piperazine-1,3-dicarboxylic acid 3-[(9-ethyl-9H-carbazol-3-yl)-amide]1-[(3-imidazol-1-yl-propyl)-amide]) 4-(thiophene-2-sulfonyl)-piperazine-1,3-dicarboxylic acid 3-[(9-ethyl-9H-carbazol-3-yl)-amide] 1-[(3-imidazol-1-yl-ethyl)-amide]) 4-pentyl-1-(thiophene-2-sulfonyl)-piperazine-2-carboxylic acid (1-oxo-2,3,4,9-tetrahydro-1H-beta-carbolin-6-yl)amide 4-heptyl-1-(thiophene-2-sulfonyl)-piperazine-2-carboxylic acid (1-oxo-2,3,4,9-tetrahydro-1H-beta-carbolin-6-yl)amide 4-(3-methylsulfanyl-propyl)-1-(thiophene-2-sulfonyl)-piperazine-2-carboxylic acid (9-ethyl-9H-carbazol-3-yl)-amide 4-(4-ethyl-furan-3-ylmethyl)-1-(thiophene-2-sulfonyl)-piperazine-2-carboxylic acid (9-ethyl-9H-carbazol-3-yl)-amide 3-(9-ethyl-9H-carbazol-3-yl)-4-(thiophene-2-sulfonyl)-piperazin-1-yl]acetic acid ethyl ester 1-benzenesulfonyl-4-hexyl-piperazine-2-carboxylic acid (1-ethyl-2-pyridin-3-yl-1H-benzoimidazol-5-yl)amide 4-pentyl-1-thiophene-2-sulfonyl)-piperazine-2-carboxylic acid (1-ethyl-2-pyridin-3-yl-1H-benzoimidazol-5-yl)amide 4-hexyl-1-thiophene-2-sulfonyl)-piperazine-2-carboxylic acid (1-ethyl-2-pyridin-3-yl-1H-benzoimidazol-5-yl)amide 1-(4-fluoro-benzenesulfonyl)-4-hexyl-piperazine-2-carboxylic acid (1-ethyl-2-pyridin-3-yl-1H-benzoimidazol-5-yl)amide 1-(2-fluoro-benzenesulfonyl)-4-hexyl-piperazine-2-carboxylic acid (1-ethyl-2-pyridin-3-yl-1H-benzoimidazol-5-yl)amide 4-octyl-1-(thiophene-2-sulfonyl)-piperazine-2-carboxylic acid (1-ethyl-2-pyridin-4-yl-1H-benzoimidazol-5-yl)amide 4-heptyl-1-(thiophene-2-sulfonyl)-piperazine-2-carboxylic acid (1-ethyl-2-pyridin-4-yl-1H-benzoimidazol-5-yl)amide 1-(butane-1-sulfonyl)-4-hexyl-piperazine-2-carboxylic acid (1-ethyl-2-pyridin-3-yl-1H-benzoimidazol-5-yl)amide 4-hexyl-1-(thiophene-2-sulfonyl)-piperazine-2-carboxylic acid (1-ethyl-2-pyridin-4-yl-1H-benzoimidazol-5-yl)amide 4-(3-methylsulfanyl-propyl)-1-(thiophene-2-sulfonyl)-piperazine-2-carboxylic acid (1-ethyl-2-pyridin-4-yl-1H-benzoimidazol-5-yl)amide 4-octyl-1-(thiophene-2-sulfonyl)-piperazine-2-carboxylic acid (1-ethyl-2-pyridin-3-yl-1H-benzoimidazol-5-yl)amide Compounds of the invention can be readily prepared. For instance, a suitable reaction sequence to provide compounds of the invention is set forth in the following Schemes 1A and 1B:
As exemplified in the above Scheme 1A of the ring nitrogens of a 2-carboxylic acid piperazine 1a (1) can be protected e.g. with FMOC chloride (9-fluorenylmethoxycarbonyl chloride) to lead a compound 2a (2). The unprotected ring nitrogen of compound 2a can be reacted with a sulfonyl reagent to introduce the �SO2R4 substituent of Formulae I to III, leading to sulfonyl derivatives of formula 3a such as for example an optionally substituted thiophene sulfonyl compound 3 as shown in Scheme 1B below.
Compounds of the invention may be administered as a �cocktail� formulation, i.e. coordinated administration of one or more compounds of the invention together with one or more other active therapeutics, particularly one or more other known fertility agents. For instance, one or more compounds of the invention may be administered in coordination with a regime of Follicle Stimulating Hormone and/or Leutinizing Hormone such as Gonal-F, Metrodin HP or Pergonal, or other agent such as clomephine citrate.
Example 1 Synthesis of 4-Hexyl-1-(thiophene-2-sulfonyl)-piperazine-2-carboxylic acid (1-ethyl-2-pyridin-3-yl-1H-benzoimidazol-5-yl)-amide The title compound was prepared as outlined in the following Scheme 2.
Part 1: Synthesis of Piperazine-1,3(R)-dicarboxylic acid-1-(9H-fluoren-9-ylmethyl)ester (Compound 2 in above Scheme 2) Piperazine-2(R)-carboxylic acid dihydrochloride (5.95 g) was added to 50 mL dioxane/water (1:1). The solution was cooled in an ice bath and aqueous sodium hydroxide (10% w/v) solution was added drop-wise to adjust the pH to 9�10. At this pH, piperazine-2-carboxylic acid dissolved completely. Then, Fmoc Chloride (2.46 g) in dioxane was added drop-wise to the ice-cooled solution of piperazine and the reaction mixture was stirred from 0� C. to RT over 5-6 hr. The mixture was poured into 800 ml of ice water and washed once with ether. Then the aqueous phase was acidified to pH 2-3 with 2N of HCl which precipitated a white solid. This solid was filtered and dried in vacuo to obtain 2.46 g of a white powder. MS (ESI pos.): 353 (M+H).
Part 2: Synthesis of 4-(Thiophene-2-sulfonyl)-piperazine-1,3(R)-dicarboxylic acid 1-(9H-fluoren-9-ylmethyl)ester (Compound 3 in above Scheme 2). 4-Fmoc protected piperazine-2(R)-carboxylic acid (352 mg) was dissolved in 10 mL anhydrous methylene chloride. The solution was cooled in an ice bath and 0.35 mL di-isopropyl ethyl amine was added. Then, 183 mg of 2-thiophene sulfonyl chloride was added and the reaction mixture was stirred at 0� C. for 5 hr. The mixture was diluted with dichloromethane, washed with 0.5N aqueous hydrochloric acid and brine. The solvent was evaporated from the organic layer to leave a yellowish solid which was dried in vacuo. This crude material was used as such for the next step without purification.
Part 3: Synthesis of 3-(1-Ethyl-2-pyridin-3-yl-1H-benzoimidazol-5-ylcarbamoyl)-4-(thiophene-2-sulfonyl)-piperazine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester (Compound 4 in above Scheme 2) The crude material from the previous step was dissolved in anhydrous DMF and to this were added 238 mg of 1-Ethyl-2-pyridin-3-yl-1H-benzoimidazol-5-ylamine followed by 258 mg of di-isopropyl ethyl amine and 380 mg of HATU. The mixture was stirred for 5 hr upon which the crude mixture was diluted with ethyl acetate and the organic layer was successively washed with saturated sodium bicarbonate, 0.5N HCl and brine. The organic layer was evaporated to dryness and the product was isolated by chromatography over silica gel (0 to 5% methanol in ethyl acetate). MS (ESI pos.): 719 (M+H).
Part 4: Deprotection of Fmoc (9H-fluoren-9-ylmethyl ester) group The Fmoc-protected piperazine derivative from step 3 was dissolved in 5 mL dichloromethane. To this were slowly added 5 mL of diethyl amine and the resulting mixture was stirred for 1.5 hr at ambient temperature. The excess reagent was evaporated in vacuo and the crude product was purified by chromatography over silica gel (0-25% methanol in ethyl acetate) to afford the piperazine 5. MS (ESI pos.): 497 (M+H)
Part 5: Synthesis of 4Hexyl-1-(thiophene-2-sulfonyl)-piperazine-2-carboxylic acid (1-ethyl-2-pyridin-3-yl-1H-benzoimidazol-5-yl)-amide (Compound 6 in above Scheme 2) The piperazine 5 (200 mg) as prepared in Part 4 above was dissolved in dichloromethane containing 5% acetic acid and 144 microliters of n-hexanal were added. After stirring for 16 hours, 500 mg of sodium cyano borohydride was added and the reaction was stirred for 5 hr at room temperature. The crude mixture was washed with saturated sodium bicarbonate, brine and dried. Purification over silica gel (0-5% methanol in ethyl acetate) afforded 126 mg of the desired product 6. MS (ESI pos.): 581 (M+H)
Example 2 FSH Assay Method Compounds of the invention were tested in the following assay.
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