AU727972B2 - Dihydropyrimidines and uses thereof - Google Patents
Dihydropyrimidines and uses thereof Download PDFInfo
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- AU727972B2 AU727972B2 AU30082/97A AU3008297A AU727972B2 AU 727972 B2 AU727972 B2 AU 727972B2 AU 30082/97 A AU30082/97 A AU 30082/97A AU 3008297 A AU3008297 A AU 3008297A AU 727972 B2 AU727972 B2 AU 727972B2
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- branched
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- 0 CC(*(C1)C1=C(N(C1c(cc2F)ccc2F)C(Oc2ccc(**)cc2)=O)OC)=C1C(*)=O Chemical compound CC(*(C1)C1=C(N(C1c(cc2F)ccc2F)C(Oc2ccc(**)cc2)=O)OC)=C1C(*)=O 0.000 description 13
- RZECDSKOFZQBBZ-IUXPMGMMSA-N CCC(NC(N(C1C(C=C2)=CC/C2=N\O)C(N)=O)=O)=C1C(O)=O Chemical compound CCC(NC(N(C1C(C=C2)=CC/C2=N\O)C(N)=O)=O)=C1C(O)=O RZECDSKOFZQBBZ-IUXPMGMMSA-N 0.000 description 1
- SJZKULRDWHPHGG-UHFFFAOYSA-N O=C1CCN(Cc2ccccc2)CC1 Chemical compound O=C1CCN(Cc2ccccc2)CC1 SJZKULRDWHPHGG-UHFFFAOYSA-N 0.000 description 1
- CZOLOCAKMPJYKP-UHFFFAOYSA-N ONC1CCN(Cc2ccccc2)CC1 Chemical compound ONC1CCN(Cc2ccccc2)CC1 CZOLOCAKMPJYKP-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/20—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D239/22—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to ring carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/08—Drugs for disorders of the urinary system of the prostate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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- C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
- C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
- C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
- C07D451/06—Oxygen atoms
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- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
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Description
-IA-
Dihvdrolprimidines and Uses Thereof Throughout this application, various references are referred to within parentheses. Disclosures of these publications in their. entireties are hereby incorporated by reference into this application to more fully describe the state of the art to which this invention pertains.
Backcround of the Invention The reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that that prior art forms part of the common general knowledge in Australia.
The designation "OlA" is the appellation recently approved by the IUPHAR Nomenclature Committee for the previously designated "ac" cloned subtype as outlined in the 1995 Receptor and Ion Channel Nomenclature Supplement (Watson and Girdlestone, 1995). The designation a 1 is used throughout this application and the supporting tables and figures to refer to this receptor subtype. At the same time, the receptor formerly designated was renamed The new nomenclature is used throughout this application.
Stable cell lines expressing these receptors are :oo: described herein; however, these cell lines were 000o o 30 deposited with the American Type Culture Collection ooo6 (ATCC) under the old nomenclature (infra).
.*0 Benign Prostatic Hyperplasia (BPH) also called Benign Prostatic Hypertrophy, is a progressive condition which is characterized by a nodular enlargement of prostatic tissue resulting in obstruction of the urethra. This results in increased frequency of urination, nocturia, a poor urine stream and hesitancy or delay in starting the urine flow. Chronic consequences of BPH can WO 97/42956 PCT/US97/08335 include hypertrophy of bladder smooth muscle, a decompensated bladder and an increased incidence of urinary tract infection. The specific biochemical, histological and pharmacological properties of the prostate adenoma leading to the bladder outlet obstruction are not yet known. However, the development of BPH is considered to be an inescapable phenomenon for the aging male population. BPH is observed in approximately 70% of males over the age of 70. Currently, in the United States, the method of choice for treating BPH is surgery (Lepor, Urol.
Clinics North Amer., 17, 651 (1990)). Over 400,000 prostatectomies are performed annually (data from 1986). A medicinal alternative to surgery is clearly very desirable. The limitations of surgery for treating BPH include the morbidity rate of an operative procedure in elderly men, persistence or recurrence of obstructive and irritative symptoms, as well as the significant cost of surgery.
a-Adrenergic receptors (McGrath, et. al. Med. Res.
Rev., 9, 407-533, 1989) are specific neuroreceptor proteins located in the peripheral and central nervous systems on tissues and organs throughout the body.
These receptors are important switches for controlling many physiological functions and, thus, represent important targets for drug development. In fact, many a-adrenergic drugs have been developed over the past years. Examples include clonidine, phenoxybenzamine and prazosin (treatment of hypertension), naphazoline (nasal decongestant), and apraclonidine (treating glaucoma). a-Adrenergic drugs can be broken down into two distinct classes: agonists (clonidine and naphazoline are agonists), which mimic the receptor activation properties of the endogenous neurotransmitter norepinephrine, and antagonists (phenoxybenzamine and prazosin are antagonists), which act to block the effects of norepinephrine. Many of these drugs are effective but also produce unwanted WO 97/42956 PCT/US97/8335 -3side effects (for example, clonidine produces dry mouth and sedation in addition to its antihypertensive effects).
During the past 15 years a more precise understanding of a-adrenergic receptors and their drugs has evolved through increased scientific scrutiny. Prior to 1977, only one a-adrenergic receptor was known to exist.
Between 1977 and 1988, it was accepted by the scientific community that at least two a-adrenergic receptors--a, and ay--existed in the central and peripheral nervous systems. Since 1988, new techniques in molecular biology have led to the identification of at least six a-adrenergic receptors which exist throughout the central and peripheral nervous systems: IA (new nomenclature), acB, aID (new nomenclature), a 2
A,
2 B, and a 2 C (Bylund, FASEB 6, 832 (1992)). In many cases, it is not known precisely which physiological responses in the body are controlled by each of these receptors. In addition, current a-adrenergic drugs are not selective for any particular a-adrenergic receptor. Many of these drugs produce untoward side effects which may be attributed to their poor a-adrenergic receptor selectivity.
Since the mid 1970's, nonselective a-antagonists have been prescribed to treat BPH. In 1976, M. Caine, et al. (Brit. J. Urol., 48, 255 (1976)), reported that the nonselective a-antagonist phenoxybenzamine was useful in relieving the symptoms of BPH. This drug may produce its effects by interacting with a-receptors located on the prostate. However, this drug also produces significant side effects such as dizziness and asthenia which severely limit its use in treating patients on a chronic basis. More recently, the a-adrenergic antagonists prazosin and terazosin have also been found to be useful for treating BPH.
However, these drugs also produce untoward side effects. It has recently been discovered that the aA receptor is responsible for mediating the contraction of human prostate smooth muscle (Gluchowski, C. et.
al., WO 94/10989, 1994; Forray, C. et. al., Mol.
Pharmacol. 45, 703, 1994). This discovery indicates that the a~A antagonists may be effective agents for the treatment of BPH with decreased side effects. Further studies have indicated that the clA receptor may also be present in other lower urinary tract tissues, such as urethral smooth muscle (Ford et al. Br. J. Pharmacol., 114, 24P, (1995)).
This invention is directed to dihydropyrimidine compounds which are selective antagonists for cloned human c~A receptors. This invention is also related to uses of these compounds for lowering intraocular S: pressure (Zhan, et. al. Ophthalmol. Vis. Sci., 34 Abst.
#1133, 928, 1993), inhibiting cholesterol synthesis 20 (D'Eletto and Javitt, J. Cardiovascular Pharmacol., 13 (Suppl. 2) S1-S4, 1989), benign prostatic hyperplasia, impotency (Milne and Wyllie, EP 0 459 666 A2, 1991) sympathetically mediated pain (Campbell, WO 92/14453, 1992), cardiac arrhythmia (Spiers, et. al., J.
25 Cardiovascular Pharmacol., 16, 824-830, 1990) and for ooo the treatment of any disease where antagonism of the alA ~receptor may be useful.
Throughout this specification and the claims which 30 follow, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or T 35 step or group of integers or steps.
'0
K.K
WO 97/42956 PCTI~S97/08335 Summarv of the Invention This invention is directed to dihydropyrimidine compounds which are selective antagonists for human a,, receptors. This invention is also related to uses of these compounds for lowering intraocular pressure, inhibiting cholesterol synthesis, relaxing lower urinary tract tissue, the treatment of benign prostatic hyperplasia, impotency, cardiac arrhythmia and for the treatment of any disease where antagonism of the a1A receptor may be useful. The invention further provides a pharmaceutical composition comprising a therapeutically effective amount of the above-defined compounds and a pharmaceutically acceptable carrier.
WO 97/42956 WO 9742956PCTIUS97/08335 -6- Detailed Description of the invention The present invention is directed to compounds having the structure: R 1 N AR 4
RR
P
2 N X R 3 1 2 R 3 n N X wherein A is 7 3 S, y 3 y 2
N
Y
1
ZI
WO 97/42956 PCT[US97/08335 -7wherein each of Y 1
Y
2 1 Y 3 and Y 5 i s independently straight chained or branched
C
1 alkyl, monofluoroalkyl. or polyfluoroalkyl; straight chained or branched C 2 alkenyl or alkynyl; C 3 C, cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -cl, -Br, or -NO 2
-N
3 -CN; -OR 3 -OCOR3, -COR 3
-CONHR
3
-CON(R
3 2 or -COOR 3 or any two of Y 1 y 2
Y
3
Y
4 and Y 5 present on adj acent carbon atoms can constitute a methylenedioxy group; wherein X is S; 0; or NR 3 wherein is -NO 2 -CN; straight chained or branched C 1 -C7 alkyl, monofluoroalkyl or polyf luoroalkyl; straight chained or branched C 2
C.
alkenyl or alkynyl;. C 3 -C7 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 wherein R 2 is straight chained or branched alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 alkenyl or alkynyl; C 3
-C,
cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; C 3
-C
1 0 cycloalkyl-C 1 -Cl-alkyl, C 3 -CIO cycloalkyl-C 1
-C
1 0 monofluoroalkyl or C 3 -CIO cycloalkyl-C,-C 0 polyfluoroalkyl; -CN; CH 2
XR
3
CH
2 X (CH 2
PN{R
3
(CH
2
),,NHR
3
CH
2 X (CH 2
PN(R
3 2
CH
2 X (CH 2
PN
3 or
CH
2 X (CH 2 PNHCXR.,; or -OR 3 wherein each p is independently an integer from 1 to 7; wherein each n is independently an integer from 0 to WO 97/42956 PCTIUS97/08335 -8wherein each R 3 is independently straight chained or branched C 1
-C
7 alkyl, monofluoroalkyl or polyf luoroalkyl; straight chained or branched c.-c 7 alkenyl or alkynyl; CC7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; wherein R 4 is R. R R 6 L7 in n N V is R 7
R
wherein ZV is (CH 2 CO, (CH 2 or CO(CH 2 wherein each V is independently 0; S; CH 2
CR
5
R
7
C(R
7 2 or NR 7 wherein each mn is independently an integer from 0 to 3; wherein o is an integer from 1 to 3; wherein each R is independently straight chained or branched CI-C, alkyl, monofluoroalkyl or polyf luoroalkyl; straight chained or branched C 2
-C
7 alkenyl or alkynyl; -N(R 3 2
-NO
2 -CN; -C0 2
R
3 or
-OR
3 wherein R 5 and R7, each independently may be F; Cl; Br; I; -COR 3 -C0 2
R
3
-CON(R
3 2 -CN; -NO 2
-N(R
3 2
-OR
3
-SR
3
-(CH
2
)POR
3
-(CH
2
)PSR
3 straight chained or branched C 1
-C
7 alkyl, aminoalkyl, carboxainidoalkyl; straight chained or branched
C
2
-C
7 alkenyl or alkynyl, or C 3 cycloalkyl or cycloalkenyl; wherein the alkyl, aminoalkyl, carboxamidoalkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl may be substituted with one or more WO 97/42956 PCTfUS97/0335 -9aryl or heteroaryl, wherein the aryl or heteroaryl may be substituted with -Cl, -Br, -NO 2 CN, -OR 3
-SR
3 Ci-C 3 alkyl, or carboxamido; aryl or heteroaryl, wherein the aryl or heteroaryl may be substituted with one or more -C1, -Br,
COR
3 C0 2
R
3
-CON(R
3 2 -CN, -NO -N(R 3 2
-OR
3
-SR
3
(CH
2
OR
3
(CH
2 )oSR 3 straight chained or branched Cl-C, alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C,-C, alkenyl, C 2 alkynyl, C 3
-C
7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; and wherein each R 6 is independently straight chained or branched Cl-C, alkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2
-C,
alkenyl or alkynyl; C 3
-C
7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; or -OR 3 or a pharmaceutically acceptable salt thereof.
The invention further provides for the enantiomer of any of the compounds described herein which is a cis isomer or a trans isomer. The invention also provides for the enantiomer of any of the compounds described herein which is a cis or a trans isomer.
The compounds of the present invention are preferably at least 80% pure, more preferably 90% pure, and most preferably 95% pure.
Ten fold selectivity differences are a minimum, but one skilled in the art will appreciate that compounds can be found that collectively have almost infinitely variable selective profiles. Compounds collectively having all possible combinations of selectivities are intended within the scope of this invention, provided WO 97/42956 PCT/JS97/08335 that each of these compounds has at least ten-fold greater affinity for the aA receptor over the aB and/or aID receptors.
In one embodiment of the present invention the compound has the structure: Y Y3 i 4 0 5 R 6
R
i2 N
R
R
7 R6 In one embodiment of the present invention Z' is Co and n is 0.
In another embodiment of the present invention the compounds have the structure: 0 II II The invention provides for compounds having the following structures: oc~.
I~r~~ ii~ i WO 97/42956 WO 9742956PCTIUS97/08335 -11- WO 97/42956 -12-
F
F
0
H
H
3 C,
H
3 C N 0 H COOCH 3 and
F
F F 0
H
N3C 0
NN,--
H
3 C N CH 3 COOCH) PCTIUS97/08335 WO 97/42956 WO 9742956PCTIUS97/08335 -2.3- The present invention is also directed to compounds having the structure:
R
1 N ,R 4 jN
R
R N X 2 1X N R 2 R 1 2 3 R3
R
wherein A is N Y 3 Y K N Y 2 3 YI
N
x wherein each of Y 2
Y
3 11 Y 4 and Y 5 is independently straight chained or branched
CI-C
7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 alkenyl or alkynyl; C 3
-C
7 cycloalkyl, monof luorocycloalkyl, WO 97/42956 PCT/US97/08335 -14polyfluorocycloalkyl or cycloalkenyl; -Cl, -Br, or -NO 2
-N
3 -CN; -OR 3
-OCOR
3
-COR
3
-CONHR
3
-CON(R
3 2 or -COOR 3 or any two of Y,,
Y
3
Y
4 and Y. present on adjacent carbon atoms can constitute a methylenedioxy group; wherein X is S; 0; or NR 3 wherein R, is -NO 2 -CN; straight chained or branched C, C 7 alkyl, monofluoroalkyl or polyf luoroalkyl; straight chained or branched C 2
-C,
alkenyl or alkynyl; C 3 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 wherein R 2 is straight chained or branched Cl-C, alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2
-C
7 alkenyl or alkynyl; C 3 cycloalkyl monof luorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; C 3
-C
10 cycloalkyl-C,-C 1 0 ,-alkyl, C 3
-C
10 cycloalkyl-Cl-Cl.monofluoroalkyl or C 3
-C
10 cycloalkyl-Cl-C 0 polyfluoroalkyl; -CN; CH 2
XR
3
CH
2 X (CH 2 P NHR,
(CH
2
),INHR
3
CH
2 X (CH 2 PN (R 3 2 1 CH 2 X (CH 2
PN
3 1 or CHX (CH 2 PNHCXR7; or -OR 3 wherein each p is independently an integer from 1 to 7; wherein each n is independently an integer from 0 to wherein each R 3 is independently straight chained or branched C 1 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 alkenyl or alkynyl; C 3 -C7 cycloalkyl, ronofluorocycloalkyl, polyfluorocycloalkyl or cycloaJlkenyl; WO 97/42956 WO 9742956PCTIUS97/08335 -Iswherein R 4 is
R
t-±N
R
Am- m M
VR
R
zR
N
m
R
R bb 0 N#K z RRp m N
RV
SUBSTITUTE SHEET (RULE 26) WO 97/42956 WO 9742956PCTIUS97/08335 -16-
N
n
R
7 R R P -C1 2 Z N V R R NP R6 03 R
R
-z x R R p Rp
R
SUBSTITUTE SHEET (RULE 26) WO 97/42956 WO 9742956PCT/US97/08335 -17- N V n w n R R 4- R R' R 6 wherein Z is C 2
-C
7 alkenyl or alkynyl; CH 2 0; Ca; C0 2
CONR
3 S; SO; S02; or NR 3 wherein Z' is (CH 2 CO, (CH 2 or CO(CH 2 wherein each D is independently CH 2 0; S; NR 3
CO;
or CS; wherein W is C=O; C=NOR 3 substituted or unsubstituted phenyl, pyridyl, thiophenyl, furanyl, pyrazinyl, pyrryl, naphthyl, indolyl, imidazolyl, benzfurazanyl, benzfuranyl or benzyimidazolyl, wherein the phenyl, pyridyl, thiophenyl, furanyl, pyrazinyl, pyrryl, naphthyl, indolyl, imidazolyl, benzfurazanyl, benzfuranyl or benzyimidazolyl is substituted with -Cl, Br, -NO 2 -CN, straight chained or branched
C
1
-C
7 alkyl, straight chained or branched C 1
-C
7 mono fluoroa lkyl, straight chained or branched CI-C 7 polyfluoroalkyl, straight chained or branched C 2 -C7, alkenyl, straight chained or branched C 2
-C,
3S SUBSTITUTE SHEET (RULE 26) WO 97/42956 PCT/US97/08335 al1k yn yl C 3 -C-1 cycloalkyl, 3-C mono f luorocyc loa lkyl, C 3
-C
7 polyfluorocycloalkyl,
C
3
-C.
1 cycloalkenyl, -N(R 3 2
-OR
3 ,I COR 3
-CO
2 RI-, or CON (R 3 2 wherein each V is independently 0; 5; CH 2
CRR
1 C 2 or NR 7 provided that when V is CRSR 7 the remaining carbons on the ring may only be substituted with R 6 wherein each m is independently an integer from 0 to 3; wherein o is an integer from 1 to 3; wherein each R is independently straight chained or branched alkyl., monofluoroalkyl or polyf luoroalkyl; straight chained or branched C 2 -C-1 alkenyl or alkynyl; -N(R 3 2
-NO
2 -CN; -C0 2
R
3 or
-OR
3 wherein R. is aryl or heteroaryl substituted with one or more of F; Cl; Br; I; COR 3 C0 2
R
3
-CON(R
3 2 CN; -NO 2 -N (R 3 2
-OR
3 ,I -SR 3
(CH
2 0R 3
(CH
2 0
SR
3 straight chained or branched C C 7 alkyl, monof luoroalkyl, polyf luoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched
C
2 alkenyl, C 2
-C
7 alkynyl, C 3 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; wherein each R 6 is independently straight chained or branched alkyl, hydroxyalkyl, arninoalkyl, alkoxyalkyl, monofluoroalkyl or polyf luoroalkyl; straight chained or branched C 2 -C-1 alkenyl or alkynyl; C 3 -C-1 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; or -OR 3 WO 97/42956 PCTfUS97/08335 -19wherein R, is aryl or het-eroaryl substituted with one or more of F; Cl; Br; I; COR 3 C0 2
R
3 -CON (R 3 2 CN; -NO 2
-N(R
3 2
-OR
3
-SR
3
(CH
2 0 0R 3
(CH
2 0
SR
3 straight chained or branched Cl-C, alkyl., mono fluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched
C
2 -C.7 alkenyl, C 2 alkynyl, C 3 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; and wherein is substituted or unsubstituted benzyl, benzoyl, phenyl, pyridyl, thiophenyl, furanyl, pyrazinyl, pyrryl, naphthyl, indolyl, imidazolyl, benzfurazanyl, benzfurany., benzimidazolyl or 2-keto-l-benzimidazolinyl, wherein the benzyl, benzoyl, phenyl, pyridyl, thiophenyl, furanyl, pyrazinyl, pyrryl, naphthyl, indolyl, imidazolyl, benzfurazanyl, benzfuranyl, benzimidazolyl or 2-keto-1-benzimidazolinyl is substituted with -Cl, -Br, -NO 2
-CN,
straight chained or branched C 1 alkyl, straight chained or branched Cl- C. ronof luoroalkyl, straight chained or branched C C7, polyf luoroalkyl, straight chained or branched C 2 alkenyl, straight chained or branched C 2 alkynyl, C 3 cycloalkyl, C 3
-C,
mnono fluorocyc loa lkyl, C 3 polyfluorocycloalkyl,
C
3
-C
7 cycloalkenyl, -N(R 3 2
-OR
3 -CaR 3 -C0 2
R
3 or
-CON(R
3 2 substituted or unsubstituted straight chained or branched Cl-C-, alkyl, monof luoroalkyl or polyfluoroalkyl; substituted or unsubstituted straight chained or branched C 2 alkenyl or alkynyl; C 3
-C
7 cycloalkyl or cycloalkenyl, wherein the al~kyl, monofluoroalkyl, polyfluoroalkyl, alkenyl, alkyny., cycloalkyl or cycloalkenyl is substituted with phenyl, pyridyl, thiophenyl, furanyl, pyrazinyl, pyrryl, naphthyl, indolyl, imidazolyl, benzfurazanyl, benzfuranyl, WO 97/42956 WO 9742956PCT/US97/08335 benzimidazolyl,
-N(R
3 2
-NO
2 -CN, -C0 2
R
3
-OR
3 -N
R
7 l orR or a pharmaceutically acceptable salt thereof.
In one embodiment of the present invention the compounds have the following structure: LA- Rm I R 3 R1CN R L Jm
R
2 N In a further embodiment of the present invention the compounds have the structure:
Y
3
Y
Y
5 R
R
0 N V z -t PF R 3 N R LM m
R
2 N1 SUBSTITUTE SHEET (RULE 26) WO 97/42956 PCT/US97/08335 -21- In one embodiment of the present invention compounds have the structure: the R R6
R
wherein V is selected from CRR 7 or NR 7 and p is selected from 1-3.
In a preferred embodiment of the present invention the compounds have the following structures: and SUBSTITUTE SHEET (RULE 26) WO 97/42956 PCTIUS97/08335 -22- WO 97/42956 WO 9742956PCTIUS97/08335 -23- The present invention is also directed to compounds having the structure: R2 N B R1N R 3 of wherein A is Y I T
YN
N
~~0 wherein each of Y 1
Y
2
Y
3
Y
4 and Y5 is independently straight chained or branched CI-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2
-C
7 alkenyl or alkynyl; C 3 cycloalkyl, mono fluorocyc loa lky 1, SUBSTITUTE SHEET (RULE 26) WO 97/42956 PCTIUS97/08335 -24polyfluorocycloalky. or cycloalkeiyl; -Cl, -Br, or -NO 2
-N
3 -CN; -OR 4 -OCOR,, -COR 4
-CONHR
4
-CON(R
4 2 or -COOR,; or any two of Y,,
Y
3 0 Y, and Y 5 present on adjacent carbon atoms can constitute a methylenedioxy group; wherein X is S; 0; or NR 4 wherein B is straight chained or branched C,-C, alkyl, monof luoroalkyl, polyf luoroalkyl, alkoxy or thioalkyl; straight chained or branched C 2
-C
7 alkenyl; -SCH 2
CH
4
OR
4
(CH
2 ICAH; -CH 2 X (CH 2 nNHR 4
-(CH
2
NHR
4 or -OR 4 wherein R, is -NO 2 -CN; straight chained or branched C C, alkyl, monofluoroalkyl or polyf luoroalkyl; straight chained or branched C 2
-C
7 alkenyl or alkynyl; C 3
-C
7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R 4 2
-OR
4
(CH
2
POR
4
-COR
4 C0 2
R
4 or -CON(R 4 2 wherein R 2 is straight chained or branched alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2
-C
7 alkenyl or alkynyl; C 3
-C
7 cycloalkyl, ronofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; C 3
-CI
0 cycloalkyl-Cl-C 1 0 -alkyl, C 3
-C
1 0 cycloalkyl-Cl-Cl 0 monofluoroalkyl or C 3
-C
1 0 cycloalkyl-Cl-C,, 0 polyfluoroalkyl; -CN; -CH 2
XR
4
-CH
2 X (CH 2 P NHR 4
I
(CH
2
,NHR
4 I -CH 2
X(CH
2 )p N(R 4 2' -CH 2
X(CH
2
PN
3 or
-CH
2 X (CH 2 PNHCXR.7; or -OR,; wherein each p is independently an integer from 1 to 7; wherein each n is independently an integer from 0 to WO 97/42956 WO 9742956PCTIUS97/08335 wherein R 3 is Rp z p
R
in
N
lz p N v I R 6
N
m6 Yi R 0-R R
RR
SUBSTITUTE SHEET (RULE 26) WO 97/42956 WO 9742956PCTIUS97/08335 -26-
-Z
-N v R R 2ci-i 2 0 R R om- yR 0
Y
R
R
1 R 8 RpR p
R
Z P-fl Rp SUBSTITUTE SHEET (RULE 26) WO 97/42956 WO 9742956PCT/US97/08335 -27-
RRR
-z-OnW-OnN
V
R ]z4p\
R
n
R
Rp 7 6 wherein Z is alkenyl or alkynyl; CH,; 0; CO; C0 2 CONR4,; S; SO; SO 2 or NR 4 wherein Z' is (CH 2 0 CO' (CH 2 or CO(CH 2 wherein each D is independently CH 2 0; S; NR 4
CO;
or CS; wherein W is C=O; C=NOR 4 substituted or unsubstituted phenyl, pyridyl, thiophenyl, furanyl, pyrazinyl, pyrryl, naphthyl, indolyl, imidazolyl, benzfurazanyl, benzfuranyl or benzyimidazolyl, wherein the phenyl, pyridyl, thiophenyl, furanyl, pyraziriyl, pyrryl, naphthyl, indolyl, imidazolyl, benzfurazanyl, benzfuranyl or benzyimidazolyl is substituted with -Cl, Br, -NO 2 -CN, straight chained or branched
C
1
-C
7 alkyl, straight chained or branched C 1
-C,
monof luoroalkyl, straight chained or branched C 1
-C,
polyf luoroalkyl, straight chained or branched C 2
-C
7 SUBSTITUTE SHEET (RULE 26) WO 97/42956 PCTfUS97/08335 -28alkenyl, straight chained or branched C 2 -c- 7 a 1k y n yl, C cycloalkyl, C mono fluorocyc loalkyl, polyfluorocycloalkyl,
C
3 cycloalkenyl, 2 -COR,, -C0 2 or CON (R 4 2 wherein each V is independently 0; S; CH,; CR5R-1;
C(R.
7 2 or provided that when V is CRR, the remaining carbons on the ring may only be substituted with R 6 wherein each m is independently an integer from 0 to 3; wherein o is an integer from 1 to 3; wherein each R is independently straight chained or branched C, alkyl, monof luoroalkyl or polyfluoroalkyl; straight chained or branched C 2
-C
7 alkenyl or alkynyl; -N(R 4 2
-NO
2 -CN; -C0 2
R
4 or
OR
4 wherein each R 4 is independently straight chained or branched C, alkyl, monof luoroalkyl or polyf luoroalkyl; straight chained or branched C 2
-C"
alkenyl or alkynyl; C 3 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; wherein R, is aryl or heteroaryl substituted with one or more of F; Cl; Br; I COR 3 C0 2
R
3 CON (R 3 2 CN; -NO 2
-N(R
3 2
-OR
3
-SR
3
.(CH
2 )c,0R 3
(CH
2 oS3; straight chained or branched C alkyl, monof luoroalkyl, polyf luoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched
C
2 7 alkenyl, C 2 alkynyl, C 3
-C
7 cycloalkyl, monofluorocycloalkyl, polyflAuorocycloalkyl or cycloalkenyl; WO 97/42956 PCTIUS97/08335 1 -29wherein each R 6 is independently straight chained or branched Cl-C, alkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched alkenyl or alkynyl; C 3 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; or -OR,; wherein R. is aryl or heteroaryl substituted with one or more of F; Cl; Br; I COR3; C0 2
R
3 CON (R3) 2 CN; -NO 2
-N(R
3 2
-OR
3
-SR
3
(CH
2 0 0OR 3
(CH
2 0
,SR,;
straight chained or branched Cl-C, alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched
C
2 alkenyl, C 2 alkynyl, C 3 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; and wherein R. is substituted or unsubstituted benzyl, benzoyl, phenyl, pyridyl, thiophenyl, furanyl, pyrazinyl, pyrryl, naphthyl, indolyl, imidazolyl, benzfurazanyl, benzfuranyl, benzimidazolyl or 2-keto-l-benzimidazolinyl, wherein the benzyl, benzoyl, phenyl, pyridyl, thiophenyl, furanyl, pyrazinyl, pyrryl, naphthyl, indolyl, iinidazolyl, benzfurazanyl, benzfuranyl, benzirnidazoly. or 2-keto-l-benzimidazoliny. is substituted with -Cl, -Br, -NO 2
CN,
straight chained or branched alkyl, straight chained or branched monof luoroalkyl, straight chained or branched polyf luoroalkyl, straight chained or branched C 2
-C
7 alkenyl, straight chained or branched C 2 -C.7 alkynyl, C 3 cycloalkyl, C 3
-C,
mono fluorocycl1oa lkyl, C 3
-C
7 polyfluorocycloalkyl,
C
3 cycloalkenyl, -N(R 4 2 -COR,, -CO,R 4 or
-CON(R
4 substituted or unsubstituted straight chained or branched C, alkyl, monof luoroalkyl or WO 97/42956 WO 9742956PCTIUS97/08335 polyf luoroalkyl; substituted or unsubstituted straight chained or branched C 2
-C
7 alkenyl or alkynyl; C 3
-C
7 cycloalkyl or cycloalkenyl, wherein the alkyl, monofluoroalkyl, polyfluoroalkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl is substituted with phenyl, pyridyl, thiophenyl, furanyl, pyrazinyl, pyrryl, naphthyl, indolyl, imidazolyl, benzfurazanyl, benzfuranyl, benzimidazolyl,
-N(R
4 2
-NO
2 -CN, -C0 2
R
4
-OR
4 Y
I
I 3
I
in Mni or a pharmaceutically acceptable salt thereof.
In one embodiment of the present invention the compounds have the following structure: 0 A R M 4 R 4 R Mx
R
SUBSTITUTE SHEET (RULE 26) WO 97/42956 PCT/US97/08335 -31- In a further embodiment of the present invention the compounds have the structure:
-Y
R
Z
R
N B The invention further provides for the embodiment having the following structures: and SUBSTITUTE SHEET (RULE 26) WO 97/42956 WO 9742956PCT/US97/08335 -32- The present invention is also directed to compounds having the structure:
A
RI N R
A
R
1 N R 3 B N R 2 wherein A is y 2
Y
N
Y
wherein each of Y1, Y 2
Y
3
Y
4 and Y 5 is independently straight chained or branched
C
1 alkyl, monof luoroalkyl or polyf luoroalkyl; straight chained or branched C 2
-C
7 alkenyl or alkyriyl; C 3 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -Cl, -Br, or -NO 2
-N
3 CN; 0OR 4 000OR 4 1 -C0R 4 SUBSTITUTE SHEET (RULE 26) WO 97/42956 WO 9742956PCTIUS97/08335 -33-
-CONHR
4 -CONRM) 2 1 or -COOR 4 or any two of Y 2 1
Y
3
Y
4 and Y 5 present on adjacent carbon atoms can constitute a methylenedioxy group; wherein X is S; 0; or NR 4 wherein B is straight chained or branched C 1
-C
7 alkyl, monof luoroalkyl, polyf luoroalkyl, alkoxy or thioalkyl; straight chained or branched C.-C 7 alkenyl; -SCH 2
C
6
H
4
OR
4
(CH
2
,C
6
H
5
-CH
2 X (CH 2
.NHR
4
-(CH
2
),NHR
4 or -OR 4 wherein R, is -NO 2 -CN; straight chained or branched C 1 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2
-C
7 alkenyl or alkynyl; CC7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R4) 2
-OR
4
-(CH
2 )pOR4; -COR4;- C0 2
R
4 or -CON(R 4 2 wherein R 2 is straight chained or branched C 1
-C
7 alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 alkenyl. or alkynyl; C 3
-C
7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; C 3
-C
10 cycloalkyl-Cl-C 1 -alkyl, C 3
-C
10 cycloalkyl-C-Cl 0 monofluoroalkyl or C 3
-CJ
0 cycloalkyl-C-Cl 0 polyfluoroalkyl; -CN; -CH 2
XR
4
-CH
2 X (CH 2
PNHR
4
(CH
2 nNHR4, -CH 2 X (CH 2 PN MR) 2
-CH
2 X (CH 2 pN 3 or
-CH
2 X (CH 2
PNHCXR
7 or -OR4; wherein each p is independently an integer from 1 to 7; wherein each n is independently an integer from 0to SUBSTITUTE SHEET (RULE 26) WO 97/42956 PCT[US97/08335 -34wherein R 3 is R R 6 7 6 wheei eac V5sidpnety ;S to wherein is an) 0 intO e from 0 0 1or 3OC; wherein each R is independently straight chained or branched CI-C 7 alkyl, monofluoroalkyl or polyf luoroaljcyl; straight chained or branched C 2
-C
7 alkenyl or alkynyl; -N(R4) 2
-NO
2 -CN; -C0 2 R4; or
-OR
4 wherein each R 4 is independently straight chained or branched Cl-C 7 alkyl, monofluoroalkyl or polyf luoroalkyl; straight chained or branched C 2
-C
7 alkenyl or alkynyl; C 3
-C
7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; wherein R 5 and R7, each independently may be F; Cl; Br; I; -COR 3 -C0 2
R
3
-CON(R
3 2 -CN; -NO 2
-N(R
3 2
-OR
3
-SR
3
-(CH
2
)POR
3
-(CH
2 pSR 3 straight chained or branched C 1 alkyl, aminoalkyl, carboxamidoalkyl; straight chained or branched
C
2
-C
7 alkeny]. or alkynyl, or C 3
-C
7 cycloalkyl or cycloalkenyl; wherein the alkyl, aminoalkyl, carboxamidoalkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl may be substituted with one or more SUBSTITUTE SHEET (RULE 26) WO 97/42956 PCTIUS97/08335 aryl or heteroaryl, wherein the aryl or heteroaryl may be substituted with -Cl, -Br, -NO, CN, -OR 3
-SR
3
C
1
-C
3 alkyl, or carboxamido; aryl or heteroaryl, wherein the aryl or heteroaryl may be substituted with one or more -Cl, -Br,
COR
3 C0 2
R
3
-CON(R
3 2 -CN, -NO 2
-N(R
3 2
-OR,,
-SR3, (CH 2
OR
3
(CH
2 oSR 3 straight chained or branched C 1 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C,-C, alkenyl, C 2 alkynyl, C 3 -C cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; and wherein each RG is independently straight chained or branched alkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C7 alkenyl or alkynyl; C 3 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; or -OR 4 or a pharmaceutically acceptable salt thereof.
In the present invention aryl includes phenyl, benzyl, benzoyl or naphthyl and heteroaryl includes pyrazinyl, pyrryl, furanyl, thiophenyl, pyridyl, imidazolyl, indolyl, aminophenyl, benzamidyl, benzimidazolyl, benzfurazanyl, benzfuranyl, 2-keto-l-benzimidazolinyl or quinolyl.
The invention further provides for a pharmaceutical composition comprising a therapeutically effective amount of any of the compounds described above and a pharmaceutically acceptable carrier. In the subject invention 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. In one embodiment the WO 97/42956 PCTIUS97/8335 -36therapeutically effective amount is an amount from about 0.01 mg per subject per day to about 500 mg per subject per day, preferably from about 0.1 mg per subject per day to about 60 mg per subject per day and most preferably from about 1 mg per subject per day to about 20 mg per subject per day. In the practice of this invention the "pharmaceutically acceptable carrier" is any physiological carrier known to those of ordinary skill in the art useful in formulating pharmaceutical compositions.
In one preferred embodiment the pharmaceutical carrier may be a liquid and the pharmaceutical composition would be in the form of a solution. In another equally preferred embodiment, the pharmaceutically acceptable carrier is a solid and the composition is in the form of a powder or tablet. In a further embodiment, the pharmaceutical carrier is a gel and the composition is in the form of a suppository or cream.
The invention provides a method of treating a subject suffering from benign prostatic hyperplasia which comprises administering to the subject any one of the compounds described herein effective to treat benign prostatic hyperplasia. In a preferred embodiment the compound of the pharmaceutical composition additionally does not cause a fall in blood pressure at dosages effective to alleviate benign prostatic hyperplasia.
In one preferred embodiment the compound effects treatment of benign prostatic hyperplasia by relaxing lower urinary tract tissue and in particular where lower urinary tract tissue is prostatic smooth muscle.
The invention further provides a method of treating a subject suffering from elevated intraocular pressure which comprises administering to the subject one of the compounds described herein effective to lower intraocular pressure.
WO 97/42956 PCTIS97/08335 -37- The invention further provides a method of treating a subject suffering from a disorder associated with elevated blood cholesterol which comprises administering to the subject one of the compounds described herein effective to inhibit cholesterol synthesis.
The invention also provides a method of treating a disease which is susceptible to treatment by antagonism of the aA, receptor which comprises administering to the subject one of the compounds described herein effective to treat the disease.
The invention further provides a method of treating a subject suffering from impotency which comprises administering to the subject one of the compounds described herein effective to treat impotency.
The invention further provides a method of treating a subject suffering from sympathetically mediated pain which comprises administering to the subject one of the compounds described herein effective to treat sympathetically mediated pain.
The invention provides a method of treating a subject suffering from cardiac arrhythmia which comprises administering to the subject one of the compounds described herein effective to treat cardiac arrhythmia.
The invention provides a method of treating a subject suffering from benign prostatic hyperplasia which comprises administering to the subject one of the compounds described herein in combination with a alpha-reductase inhibitor effective to treat benign prostatic hyperplasia. In one preferred embodiment the reductase inhibitor is finasteride. The dosage administered to the subject is about 0.01 mg per subject per day to 50 mg per subject per day of finasteride in combination with an UIA antagonist. A WO 97/42956 PCTIUS97/0335 -38more preferred dosage administered to the subject is about 1 mg per subject per day to 7 mg per subject per day of finasteride in combination with an a, antagonist. The most preferred dosage administered to the subject is about 5 mg per subject per day of finasteride in combination with an antagonist.
The invention also provides for a pharmaceutical composition comprising a therapeutically effective amount of a combination of any of the compounds described herein in combination with finasteride and a pharmaceutically acceptable carrier. In one embodiment the pharmaceutical composition is a therapeutically effective amount of a combination comprising an amount from about 0.01 mg per subject per day to about 500 mg per subject per day of any one of the compounds described herein and an amount of finasteride of about mg per subject per day. A more preferred embodiment of the pharmaceutical composition is a therapeutically effective amount of a combination comprising an amount from about 0.1 mg per subject per day to about 60 mg per subject per day of any one of the compounds described herein and an amount of the finasteride of about 5 mg per subject per day. The most preferred embodiment of the pharmaceutical composition is a therapeutically effective amount of a combination comprising from about 1 mg per subject per day to about mg per subject per day of any one of the compounds described herein and an amount of finasteride of about 5 mg per subject per day.
The invention further provides a method of relaxing lower urinary tract tissue which comprises contacting the lower urinary tract tissue with an amount of one of the compounds described herein effective to relax lower urinary tract tissue. In one embodiment the lower urinary tract tissue is prostatic smooth muscle. In one preferred embodiment the compound additionally does not cause a fall in blood pressure when it is effective WO 97/42956 PCT[US97/08335 -39to relax lower urinary tract tissue.
The invention provides a method of relaxing lower urinary tract tissue in a subject which comprises administering to the subject an amount of one of the compounds described herein effective to relax lower urinary tract tissue. In one preferred embodiment the compound does not cause a fall in blood pressure and the lower urinary tract tissue is prostatic smooth muscle.
The invention further provides for a method of inhibiting contraction of prostatic tissue, which comprises administering to the subject an amount of any of the compounds described herein effective to inhibit contraction of prostatic tissue. In one preferred embodiment the prostatic tissue is prostatic smooth muscle and the compound additionally does not cause a fall in blood pressure.
The invention provides for the use of the compounds described herein for the preparation of a pharmaceutical composition for lowering intraocular pressure, inhibiting cholesterol synthesis, and the treatment of: benign prostatic hyperplasia, impotency, cardiac arrhythmia and any disease where antagonism of the a1A receptor may be useful. The invention provides for the use of the compounds described herein for the preparation of a pharmaceutical composition for relaxing lower urinary tract tissue and in particular prostatic smooth muscle. The invention further provides for the use of any of compounds described herein for the preparation of a pharmaceutical composition, where the compound additionally does not cause a fall in blood pressure at dosages effective to lower intraocular pressure, to inhibit cholesterol synthesis, and for the treatment of: benign prostatic hyperplasia, impotency, cardiac arrhythmia and any disease where antagonism of the alA receptor may be WO 97/42956 PCT/US97/08335 useful.
The invention provides for the use of the compounds described herein in the preparation of a medicament for lowering intraocular pressure, inhibiting cholesterol synthesis, and for the treatment of: benign prostatic hyperplasia, impotency, cardiac arrhythmia and any disease where antagonism of the acA receptor may be useful. The invention provides for the use of the compounds described herein in the preparation of a medicament for relaxing lower urinary tract tissue and in particular prostatic smooth muscle. The invention further provides for the use of any of compounds described herein in the preparation of a medicament, where the compound additionally does not cause a fall in blood pressure at dosages effective to lower intraocular pressure, to inhibit cholesterol synthesis, and for the treatment of: benign prostatic hyperplasia, impotency, cardiac arrhythmia and any disease where antagonism of the oaA receptor may be useful.
The invention provides for a drug which is useful for lowering intraocular pressure, inhibiting cholesterol synthesis, and the treatment of: benign prostatic hyperplasia, impotency, cardiac arrhythmia and any disease where antagonism of the acA receptor may be useful, the effective ingredient of the said drug being any of the compounds described herein. The invention further provides the drug described herein additionally does not cause a fall in blood pressure at dosages effective to lower intraocular pressure, to inhibit cholesterol synthesis, and for the treatment of: benign prostatic hyperplasia, impotency, cardiac arrhythmia and any disease where antagonism of the cIA receptor may be useful.
The invention provides for a drug which is useful for relaxing lower urinary tract tissue and in particular prostatic smooth muscle, the effective ingredient of WO 97/42956 PCT/US97/08335 -41the drug being any of the compounds described herein.
The invention further provides the drug which is useful for relaxing lower urinary tract tissue additionally does not cause a fall in blood pressure at dosages effective to relax lower urinary tract tissue.
The invention also provides for the and enantiomers of all compounds of the subject application described herein. Included in this invention are pharmaceutically acceptable salts and complexes of all of the compounds described herein. The salts include but are not limited to the following acids and bases.
The following inorganic acids; hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and boric acid. The organic acids; acetic acid, trifluoroacetic acid, formic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, maleic acid, citric acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzoic acid, glycolic acid, lactic acid and mandelic acid. The following inorganic bases; ammonia, hydroxyethylamine and hydrazine. The following organic bases; methylamine, ethylamine, propylamine, dimethylamine, diethylamine, trimethylamine, triethylamine, ethylenediamine, hydroxyethylamine, morpholine, piperazine and guanidine. This invention further provides for the hydrates and polymorphs of all of the compounds described herein.
In one preferred embodiment the pharmaceutical carrier may be a liquid and the pharmaceutical composition would be in the form of a solution. In another equally preferred embodiment, the pharmaceutically acceptable carrier is a solid and the composition is in the form of a powder or tablet. In a further embodiment, the pharmaceutical carrier is a gel and the composition is in the form of a suppository or cream. In a further embodiment the compound may be formulated as a part of a pharmaceutically acceptable transdermal patch.
WO 97/42956 PCT/US97/8335 -42- 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. In powders, the carrier is a finely divided solid which is in admixture with the finely divided active ingredient.
In tablets, 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 osmoregulators. 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 fractionated coconut oil and arachis oil). For parenteral administration, the carrier can also be an oily ester such as ethyl WO 97/42956 PCTIUS97/9335 -43oleate 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.
The compound can also be administered orally either in liquid or solid composition form. 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.
Optimal dosages to be administered may be determined by WO 97/42956 PCTIS97/08335 -44those 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.
One skilled in the art will readily appreciate that appropriate biological assays will be used to determine the therapeutic potential of the claimed compounds for the treating the above noted disorders.
This invention will be better understood from the Experimental Details which follow. However, one skilled in the art will readily appreciate that the specific methods and results discussed are merely illustrative of the invention as described more fully in the claims which follow thereafter.
WO 97/42956 PCT/US97/08335 Experimental Details For Examples 1-92 Scheme 1 describes the general synthetic preparation. All NMRs were obtained using a 300MHz GE QEPLUS NMR machine.
Example 1 1, 6-Dihydro-5-methoxycarbonyl-2- (4-methoxyphenyl)me thyl}thio]-4-methyl-6-(4-nitrophenyl)-1-{N-[3- (4,4-diphenylpiperidin-l-yl)propyl] }carboxamido pyrimidine.
a. 4,4-Diphenylpiperidine hydrochloride. A mixture of 4-piperidone monohydrate hydrochloride (15.0 g, 0.0976 mol) and AlC1 3 (130 g, 0.976 mol, 10.0 eq) in anhydrous benzene (600 mL) were stirred at reflux for 4 hours.
The mixture was cooled to room temperature, poured into ice (300 g) and water (50 mL), and filtered. The solid was washed with toluene and dried to afford 19.2 g of an off-white solid, which was characterized spectroscopically.
b. 3-(4,4-Diphenylpiperidin-l-yl)propionitrile. To a suspension of 4,4-diphenylpiperidine hydrochloride (0.195 g, 0.712 mmol) in EtOH (1.5 mL) was added Et 3
N
(0.25 mL, 1.8 mmol, 2.6 eq) followed by acrylonitrile (0.13 mL, 2.01 mmol, 2.8 eq). The resulting solution was stirred at room temperature under argon for 15 min and then concentrated. Water was added, and the mixture was extracted with EtOAc (3 X 10 mL). The combined organic extracts were dried (MgSO 4 and concentrated to give 170 mg of a tan solid, which was characterized spectroscopically and used in the next reaction without purification.
c. 3-(4,4-Diphenylpiperidin-l-yl)propylamine. To a stirred solution of 3-(4,4-diphenylpiperidin-1- WO 97/42956 PCTIUS97/8335 -46yl)propionitrile (2.00 g, 6.89 mmol) in anhydrous THF mL) under argon was added a solution of BH 3 in THF M, 24.1 mL, 24 mmol, 3.5 eq) at room temperature.
The mixture was refluxed for 4.5 hours and then cooled to room temperature. Aqueous HC1 (6 N, 50 mL) was added and stirring was continued for 1 hour. The mixture was basified to pH 9 by addition of 6 N aq.
NaOH, extracted with CH 2 Cl1 (3 X 10 mL), dried (MgSO,) and concentrated. The residue was purified by flash chromatography (SiO 2 EtOAc-MeOH-isopropylamine 9:1:0 to 4:1:0.2) to give 1.35 g of tan solid, which was characterized spectroscopically.
d. 2-(4-Methoxybenzyl)-2-thiopseudourea hydrochloride.
To a well-stirred suspension of thiourea (7.6 g, 0.1 mol) in THF (50 mL) at 0 OC, 4-methoxybenzyl chloride (16 g, 0.1 mol) was added in 10 min and the mixture was allowed to warm to room temperature. After 2 hours the mixture was heated to 65 OC and kept at that temperature for 5 hours. It was cooled to room temperature and diluted with diethyl ether (200 mL). The white precipitate formed was filtered and dried (22.5 g, 96%) m. p. 161-163 OC.
e. Methyl 2-{(4-nitrophenyl)methylene}-3-oxobutyrate.A mixture of 4-nitrobenzaldehyde (15.1 g, 0.1 mol), methyl acetoacetate (12.773 g, 0.11 mol), piperidine (0.41 g, 476 mL, 4.8 mmol), and acetic acid (0.288 g, 274 mL, 4.8 mmol) in 2-propanol (400 mL) was stirred at room temperature for 48 hours. The white solid, methyl 2-{(4-nitrophenyl)methylene}-3-oxobutyrate, formed was filtered, washed with 2-propanol (2 X 50 mL) and dried (21.80 g, 93%).
f 6-Dihydro-5-methoxycarbonyl-2- (4-methoxyphenyl) methyl}thio]-4-methyl-6-(4-nitrophenyl)pyrimidine. A WO 97/42956 PCTIUS9708335 -47mixture of methyl 2- (4 -nitrophenyl)methylene}-3oxobutyrate (8.96 g, 0.04 mol), 2-(4-methoxybenzyl)-2thiopseudourea hydrochloride (9.28 g, 0.04 mol), and NaOAc (3.28 g, 0.04 mol) in DMF (100 mL) was stirred and heated at 70-75 OC for 4.5 hours. The mixture was cooled, poured into ice-water (300 mL), extracted with EtOAc (2 X 400 mL). The combined EtOAc extracts were washed with 10% NaHCO 3 solution (2 X 60 mL), brine (100 mL), and dried (MgS04). Solvent was evaporated and the crude product was purified by flash column chromatography on silica gel using 10% through EtOAc in hexane as the gradient eluent, to leave the product as an oil, which on trituration with EtOAc/hexane became a yellow solid (11.4 g, 66.7%); m.p. 138-139 OC; 1 H-NMR (CDC3) 6 2.15 3 3.62 3 3.72 3 4.05, 5.78 d, J 3 Hz, 1 4.08, 4.20 (AB q, J 12.5 Hz, 2 4.21, 6.40 (s, d, J 3 Hz, 1 6.66 (2 d, J 8.5 Hz, 2 7.08 (2 d, J 8.5 Hz, 2 7.37 (2 d, J 8.8 Hz, 2 8.7 (2 d, J 8.8 Hz, 2 Anal. Calcd. for C 21
H
21
N
3 0sS: C, 59.00; H, 4.95; N, 9.83. Found: C, 59.02; H, 4.93; N, 9.77.
g. 1,6-Dihydro-5-methoxycarbonyl-2- [{(4-methoxyphenyl) methyl}thio] -4-methyl-6- (4-nitrophenyl) (4-nitroph enyloxy)carbonyl]pyrimidine.
To a well-stirred mixture of 1,6-dihydro-5-methoxy carbonyl-2- (4-methoxyphenyl)methyl}thio] -4-methyl-6 -(4-nitrophenyl)pyrimidine (4.5 g, 0.0105 mol), NaHCO 3 (3.69 g, 0.044 mol), CH 2 C1, (200 mL), and water (50 mL) at 0-5 oC, 4-nitrophenyl chloroformate (2.4 g, 0.0119 mol) was added in 5 min and the mixture was allowed to warm to room temperature. After 10 hours, the TLC analysis of the reaction mixture showed the presence of a small amount of starting pyrimidine, therefore, more 4-nitrophenyl chloroformate (0.65 g, 0.0032 mol) was added and the stirring continued for an additional 4 WO 97/42956 PCTIUS97/08335 -48hours. The two layers were separated, the CH,C1, layer was washed with saturated aqueous NaHCO 3 solution (3 X mL), dried (MgSO 4 and the solvent evaporated. The residue was recrystallized from CH 2 C1 2 and hexane to give the product as white crystals (5.5 g, m.p.
156-157 OC; -H-NMR (CDC1 3 6 2.53 3 3.70 3 3.81 3 4.06, 4.36 (AB q, J 13.5 Hz, 2 H), 6.30 1 6.78 J 8.7 Hz, 2 7.17 J Hz, 2 7.20 J 8.7 Hz, 2 7.32 J 8.8 Hz, 2 7.97 J 8.8 Hz, 2 8.25 J 8.8 Hz, 2 Anal. Calcd. for C 2
,H
24
N
4 0 9 S: C, 56.75; H, 4.08; N, 9.45. Found: C, 56.49; H, 4.28; N, 9.25.
h. 1,6-Dihydro-5-methoxycarbonyl-2-[{ (4-methoxyphenyl) methyl}thio]-4-methyl-6-(4-nitrophenyl)-1-{N-[3-(4,4diphenylpiperidin-1 -yl)prop-yl] carboxamido pyrimidine.
To a stirred solution of 1,6-dihydro-5-methoxycarbonyl -2-[{(4-methoxyphenyl)methyl)thio]-4-methyl-6-(4-nitr ophenyl)-1-[(4-nitrophenyloxy)carbonyl]pyrimidine (0.592 g, 1 mmol) in anhydrous THF (10 mL) at room temperature under argon atmosphere, a solution of 3- [4,4-diphenylpiperidin-1-yl]propylamine (0.441 g, mmol, 1.5 eq) in THF (5 mL) was added and the stirring continued for 1 hours. Solvent was evaporated from the reaction mixture and the residue was redissolved in
CH
2 C1, (50 mL), washed with 5% NaHCO 3 (3 X 25 mL), brine mL), and dried (MgSO 4 Solvent was evaporated and the residue was purified by flash chromatography on silica gel using 10% methanol in EtOAc as the eluent to give the desired product as an oil, which on trituration with hexane and drops of EtOAc became a white powder (0.32 g, m.p. 79-80 oC; 1
H-NMR
(CDC1 3 6 1.61-1.82 4 2.27 3 2.30-2.51 8 3.19-3.36 1 3.42-3.60 1 3.68 3 3.76 3 3.95, 4.22 (AB q, J 13.6 Hz, 2 6.16 1 6.70 J 8.6 Hz, 2 7.04 WO 97/42956 PCTfUS97/08335 -49- J 8.6 Hz, 2 7.11-7.29 12 7.68 (br t, 1 H, NH), 7.91 J 8.8 Hz, 2 Anal. Calcd. for
C
42
H
4 5NO 6 S.0.33 CH 2 C1 C, 65.52; H, 5.93; N, 9.03.
Found: C, 65.52; H, 6.01; N, 9.20.
Example 2 1, 6-Dihydro-5-methoxycarbonyl-2- (4-methoxyphenyl)me thyl}thio]-4-methyl-6-(4-nitrophenyl)-1-{N-[3- (4-phenylpiperidin- l-yl) propyl] }carboxamidopyrimidine.
a. 3-(4-Phenylpiperidin-l-yl)propionitrile.
Acrylonitrile (3.1 mL, 44 mmol, 2.5 eq) was added to a solution of 4-phenylpiperidine (3.0 g, 18 mmol) in EtOH (40 mL) and the mixture was stirred at room temperature for 1.5 hours. The volatiles were removed to give 3.8 g of pure product (brown oil, which was characterized spectroscopically.
b. 3-(4-Phenylpiperidin-l-yl)propylamine. To a stirred solution of 3-(4-phenylpiperidin-l-yl)propionitrile (5.1 g, 24 mmol) in anhydrous THF (20 mL) under argon was added a solution of BH 3 in THF (1.0 M, 83 mL, 83 mmol, 3.5 eq) at room temperature. The mixture was refluxed for 4.5 hours and then cooled to room temperature. Aqueous HC1 (6 N, 130 mL) was added and stirring was continued for 2 hours at 50-70 oC. The mixture was basified to pH 9 by addition of 6 N aq.
NaOH and extracted with EtOAc (100 mL) and CH 2 C1 (3 x 100 mL). The combined organic extracts were dried (MgSO 4 and concentrated. The residue was dissolved in
CH
2 C1 (20 mL) and treated with HC1 in ether (1.0 M, 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, the pH was adjusted to 10-11 with 1 N NaOH, and the aqueous phase was extracted with WO 97/42956 PCT/US97/08335
CH
2 C1, (3 X 50 mL). The combined extracts were dried (MgSO 4 and the solvents evaporated to give 4.5 g (87%) of pure product (light brown solid), which was characterized spectroscopically.
c. 1,6 -Dihydro- 5 -methoxycarbonyl 2 (4-methoxyphenyl) methyl}thio]-4-methyl-6-(4-nitrophenyl) [3- (4-phenylpiperidin-1-yl)propyl] }carboxamido pyrimidine. This compound was prepared from 1,6-dihydro-5-methoxycarbonyl-2-[{ (4-methoxyphenyl) methyl}thio] -4-methyl-6- (4-nitrophenyl) [(4-nitroph enyloxy)carbonyl]pyrimidine (0.77 g, 1.3 mmol), 3-[4phenylpiperidin-1-yl] propylamine (0.34 g, 1.56 mmol, 1.2 eq) and purified using similar conditions described in Example 1 (0.63 g, m.p. 123-124 OC; 'H-NMR (CDC1 3 6 1.65-2.10 8 2.41 3 2.41-2.55 3 2.99-3.06 2 3.2-3.35 1 3.45- 3.60 1 3.67 3 3.75 3 4.10, 4.33 (AB q, J 13.6 Hz, 2 6.19 1 6.71 J 8.6 Hz, 2 7.09 J 8.6 Hz, 2 7.20-7.34 (m, 7 7.97 (br t, 1 H, NH), 7.97 J 8.8 Hz, 2 H); Anal. Calcd. for C 36
H
41 NsOS.0.25 CH 2 Cl 2 C, 62.82; H, 6.04; N, 10.11. Found: C, 62.54; H, 6.13; N, 10.03.
Example 3 1-{N-[3-(4-Cyano-4-phenylpiperidin-1-yl)propyl]} carboxamido-1, 6-dihydro-5-methoxycarbonyl-2- (4-meth oxyphenyl)methyl}tio] -4-methyl-6-(4-nitrophenyl) pyrimidine.
a. 3-(4-Cyano-4-phenylpiperidinlyl)propylamine. 4- Cyano-4-phenylpiperidine hydrochloride (5.01 g, 22.5 mmol) was added to water (100 mL) and the solution was basified to pH 10-11 by addition of 6 N aqueous NaOH.
The mixture was extracted with CHC1 2 (3 x 100 mL). The combined organic extracts were dried (MgSO 4 and WO 97/42956 PCTIUS97/08335 -51concentrated. To the residue were added 3bromopropylamine hydrobromide (4.92 g, 22.5 mmol) anhydrous K 2 C0 3 (3.42 g, 24.8 mmol, 1.10 eq), and 1,4dioxane (100 mL) The mixture was stirred at ref lux for 24 hours under a CaSO, drying tube. The solvent was evaporated, and the product was purified by flash chromatography (SiO 2 1 CHCl 3 /MeOH/2 M NH 3 in MeOH (100:8:4 to 100:20:8) to give 3.23 g (59t) of colorless oil, which was characterized spectroscopically.
b. (4-Cyano-4-phenylpiperidin-1-yl)propylJ carboxamido-1, 6-dihydro-5-methoxycarbonyl-2 (4-metho xy-phenyl)methyl~thio] -4-methyl-6- (4-nitrophenyl) pyrimidine.
This compound was prepared from 1,6-dihydro-5-methoxy carbonyl-2- (4-rethoxyphenyl)methyl~thio] -4-methyl-6 (4-nitrophenyl) (4-nitrophenyloxy) carbonyl] pyrimi dine (0.592 g, 1 mmol), 3-[4-cyano-4-phenyl piperidin-i-yllpropylamine (0.292 g, 1.2 mmol, 1.2 eq) and purified using similar conditions described in Example 1 (0.445 g, 64%0) m.p. 143-144 0 C; 1
H-NMR
(CDCl 3 6 1.70-1.86 (in, 2 H) 2.02-2.09 (in, 4 H) 2.38 3 2.41-2.56 (in, 4 2 .95 02 (in, 2 H) 3.24- 3.40 (mn, 1 3.42-3.58 (in, 1 3.68 3 3.76 3 4.08, 4.23 (AB q, J 13.5 Hz, 2 6.23 (s, 1 H) 6.72 J 8.6 Hz, 2 H) 6. 94 (br t, 1 H, NH) 7. 08 J 8. 6 Hz, 2 H) 7.2 9 J 8. 7 Hz, 2 H) 7.33-7.49 (mn, 5 H) 7.94 J 8 Hz, 2 Anal.
Calcd. f or C 3 -7H 4 0
N
6
Q
6 S: C, 63.78; H, 5.79; N, 12.06.
Found: C, 63.86; H, 5.90; N, 11.92.
Example 4 (4methoxycarbonyl -4 -phenylpiperidin- 1-yl) propyl) carboxamido-2- (4-methoxyphenyl)methyl~thio] -4-methyl- 6- (4-nitrophenyl) pyrimidine.
WO 97/42956 PCT/US97/08335 -52a. 4-Methoxycarbonyl-4-phenylpiperidine. T o a stirred solution of H 2 S0 4 (16 mL) in MeOH (400 mL), 4phenyl-4-piperidinecarboxylic acid 4-methyl benzenesulfonate (37.7 g, 0.21 mole) was added and the mixture was stirred and ref luxed for 8 hours. Excess methanol was evaporated at reduced pressure and the residue was poured into a mixture-of ice and 6 N NaOH.
The pH was adjusted to 10-11 by adding more 6 N NaOH and extracted with CH 2 Cl 2 (3 X 150 mL) The combined
CH
2 C1 2 extracts were dried (MgSO 4 and the solvent evaporated to leave the desired product as a viscous oil. The product (20.2 g, 92%) was used without further purification.
b. 3- (4-Methoxycarbonyl-4-phenylpiperidin-lyl) propylamine.
A mixture of 4-methoxycarbonyl-4-phenylpiperidine g, 0. 03 9 mol) 3 -bromopropylamine hydrobromide (12. 7 g, 0.058 mol), potassium carbonate (13.475 g, 0.0957 mole), and KI (3.24 g, 0.0195 mol) in 1,4-dioxane (200 mL) was stirred and ref luxed for 24 hours. Dioxane was evaporated at reduced pressure, the residue was treated with ice-cold 6 N NaOH (400 mL) and extracted with
CH
2 C1 2 (4 X 120 mL) Solvent was evaporated from the combined dried (K 2 C0 3 extracts and the residue was purified by column chromatography on silica gel using CHC1 3 /MeOH/2 M NH 3 in MeOH (20:2:1) as the eluent to afford the product as a viscous oil g, 72%1).
C. 1,6-Dihydro-5-methoxycarbonyl-l-{N-[3-(4methoxycarbonyl-4 -phenylpiperidin- l-yl) propyl] }carbox amido-2- (4-methoxyphenyl)methyl)thioj -4-methyl- 6- (4-nitrophenyl)pyrimidine. This compound was prepared from 1, 6-dihydro- 5 -rethoxycarbonyl 2- (4 -methoxyphenyl) methyl) thio] 4-methyl- 6 -nitr ophenyl) (4-nitrophenyl-oxy) carbonyl] pyrimidine g, 1.69 mmol), 3- [4-methoxycarbonyl-4-phenyl WO 97/42956 PCT/US97/08335 -53piperidin-1-yllpropylamine (0.56 g, 2.03 mmol, 1.2 eq) and purified using similar conditions described in Example 1 (1.085 g, m.p. 140-141 OC; IH-NMR (CDCl 3 6 1.62-1.74 (in, 2 1.82-2.18 (mn, 4 2.21 3 2.35-2.58 (in, 4 2.75-2.89 (mn, 2 3.18- 3.30 (in, 1 H) 3.42-3.58 (in, 1 H) 3.6. 3 H) 3. 66 3 H) 3.75 3 H) 3.91, 4. 15 (AB q, J 13.6 Hz, 2 HI), 6. 14 1 H) 6. 69 J 8. 6 Hz, 2 H) 7.0 2 J 8. 6 Hz, 2 H) 7. 20 7.3 7 (in, 7 H) 7. 56 (br t, 1 H, NH), 7.90 J 8.8 Hz, 2 Anal. Calcd. for
C
3 8
H
4 3
N
5 0 8 S: C, 62.54; H, 5.94; N, 9.60. Found: C, 62.41; H, 6.06; N, 9.34.
Example 5 -Methoxycarbonyl -4 -methyl- 6 -nitrophenyl) 1- [3 4-diphenyl-piperidin-1-yl) propyl] )carboxamido-1, 2, 3, 6- tetrahydro- 2- thioxo-pyrimidine.
To a stirred solution of 1,6-dihydro-6-methoxycarbonyl- 2- [{(4-methoxyphenyl)methyl~thio] -4-met"hyl-6- (4-nitro phenyl)-l-{N-.[3-(4,4-diphenylpiperidin-1-yl)propyl]) carboxainidopyrimidine (0.14 g, 0.187 minol) and ethanethiol 5 mL) in CH 2 C1 2 (5 inL) at 5 'C under argon, TFA 5 mL) was added and the mixture was allowed to warm to room temperature. Af ter 3 hours, solvents were evaporated completely, the residue was redissolved in EtOAc (10 inL), washed with 5% NaHCO 3 X 1 mL) and dried (MgSO 4 Solvent was evaporated and the residue was purified by column chromatography using 1:1 hexane/EtOAc to 100% EtOAc as gradient eluent. The oily product was crystallized from hexane and EtOAc (0.096 g, 82%) in.p. 130-131 0 C; 1 H-NMR (CDCl 3 6 1.65- 1.80 (in, 2 H) 2.31 3 H) 2.31-2.49 (in, 10 H) 3.2 5 55 (in, 2 H) 3. 76 3 H) 7. 01 1 H) 7. 09 7.29 (in, 6 H) 7.41 J 8.2 Hz, 2 H) 8.11 J 8. 8 Hz, 2 H) 9.76 (br t, 1 H, NH) Anal. Calcd. for
C
34
H
3 7
N
5 0rS.0.3 H420: C, 64.50; H, 5.89; N, 11.06. Found: C, 64.45; H, 6.05; N, 10.87.
WO 97/42956 PCT/US97/08335 -54- Example 6 (4-Methoxyphenyl)-4-phenylpiperidin-1-yl) propyl] }carboxamido-5-methoxycarbonyl-4-methyl- 6-(4-nitrophenyl)-1,2,3,6-tetrahydro-2-thioxo pyrimidine.
a. 4-(4-Methoxyphenyl)-4-phenylpiperidine. 4-Hydroxy- 4-phenylpiperidine (5.00 g, 28.2 mmol) was added to a suspension of A1C1 3 (18.8 g, 0.141 mol, 5.00 eq) in anhydrous anisole (100 mL). The mixture was stirred at room temperature for 1 hours and then heated to 50 °C for 3.5 hours. It was cooled to room temperature and poured cautiously into ice-water. The mixture was basified to pH 11 by addition of 6 N aqueous NaOH, and extracted with EtOAc (3 x 75 mL) The combined organic extracts were applied directly to a flash chromatography column, which was eluted with CH 2 C1 2 /0.67 M NH 3 in MeOH to afford 1.683 g of light yellow oil, which was characterized spectroscopically.
b. 3- [4-(4-Methoxyphenyl)-4-phenylpiperidin-lyl]propionitrile. Acrylonitrile (1.03 mL, 15.7 mmol, 2.50 eq) was added at 0 OC to a solution of 4-(4methoxyphenyl)-4-phenylpiperidine (1.68 g, 6.28 mmol) in EtOH (20 mL) and the resulting solution was stirred for 1.5 hours at room temperature. After removal of the solvent, the residue was purified by flash chromatography (SiO 2 EtOAc-CHC1 3 1:3) to give 1.41 g of colorless oil, which was characterized spectroscopically.
c. 3-[4-(4-Methoxyphenyl)-4-phenylpiperidin-lyl]propylamine. To a stirred solution of methoxyphenyl)-4-phenylpiperidin-l-yl]pro pionitrile (1.41 g, 4.40 mmol) in anhydrous THF (10 mL) under argon was added a solution of BH 3 in THF (1.0 M, 11.0 mL, 2.5 eq) at room temperature. The mixture was WO 97/42956 PCTfUS97/08335 refluxed for 4.5 hours and then cooled to room temperature. Aqueous HC1 (6 N, 15 mL) was added and stirring was continued for 2 h at 55-60 OC. The mixture was basified to pH 9 by addition of 6 N aq.
NaOH and extracted with CH 2 C1 2 (3 x 75 mL) The combined organic solutions were dried (MgSO,) and concentrated. The residue was dissolved in CH 2 C1 2 mL) and treated with HC1 in ether (1.0 M, 9.0 mL, eq). The solvents were removed, ether (30 mL) was added, the mixture was filtered, and the filter cake was washed with ether (2 x 10 mL). Water (20 mL) was added to the resulting white solid, the pH was adjusted to 10 with 1 N NaOH, and the aqueous phase was extracted with CH 2 C1 2 (3 x 40 mL) The combined organic extracts were dried (MgSO) and concentrated to give 610 mg of white solid, which was characterized spectroscopically.
d. (4-Methoxyphenyl) -4-phenylpiperidin-1-yl) propyl] carboxamido-5-methoxycarbonyl-4-methyl-6- (4-nitrophenyl)-1,2,3,6-tetrahydro-2 -thioxopyrimidine.
To a stirred mixture of 1,6-dihydro-5-methoxycarbonyl-2 -[{(4-methoxyphenyl)methyl}thio]-4-methyl-6-(4-nitrop henyl)-1-[(4-nitrophenyloxy)carbonyl]pyrimidine (0.592 g, 1 mmol) and KCO 3 (0.276 g, 2 mmol) in anhydrous THF mL) at room temperature under argon atmosphere, a solution of 3-[4-(4-methoxyphenyl)-4-phenyl piperidin-l-yl]propylamine (0.390 g, 1.2 mmol, 1.2 eq) in THF (10 mL) was added and the stirring was continued for 1 hour. Solvent was evaporated from the reaction mixture and the residue was redissolved in CH 2 C1 2 mL), washed with 5% NaHCO 3 (3 X 25 mL), brine (50 mL), and dried (MgSO 4 The CH 2 Cl 2 solution was filtered and cooled to 5 To this, ethanethiol (0.5 mL) and TFA mL) were added and the mixture was stirred and allowed to warm to room temperature. After 3 hours, WO 97/42956 PCTIUS97/8335 -56solvents were evaporated completely, the residue was redissolved in EtOAc (10 mL), washed with 5% NaHCO, X 1 mL), and dried (MgSO 4 Solvent was evaporated and the residue was purified by column chromatography using 1:1 hexane/EtOAc to 100% EtOAc as gradient eluent. The oily product was crystallized from hexane and EtOAc (0.41 g, m.p. 120-121 oC; 1 H-NMR (CDC1 3 6 1.60- 1.80 2 2.31 3 2.31-2.51 8 3.32- 3.43 2 3.75 3 3.76 3 6.77 (d, J 8.8 Hz, 2 7.02 1 7.12 J 8.6 Hz, 2 7.20-7.27 6 7.41 J 8.6 Hz, 2 H), 8.11 J 8.8 Hz, 2 9.76 (br t, 1 H, NH); Anal.
Calcd. for C 3 asH, 3 N0 6 S: C, 63.91; H, 5.98; N, 10.65.
Found: C, 64.19; H,6.22; N, 10.36.
Example 7 a. 4-Ethoxycarbonyl-4-phenylpiperidine. To a stirred solution of H 2 SO, (1.62 g, 16.56 mmol) in EtOH (200 mL), 4-phenyl-4-piperidine-carboxylic acid 4-methyl benzenesulfonate (25 g, 66.23 mmol) was added and the mixture was stirred and refluxed for 12 hours. Excess ethanol was evaporated at reduced pressure and the residue was poured into a mixture of ice and 6 N NaOH.
The pH was adjusted to 10-11 by adding more 6 N NaOH and extracted with CH 2 Cl 2 (3 X 100 mL). The combined
CH
2 Cl 2 extracts were dried (MgSO 4 and the solvent evaporated to leave the desired product as a colorless viscous oil, the 1 H-NMR showed it to be pure (14.68 g, and was used without any further purification.
b. 3-(4-Ethoxycarbonyl-4-phenylpiperidin-l-yl) propylamine.
A mixture of 4-ethoxycarbonyl-4-phenylpiperidine (30.5 g, 0.131 mol), 3-bromopropylamine hydrobromide (42.93 g, 0.196 mol), potassium carbonate (36.14 g, 0.241 mole), and KI (10.8 g, 0.065 mol) in 1,4-dioxane (500 mL) was stirred and refluxed for 24 hours. Dioxane was WO 97/42956 PCT/US97/08335 -57evaporated at reduced pressure, the residue was treated with ice-cold 6 N NaOH (400 mL) and extracted with
CH
2 C1 2 (4 X 120 mL). Solvent was evaporated from the combined dried (K 2
CO
3
CH
2 C1 2 extracts and the residue was purified by column chromatography on silica gel using CHC1 3 /MeOH/2 M NH 3 in MeOH (20:2:1) as the eluent to afford the product as a viscous oil (24.2 g, 83.3%) c. 1-{N-[3-(4-Ethoxycarbonyl-4-phenylpiperidin-1-yl) propyl] carboxamido-5-methoxycarbonyl-4-methyl-6- (4-nitrophenyl)-1,2,3,6-tetra-hydro-2thioxopyrimidine. This compound was prepared from 1, 6-dihydro-5-methoxycarbonyl-2 (4 -methoxyphenyl) me thyl}thio] -4-methyl-6- (4-nitrophenyl) [(4-nitrophen yloxy)carbonyllpyrimidine (0.592 g, 1 mmol), K 2
CO,
(0.276 g, 2 mmol), 3-[4-ethoxycarbonyl-4-phenyl piperidin-l-yl]propylamine (0.350 g, 1.2 mmol, 1.2 eq), ethanethiol (0.5 mL), and TFA (0.5 mL) using the procedure described in Example 7 and purified by flash column chromatography (0.295 g, m.p. 125-126 OC; 1 H-NMR (CDC1 3 6 1.13 J 7 Hz, 3 1.62-1.80 (m, 2 1.87-2.0 2 2.06-2.18 2 2.31 (s, 3 2.34-2.39 2 2.50-2.55 2 2.79-2.83 2 3.30-3.51 2 3.74 3 4.07 (q, J 7 Hz, 2 7.03 1 7.18-7.36 6 7.40 J 8.8 Hz, 2 8.08 J 8.8 Hz, 2 9.78 (br t, 1 H, NH); Anal. Calcd. for C 3
,H
3 ,NOS: C, 59.70; H, 5.98; N, 11.23. Found: C, 59.55; H, 5.99; N, 11.43.
Example 8 1, 6-Dihydro-l-{N- (4,4-diphenylpiperidin-1-yl)propy }carboxamido-2-methoxy-5-methoxycarbonyl-4-methyl- 6-(4-nitrophenyl)pyrimidine. To a stirred mixture of 1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-methyl (4-nitrophenyl) [(4-nitrophenyloxy)carbonyl]pyri midine (0.940 g, 2 mmol) and K 2
CO
3 (0.552 g, 4 mmol) in anhydrous THF (20 mL) at room temperature under argon WO 97/42956 PCT/US97/8335 -58atmosphere, a solution of 3 [4,4-diphenylpiperidin-l-yl] propylamine (0.882 g, 3 mmol, 1.5 eq) in THF (5 mL) was added and the stirring was continued for 1 hour.
Solvent was evaporated from the reaction mixture, the residue was redissolved in CH 2 Cl 2 (50 mL), washed with NaHCO3 (3 X 25 mL), brine (50 mL), and dried (MgSO 4 Solvent was evaporated and the residue was purified by flash chromatography on silica gel using 10% methanol in EtOAc as the eluent to give the desired product as an oil, which on trituration with hexane and drops of EtOAc became a white powder (1.10 g, m.p. 95-96 1 H-NMR (CDC1 3 6 1.61-1.71 2 2.26-2.33 (m, 2 2.38 3 2.39-2.50 8 3.20-3.41 (m, 2 3.65 3 3.89 3 6.65 1 6.84 (br t, 1 H, NH), 7.08-7.29 10 7.40 J 8.7 Hz, 2 8.03 J 8.6 Hz, 2 Anal. Calcd. for
C
3 5H 3 ,NsO6.0.75 CH 2 C1,: C, 62.28; H, 5.92; N, 10.16.
Found: C, 62.23; H, 5.76; N, 10.12.
Example 9 5-Methoxycarbonyl-4-methyl-6- (4-nitrophenyl) [3- (4,4-diphenyl-piperidin-1-yl)propyl] }carboxamido- 2-oxo-1,2,3,6-tetrahydropyrimid-ine.
a 1,6-Dihydro-5-methoxycarbonyl-2-methoxy-4-methyl-6-(4nitro-phenyl)pyrimidine.
A mixture of methyl 2-{(4-nitrophen-yl)methylene}-3oxobutyrate (12.46 g, 0.05 mol), O-methylisourea hydrogen sulfate (10.32 g, 0.06 mol), and NaOAc (9.84 g, 0.06 mol) in DMF (50 mL) was stirred and heated at 70-75 OC for 4 hours. The mixture was cooled and poured into ice-water (300 mL). The precipitate formed was filtered, washed with water, and dried. The crude product was purified by flash column chromatography on silica gel using 10% through 30% EtOAc in hexane as the gradient eluent (9.8 g, The 'H-NMR analysis of WO 97/42956 PCTfUS97/08335 -59the product showed it to be a 19:1 mixture of the amine/imine tautomers which was used as such in the next step. 'H-NMR (CDCl 3 6 2.32, 2.38 (2 s, 3 H) 3.59, 3.70 (2 s, 3 H) 3. 70, 3.85 (2 s, 3 5. 5.66 d, J 3 Hz, 1 H) 5. 50, 6 .08 d, J =3 Hz, 1 7.43, 7. 45 (2 d, J 9 Hz, 2 H) 8. 10, 8. 11 (2 d, J 9 Hz, 2 H).
b.1, 6-Dihydro-2-methoxy-5-maethoxycarbonyl-4-methyl-6- (4-nitrophenyl) (4-nitrophenyloxy) carbonyl] pyrimi dine.
To a well-stirred mixture of 1,6-dihydro-2-methoxy-5methoxycarbonyl -4 -methyl -6 (4 -nitrophenyl) pyrimidine 7 g, 0. 0187 mol) NaHCO 3 (6 .27 g, 0. 074 mol) CHCl, (200 mL) and water (50 mL) at 0-5 0 C, 4-nitropheny.
chioroformate (3.76 g, 0.0186 mol) was added in 5 min and the mixture was allowed to warm to room temperature. After 10 hours, the TLC analysis of the reaction mixture showed the presence of a small amount of starting pyrimidine, therefore, more 4-nitrophenyl chioroformate (0.65 g, 0.0032 mol) was added and the stirring continued for an additional 4 hours. The two layers were separated, the CHC1 2 layer was washed with saturated aqueous NaHCO 3 Solution (3 X 50 mL) dried (MgSO,) and the solvent evaporated. The residue was recrystallized from CH 2 C1 2 and hexane to give the product as white crystals (12. 8 g, 89%) 'H-NMR (CDCl 3 6 2.48 3 H) 3. 69 3 H) 3. 94 3 6.34 (s, 1 7.36 J 9.1 Hz, 2 H) 7.46 J 8.7 Hz, 2 8. 14 J 8. 7 Hz, 2 H) 8. 26 J 1 Hz, 2 m.p. 168-169 OC. Anal. Calcd. for C 21 HlN 4 0 9
C,
53.62; H, 3.86; N, 11.91. Found: C, 53.69; H, 3.92; N, 11.85.
C. 5-Methoxycarbonyl-4-methyl-6- (4-nitrophenyl) 1-{N-(3-(4,4-di-phenylpiperidin-1-yl)propyl]} carboxamido-2-oxo-1, 2,3, 6-tetrahydro-pyrimidine.
WO 97/42956 PCT/US97/08335 To a stirred solution of 1,6-dihydro-2-methoxy-6tethoxycarbonyl-4-methyl-6- (4-nitrophenyl) [3- 4-diphenylpiperidin-1-yl)propyl] }carboxamidopyrimi dine 208 g, 0. 33 mmol) in THF (10 mL) at 5 'C under argon, 3 N HC1 (6 mL) was added and the mixture was allowed to warm to room temperature. After 2 hours, solvents were evaporated completely, the residue was treated with 40 mL of 10%- NaHCO 3 the product was extracted with CH 2 Cl 2 (2 X 15 mL) and the combined extracts were dried Solvent was evaporated and the residue was crystallized from hexane and EtOAc (0.20 g, 9711); m.p. 1-97-198 0 C; 'H-NMR (CDC1 3 :6 1.63- 1.67 (in, 2 2.23-2.28 (in, 2 2.34 3 H) 2.37- 2.42 (in, 8 3 .20-3.41 (in, 2 H) 3.69 3 H) 6.75 1 H) 7.0 8 26 (mn, 11 H) 46 J 8. 7 Hz, 2 H) 8. 08 J 8 .7 Hz, 2 8. 77 (br t, 1 H, NH); Anal. Calcd. for C 34
H
37 N.0 6 C, 66.76; H, 6.10; N, 11.45.
Found: C, 66.48; H, 5.97; N, 11.25.
Example (4-Methoxyphenyl) -4-phenylpiperidin-1-yl) propyl)] carboxaziido- 5-methoxycarbonyl-4 -methyl -6 (4-nitropheny.) -2-oxo-1,2,3, 6-tetrahydropyrimidine.
To a stirred mixture of 1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-methyl-6-(4-nitrophenyl) -1-Il(4-nitrophenyloxy)carbonyllpyrimidine (0.47 g, 1 inmol) and K 2 C0 3 (0.552 g, 4 inmol) in anhydrous THF mL) at room temperature under argon atmosphere, a solution of 3- (4-methoxyphenyl) -4-phenyl piperidin-1-yl)propyl-anine (0.390 g, 1.2 mmiol, 1.2 eq) in THE (10 mL) was added and the stirring was continued for 2 hours. The solid was removed by filtration and the solution was cooled to 0-5 0 C. 6N HC1 (2 inL) was added to the solution and stirring was continued.
After 3 hours, solvents were evaporated completely, the residue was redissolved in CH 2 C1 2 (20 mL), washed with NaHCO 3 (2 X 10 mL) and dried (MgSO,) Solvent was WO 97/42956 PCT/US97/08335 -61evaporated and the residue was purified by column chromatography using 1:1 hexane/EtOAc to 100% EtOAc as gradient eluent. The oily product was crystallized from hexane and EtOAc (0.55 g, m.p. 100-102 oC; 'H-NMR (CDC1 3 6 1.65-1.80 2 2.26-2.31 2 2.35 3 2.39-2.44 6 3.18-3.40 2 3.69 3 3.73 3 6.75 1 7.60 J 8.7 Hz, 2 6.84 (br s, 1 H, NH), 7.10 J 8.7 Hz, 2 7.18-7.26 5 7.46 J 8.6 Hz, 2 8.08 J 8.6 Hz, 2 8.78 (br t, 1 H, NH); Anal. Calcd. for C 35
H
3 9 Ns0 7 .0.12 CHC1 2 .0.12 EtOAc: C, 64.54; H, 6.12; N, 10.57. Found: C, 64.44; H, 6.12; N, 10.28.
Example 11 1-{N-[3-(4-Methoxycarbonyl-4-phenylpiperidin-1yl)propyl]}carboxamido-5-methoxycarbonyl-4-methyl- 6- (4-nitrophenyl) -2 -oxo-1,2,3,6-te trahydropyrimidine (Scheme 2).
To a stirred mixture of 1,6-dihydro-2-methoxy-5methoxycarbonyl-4-methyl-6-(4-nitrophenyl)-1- [(4-nitrophenyloxy)carbonyl]pyrimidine (0.47 g, 1 mmol), K 2
CO
3 (0.276 g, 2 mmol) in anhydrous THF (10 mL) at room temperature under argon atmosphere, a solution of 3-[4-methoxycarbonyl-4-phenylpiperidin-l-yl] propylamine (0.332 g, 1.2 mmol, 1.2 eq) in THF (10 mL) was added and the stirring was continued for 2 hours.
The solid was removed by filtration and the solution was cooled to 0-5 To this, 6 N HC1 (2 mL) was added and the stirring continued. After 3 hours, solvents were evaporated completely, the residue was redissolved in CH 2 C1 2 (20 mL), washed with 10% NaHCO 3 (2 X 10 mL), and dried (MgSO 4 Solvent was evaporated and the residue was purified by column chromatography using 1:1 hexane/EtOAc to 100% EtOAc as gradient eluent. The oily product was crystallized from hexane and EtOAc (0.55 g, m.p. 180-181 'H-NMR (CDC1 3 6 1.60- WO 97/42956 PCTIUS97/08335 -62- 1.80 2 1.85-1.95 2 2.03-2.10 2 H), 2.28-2.33 2 2.35 3 2.48-2.50 2 H), 3.20-3.40 2 3.60 3 3.68 3 6.75 1 7.20-7.34 6 7.46 J 8.8 Hz, 2 H) 8.07 J 8.8 Hz, 2 H) 8.78 (br t, 1 H, NH) Anal. Calcd. for C 30
H
35 N.0 8 C, 60.70; H, 5.94; N, 11.80.
Found: C, 60.71; H, 5.99; N, 11.43.
Examples 11a 11 b (+)-1-{N-(3-(4-Methoxycarbonyl-4-phenylpiperidin-1-yl) propyl] carboxamido-5-methoxycarbonyl-4-methyl-6- (4-nitrophenyl) -2-oxo-1, 2,3,6-tetrahydropyrimidine and (4-Methoxycarbonyl-4-phenyl-piperidin-1-yl) propyl]}carboxamido-5-methoxycarbonyl-4-methyl-6-(4nitrophenyl) -2-oxo-l, 2,3, 6-tetrahydropyrimidine (Scheme 3).
a. (-)-1,6-Dihydro-2-methoxy-5-methoxycarbonyl-4methyl-6- (4-nitro-phenyl)-l-{N-E(2-phenyl) ethyl]) carboxamidopyrimidine and (+)-1,6-Dihydro-2-methoxy-5methoxycarbonyl-4-methyl-6-(4-nitrophenyl)-l-{N-[(2phenyl)ethyl] carboxamidopyrimidine.
To a stirred solution of (±)-1,6-dihydro-2-methoxy-5iethoxycarbonyl-4-methyl-6- (4-nitrophenyl) [(4-nitr ophenyloxy) carbonyl I pyrimi dine (2.66 g, 5.6 imol) in anhydrous THF (80 mL) at room temperature under argon atmosphere, a solution of (S)-(-)-cy-methylbenzylaine (0.82 g, 6.78 imol, 1.2 eq) in THF (5 mL) was added and the stirring was continued for 6 hours. Solvent was evaporated from the reaction mixture, the residue was redissolved in CH 2 C1 2 (50 mL), washed with 5% NaHCO 3 (3 X 25 rnL), brine (50 mL), and dried (MgSOJ). Solvent was evaporated and the residue was purified by flash chromatography on silica gel using 5% to 30% EtOAc in hexane as the gradient eluent. The first major product to elute was (-)-1,6-dihydro-2-ethoxy-5-methoxy carbonyl-4-methyl-6-(4-nitrophenyl)-l-(N-[(2-phenyl) WO 97/42956 PCT/US97/08335 -63ethyl)}carboxamidopyrimidine and this compound was crystallized from isopropyl ether (0.85 g, m.p.
119-120 oC; [a]D -329.32 (CH 2 C1 2 10.3 g/100 mL) 'H- NMR (CDC13) 6 1.47 J 7 Hz, 3 2.40 3 H), 3.61 3 3.95 3 4.96 (quint, J 6.5 Hz, 2 6.66 1 6.82 J 6.8 Hz, 1 H, NH), 7.22-7.36 5 7.43 J 8.6 Hz, 2 8.09 (d, J 8.6 Hz, 2 Anal. Calcd. for C 23
H
24
N
4 0 6 C, 61.06; H, 5.35; N, 12.38. Found: C, 60.85; H, 5.13; N, 12.42.
The second major compound to elute was 1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-methyl-6- (4-nitrophenyl)-1-{N-[(2-phenyyl)ethyl}carboxamido pyrimidine and this compound was crystallized from isopropyl ether (0.92 g, m.p. 138-140 OC; [a]D +171.81 (CH 2 Cl 2 11.31 g/100 mL) 'H-NMR (CDC1 3 :6 1.47 J 7 Hz, 3 2.42 3 3.644 3 H), 3.917 3 4.989 (quint, J 6.5 Hz, 2 6.70 1 6.81 J 6.8 Hz, 1 H, NH), 7.22-7.35 (m, 7.36 J 8.6 Hz, 2 8.04 J 8.6 Hz, 2 Anal. Calcd. for C 2 3
H
24
N
4 0 6 C, 61.06; H, 5.35; N, 12.38. Found: C, 60.95; H, 5.20; N, 12.38.
b. (+)-1-{N-[3-(4-Methoxycarbonyl-4-phenyl piperidin-1-yl)propyl] }carboxamido-5-methoxycarbonyl-4methyl-6-(4-nitrophenyl)-2-oxo-1,2,3,6-tetrahydro pyrimidine.
A solution of (+)-1,6-dihydro-2-methoxy-5-methoxy carbonyl-4-methyl-6-(4-nitrophenyl)-1-{N-[(2-phenyl) ethyl] }carboxamidopyrimidine (0.226 g, 0.5 mmol) and 1,8-diazabicyclo[5.4.0]-unde-7-ene (DBU) (0.076 g, mmol) in CH 2 Cl 2 (10 mL) was stirred and refluxed for 4 hours and the solvent evaporated. The product was purified by column chromatography using 30% EtOAc in hexane as the eluent. The product was found to be a mixture of the amine-imine tautomers (0.120 g, 78.7%); [ao, +14.5 (CH 2 C1 2 6 g/100 mL) WO 97/42956 PCT/US97/08335 -64- To a well-stirred solution of (+)-1,6-dihydro-5-methoxy carbonyl 2 -methoxy-4-methyl 6 (4 -nitrophenyl) pyrimidine (0.12 g, 0.393 mmol) and pyridine (0.5 mL) in CHC1 mL) at 0-5 oC, 4-nitrophenyl chloroformate (0.095 g, 0.472 mmol) was added in 5 min and the mixture was allowed to warm to room temperature. After 2 h, saturated aqueous NaHCO 3 solution (10 mL) was added and the stirring continued for 30 min. The two layers were separated, the CH 2 C1, layer was washed with saturated aqueous NaHCO 3 solution (3 X 5 mL), dried (Na 2
SO
4 and the solvent evaporated. The residue was redissolved in THF (10 mL) and mixed with K 2
CO
3 (0.11 g, 0.8 mmol). To this, a solution of 3-[4-methoxycarbonyl-4-phenyl piperidin-l-yl]propylamine (0.138 g, 0.5 mmol) in THF (5 mL) was added and the mixture was stirred for 2 hours. The solid was removed by filtration and the solution was cooled to 0-5 OC. To this, 6 N HC1 mL) was added and the stirring continued. After 3 hours, solvents were evaporated completely, the residue was redissolved in CH 2 C1 2 (20 mL), washed with NaHCO 3 (4 X 5 mL), and dried (MgSO 4 Solvent was evaporated and the residue was purified by column chromatography using 1:1 hexane/EtOAc to 100% EtOAc as gradient eluent. The oily product was crystallized from hexane and EtOAc (0.19 g, m.p. 138-140 OC; +108 (CH 2 Cl 2 6.65 g/100 mL); 'H-NMR (CDC1 3 :6 1.60-1.80 2 1.85-1.95 2 2.03-2.10 (m, 2 2.28-2.33 2 2.35 3 2.48-2.50 (m, 2 3.20-3.40 2 3.60 3 3.68 3 H), 6.75 1 7.20-7.34 5 7.46 J 8.8 Hz, 2 7.60 (br s, 1 H, N 8.07 J 8.8 Hz, 2 H), 8.78 (br t, 1 H, NH); Anal. Calcd. for C 3 oH 3 ,sNsO.0.2 CHC1 2 .0.2 EtOAc: C, 59.27; H, 5.94; N, 11.15. Found: C, 59.07; H, 5.76; N, 10.99.
c. [3-(4-Methoxycarbonyl-4-phenyl piperidin-l-yl)propyl] WO 97/42956 PCTIUS97/08335 carbonyl-4-methyl-6- (4-nitrophenyl)-2-oxo- 1,2,3,6-tetrahydropyrimidine.
A solution of (-)-1,6-dihydro-2-methoxy-5-methoxy carbonyl-4-methyl-6-(4-nitrophenyl)-1-{N-[(2-phenyl) ethyl]}carboxamidopyrimidine (0.35 g, 0.774 mmol) and 1,8-diazabicyclo[5.4.03-unde-7-ene (DBU) (0.117 g, 0.774 mmol) in CH 2 C1, (10 mL) was stirred and refluxed for 8 hours and the solvent evaporated. The product was purified by column chromatography using 30% EtOAc in hexane as the eluent. The product, 1,6-dihydro-5-methoxycarbonyl-2-methoxy-4-methyl-6- (4-nitrophenyl)pyrimidine, was found to be a mixture of the amine-imine tautomers (0.170 g, To a wellstirred solution of (-)-1,6-dihydro-5-methoxy carbonyl-2-methoxy-4-methyl-6-(4-nitrophenyl)pyrimidine (0.152 g, 0.5 mmol) and pyridine (0.5 mL) in CH 2 C1 2 mL) at 0-5 OC, 4-nitrophenyl chloroformate (0.121 g, 0.6 mmol) was added in 5 min and the mixture was allowed to warm to room temperature. After 2 hours, saturated aqueous NaHCO 3 solution (10 mL) was added and the stirring continued for 30 min. The two layers were separated, the CH 2
CI
2 layer was washed with saturated aqueous NaHCO 3 solution (3 X 5 mL), dried (Na 2
SO
4 and the solvent evaporated. The residue was redissolved in THF (10 mL) and mixed with K 2 CO (0.165 g, 1.2 mmol).
To this, a solution of 3-[4-methoxycarbonyl- 4-phenylpiperidin-1-yl]propylamine (0.166 g, 0.6 mmol) in THF (5 mL) was added and the mixture was stirred for 2 hours. The solid was removed by filtration and the solution was cooled to 0-5 oC. To this, 6 N HC1 mL) was added and the stirring continued. After 3 hours, solvents were evaporated completely, the residue was redissolved in CH 2 C1 2 (20 mL), washed with NaHCO 3 (4 X 5 mL), and dried (MgSO,). Solvent was evaporated and the residue was purified by column chromatography using 1:1 hexane/EtOAc to 100% EtOAc as gradient eluent. The oily product was crystallized WO 97/42956 PCT/US97/08335 -66from hexane arnd EtOAc (0.19 g, 6401) m.p. 138-140 OC; [011D -106 (CH 2 C1 2 3.95 g/100 mL) 'H-NMR (CDCl 3 :6 1. 60-1. 80 (mn, 2 H) 1. 85-1. 95 (in, 2 H) 2.03-2. 10 (in, 2 2.28-2.33 (mn, 2 2.35 3 2.48-2.50 (in, 2 3.20-3.40 (in, 2 3.60 3 3.68 3 H), 6.75 1 7.20-7.34 (mn, 6 H) 7.46 J 8.8 Hz, 2 H) 8. 07 J 8. 8 Hz, 2 H) 8. 78 (br t, 1 H, NH) Anal. Calcd. for C 3 0H 35 NsO9.0.
4
CH
2 C1 2 C, 58.18; H, 5.75; N, 11.16. Found: C, 58.25; H, 5.67; N, 10.98.
Example 12 (4-methoxycarbonyl- 4-phenylpiperidin-l-yl)propyl] )carboxamido-4-methyl-6 (3,4-methylenedioxyphenyl) -2-oxo-1,2,3,6-tetra hydropyrimidine.
To a stirred solution of 5-benzyloxycarbonyl-1-{N- [3- (4-methoxycarbonyl-4-phenylpiperidin-1-yl)propyl]) carboxamido-4-methyl-6- (3,4-iethylenedioxyphenyl) -2-o xo-1,2,3,6-tetrahydropyrimidine (0.320 g, 0.48 mmol) in methanol (20 mL) and HCOOH (1 mL) at 0-5 OC, 100i Pd-C (0.26 g) was added in portions and the cooling bath was removed. TLC analysis of the reaction mixture at frequent intervals showed the completion of the reaction after 2 hours. The catalyst was removed by filtration and the solvent was evaporated to leave (4-methoxycarbonyl-4-phenylpiperidin-1-yl) propyl] }carboxamido-4-methyl-6- (3,4-methylenedioxy phenyl) -2-oxo-1, 2,3, acid as a white solid (0.275 g, 99;) The product was used in the next step without any further purification and characterization. A mixture of rethoxycarbonyl-4-phenylpiperidin-1-yl)propylI carboxamido-4-methyl-6- (3 ,4-methylenedioxy phenyl)-2-oxo-1,2,3,6-tetrahydropyrimidine-5carboxylic acid 2 g, 0. 346 mmcl) 1- (3 -dimethylamino propyl) -3 -ethyl carbodi imide hydrochloride (0.382 g, 2 mmol), and 4-(N,N-dimethylamino)pyridiie (0.488 4 WO 97/42956 PCTIS97/08335 -67mmol), in methanol (20 mL) was stirred and refluxed for h and the solvent evaporated. The residue was redissolved in CHCl 2 (15 mL), washed with saturated aqueous ammonium chloride solution (3 X 10 mL) and dried (Na 2 Evaporation of the solvent left the pure product as white powder (0.202 g, m.p. 139- 141 'H-NMR (CDC1 3 1.62-1.80 2 1.95-2.20 4 2.35 3 2.30-2.55 4 2.76-2.90 2 3.21-3.40 2 3.61 3 3.67 (s, 3 5.89 2 6.61-6.82 3 6.63 1 H), 7.21-7.35 6 8.79 (br t, 1 H, NH); Anal. Calcd.
for C 3
H
3
,N
4 Os.0.3 EtOAc: C, 62.47; H, 6.25; N, 9.05.
Found: C, 62.64; H, 6.25; N, 8.87.
Example 13 -5-Carboxamido-4-ethyl- (4-methoxycarbonyl- 4-phenylpiperidin-1-yl)propyl].}carboxamido-6- (4-nitro phenyl)-2-oxo-1,2,3,6-tetrhydropyrimidine (Scheme 4).
a. 2-Cyanoethyl 3-{(4-nitrophenyl)methylene}-4oxopentanoate.
A mixture of ethyl propionylacetate (25 g, 0.173 mol) and 3-hydroxypropionitrile (18.48 g, 0.26 mol) was stirred and heated at 200-205 OC for 2 h and the ethanol formed was removed by distillation. The residue was subjected to high vacuum distillation and the fraction distilling at 120-125 OC at 0.4 mm of Hg was collected to get 2-cyanoethyl propionylacetate (21.5 g, 73.4%).
A mixture of 4-nitrobenzaldehyde (14.46 g, 0.957 mol), 2-cyanoethyl propionylacetate (17.0 g, 0.1005 mol), piperidine (0.41 g, 476 mL, 4.8 mmol), and acetic acid (0.288 g, 274 mL, 4.8 mmol) in 2-propanol (400 mL) was stirred at room temperature for 24 h. The white solid, 2-cyanoethyl 3-{(4-nitrophenyl) methylene}-4-oxo pentanoate, formed was filtered, washed with 2-propanol (2 X 50 mL) and dried (28.34 g, m.p. 98-100 oC.
WO 97/42956 PCT/US97/08335 -68b. 5- (2-Cyanoethoxycarbonyl) -1,6-dihydro-2-methoxy-4ethyl-6-(4-nitrophenyl)pyrimidine.
A mixture of 2-cyanoethyl 3- (4 -nitrophenyl)methylene} -4-oxopentanoate (5.00 g, 16.54 mmol), O-methylisourea hydrogen sulfate (3.422 g, 19.85 mmol), and NaHCO 3 (2.78 g, 33.08 mol) in EtOH (70 mL) was stirred and heated at 85-90 OC for 5 h. The solid was removed by filtration and ethanol was evaporated from the filtrate. The residue was redissolved in EtOAc (300 mL), washed with water (2 X 100 mL), dried (Na 2
SO
4 and the solvent evaporated. The crude product was purified by flash column chromatography on silica gel using CHCl 3 /methanol (30:1) as the eluent, to leave the product as a white solid (2.95 g, The 1 H-NMR analysis of the product showed it to be a 5:1 mixture of the amine/imine tautomers and was used as such in the next step.
c. 5-(2-Cyanoethoxycarbonyl)-4-ethyl-1,6-dihydro-2methoxy-6-(4-nitrophenyl)-1-[(4-nitrophenyloxy) carbonyl]pyrimidine.
To a well-stirred solution of 5-(2-cyanoethoxy carbonyl)-4-ethyl-1,6-dihydro-2-methoxy-6- (4-nitrophenyl)pyrimidine (2.64 g, 7.36 mmol) and pyridine (1.19 mL, 14.72 mmol) in CH 2 C1 (100 mL) at oC, 4-nitrophenyl chloroformate (1.485 g, 7.36 mmol) was added in 5 min and the mixture was allowed to warm to room temperature. After 16 h, saturated aqueous NaHCO 3 solution (25 mL) was added and the stirring continued for 30 min. The two layers were separated, the CH 2 Cl 2 layer was washed with saturated aqueous NaHCO 3 solution (3 X 50 mL), dried (Na 2 and the solvent evaporated.
The crude product was purified by flash column chromatography on silica gel using CHC1 3 /EtOAc (25:1) as the eluent to give the product as a viscous oil (1.70 g, 1 H-NMR (CDC13) 6 1.24 J 7 Hz, 3 H), WO 97/42956 PCTIUS97/08335 69- 2. 61-2. 68 (mn, 2 H),1 2. 88-2. 92 (in, 2 H) 3. 97 3 H), 4.32 J 7 Hz, 2 H) 6.34 1 7.37 J 9. 2 Hz, 2 H) 7. 50 J 8 8.7 Hz, 2 8. 18 J= 8. 7 Hz, 2 H) 8. 28 J 2 Hz, 2 H).
d. 5- (2-Cyanoethoxycarbonyl)-4-ethyl-1,6-dihydro-2methoxy-6- (4-nitrophenyl) [(2-phenyl) ethyl] carboxamidopyrimidine.
To a stirred solution of 5-(2-cyanoethoxycarbonyl)-4ethyl-1,6-dihydro-2-methoxy-6 (4-nitrophenyl) -1- (4 -nitrophenyloxy) carbonyl Ipyrimi dine (17.5 g, 33.43 mmol) in anhydrous THF (200 mL) at room temperature under argon atmosphere, -a-methylbenzylamine (4.86 g, 40.11 mmol) was added and the stirring was continued for 16 h. Solvent was evaporated from the reaction mixture and the residue was purified by flash chromatography on silica gel using toluene/EtOAc (20:3) as the eluent. The first major product to elute was 5 -cyanoethoxycarbonyl.) 4 -ethyl 6- dihydro- 2 methoxy- 6 -ni trophenyl) [1(2 -phenyl) ethyl]I carboxainidopyrimidine and obtained as a viscous oil (6.11 g, 36.2%) D +299.5 (c 1.95, CHCl 3
;'H-NMR
(CDCl 3 61.18 J =7 Hz, 3 H) 1.47 J =7 Hz, 3 2.61 2 2.7-2.92 (in, 2 3.98 3 H), 4.20-4.32 (in, 2 H) 4.96 (quint, J 6.5 Hz, 2 H) 6.66 1 6.82 J 6.8 Hz, 1 H, NH), 7.22-7.36 (in, H) 7. 45 J 6 Hz, 2 H) 8. 11 J 8. 6 Hz, 2 H) The second maj or compound to elute was 5- (2 cyanoethoxycarbonyl) -4-ethyl-l, 6-dihydro-2methoxy-6- (4-nitrophenyl) [(2-phenyl)ethyl]) c arboxami dopyrimi dine and obtained as a viscous oil (5.92 g, 35%) [a]D -105.1 (c CHCl 3
'H-NNR
(CDCl 3 :6 1.20 J 7 Hz, 3 H) 1.48 J =7 Hz, 3 2. 62 2 H) 2 .82 2 H) 3. 94 3 H) 4.20-4.32 (in, 2 H) 4. 96 (quint, J 6 .5 Hz, 2 H) 6 .69 1 6.84 J =6.8 Hz, 1 H, NH), 7.22-7.36 (in, H) 7.39 J 8.6 Hz, 2 8.06 J 8.6 Hz, WO 97/42956 PCT/US97/08335 2 H).
e.(+)-5-(2-Cyanoethoxycarbonyl)-1,6-dihydro-2methoxy-4-ethyl-6-(4-nitrophenyl)pyrimidine.
To a stirred solution of cyanoethoxycarbonyl)-4-ethyl-1,6-dihydro-2-methoxy-6- (4-nitrophenyl)-1-{N-[(2-phenyl)ethyl]}carboxamido pyrimidine (2.62 g, 5.182 mmol) in toluene (40 mL) was added 1,8-diazabicyclo[5,4,0]-undec-7-ene (0.237,1.55 mmol) at room temperature and the resulting solution was heated at 90 °C for 3.5 minutes. The solvent was evaporated and the residue was purified by flash column chromatography on silica gel using 9:1 CHC1 3 /EtOAc as the eluent, to give 1.32 g (71%)of cyanoethoxycarbonyl) -1,6-dihydro-2-methoxy-4-ethyl-6- (4-nitrophenyl)pyrimidine; +4.0 (c 3.25, CHC1 3 f. (2-Cyanoethoxycarbonyl) -4-ethyl-1,6-dihydro-2methoxy-6-(4-nitrophenyl)-l-[(4-nitrophenyloxy) carbonyl]pyrimidine.
To a well-stirred solution of 5-(2-cyanoethoxycarbonyl) -4-ethyl-1,6-dihydro-2-methoxy-6-(4-nitrophenyl) pyrimidine (1.62 g, 4.52 mmol) and 4-(N,Ndimethylamino)pyridine (0.663 g, 5.43 mmol) in CH 2 C1 2 mL) at 0-5 OC, 4-nitrophenyl chloroformate (1.094 g, 5.43 mmol) was added in 5 minutes and the mixture was allowed to warm to room temperature. After 3 hours the solvent evaporated and the product was purified by flash column chromatography on silica gel using CHCl 3 /EtOAc (25:1) as the eluent to give the product as a white solid (2.25 g, 'H-NMR (CDC1 3 6 1.24 (t, J 7 Hz, 3 2.61-2.68 2 2.88-2.92 2 H), 3.97 3 4.32 J 7 Hz, 2 6.34 1 H), 7.37 J 9.2 Hz, 2 H) 7.50 J 8.7 Hz, 2 H), 8.18 J 8.7 Hz, 2 8.28 J 9.2 Hz, 2 H); WO 97/42956 PCT/US97/08335 -71- [a]D +317.2 (c 3.9, CHC1 3 g. (2-Cyanoethoxycarbonyl) -4-ethyl-l-{N- (4methoxycarbonyl-4-phenylpiperidin-1-yl)propyl]} carboxamido-6-(4-nitrophenyl) -2-oxo-1,2,3,6-tetrhydro pyrimidine.
To a stirred mixture of (+)-5-(2-cyanoethoxycarbonyl) -4-ethyl-1,6-dihydro-2-methoxy-6-(4-nitrophenyl) -1-[(4-nitrophenyloxy)carbonyl]pyrimidine (3.60 g, 6.878 mmol) in anhydrous THF (100 mL) at room temperature under argon atmosphere, a solution of 3- [4methoxycarbonyl-4-phenylpiperidin-l-yl]propylamine (2.47 g, 8.94 mmol, 1.3 eq) in THF (10 mL) was added and the stirring was continued for 12 hours. The mixture was cooled to 0 OC and aqueous 6N hydrochloric acid (10 mL). The mixture was allowed to warm to room temperature and the stirring was continued for 5 h.
Solvent was evaporated from the reaction mixture, the residue was purified by flash chromatography on silica gel using ethyl acetate (800 mL) followed by chloroform-methanol-2M ammonia in methanol (90/8/4) as the eluent, to obtain the desired product as a white powder (4.40 g, 98.5%) ;H-NMR (CDC3) 6 1.23 J 7.5 Hz, 3 2.0-2.1 2 2.40-2.95 12 H), 3.25-3.50 4 3.65 3 4.27-4.32 2 H), 6.64 1 7.20-7.33 5 7.49 J 7.8 Hz, 2 8.08 J 7..8 Hz, 2 8.70-8.90 2 H); +112.1 (c 2.15, CHC1 3 This product was used in the next step without any additional analysis.
h. -5-Carboxamido-4-ethyl-1-{N- (4-methoxycarbonyl- 4-phenylpiperidin-1-yl)propyl] carboxamido-6-(4-nitro phenyl)-2-oxo-1,2,3,6-tetrhydropyrimidine.
To a stirred solution of 5-(2-cyanoethoxycarbonyl)-4ethyl-l-{N- [3-(4-methoxycarbonyl-4-phenyl WO 97/42956 PCT/US97/08335 -72piperidin-l-yl)propyl]}carboxamido-6-(4-nitrophenyl)-2oxo-l,2,3,6-tetrhydropyrimidine (4.40 g, 6.8 mmol) in acetone (50 mL) at 0 OC, sodium hydroxide solution (1 N, 27.2 mL, 4 eq.) was added drop wise and the stirring was continued until the disappearance of the starting material (1 hour). Most of the acetone from the mixture was evaporated under reduced pressure while keeping the temperature at 0 oC and the residue was adjusted to pH 7.0 by the addition of IN hydrochloric acid. The white precipitate of methoxycarbonyl-4-phenylpiperidin-l-yl)propyl]} carboxamido-6-(4-nitrophenyl)-2-oxo-l,2,3,6-tetrhydro acid formed was filtered and dried under vacuum (3.59 g, 'H-NMR (CDC1 3 6 1.07 J 7.5 Hz, 3 1.55-1.70 2 1.72- 1.84 2 1.84-2.15 2 2.20-2.40 4 H), 2.70-2.90 2 3.10-3.40 4 3.51 3 H), 6.54 1 7.18-7.38 6 7.41 J 7.8 Hz, 2 8.15 J 7.8 Hz, 2 8.79 (br t, 1 H, N H), 10.05 (br S, 1 H, COOH); This product was used in the next step without any additional analysis.
A mixture of (+)-4-ethyl-1-{N-[3-(4-methoxycarbonyl- 4-phenylpiperidin-1-yl)propyl] }carboxamido-6-(4-nitro phenyl)-2-oxo-l,2,3,6-tetrhydropyrimidine-5-carboxylic acid (0.350 g, 0.59 mmol), 1-(3-dimethylaminopropyl)-3ethylcarbodiimide hydrochloride (0.2264 g, 1.181 mmol, 2eq.), and 4-(N,N-dimethylamino)pyridine (0.1443 g, 1.181 mmol, 2 eq) in anhydrous dichloromethane was stirred at room temperature for 2 h. To this, aqueous ammonia (0.6 mL) was added and the stirring was continued for 12 h. The mixture was diluted with 100 mL of dichloromethane and washed with saturated aqueous ammonium chloride solution (3 X 20 mL). Solvent was evaporated from the dried magnesium sulfate) dichloromethane solution and the residue was purified by column chromatography on silica gel using WO 97/42956 PCT/US97/08335 -73chloroform-methanol-2M ammonia in methanol (500/16/8) as the eluent, to obtain the desired product as a white powder (0.24 g, m.p. 107-109 OC;'H-NMR (CDC1) 6 1.20 J 7.5 Hz, 3 1.66-1.72 2 1.79- 2.00 3 2.00-2.20 2 2.29-2.35 2 H), 2.42-2.60 2 2.62-2.82 3 3.20-3.40 (m, 2 3.60 3 5.70 (br m, 2 H, NH_ 2 6.59 1 7.20-7.39 6 7.52 J 7.8 Hz, 2 8.13 J 7.8 Hz, 2 8.82 1 H) [a]D +115.71 (c 1.4, CHC1 Anal. Calcd. for C 30
H
36
N
6 0 7 .0.8 H 2 0: C, 59.36; H, 6.24; N, 13.84. Found: C, 59.47; H, 6.07; N, 13.64.
Example 14 (+)-5-Carboxamido-6-(3,4-difluorophenyl)-4-ethyl- 1-{N-[3-(4-methoxycarbonyl-4-phenylpiperidin-1-yl) propyl] }carboxamido-2-oxo-1, 2,3,6-tetrhydropyrimidine (Scheme a. Benzyl 3-[(3,4-difluorophenyl)methylene]-4oxopentanoate. A solution of benzyl propionylacetate (36.3 g, 176 mmol), 3,4-difluorobenzaldehyde (25.0 g, 176 mmol), piperidine (0.86 mL, 9.0 mmol) and acetic acid (0.49 mL, 9.0 mmol) were refluxed with removal of water using Dean-Stark apparatus for 5h. The solvent was removed in vacuo and the residue was dissolved in EtOAc. It was washed with water (100 mL) followed by brine (100 mL) and dried over anhydrous Na 2 SO,. Solvent was evaporated to get pale yellow syrup (60.2 It was used in the next step without further purification.
b. 5- (Benzyloxycarbonyl) 6-dihydro-2-methoxy-4-ethyl- 6-(3,4-difluorophenyl)pyrimidine. A suspension of benzyl 3- [(3,4-difluorophenyl)methylene]-4oxopentanoate (16.0 g, 48.0 mmol), O-methylisourea hydrogen sulfate (16.65 g, 97.02 mmol), NaHCO 3 (16.3 g, WO 97/42956 PCTIUS97/08335 -74- 130.2 mmol) in DMF (190 mL) was stirred at 70 0 C for After cooling to room temperature, the mixture was filtered and the filtrate was diluted with EtOAc (300 mL) and then washed with water (4X100 mL), brine (200 mL) and dried over Na 2
SO
4 After removal of solvent, the residue was purified by column chromatography (Sio.,, EtOAc/Hexane, 10-1-30%) to get 5- (benzyloxycarbonyl) 1 ,6 -dihydro- 2-methoxy- 4 -methyl- 6- (3 ,4 difluorophenyl)pyrimidine as a colorless oil (10.6 g, 58%0) The NMR analysis showed it to be a mixture of amine/imine tautomers and was used as is in the next step.
c. 5- (Benzyloxycarbonyl) -4-ethyl-i, 6-dihydro-2-methoxy- 6- (3,4-difluorophenyl) -l-f(4-nitrophenyloxy)carbonyl] pyrimidine. To a well stirred solution of 5- (benzyloxy carbonyl) 1, 6-dihydro-2 -methoxy-4 -ethyl -6 4-dif luoro phenyl) pyrimi dine (17.0 g, 44.04 mmol) and 4-dimethyl aminopyridine (6.99 g, 57.25 mmol) in CH 2 Cl 2 (200 mL) was added a powder of 4-nitrophenyl chloroformate 11.54 g, 57.25 mmol) at room temperature. The reaction mixture was stirred for 12 hours and then the solvent was removed in vacuo. The residue was purified by chromatography (SiO2, EtOAc/Hexane 10-30%) to get (benzyloxycarbonyl) -4-ethyl-i, 6-dihydro-2-methoxy-6- (3 4 d i fl1u o r o p h e n y 1 1 4 nitrophenyloxy)carbonyllpyrirnidine as a colorless viscous oil(12.6 g, 50%i).'H NMR (CDCl 3 6 1.24 (t, J=7.2 Hz, 3H), 2.81-2.98 (mn, 3H), 3.97 3H), 5.14 (ABqf 6 A=5 .08, 6 B= 5.20, J= 12.3 Hz, 2H), 6.28 3H), 7.03-7.29 (in, 8H), 7.35 J=9.2 Hz, 2H) 8.26 (d, J=9.2 Hz, 2H).
d. 5- (Benzyloxycarbonyl)-4-ethyl-1,6-dihydro-1-{N- [2phenyl) ethyl])}carboxamido-2-mnethoxy-6- (3,4-dif luoro phenyl)pyrimidine. To a stirred mixture of (benzyloxycarbonyl) -4-ethyl-i, 6-dihydro-2-methoxy-6- WO 97/42956 PCT/US97/08335 -di fluorophenyl) -1I- (4 n itrophenyl oxy) c arbonyl]1 pyrimidine (12.6 g, 22.86 mmcl) in THF (150 mL) was added a solution of R-(+)-a-methyl benzylamine (3.53 mL, 27.44 mmol) at room temperature. The stirring was continued for 12 hours. Solvent was removed in vacuo.
The yellow residue was dissolved in chloroform (200 mL) and was washed with 10%* K 2 C0 3 solution (2x30 mL) The organic layer was dried over Na 2
SO
4 filtered and solvent was removed in vacuo. The resulting mixture of diastereomers was separated by column chromatography over silica gel with 9:1 Pet. ether:Ether to 4:1 Pet.
ether:Ether. First major product to elute was (benzyloxycarbonyl) -4-ethyl-1, 6-dihydro-1-{(N- [2phenyl) ethyl) )carboxamido- 2-methoxy- 6 diflurophenyl)pyrimidine. Colorless oil, Rf= 0.31(4:1 Pet ether:ether) wt. 3. 8 g [ce] +267. 05 (c 0. 76, CHCl 3 IH NMR: 6 1. 22 J=7.5 Hz, 3H) 1. 52 (d, J=6. 9 Hz, 3H),2. 88 J=6. 0 Hz, 2H) 3. 99 3H) 4 .99 (in, 1H) 5.09 (A~qF 6 0-5. 00, be= 5.19, J= 12.6 Hz, 2H) 6. 66 lH) 6.9 9 -7.3 6 (in, 13H) Second maj or product to elute was (benzyloxycarbonyl) -4-ethyl- 1,6-dihydro-l-{N- [2-phenyl)ethyll)lcarboxamido-2methoxy-6- (3,4-dif lurophenyl) pyrimi dine. Colorlessoil.
Rf= 0.22(4:1 Pet ether:ether), wt.= 3.2 g WD) -146.89 (c 0.38, CHCl 3 1 H NNR: 6 1.22 J=7.2 Hz, 3M), 1.49 J=6.6 Hz, 3H) ,2.88 J=6.0 Hz, 2H), 3.94 3M) 5.03 (mn, 1H) 5. 11 (ABqi 6A=5.02, 6 be 5.19, J= 12.6 Hz, 2H) 6.68 1H) 6.91-7.34 (mn, 13H).
e. (Benzyloxycarbonyl) 6-dihydro-2-methoxy-4ethyl- 6- (3,4 -dif lurophenyl) pyrimidine. To a stirred solution of -5-(benzyloxycarbonyl) -4-ethyl--l,6dihydro-1-{N- [2-phenyl) ethyl) }carboxamido-2-methoxy-6-.
(3,4-diflurophenyl)pyrimidine (1.83 mmol, 1.0 g) in toluene (10 mL) was added 1,8-diazabicyclo[5,4,0)undec-7-ene (0.81 mmol,0.12 mL) at room temperature and WO 97/42956 PCTfUS97/08335 -76the resulting solution was heated to ref lux for 5h and then stirred for 12h at room temperature. The solvent was evaporated and the residue was purified by flash *column .chromatography on silica gel with 3:1 EtOAc/Hexanes as the eluting system. 0. 56 g of the (benzyloxycarbonyl) 6-dihydro-2-methoxy-4- ethyl-6- 4-dif lurophenyl) pyrimidine was obtained f. (Benzyloxycarbonyl) -4-ethyl-1,6-dihydro-2methoxy-6- (3,4-diflurophenyl) -1-[((4-nitrophenyloxy) carbonyljpyrimidine. To a well stirred solution of()- (benzyloxycarbonyl) 6 -dihydro- 2-methoxy-4 -ethyl -6 (3,4-diflurophenyl)pyrimidine (17.0 g, 44.04 mmol) and 4 -dimet hyl aminopyri dine (6.99 g, 57.25 mmol) in CH 2 C1 2 (200 mL) was added a powder of 4-nitrophenyl chloroformate 11.54 g, 57.25 mmol) at room temperature.
The reaction mixture was stirred for 12 hours and then the solvent was removed in vacuo. The residue was purified by chromatography (SiO2, EtOAc/Hexane 10-30%) toget (benzyloxycarbonyl) -4 -ethyl-1, 6-dihydro-2methoxy-6- (3,4-diflurophenyl) [14-nitrophenyloxy) carbonyllpyrimidine as a colorless viscous oil(19.3 g, 76!k) g. (Benzyloxycarboflyl)-6- (3,4-difluorophenyl) -4ethyl-l-{N- (4-methoxycarbonyl-4 -phenyl piperidin-l1-yl) propyl] )carboxamido -2 -oxo 1,2,3,6-tetrhydropyrimidine. To a stirred mixture of (benzyloxycarbonyl) -4 -ethyl- 1, 6-dihydro- 2methoxy-6- (3,4-difluorophenyl) -1-[(4-nitrophenyloxy) c arbonyl Ipyrimi dine (0.55 g, 1.12 mmol) in THF (5 mL) was added a solution of 3- [4-methoxycarbonyl-4phenylpiperidin-l-yllpropylamine (0.31 g, 1.12 mmol) in THF (S mL) at room temperature. The stirring was continued for 12 hours. A solution of 10% HCl in water (2 niL) was added and stirred for 2 h. The solvent was WO 97/42956 PCT/US97/08335 -77then removed in vacuo and the residue was extracted with ethyl acetate (3 X 10 mL) It was washed with aq. KOH solution, dried over Na 2 SO, and solvent was removed in vacuo to obtain (benzyloxycarbonyl)- 6- (3,4-difluorophenyl) -4-ethyl-l-{N- (4methoxycarbonyl-4-phenylpiperidin-l-yl)propyl]} carboxamido-2-oxo-1,2,3,6-tetrhydropyrimidine as a white foamy compound (0.73 g, 96.6%) the purity of which was characterized as its HCI salt. It was used in the next step without further purification. Anal.
Calcd. for C 3
,H
41 C1F 2
N
4 0 6 .0.5CHCl3:C, 58.43; H, 5.43; N, 7.27. Found: C, 58.11, H; 5.85; N, 7.64.
h. 6-(3,4-Difluorophenyl)-4-ethyl-l-{N-[3-(4-methoxy carbonyl-4-phenylpiperidin-1-yl)propyl] carboxamido- 1,2,3, 6-tetrhydro-2-oxopyrimidine-5-carboxylic acid. To a suspension of 10% Pd-C (0.14 g, 20% by wt.) in MeOH (3 mL) was added the solution of (benzyloxycarbonyl) (3,4-difluorophenyl) -4-ethyl- 1-{N-[3-(4-methoxycarbonyl-4-phenylpiperidin-1-yl) propyl] }carboxamido-2-oxo-1,2,3,6-tetrhydropyrimidine at room temperature with constant stirring. A balloon filled with H 2 was attached and the reaction mixture was stirred for 48 hours. The black suspension was filtered through a pad of celite and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (SiO 2 10% MeOH in EtOAc) to obtain (+)-6-(3,4-difluorophenyl)-4-ethyl-l-{N-[3-(4methoxycarbonyl-4-phenylpiperidin-1-yl) propyl] }carboxamido-1,2,3,6-tetrhydro-2-oxopyrimidineacid as a white solid. M.P. 184-186 'C; [a]D +142.2 (c 0.25, CHC13) The purity was checked by combustion analysis as a HCl salt. Anal. Calcd. for
C
3 oH 3 5ClF 2 N40 6 .0.3CHCl 3 55.40; H, 5.42; N, 8.53. Found: C, 55.34; H; 5.80; N, 8.13.
i. (+)-5-Carboxamido-6-(3,4-difluorophenyl)-4-ethyl- WO 97/42956 PCT/US97/08335 -78- [3-(4-methoxycarbonyl-4-phenylpiperidin-1-yl) propylj )carboxamido-2-oxo-1,2,3, 6-tetrhydro pyri.midine.
To a solution of (3,4-dif luorophenyl) -4 -ethyl 1- (4-methoxycarbonyl-4-phenylpiperidin-1-yl) propyll )}carboxamido- 1, 2, 3, 6 -tetrhydro- 2 -oxopyrimidine acid (0.22 g, 0.375 mmol) in CH 2 C1 2 (3 mL) was added 4-N,N-dimethylamino pyridine (0.14 g, 1.12 mmol) and 1- (3 -dime thylaminopropyl) 3 ethylcarbodi iride hydrochloride (0.21 g, 1.12 mmol) under argon and the resulting solution was stirred at room temperature for 2h. Three drops of saturated NH 4 0H was then added and the solution was stirred for 48 h. The solution was washed with water (5 ml) and dried over Na 2
SO
4 The solvent was removed in vacuo and the residue was purified by -column chromatography (SiC 2 10% MeOH in CHCl 3 to obtain 5- carboxamido 6- ,4-di fluorophenyl) -4 ethyl-1-{N-[3-(4-methoxycarbonyl- 4-phenylpiperidin-1-yl)propyl] }carboxamido-2-oxo- 1,2,3,6-tetrhydropyrimidine as a beige solid (0.1 g, Characterized as HC1 salt. M.P. 136-138 0 C, [u]D =+111. 44 (c 0. 18, MeOH): 1. 21 Ct, J=7. 5 Hz, 3H), 1.60-1.75 Cm, 1.92-2.1 m,8H), 2.33 Ct, J=6.6 Hz, 2H) 2.44-2. 52 2H) 2.53-2 .84 Cm, 4H) 3. 27-3 .32 Cm, 2H) 3 .60 3H) 5.60 (br s, 2H) 6.47 1H) 7. 05-7.33 8H) 8. 80 (br t, 1H) Anal. Calcd. for
C
3 0
H
3 5 ClF 2
N
4 01 6 .l.0 CHC1 3 50.35; H, 5.04; N, 9.47.
Found: C, 50.40; H; 5.33; N, 9.13.
Example 6- (3,4-Difluorophenyl) -5-methoxycarbonyl-4-methyl-2oxo-1-{N-[4-(2-pyridyl)-piperidine-lyll propyl)carboxamido-1, 2,3, 6 -te trahydropyrimi dine dihydrochioride (Scheme 7).
a. 1-Benzyl-4-cyano-4- (2-pyridyl)piperidine. To a mixture of N,N-bis- (2-chloroethyl)benzylamine WO 97/42956 PCTIUS97/08335 -79- (E.Szarvasi, Eur. J. Med. Chem. Chim. Ther. 11(2), 115- 124, 1976) (60 g, 22 mmol), 2-pyridylacetonitrile (2.51 ml, 22 mmol) and tetrabutylammonium hydrogen sulfate (0.26 g, 0.7 mmol) in toluene (10 ml), sodium hydroxide solution (2.43 g in 4.86 ml H 2 0) was added over a minute period. The reaction mixture was heated at OC for 4 hours. The reaction mixture was cooled to room temperature, 10 ml of water was added and the solution partitioned between ethyl acetate (45 ml) and water.
The organic layer was dried over sodium sulfate, filtered and concentrated. Purification of the crude product by column chromatography (hexane:EtOAc,2:3) gave 6.2 g of the title compound as a red solid; 1H-NMR (CDC1 3 6 2.05 J 13.1 Hz, 2 2.30 (t, J 13.2 Hz, 2 2.48 J 13.2 Hz, 2 2.97 (d, J 12.1 Hz, 2 3.57 2 7.19-7.27 6 H), 7.30 J 7.6 Hz, 1 7.6.0 J 7.6 Hz, 1 H), 8.58 J 4.6 Hz,lH).
b. l-Benzyl-4-carboxamido-4-(2-pyridyl)piperidine. To 1-benzyl-4-cyano-4-(2-pyridyl)piperidine (4.5 g, 14.3 mmol), 10 ml of conc.H 2 SO, was added and the solution was stirred at room temperature for 24 hours. It was cooled to 0 OC, diluted with ice pieces and poured into crushed ice. The mixture was then carefully neutralized with 50 NaOH solution. The reaction mixture was repeatedly extracted with chloroform (3 x ml), dried over sodium sulfate, filtered and concentrated to give 4.5 g (95%)of the crude product which was used as such for the subsequent step; 'H-NMR (CDC1 3 6 2.21-2.28 2 2.47 6 3.41 (s, 2 5.23 1 6.40 1 7.12-7.29 6 H), 7.33 J 7.6 Hz, 1 7.63 J 7.6 Hz, 1 H), 8.55 J 4.6 Hz, 1 H).
c. l-Benzyl-4-(2-pyridyl)-piperidine. To l-benzyl-4carboxamido-4-(2-pyridyl)piperidine (4.5 g, 13.5 mmol) WO 97/42956 PCT/US97/08335 in anhydrous methanol (100 ml), HC1 gas was bubbled through the solution at 0 oC for 15 minutes. The reaction mixture was then refluxed for 24 hours. It was cooled to room temperature, concentrated, neutralized with 50 NaOH and repeatedly extracted with chloroform (3 x 25 ml). The combined organic layer was then dried over sodium sulfate, filtered and concentrated. Flash chromatography (hexane:ethylacetate, 1:4) of the crude product yielded 1.72 g of the product as a syrup; 'H-NMR (CDC1 3 6 1.8-1.94 4 2.11 J 11.4 Hz, 2 2.70- 2.72 1 H),3.02 J 11.4 Hz, 2 3.54 2 7.07-7.36 7 7.58 J 7.6 Hz, 1 8.52 J 4.6 Hz, 1 H).
d. 3-[4-(2-Pyridyl)-piperidine-1-yl]propylamine (Scheme To 1-Benzyl-4-(2-pyridyl)-piperidine (3.26 g, 12.9 mmol) in dry methanol (25 ml), 10% palladium hydroxide (1.9 g) was added and the solution was hydrogenated at 200 psi for 24 hours. The solution was filtered over celite, concentrated to give 2.1 g of 4-(2pyridyl)-piperidine which was used as such for the subsequent step. A mixture of 3-bromopropylamine hydrobromide (20 g, 91.3 mmol), potassium carbonate (37.85 g, 273.9 mmol) and di-tert-butyldicarbonate (21.90 g, 100 mmol) in methanol was stirred at room temperature for 24 hours. The reaction mixture was concentrated and partitioned between 250 ml EtOAc and ml water, dried over sodium sulfate, filtered and concentrated. Purification of the crude product by column chromatography (Hexane: EtOAc, 4.5:0.5) gave 17.5 g of the product as a pale yellow oil. To a stirred solution of the 4-(2-pyridyl)-piperidine (1.86 g, 11.4 mmol) in dioxane 20 ml), N-(tertbutoxycarbonyl)-3-bromopropylamine (2.82 g, 11.4 mmol) and potassium carbonate (3.16 g, 22.9 mmol) were added and the solution refluxed for 24 hours. The reaction WO 97/42956 PCT/US97/08335 -81mixture was cooled to room temperature, concentrated and partitioned between 40 ml chloroform and 5 ml water. The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (ethyl acetate: methanol, 4:1) to yield 1.86 g (49 of the required product as a colorless oil; 'H-NMR (CDC1) 6 1.45 (s, 9 H),1.54-1.69 8 2.21-2.68 2 2.74-2.80 1 3.02-3.22 4 5.41 1H), 7.13-7.17 1 7.33 J 7.93 Hz, 1 H).7.63 J 7.6 Hz, 1 8.54 J 4.6 Hz, 1 To N-(tertbutoxycarbonyl)-3-[4-(2-pyridyl)-piperidin-1yllpropylamine (0.15g, 0.45 mmol) in 5 ml of dichloromethane, 1 ml of trifluoroacetic acid was added and the solution stirred at room temperature for 1 hour. The solution was concentrated, neutralized with KOH solution and extracted into 25 ml of dichloromethane. The organic layer was dried over sodium sulfate, filtered and concentrated to give 0.098 g (100%) of 3-[4-(2-pyridyl)-piperidin-1-yl]propylamine which was used as such for the subsequent step (step h).
e. Methyl 2-{(3,4-difluorophenyl)methylene}-3oxobutyrate. A mixture of 3,4-difluorobenzaldehyde (14.2 g, 0.1 mol)., methyl acetoacetate (12.2 g, 0.105 mol), piperidine (0.430 g, 5 mmol), and acetic acid (0.30 g, 5 mmol) in benzene (150 mL) was stirred and refluxed with a Dean-Stark trap for 8 hours. Benzene was evaporated, the residue was dissolved in ethyl acetate (200 mL) and washed with brine (50 mL), saturated potassium bisulfate solution (50 mL), and saturated sodium bicarbonate solution in sequence. The ethyl acetate solution was dried (magnesium sulfate), solvent removed under reduced pressure and the residue was purified by column chromatography (SiO2, EtOAc/hexane, The product, methyl WO 97/42956 PCT/US97/08335 -82difluorophenyl)methylene}-3-oxobutyrate, was obtained as a yellow oil (0.98 g, 98.3%) and was used in the next step without any further characterization.
f. 6-(3,4-Difluorophenyl)-1,6-dihydro-2-methoxy- 5-methoxycarbonyl-4-methylpyrimidine. A mixture of methyl 2- (3,4-difluorophenyl) methylene}-3-oxobutyrate (8.8 g, 36.6 mmol), O-methylisourea hydrogen sulfate (9.4 g, 55 mmol), and NaHCO 3 (12.3 g, 0.146 mol) in DMF (30 mL) was stirred and heated at 70 oC for 16 hours.
The mixture was cooled, diluted with EtOAc (300 mL) and washed with water (5 X 300 mL), brine (300 mL), and dried (MgSO 4 Solvent was evaporated and the crude product was purified by flash column chromatography on silica gel using 10% through 20% EtOAc in hexane as the gradient eluent, to leave the product as an oil (3.82 g, 1 H-NMR (CDC1 3 2.32,2.39 (2 s, 3 3.58, 3.64 (2 s, 3 3.72, 3.85 (2 s, 3 5.55 s, 1 H), 6.13-7.8 4 H).
g. 6-(3,4-Difluorophenyl)-1,6-dihydro-2-methoxy- 5-methoxycarbonyl-4-methyl-1- (4-nitrophenyloxy) carbo nyl]pyrimidine.
To a solution of 6-(3,4-difluorophenyl)-1,6-dihydro-2methoxy-5-methoxycarbonyl-4-methylpyrimidine (2.82 g, 9.52 mmol) and 4-dimethylaminopyridine (1.16 g, 9.52 mmol) in CH 2 C1, (50 mL),at 0-5 OC, 4-nitrophenyl chloroformate (1.82 g, 9.04 mmol) was added and the mixture was allowed to warm to room temperature. After 12 hours solvent was evaporated and the residue was purified by flash column chromatography (SiO 2 EtOAc/hexane, 10%-15%)to obtain the product as white crystals (3.72, m.p. 172-174 OC; 'H-NMR (CDC1 3 :6 2.51 3 3.72 3 3.97 3 H), 6.26 1 7.0-7.3 3 7.38 J 9.3 Hz, 2 8.32 J 9.3 Hz, 2 H).
WO 97/42956 PTU9/83 PCTfUS97/08335 -83h. 6- 4-Difluorophenyl) -5-methoxycarbony1-4-methyl-2oxo-1-{N- (2-pyridyl) -piperidine-l-yl] propyl} carboxamido-1,2,3,6-tetrahydropyrimidine dihydrochioride. To 6- (3 ,4-difluorophenyl) 6dihydro-2-methoxy-5-methoxycarbonyl-4-methyl l(4nitrophenoxy)carbonylpyrimidine (0.04 g,0.086 mmol) in ml of dry dichioromethane, 3 (2-pyridyl) piperidine-l-yllpropylamine (0.038 g, 0.17 mmol) was added and the solution was stirred at room temperature f or 24 hours. The reaction mixture was stirred for another 1 hour after addition of 2 ml of 6N HCl. After neutralization with 10% aqueous KOH solution, the reaction mixture was extracted into dichloromethane (3 x 10 The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography EtOAc: MeOH, 4.5:0.5) to give 0.040 g (8901) as a syrup 'H-NMR (CDCl 3 6 1.73-2.11 (in, 7 H) 2.41 6 H) 2.69 (mn, 1 3.04 J =12.1 Hz, 2 H) 3.31-3.48 (in, 2 H), 3.71 s, 3 H) 6.70 1 H) 7.24-7.27 (in, 5 7.61 J 0 Hz, 2 H) 8. 51 J 4. 6 Hz,. 1 8 .8 9 J 5.1 Hz, 2 H).
To the free base (0.04g, 0.07 iniol) in 4 ml of dichloromethane, 5 ml of 1N HC1 in ether was added, and the solution concentrated under reduced pressure.
Recrystallization from ether gave 0.046 g of 6- (3,4-difluorophenyl) -5-methoxycarbonyl-4-inethyl-2-oxo- 1- (2-pyridyl) -piperidine-l-yl] propyl }carboxainido- 1, 2, 3, 6-tetrahydropyrinidine dihydrochloride as a white solid; Mn.P. 170-174 0 C Anal. Calcd. for
C
2
?H
33 C1 2
F
2
N
5
O
4 .1.0 H 2 0: C, 52.43; H,5.70, N 11.30. Found: C, 52.16; H 5.35; N 11.10.
Example 16 6- 4-Benzofurazan-5-yl) -5-methoxycarbonyl-4-methyl-2oxo-l-{N- (2-pyridyl) -piperidin-1-yljpropyl~carbox WO 97/42956 PCT/US97/08335 -84amido-1,2,3,6-tetrahydropyrimidine dihydrochloride (Scheme 8).
4-Methyl-2-nitroaniline (100 g, 0.650 mol) was suspended in saturated alcoholic sodium hydroxide solution (1.50 To this suspension was added with cooling (5 commercial aqueous sodium hypochlorite till the red color disappeared. The fluffy yellow precipitate formed was filtered, washed with cold water and recrystallized from ethanol to get (88.2 g, 89 yield) as a pale solid.
To 5-Methylbenzfuroxan (88.2 g, 0.59. mol) in refluxing EtOH (75 ml) was added dropwise P(OEt) 3 (150 ml When addition was complete, refluxing was continued for 1 more hour. The solvent was removed by rotary evaporation and the residue shaken with water (200 mL) and allowed to stand overnight at (0-5 The brown solid so obtained was filtered, washed with water and chromatograghed on silica gel to yield 5-Methylbenzofurazan (70 g, 87 as white needle.
5-Dibromomethylbenzofurazan. g, 0.52 mol), NBS (325 and benzoyl peroxide g) were refluxed with stirring in carbon tetrachloride (1.5 L) with exclusion of moisture for hours. The reaction mixture was washed with water (2X0.5L), dried (NaSO,), and the solvent was removed in vacuo. The residue was chromatographed (silica, EtOAchexane, 1:150) to give 122 g of the title compound. The resulting white solid was used in the next step without any further characterization.
To a refluxing mixture of the dibromomethylbenzofurazan (122 g, 418 mmol) in EtOH (1 WO 97/42956 PCT/US97/08335 L) was added AgNO 3 (163 g) in 2 L of water. Refluxing was continued for 2 hours. The mixture was cooled and the AgBr was removed by filtration through Celite, and the solvent was concentrated to a small volume. The resulting solution was extracted with toluene (10 X 100 mL), dried (MgSO,), and the solvent was removed in vacuo. The residue was chromatographed on silica (EtOAc-hexane, 8:1000) to give 48.2 g of the title aldehyde as a white solid.
a. Methyl2-{ (benzofuran-5-yl)methylene}-3-oxobutyrate.
A mixture of 5-Formylbenzofurazan (0.6 g, 4.1 mmol), methyl acetoacetate (0.52 g, 4.5 mmol), piperidine (0.019 g, 0.225 mmol), and acetic acid (0.014 g, 0.225 mmol) in benzene (30 mL) was stirred and refluxed with a Dean-Stark trap for 8 h. Benzene was evaporated, the residue was dissolved in ethyl acetate (80 mL) and washed with brine (50 mL), saturated potassium bisulfate solution (50 mL), and saturated sodium bicarbonate solution in sequence. The ethyl acetate solution was dried (magnesium sulfate), solvent removed under reduced pressure and the residue was purified by column chromatography .(Si02, EtOAc/hexane, 10%-15%).
The product, methyl 2-{(benzofuran-5-yl)methylene}-3oxobutyrate, was obtained as an oil (0.98 g, 98.3%) and was used in the next step without any further characterization.
b. 6-(Benzofurazan-5-yl)-1,6-dihydro-2-methoxy- 5-methoxycarbonyl-4-methylpyrimidine. A mixture of methyl 2-{(benzofuran-5-yl)methylene}-3-oxobutyrate (1.02 g, 4.1 mmol), O-methylisourea hydrogen sulfate (1.06 g, 6.2 mmol), and NaHCO 3 (1.3 g, 16.4 mmol) in DMF (15 mL) was stirred and heated at 70 °C for 16 h. The mixture was cooled, diluted with EtOAc (50 mL) and washed with water (5X 50 mL), brine (50 mL), and dried WO 97/42956 WO 9742956PCT/US97/08335 -86- (MgSO 4 Solvent was evaporated and the crude product was purified by flash column chromatography on silica gel using 10% through 20%1 EtOAc in hexane as the gradient eluent, to leave the product as an oil (0.52 g, 43*U); 'H-NMR (CDCl 3 :6 2.38,2.42 (2 s, 3 H) 3.60, 3 .66 (2 s, 3 H) 3 .74, 3 .82 (2 s, 3 H) 5.-53, 5. 68 (2 s, 1 6.31, 6.32 (br s, 1 7.0-7.8 (in, 3 H).
C. 6-(Benzofurazan-5-yl) -1,6-dihydro-2-methoxy- 5 -methoxycarbonyl -4 -methyl- 1- -nitrophenyloxy) carbo nyl] pyrimidine.
To a solution of 6- (benzofuran-5-yl) -1,6-dihydro-2iethoxy-5-methoxycarbonyl-4-methylpyrimidine (0.485 g, 1.6 inmol) and 4 -dimethylaminopyri dine (0.2 g, 1.6 mmol) in CH 2 C1 2 (20 mL),at 0-5 was added 4-nit rophenyl chloroformate (0.307 g, 1.52 mmol) and the mixture was allowed to warm to room temperature. After 12 hours solvent was evaporated and the residue was purified by flash column chromatography (SiO2, EtOAc/hexane, 15%)to obtain the product as white crystals (0.665 g, 89%) m.p. 180-183 0 C; 'H-NMR (CDC13) :6 2.54 3 H), 3.75 3 3.98 3 H) 6.37 1 7.40 (d, J 9.3 Hz, 2 7.52 J 9.0 Hz, 1 7.68 (s, 1 H) 7. 84 J 9. 0 Hz, 1 H) 8. 32 LT 9. 3 Hz, 2 H).
d. 6- (3,4-Benzofurazan-5-yl) -5-methoxycarbonyl-4methyl-2-oxo-1-{N- (2-pyridyl) -piperidin-1-yllpropyl} carboxamido-1,2,3,6-tetrahydropyrimidine dihydrochioride. To 6- (benzofurazan-5-yl) 6-dihydro- 2-methoxy-5-methoxycarbonyl-4-methyl-1- (4nitrophenoxy) carbonylpyrimidine (0.04 g, 0.085 inmol) in ml of dry dichloromethane, 3-[4-(2-pyridyl)piperidine-1-yllpropylamine (0.037 g, 0.17 inmol) was added and the solution was stirred at room temperature f or 24 hours. The reaction mixture was stirred for another 1 hour after addition of 2 ml of 6N HCl. After WO 97/42956 WO 9742956PCT/US97108335 -87neutralization with 100i aqueous KOH solution, the reaction mixture was extracted into dichloromethane (3 x 10 ml) The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography EtOAc: MeOH, 4.5:0.5) to give 0.040 g (89-0) as a syrup 'H-NMR (CDC1 3 1. 74-2. 10 (in, 7 H) 2.46 6 H) 2. 70-2. 72 1 H) 3.-0 5 J 12. 1 Hiz, 2 H) 3. 34 3.4 8 Cm, 2 H) 3. 76 s, 3 H) 6.82 1 H) 7.11-7.32 (mn, 3 H), 7. 54 -7.78 (in, 4 H) 8. 53 J 4.6 Hz, 1 H) 8. 89 t, J 5.16 Hz, 2 H).
To the free base 0.04g, 0.07 mmol)in 4 ml of dichloromethane, 5 ml of 1N HCl in ether was added, and the solution concentrated under reduced pressure.
Recrystallization from ether gave 0.040 g of 6- (3,4-benzofurazan-5-yl) -5-methoxycarbonyl-4-methyl-2oxo-1-{(N- [4 -(2-pyridyl) -piperidine-1-yll propyl} carboxamido-1,2,3,6-tetrahydropyrimidine dihydrochloride as a white solid; m.p. 200-204 OC; Anal.
Calcd. for C 2
,H
33 C1 2 N70 5 .2.5 H 2 0: C, 49.77; H,5.88. Found: C, 49.41; H 5.20.
Example 17 6- (3,4-Difluorophenyl) (4-methoxycarbonyl-4-phenylpiperidin-1-yl) -pentyl) 2,4-dimethylpyrimidine (Scheme 9).
a. 6-(3,4-Difluorophenyl) -1,6-dihydro-2,4-dimethyl- 5-methoxycarbonylpyrimidine. To a solution of acetamidine hydrochloride (1.53 g, 16.2 inmol.) in DMF mL) were added a solution of potassium tertbutoxide (1.33 g, 11.8 minol.) in DMF (10 mL) and a solution of methyl (3,4-difluorophenyl) rnethylene}- 3-oxobutanoate (2.6 g, 10.8 mmol.) in DMF (10 mL) at 0 0 C. After the mixture was stirred for 0.5 hour at 0 0
)C,
p-toluenesulfonic acid monohydrate (4.1 g, 21.5 minol.) WO 97/42956 PCTIUS97/08335 -88was added. The mixture was heated at 100-120 0 C for 2 hrs. The reaction mixture was cooled to room temperature, quenched with aqueous NaOH solution (2N, mL), and extracted with ether. The organic layer was dried over Na 2 SO, and evaporated. The residue was flash chromatographed over silica gel (eluent: ethyl acetate) to give the product in 59% yield (1.8 g) as a yellow solid: IH NMR (300 MHz, CDC13) 6 1.98 (3H, 2.31 (3H, 3.59 (3H, 5.47 (1H, 7.03-7.05 (3H, m).
b. 1-(5-Chloropentyl)-6-(3,4-difluorophenyl)-1,6dihydro-2,4-dimethyl-5-methoxycarbonylpyrimidine. To a suspension of NaH (90 mg, 60% dispersion in mineral oil, 2.25 mmol.) in THF (7 mL) was added a solution of the above yellow solid (0.6 g, 2.14 mmol.) in THF (8 mL) at 0°C. After 20 min, l-bromo-5-chloropentane (1 mL, d 1.408, 7.59 mmol.) was added. The reaction mixture was then refluxed overnight. After the removal of the solvent, the residue was flash chromatographed over silica gel (eluent: ethyl acetate) to give the product in 75% yield (0.614 g) as a yellow oil: 'H NMR (300 MHz, CDC13) 6 1.42-1.75 (6H, 2.17 (3H, 2.28 (3H, s), 3.05-3.45 (2H, m) 3.49 (2H, t, J=5.88Hz), 3.63 (3H, 5.23 (1H, 7.01-7.15 (3H, m).
c. 6-(3,4-Difluorophenyl)-1,6-dihydro-5methoxycarbonyl-l- (5-(4-methoxycarbonyl-4phenylpiperidin-1-yl)-pentyl)-2,4-dimethylpyrimidine.
A mixture of the above yellow oil (0.667 g, 1.73 mmol.), 4-methoxycarbonyl-4-phenyl piperidine (0.76 g, 3.47 mmol.), potassium carbonate (0.96 g, 6.95 mmol.), sodium iodide (0.52 g, 3.47 mmol.) and 1,4-dioxane mL) was refluxed overnight. The undissolved solid was then filtered off and the solvent was evaporated. The residue was flash chromatographed over silica gel (eluent: 80:20 v/v ethyl acetate-2M ammonia in methanol) to give the title compound in 78% yield WO 97/42956 WO 9742956PCT[US97/08335 -89- (0.768 g) as a yellow oil: CIMS, m/z 568 1H NMP.
(300 MHz, CDCl 3 1.23-1.28 (2H, in), 1.43-1.51 (2H, in), 1.77-2.13 (8H, mn), 2.16 O3H, 2.28 (3H, s) 2.47- 2.55 (2H, mn), 2. 74 81 (2H, mn), 3.0 0 -3 .12 (1H, in), 3.22-3.38 (lH, mn), 3.613 (3H, 3. 615 (3H, s) 5.22 (1Hi, 6.99-7.35 (3H, in).
Treatment of the free base with 2 equivalents of iM Hcl in ether gave the HCl salt as a yellow foam: m.p. 170- 176'C. Anal. Calc. for C 3 2
H
39
F
2
N
3 0 4 2HClP2.3H 2 0: C, 56.35; H, 6.74; N, 6.16; Found: C, 56.34; H, 6.62; N, 5.86.
Example 18 (3,4-Difluorophenyl) -5-methoxycarbonyl-4-methyl- 2-oxo-l-{N- (2-pyridyl)-4-hydroxypiperidin-lyl) propyl] }carboxamido- 1, 2, 3, 6 -te trahydropyrimi dine dihydrochioride.
Asolutionof (3,4-difluorophenyl)-1,6-dihydro-2methoxy-5-methoxycarbonyl-4-methyl-1- (4-nitrophenoxy) carbonylpyrimidine (0.894 g, 2mrmol), 3-E4-(2-pyridyl)- 4-hydroxypiperidin-l-yllpropylamine (0.517 g, 2.2 mmol) in tetrahydrofuran (100 m.L) was stirred at room temperature for 24 hours. The reaction mixture was stirred for another 1 hour after addition of 2 ml of 6N I-Id. Solvent was evaporated at reduced pressure and the residue was basified by treatment with 10% aqueous KOH solution, extracted with dichloromethane (3 x mL) The combined extracts were dried over potassium carbonate, and solvent evaporated. The crude product was purified by flash chromatography on silica gel (dichloromethane:MeOH:2M ammonia in MeOH, 90:8:4) to give 1.20 g (97%6) as a syrup. The f ree base was dissolved in 20 mL anhydrous ether, cooled to 0-5 0 C and treated with 10 mL of 1N HCl in ether. The white powder was filtered and dried to give 6-(3,4-difluorophenyl)- -iethoxycarbonyl-4-methyl-2-oxo--{(N- (4 pyridyl) -4-hydroxypiperidin-1-yl)propyl] }carboxamido- WO 97/42956 WO 9742956PCTIUS97/08335 1, 2, 3, 6 -te trahydropyrimi dine di hydrochloride; m.p. 200- 206 [ce]D +91 (c 1.15 g, i~n 100 mL of chloroform) Anal. Calcd. for C 2
-,H
3 3
C
2
F
2
N
5 0 4 0.4CHC 1 3
C,
48.18; 4.92; N, 10.18. Found: C, 48.34; H, 5.01; N, 10.08.
Example 19 2,3,6-Tetrahydro-l-{N- [4 (2-pyridyl) -piperidinl-yl] (2 -hydroxypropyl) -2-oxo-6- (3,4-difluorophenyl) 4- methylpyrimi dine dihydrochioride a) 3 (2-Pyridyl) piperidin-l-yl] (2-hydroxypropyl) phthal imide A mixture of 4-(2-pyridyl)piperidine (3.25 g, 19.90 mmol) and 2,3-epoxypropylphthalimide (4.449 g, 21.89 mmol) in DMF (20' mL) was stirred and heated at 70 0 )C for 48 h. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using chloroform-methanol- 2M ammonia in methanol (1000/28/14) as the eluent, to obtain the desired product as a viscous oil (6.15 g, 8406) b) 3-[4-(2-Pyridyl)-piperidin-l-yl]-2-hydroxy propylamine A mixture of 3 4-(2-pyridyl)- piperidin-1-yi] (2hydroxypropyl)phthalimide (1.35 g, 3.68 mmcl) and hydrazine (0.588 g, 18.4 mmol) in methanol (15 mL) was stirred and ref luxed for 4.5 h. It was cooled, filtered, and the solid was washed with methanol mL) Evaporation of solvent from the filtrate gave the product as a viscous oil (0.85 g, 98%).
c) -l,2,3,6-Tetrahydro-l-{N- (2-pyridyl) -piperidi n-l-yl] (2 -hydroxypropyl) yl -2 -oxo 6- 4 -di fluorophenyl) 4-me thylpyrimidine WO 97/42956 WO 9742956PCTIUS97/08335 -91dihydrochioride A solution of (+)-6-(3,4-difluorophenyl)-1,2,3,6tetrahydro-2-oxo-5-methoxycarbonyl-4-methyl-1- (4nitrophenoxy) carbonylpyrini dine (105 mg, 0. 23 mind) 3- (2-pyridyl)piperidin-1-yl] -2-hydroxypropylamine mg, 0.23 mmol) in tetrahydrofuran (20 mL) was stirred at room temperature for 24 hours. Solvent was evaporated at reduced pressure and the residue was basified by treatment with 101i aqueous KOH solution, extracted with dichloromethane (3 x 10 mL). The combined extracts were dried over potassium carbonate, and solvent evaporated. The crude product was purified by flash chromatography (dichloromethane :MeOH: 2M ammonia in MeOH,90:8:4) to give 120 mg (9711) as a syrup; The HCl salt was prepared by treatment with 1N HCl in ether; m.p. 215-220 0 C; [UlD +41 (c 1.15 g, in 100 mL of methanol) Anal. Calcd. for C 2 7
H
3 3
N
5 0 6
F
2 C1 2 0.-8 MeOH: C, 52.00; H, 5.68; N, 10.90. Found: C, 52.08; H; 5.70; N, 10.53.
Example 20 and Example 21 (+)-1,2,3,6-Tetrahydro-l-{N-[3-(4-(2-pyridyl)piperidin-l-yl) (2-f luoro)propylJ xycarbonyl-2-oxo-6- 4-difluorophenyl) -4-methylpyrim idine dihydrochioride A mixture of (+)-1,2,3,6-tetrahydro-l-{N-[3- (2-pyridyl) -piperidine-1-yl) (2-hydroxy)propyl )}ca rboxamido-5-methoxycarbonyl-2-oxo-6- 4-difluorophen yl)-4-methylpyrimidine (0.50 g, 0.92 minol), diethylaminosulfur trifluoride (DAST, 0.222 g, 1.38 inmol, 1.5 and benzene (50 mL) was stirred at 0 C under dry argon atmosphere for 24 h. The TLC analysis of reaction mixture showed the complete disappearance of the starting material. Solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel (20 using chloroform/methanol/2 M ammonia in methanol (500/16/8) WO 97/42956 PCT/US97/08335 -92as the eluent to give two products as a mixture of two diastereomers. These diastereomers were purified by chiral HPLC separation on Chiralpak A3, 4.6 X 250 mm column, using isocratic condition (90% hexane and ethanol containing 0.5% DEA). The retention time for the first product (example 26) was 12.97 minutes and for the second product (example 27) was 16.18 minutes.
The combined yield of these products is (65 mg 65 mg) 24%. The HC1 salt was prepared by treatment with IN HC1 in ether; Example 20: m.p. 132-134 +108 (c 0.715 g, in 100 mL of chloroform). Anal. Calcd.
for C 8
H
32
N
5 0O 4
F
3 C1 2 .2.0 H 2 0: C, 53.38; H, 5.60; N, 11.12.
Found: C, 53.28; H; 5.89; N, 10.96. Example 21: m.p.
130-132 OC; [a)D +100 (c 0.7 g, in 100 mL of chloroform). Anal. Calcd. for Cz 2
H
32 NsO 4
F
3 C1 2 .1.5 H 2 0: C, 54.15; H, 5.52; N, 11.28. Found: C, 54.17; H; 5.57; N, 11.00.
Note: Examples 14 and 15 are two diastereomeric products derived from the (+)enantiomer at the pyrimidine part and the two possible enantiomeric compounds with respect to the fluoromethylene chiral center.
Example 22 (+)-5-Carboxamido-6-(2,4-difluorophenyl)-4-ethyl- 1-{N-[3-(4-cyano-4-phenylpiperidin-l-yl)propyl]} carboxamido-2-oxo-l,2,3,6-tetrahydropyrimidine.
a) 3-(4-Cyano-4-phenylpiperidin-l-yl)propylphthalimide.
A mixture of 4-cyano-4-phenylpiperidine hydrochloride (111 g, 0.5 mol), 3-bromopropylphthalimide (135.39 g, 0.505 mol), potassium carbonate (276.42 g, 2 mol), and potassium iodide (5.4 g) in DMF (1 L) was stirred and heated at 100-110 OC for 8 h. About 80% of the solvent was evaporated at reduced pressure, the residue was diluted with dichloromethane (1 L) and washed with brine (3 X 300 mL) and dried (Na 2
SO
4 Solvent was WO 97/42956 PCT/US97/08335 -93evaporated from the dichloromethane solution and the residue was treated with isopropanol (400 mL) and cooled. The pale yellow crystalline product formed was filtered, washed with ice-cold isopropanol and dried (168.6 g, M.p. 96-98 OC.
b) 3-(4-Cyano-4-phenylpiperidin-l-yl)propylamine.
To a solution of 3-(4-cyano-4-phenylpiperidin-1-yl) propylphthalimide (112 g, 0.3 mol) in methanol hydrazine (30 mL) was added and the mixture was stirred and refluxed for 20 h. It was cooled, the white solid formed was filtered and washed with more methanol (200 mL) Solvent was evaporated from the filtrate and residue was dried under vacuum for 4 h.
Chloroform (500 mL) was added to this, stirred for 1 h and filtered. The white solid was washed with more chloroform (200 mL), the solvent was evaporated from the combined filtrates to leave the product as an oil g, 96%).
c) Benzyl 2-[(2,4-difluorophenyl)methylene]-3oxopentanoate. A solution of benzyl propionylacetate (157 g, 0.758 mol), 2,4-difluorobenzaldehyde (107.65 g, 0.758 mol), and piperidinium acetate (5.49 g, 38 mmol) in benzene (1 L) were stirred at room temperature for 96 h. The mixture was washed with water (2 X 100 mL), dried (magnesium sulfate) and the solvent evaporated under reduced pressure to get the product as a pale yellow syrup (251.2 It was used in the next step without further purification.
d) 5- (Benzyloxycarbonyl) 6-dihydro-2-methoxy-4-ethyl- 6-(2,4-difluorophenyl)pyrimidine.
A suspension of benzyl 2-[(2,4-difluorophenyl) methylene]-3-oxopentanoate (80.0 g, 0.241 mol), Omethylisourea hemisulfate (63.8 g, 0.362 mol, 1.5 eq.), NaHCO 3 (60.48 g, 0.72 mol) in ethanol (800 mL) was WO 97/42956 PCT/US97/08335 -94stirred at 60-70 OC for 20 h. After cooling to room temperature, the mixture was filtered, and the solid was washed with ethanol (200 mL). The solvent was evaporated from the combined filtrates and the residue was purified by column chromatography (SiO,, EtOAc/Hexane, 10%-30%) to get 5-(benzyloxycarbonyl) 1,6-dihydro-2-methoxy-4-ethyl-6-(2,4-difluorophenyl) pyrimidine as a pale yellow oil (39 g, The 'H-NMR analysis showed it to be a mixture of amine/imine tautomers and was used as is in the next step.
e) 5- (Benzyloxycarbonyl) -4-ethyl-1, 6-dihydro-2-methoxy- 6- (2,4-difluorophenyl) [(4-nitrophenyloxy) carbonyl] pyrimidine.
To a well stirred solution of 1,6-dihydro-2-methoxy-4-ethyl-6-(2,4-difluorophenyl) pyrimidine (22.5 g, 59.3 mmol) and 4-(N,N-dimethyl amino)pyridine (9.3 g, 75.8 mmol) in CH 2
C
2 1 (200 mL) was added a powder of 4-nitrophenyl chloroformate (15.3 g, 75.8 mmol) at 0 OC. The reaction mixture was stirred for 12 h at room temperature and then water (50 mL) was added. The pH of the aqueous layer was adjusted to 11 by the addition of 6 N sodium hydroxide. The dichloromethane layer was separated and dried (Na 2
SO
4 Solvent was evaporated in vacuo and the residue was purified by column chromatography (SiO 2 dichloromethane /hexane, 20%-50%) to give the product as a viscous oil (32.0 g, 98%).
f) 5-(Benzyloxycarbonyl)-4-ethyl-l,6-dihydro-l-{N-[2phenyl)ethyl]}carboxamido-2-methoxy-6-(2,4difluorophenyl)pyrimidine.
To a stirred solution of 5- (benzyloxycarbonyl) -4-ethyl- 1,6-dihydro-2-methoxy-6-(2,4-difluorophenyl)-1- nitrophenyloxy) carbonyl]pyrimidine (32 g, 58.17 mmol) in dichloromethane (200 mL) was added methylbenzylamine (9.16, 75.6 mmol) at room temperature WO 97/42956 WO 9742956PCTIUS97/08335 and the stirrinig was continued for 12 h. The mixture was diluted with more dichioromethane (200 mL) and washed with 0.5 N NaOH solution (2 x 60 mL) The organic layer was dried over Na 2
SO
4 filtered and solvent was evaporated. The resulting mixture of diastereomers was separated by column chromatography(Sia 2 3% EtOAc in toluene) The first major product to elute was 5- (benzyloxycarbonyl) -4 ethyl-l,6-dihydro-l-{N- [2-phenyl) ethyl] }carboxamido-2methoxy-6- (2,4-difluorophenyl)pyrimidine (12.15 g, 38%) [all) +214 (c 1. 5 g in 100 mL CHCl 3 The second major product to elute was the other diastereomer and no effort was made to isolate it.
g) (Eenzyloxycarbonyl)-1,6-dihydro-2-methoxy-4ethyl-6- 4-difluorophenyl) pyrimidine.
To a stirred solution of (+)-5-.(benzyloxycarbonyl)-4ethyl-l,6-dihydro-l-{N- [2-phenyl) ethyl] }carboxamido-2methoxy-6- (2,4-difluorophenyl)pyrimidine (11.15 g, 20.41 mmol) in toluene (250 mL) was added 1,8diazabicyclo[5,4,0)-undec-7-ene (4.04 g, 26.53 mmol) and the mixture was stirred at room temperature for 14 h. The solvent was evaporated and the residue was purified by flash column chromatography on silica gel with 3:1 EtOAc/hexane as eluent to give (benzyloxycarbonyl) 6-dihydro-2-methoxy-4-ethyl-6- (2,4-difluorophenyl)pyrimidine as a viscous oil (6.15 g, 78%).
h) (Benzyloxycarbonyl) -4-ethyl-1,6-dihydro-2methoxy- 6- 4-dif luorophenyl) 1- (4 -nitrophenyloxy) carbonyl] pyrimidine.
To a well stirred solution of (benzyloxycarbonyl) 6 -dihydro- 2-methoxy-4 -ethyl -6 4-dif luorophenyl) pyrimidine g, 10.62 mmol) and 4-(N,Ndime thylamino) pyri dine (1.69 g, 13.80 mmol) in CH 2 C1 2 (200 mL) was added a powder of 4-nitrophenyl WO 97/42956 PCT/US97/08335 -96chioroformate (2.78 g, 13.80 mmol) at room temperature.
The reaction mixture was stirred for 12 h and washed with 0.5 N NaOH solution (2 X 50 mL). The organic layer was separated and dried (Na 2
SO
4 The solvent was evaporated and the residue was purified by column chromatography on silica gel using dichloromethane/hexane as the eluent to give (benzyloxycarbonyl) -4-ethyl-1,6-dihydro-2methoxy-6-(2,4-difluorophenyl)-l-[(4nitrophenyloxy)carbonyl pyrimidine (5.37 g, 92%) as a viscous oil.
i) S (Benzyloxycarbonyl)-6-(2,4-difluorophenyl)-4ethyl-1-(N- (4-cyano-4-phenylpiperidin-1-yl)propylJ carboxamido-2-oxo-1,2,3,6-tetrahydropyrimidine.
A mixture of (benzyloxycarbonyl) -4-ethyl-1,6dihydro-2-methoxy-6-(2,4-difluorophenyl)-l-[(4nitrophenyloxy)carbonyl]pyrimidine (6.50 g, 11.81 mmol) and3- [4-cyano-4-phenylpiperidin-l-yli propylamine (3.60 g, 15.36 mmcl) in THF (500 mL) was stirred at room temperature for 18 h. It was cooled to 0 0 C and 10% HCl in water (2 mL) was added and stirred for 2 h. The mixture was washed with 0.5 N aq. NaOH solution mL), dried over Na 2
SO
4 and the solvent evaporated. The residue was purified by column chromatography on Si0 2 using CHCl 3 /MeOH/2M NH 3 in MeOH (100/2/1) as eluent to obtain (+)-5-(benzyloxycarbonyl)-6-(2.,4difluorophenyl)-4-ethyl-I-(N-[3-(4-cyano- 4-phenylpiperidin--yl).propyl] }carboxamido-2-oxo- 1,2,3,6-tetrahydropyrimidine as a white foamy solid (7.05 g, 93%).
j) 6-(2,4-Difluorophenyl)-4-ethyl-l-{N-[3-(4-cyano- 4-phenylpiperidin-l-yl)propylJ )carboxamido- 1,2,3,6-tetrahydro-2-oxopyrimidine-5-carboxylic acid.
To a suspension of 10% Pd-C (2.1 g) in MeOH (100 mL) WO 97/42956 WO 9742956PCT/US97/08335 -97and H 2 0 (20 mL) was added a solution of (benzyloxycarbonyl) 4-dif luorophenyl) -4-ethyl- (4-cyano-4-phenylpiperidin-l-yl) propyll carboxamido-2-oxo-1,2,3,6-tetrahydropyrimidine (7.55g, 11.2 mL) in methanol (100 mL) and the mixture was hydrogenated at 80 psi for 14 h. The black suspension was filtered through a pad of celite and washed thoroughly with MeOH (2.0 L) and methanol /chloroform 200 mL). Solvent was evaporated from the combined filtrate to leave the product difluorophenyl) -4-ethyl-1-{(N- (4-cyano- 4-phenylpiperidin-l-yl)propyl]}Icarboxamido- 1, 2,3, 6-tetrahydro-2-oxopyrimidine-5-carboxylic acid as a white solid (6.06 g, 98-1). It was used in the next step without further purification.
k) (+)-5-Carboxamido-6-(2,4-difluorophenyl)-4-ethyl- (4-cyano-4-phenylpiperidin-l-yl)propyl]} carboxamido-2-oxo-1, 2,3, 6-tetrahydropyrimidine.
A mixture of (+)-6-(2,4-difluorophenyl) -4-ethyl- (4-cyano-4-phenylpiperidin-1-yl) propyl] carboxamido-l,2,3,6-tetrahydro-2-oxopyrimidine-scarboxylic acid (6.30 g, 11.18 mmol), 1-(3dime thylaminopropyl) -3 -ethylcarbodiimide hydrochloride (4.29 g, 22.36 mmol, 2 and 4-(N,Ndimethylamino)pyridine (3.41 g, 27.95 mmol, 2.5 eq) in anhydrous dichloromethane (400 mL) was stirred at room temperature for 2 h. To this, 40% aqueous ammonia (6.13 g, 5 eq) was added and the stirring was continued for 12 h. The mixture was diluted with 200 mL of dichloromethane and washed with saturated aqueous ammonium chloride solution (3 X 200 mL). Solvent was evaporated from the dried (sodium sulfate) dichloromethane solution and the residue was purified by column chromatography on silica gel using chloroform-methanol-2M ammonia in methanol (100/2/1) as the eluent, to obtain the desired product as a white WO 97/42956 PCT/US97/08335 -98powder (5.45 g, m.p. 210-211 OC; Part of the compound (300 mg) was dissolved in dichloromethane (3 mL), cooled to 0-5 OC and treated with IN HC1 in ether mL) followed by anhydrous ether (20 mL). The white powder formed was filtered, washed with ether (100 mL) and dried (320 mg, 100%); m.p. 196-97 OC; +126 (c 0.505 g, in 100 mL of 1:1 chloroform/MeOH). Anal.
Calcd. for C 29
H
33
N
6 0 3
F
2 Cl: C, 59.27; H, 5.78; N, 14.24.
Found: C, 59.33; H; 5.67; N, 14.32.
Example 23 (+)-5-Carboxamido-6-(3,4-difluorophenyl)-4methoxymethyl-l-{N- (4(2-pyridyl)piperidin-1-yl) propyl]}carboxamido-2-oxo-l,2,3,6-tetrahydropyrimidine dihydrochloride.
a) 2-Cyanoethyl 4-methoxyacetoacetate.
A mixture of methyl 4-methoxyacetoacetate (50 g, 0.342 mol) and 3-hydroxypropionitrile (31.61 g, 0.444 mol) was heated to 160-180 OC in a distillation set-up. It was kept at that temperature for 2 h until the distillation of the methanol stopped. The residual yellow oil of 2-cyanoethyl 4-methoxyacetoacetate (56.4 g, 90%) was used as is without any further purification.
b) 2-Cyanoethyl 2-[(3,4-difluorophenyl)methylene]-3oxo-4-methoxybutyrate.
A solution of 2-cyanoethyl 4-methoxyacetoacetate (17.8 g, 0.125 mol), 3,4-difluorobenzaldehyde (25.5 g, 6.26 mmol), acetic acid (0.376 g, 6.26 mmol), and piperidine (0.533 g, 6.26 mmol) in benzene (500 mL) were added molecular sieves (200 g) and the mixture was stirred at room temperature for 24 h. Then the solvent was evaporated under reduced pressure and the residue was purified by column chromatography using chloroform/ethyl acetate (100:5) to get the product as an oil (29 g, WO 97/42956 WO 9742956PCT/US97/08335 -99- C) 5- (2-Cyanoethoxycarbonyl) 6-dihydro-2-methoxcy-4methoxymethyl (3,4 -difluorophenyl) pyrimidine.
A suspension of 2-cyanoethyl 2[34 difluorophenyj.)methylene] -3-oxo-4-methoxybutyrate (29 g, 0.094 mol) O-methylisourea hernisulf ate (21 g, 0. 121 moi, 1.3 dimethylaminopyridine (29.67 g, 0.243 mol, 2.5 eq.) *in ethanol (400 mL) was stirred at 50-55 'C f or 6 h. The solvent was evaporated f rom the combined filtrates and the residue was purified by column chromatography (Si0 2 EtOAc/hexane, 1001-3011) to get 5- (2-cyanoethoxycarbonyl) 6-dihydro-2--methoxy-4methoxymethyl-6- 4-difluorophenyl)pyrimidine as a pale yellow oil (10.5 g, 310-) The 'H-NMR analysis showed it to be a mixture of amine/imine tautomers and was used as is in the next step.
d) 5- (2-Cyanoethoxycarbonyl) -4-methoxymethyl-1, 6dihydro-2-methoxy-6-(3,4-difluorophenyl)-l-((4nitrophenyloxy) carbonyl] pyrimidine.
To a well stirred solution of 5-(2-cyanoethoxy carbonyl) 1, 6-dihydro- 2-methoxy- 4-methoxymethyl 6- (3,4 difluorophenyl)pyrimidine (10.5 g, 28.74 mmol) and 4- (N,N-dimethylamino)pyridine (6.95 g, 34.49 mmol) in
CH
2 C1 2 (100 mL) was added a powder of 4-nitrophenyl chloroformate (4.21 g, 34.49 mmol) at 0 0 C. The reaction mixture was stirred for 12 h at room temperature and then the solvent was evaporated. The residue was purified by column chromatography (SiO 2 dichioromethane/hexane, 20%-500%) to give the product as a viscous oil (6.5 g, 43%).
e) 5- (2-Cyanoethoxycarbonyl) -4-methoxymethyl-1, 6dihydro-l-{N- [2-phenyl) ethyl] }carboxazido-2-methoxy-6- (3,4 -difluorophenyl) pyrimidine.
To a stirred solution of 5-(2-cyanoethoxycarbonyl)-4methoxymethyl-1,6-dihydro-2-methoxy-6-(3,4difluorophenyl)-j.-[(4-nitrophenyloxy)carbonyl] WO 97/42956 WO 9742956PCT/US97/08335 -100pyrimidine (6.5 g, 12.25 mmol) in dichioromethane (150 rnL) was added R-(+)-a-methylbenzylamine (1.78 g, 14.7 mmol) at room temperature and the stirring was continu ed for 12 h. Solvent was evaporated and the residue was purified by column chromatography (SiO 2 2001 EtOAc in hexane). The first major product to elute was (2-cyanoethoxycarbonyl) methoxmethyl-1, 6dihydro-1-{(N- [2-phenyl) ethyl] }carboxamido-2-methoxy-6- (3,4-difluorophenyl)pyrimidine (2.54 g, 44.50i) .[CeID +177.8 (c 9.2 g in 100 mL CHCl 3 The second major product to elute was the other diastereomer and no effort was made to isolate it.
f) (2-Cyanoethoxycarbonyl) 6-dihydro-2-methoxy- 4-ethyl-6- (3,4-difluorophenyl)pyrimidine.
To a stirred solution of (2-cyanoethoxycarbonyl) 4-methoxymethyl-1, 6-dihydro-1-{(N- [2-phenyl) ethyl]) carboxamido-2-methoxy-6- 4-dif luorophenyl) pyrimi dine (2.80 g, 5.46 mmol) in toluene (80 mL) was added 1,8diazabicyclo[5,4,01-undec-7-ene (0.250 g, 1.64 mmcl) and the mixture was stirred at 75 0 C for 1 h. The solvent was evaporated and the residue was purified by flash column chromatography on silica gel with 3:1 EtOAc/hexane as eluent to give cyanoethoxycarbonyl)-1,6-dihydro-2-methoxy-4methoxymethyl-6- (3 ,4-difluorophenyl) pyrimidine as a viscous oil (0.82 g, 40.5%).
g) -5-(2-Cyanoethoxycarbonyl) -4-methoxymethyl-l, 6dihydro-2-methoxy-6-(3,4-difluorophenyl)-1-[(4nitrophenyloxy) carbonyl] pyrimidine.
To a well stirred solution of cyanoethoxycarbonyl) 6-dihydro-2-methoxy-4methoxymethyl-6- (3,4-difluorophenyl)pyrimidine (0.82g, 2.24 mmcl) and 4-(N,N-dimethylamino)pyridine (0.329 g, 2.69 mmcl) in CH 2 Cl 2 (200 niL) was added a powder of 4nitrophenyl chloroformate (0.543 g, 2.69 mmcl) at room WO 97/42956 PCTfUS97/08335 -101temperature. The solvent was evaporated and the residue was purified by column chromatography on silica gel using dichioromethane/hexane as the eluent to give (2-cyanoethoxycarbony.) -4rethoxymethyl-,6-dihydro-2-methoxy-6-(3,4difluorophenyl) [(4-nitrophenyloxy) carbonyl] pyrimidine (0.80 g, 67%) as a viscous oil.
h) (+)-5-(2-Cyanoethoxycarbonyl)-6-(3,4difluorophenyl)-4-methoxymethyl-1-{N-[3-(4-(2pyridyl)piperidin-1-yl)propyl] }carboxamido-2-oxo- 1,2,3,6- tetrahydropyrimidine.
A mixture of -5-(2-cyanoethoxycarbonyl) -4methoxymethyl-1,6-dihydro-2-methoxy-6-(3,4difluorophenyl)-l-[ (4-nitrophenyloxy)carbonylI pyrimidine (0.44 g, 0.83 mmol) and 3 pyridyl)piperidin-l-yllpropylamine (0.218 g, 0.996 mmol) in THFf (15 mL) was stirred at room temperature for 12 h. It was cooled to 0 'C and 10%; HCl in water (2 mL) was added and stirred for 2 h. Solvent was evaporated and the residue was purified by column chromatography on Si0 2 using CHCl 3 /MeOH/2M NH 3 in MeOH (100/2/1) as eluent to obtain cyanoethoxycarbonyl) (3,4-difluorophenyl) -4methoxymethyl-l-{N- (4-(2-pyridyl)piperidin-l-yl) propyl] )}carboxamido-2 -oxo- 1, 2, 3, 6 -tetrahydropyrimidine as a white foamy solid (0.41 g, 83%).
i) 6-(3,4-Difluorophenyl)-4-methoxymethyl-1-{N- (4- (2-pyridyl)piperidin-1-yl)propyl]}carboxamido- 1,2,3, 6-tetrahydro-2-oxopyrimidine-5-carboxylic acid.
To a stirred solution of (2-cyanoethoxycarbonyl) 6 4 -di fluorophenyl) 4-methoxymethyl 3- (4 (2pyridyl)piperidin-1-yl)propyll)}carboxamido-2-oxo- 1,2,3,6-tetrahydropyrimidine (0.34 g, 0.57 mmol) in acetone (5 mL) at 0 0 C, sodium hydroxide solution (1 N, WO 97/42956 PCTIUS97/08335 -102- 1.71 mL) was added drop wise and the stirring was continued until the disappearance of the starting material (1 hour). Most of the acetone from the mixture was evaporated under reduced pressure while keeping the temperature at 0 OC and the residue was adjusted to pH 7.0 by the addition of IN hydrochloric acid. The white precipitate of 6-(3,4difluorophenyl)-4-methoxymethyl-l-{N-[3-(4-(2pyridyl)piperidin-l-yl)propyl] }carboxamido- 1,2,3,6-tetrahydro-2-oxopyrimidine-5-carboxylic acid formed was filtered and dried under vacuum (0.30 g, 96%).
j) (+)-5-Carboxamido-6-(3,4-difluorophenyl)-4methoxymethyl-l-{N-[3-(4-(2-pyridyl)piperidin-1-yl) propyl]}carboxamido-2-oxo-1,2,3,6-tetrahydropyrimidine.
A mixture of (+)-6-(3,4-difluorophenyl)-4methoxymethyl-1-{N-[3-(4- (2-pyridyl)piperidin-1-yl) propyl]}carboxamido-1,2,3,6-tetrahydro-2-oxopyrimidineacid (0.30 g, 0.55 mmol), 1-(3dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.212 g, 1.1 mmol, 2 and 4-(N,Ndimethylamino)pyridine (0.134 g, 1.1 mmol, 2 eq) in anhydrous dichloromethane (20 mL) was stirred at room temperature for 2 h. To this, 40% aqueous ammonia (0.64 g, 10 eq) was added and the stirring was continued for 12 h. The mixture was diluted with 20 mL of dichloromethane and washed with saturated aqueous ammonium chloride solution (3 X 200 mL). Solvent was evaporated from the dried (sodium sulfate) dichloromethane solution and the residue was purified by column chromatography on silica gel using chloroform-methanol-2M ammonia in methanol (100/2/1) as the eluent, to obtain the desired product as a white powder (0.232 g, The HC1 salt of this compound was prepared by treatment with 1 N HC1 in ether. m.p.
WO 97/42956 PCT/US97/08335 -103- 95-97 +139 (c 2.1 g, in 100 mL of chloroform) Anal. Calcd. for C2,H 34
N
6 0 4
F
2 C1 2 .2.2 HO0: C, 49.50; H, 5.91; N, 12.83. Found: C, 49.50; H, 5.89; N, 12.43.
Example 24 (+)-5-Methoxycarbonyl-6-(3,4-difluorophenyl)-4methoxymethyl-l-{N- (2-pyridyl)piperidin-1-yl) propyl]}carboxamido-2-oxo-1,2,3,6-tetrahydropyrimidine.
A mixture of (+)-6-(3,4-difluorophenyl)-4methoxymethyl-1-{N-[3-(4-(2-pyridyl)piperidin-1-yl) propyl])carboxamido-1,2,3,6-tetrahydro-2-oxopyrimidineacid (0.30 g, 0.55 mmol), 1-(3dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.212 g, 1.1 mmol, 2 and 4-(N,N-dimethylamino) pyridine (0.134 g, 1.1 mmol, 2 eq) in methanol (20 mL) was stirred at room temperature for 20 h. Solvent was evaporated and the residue was dissolved in 20 mL of dichloromethane and washed with saturated aqueous ammonium chloride solution (3 X 200 mL). Solvent was evaporated from the dried (sodium sulfate) dichloromethane solution and the residue was purified by column chromatography on silica gel using chloroform-methanol-2M ammonia in methanol (100/2/1) as the eluent, to obtain the desired product as a white powder (278 mg, The HC1 salt of this compound was prepared by treatment with 1 N HC1 in ether. m.p. 180- 184 OC; [a]D +122 (c 1.25 g, in 100 mL of methanol).
Anal. Calcd. for C 28
H
3 aN s
O
s
F
2 C1 2 .1.0 H 2 0: C, 51.86; H, 5.75; N, 10.80. Found: C, 52.14; H, 5.72; N, 10.53.
Example (+)-1,2,3,6-Tetrahydro-1-{N-[3-(4-(2-pyridyl)piperidine--yl) carbonyl-2-oxo-6-(3,4-difluorophenyl)-4-methoxymethyl pyrimidine dihydrochloride WO 97/42956 PCTfUS97/08335 -104a) Methyl 2-H(3,4-difluorophenyl) methylene] -3-oxo-4methoxybutyrate.
A solution of methyl 4 -methoxyacetoace tat e (84.32 g 0.577 mol), 3,4-difluorobenzaldehyde (82 g, 0.577 mmol), and piperidinium acetate (5.86 g, 0.068 mol) in benzene (1.5 L) were added molecular sieves (400 g) and the mixture was stirred at room temperature for 48 h.
The molecular sieves were removed by filtration and the solvent was evaporated from the filtrate under reduced pressure. The residue was purified by column chromatography on silica gel using chloroform/ethyl acetate (100:3) to get the product as an oil (67 g 47%).
b) 5-Hethoxycarbonyl-1,6-dihydro-2-methoxy-4methoxymethyl- 6- (3,4 -difluorophenyl) pyrimidine.
A suspension of methyl 2-[(3,4-difluorophenyl) methylene] -3-oxo-4-methoxybutyrate (7.50 g, 27.75 mmol) O-methylisourea hemisulf ate (7.17 g, 41. 63 mmol, 1.5 sodium bicarbonate (6.99 g, 83.25 mmol, 3 eq.) in ethanol (400 mL) was stirred at 50-55 0 C for 6 h. The solvent was evaporated from the combined filtrates and the residue was purified by column chromatography (Si0 2 EtOAc/hexane, 10%-30%) to get methoxycarbonyl-1, 6-dihydro-2-methoxy-4-methoxymethyl- 6-(3,4-difluorophenyl)pyrimidine as a pale yellow oil 3 g, 4 7 The 1 H-NMR analysis showed it to be a mixture of amine/imine tautomers and was used as is in the next step.
C) 5-Methoxycarbonyl-4-methoxymethyl-1, 6-dihydro-2methoxy- 6- 4 -dif luorophenyl) 1- (4 -nitrophenyloxy) carbonyl] pyrimidine.
To a well stirred solution of 5-methoxycarbonyl-1,6dihydro-2-methoxy-4-methoxymethyl-6-(3,4di fluorophenyl) pyrimi dine (4.3 g, 13.18 mmol) and 4- N -dimethyl amino) pyridine (2.09 g, 17.13 mmol) in WO 97/42956 PCTIUS97/08335 -105- C11 2 C1 2 (100 mL) was added a powder of 4-nitrophenyl chioroformate (3.45 g, 17.13 mmol) at 0 OC. The reaction mixture was stirred for 12 h at room temperature and the solid formed was removed by filtration. Solvent was evaporated from the filtrate and the residue was purified by column chromatography (Si0 2 dichioromethane/hexane, 20%-5016) to give the product as a viscous oil (3.85 g, 59%).
d) 5-Methoxycarbonyl-4-methoxymethyl-1, 6-dihydro-l-{N- [2-phenyl) ethyl] lcarboxamido-2 -methoxy- 6- (3 4difluorophenyl) pyrimidine.
To a stirred solution of 5-methoxycarbonyl-4methoxymethyl-1,6-dihydro-2-methoxy-6-(3,4difluorophenyl)-l-[(4-nitrophenyloxy)carbonyl) pyrimidine (3.82 g, 7.77 mmol) in THF (140 mL) was added R- -a-methylbenzylamine (1 .13 g, 9. 33 mmol, 1'.2 eq.) at room temperature and the stirring was continued f or 12 h. Solvent was evaporated and the residue was purified by column chromatography (SiO 2 1 10-20% EtOAc in hexane). The first major product to elute was methoxycarbonyl -4 -methoxmethyl 6 -dihydro- [2 phenyl)ethyl]}carboxamido-2-methoxy-6-(3,4difluorophenyl)pyrimidine (1.74 g, 44.511) +205.5 (c 5.1 g in 100 mL CHCl 3 The second major product to elute was the other diastereomer and no effort was made to isolate it.
e) -5-Hethoxycarbonyl-l, 6-dihydro-2-methoxy-4methoxymethyl 6 ,4-di fluorophenyl) pyrimidine.
To a stirred solution of (+)-5-methoxycarbonyl-4methoxymethyl-1,6-dihydro-l-{(N- [2-phenyl) ethyl] carboxamido-2-methoxy-6- 4-difluorophenyl) pyrimidine (1.74 g, 3.67 mmol) in toluene (40 mL) was added 1,8diazabicyclo[5,4,0]-undec-7-ene (0.250 g, 1.64 mmol) and the mixture was stirred at 70-80 0 C for 1.5 h. The solvent was evaporated and the residue was purified by WO 97/42956 PCTITS9708335 -106flash column chromatography on silica gel with 9:1 CHCl 3 /EtOAc as eluent to give -5-methoxycarbonyl- i, 6dihydro-2-methoxy-4-methoxymethyl-6-(3,4di fluorophenyl) pyrimidine as a viscous oil (1.11 g, 92.5%).
f) (+)-5-Methoxycarbonyl-4-methoxymethyl-1,6-dihydro-2methoxy-6-(3,4-difluorophenyl)-l-[(4-nitrophenyloxy) carbonyl]pyrimidine.
To a well stirred solution of 1,6-dihydro-2-methoxy-4-methoxymethyl-6-(3,4dif luorophenyl) pyrimidine (1.11 g, 3.4 mmol) and 4- (N,N-dimethylamino)pyridine (0.54 g, 4.42 mmol) in
CH
2 C1 2 (200 mL) was added a powder of 4-nitrophenyl chloroformate (0.891 g, 4.42 mmol) at room temperature.
The solvent was evaporated and the residue was purified by column chromatography on silica gel using CHCl 3 /EtOAc as the eluent to give 4-methoxymethyl-1,6-dihydro-2-methoxy-6-(3,4difluorophenyl)-l-[(4-nitrophenyloxy)carbonyl] pyrimidine (1.30 g, 78%) as a viscous oil. IUID +262.2 (c 2.3 g in 100 mL CHC 3 g) (+)-1,2,3,6-Tetrahydro-1-{N-[3-(4-(2-pyridyl)piperidine-l-yl) (2-hydroxy)propylJ hoxycarbonyl-2-oxo-6- (3,4-difluorophenyl) -4-methoxyme thylpyrimidine.
Asolutionof (+)-6-(3,4-difluorophenyl)-1,6-dihydro-2methoxy-5-methoxycarbonyl-4-methoxymethyl-l- (4nitrophenoxy) carbonylpyrimidine (0.450 g, 0.91 mmol), 3-[4-(2-pyridyl)piperidin-l-yl]-2-hydroxypropylamine (0.280 g, 1.19 mmol) in tetrahydrofuran (100 mL) was stirred at room temperature for 24 hours. The reaction mixture was stirred for another 1 hour after addition of 2 ml of 6N HC1. Solvent was evaporated at reduced pressure and the residue was basified by treatment with aqueous KOH solution, extracted with WO 97/42956 PCTfUS97/08335 -107dichioromethane (3 x 10 mL) The combined extracts were dried over potassium carbonate, and solvent evaporated. The crude product was purified by flash chromatography (dichloromethane:MeOH:2M ammonia in MeOH,90:8:4) to give 0.514 g as a syrup.
h) -l,2,3,6-Tetrahydro-1-{N- (2-pyridyl) piperidine-1-yl) (2-oxo)propyl] carbonyl-2-oxo-6- (3,4 -difluorophenyl) -4-methoxymethyl pyrimidine dihydrochioride To a stirred solution of DMSO (0.174 g, 2.23 mmcl) in dichloromethane (5 mL) at -78 OC, oxalyl chloride (0.135 g, 1.07 mmol) in dichioromethane (5 mL) was added and the mixture was stirred for 3 min. To this, a solution of (+)-1,2,3,6-tetrahydro-l-{N-[3-(4-(2-pyridyl) piperidine-l-yl) (2-hydroxy)propyl] hoxycarbonyl- 2 -oxo,- 6- 4 -di fluorophenyl) 4 -methoxyme thylpyrimidine (0.51 g, 0.889 mmol) in dichioromethane mL) was added and the stirring was continued f or min. It was warmed to room temperature and added 5 mL of water. The pH of the mixture was adjusted to 10-11 by adding 1N NaOH and the dichioromethane layer was separated. The aqueous layer was extracted with more dichloromethane (3 X 10 mL). The combined dichloromethane extracts were dried (magnesium sulfate) solvents evaporated, and the residue was purified by flash chromatography (dichloromethane:MeOH:2M ammonia in MeOH, 90:8:4) to give 0.32 g of the product as a syrup. WaD +122 (c 0.55 g in 100 mL CHCl 3 Anal. Calcd. for
C
29
H
33 Ns0 6
F
2 C1 2 2 .5 H 2 0: C, 48.77; H, 5.55; N, 10.16.
Found: C, 48.71; H, 5.72; N, 9.87.
Example 26 and Example 27 Syn and anti isomers of W+)-l,2,3,6-tetrahydro-l-{N- [3- (4 (2 -pyridyl) -piperidine-l1-yl) (2 -hydroximino) propyl )carboxamido-5-methoxycarbonyl-2-oxo-6- 4-dif luoro WO 97/42956 PCTfUS97/08335 -108phenyl) -4-methoxymethylpyrimidine dihydrochioride A solution of (+)-1,2,3,6-tetrahydro*-l-{N- [3- (2-pyridyl) -piperidin-J.-yl) (2-oxo)propyl] }carboxa mido-5-methoxycarbonyl-2-oxo-6- (3,4-difluorophenyl) -4 -methoxymethylpyrimidine (0.14 g, 0.22 rnmol), hydroxylamine hydrochloride (19.6 mg, 0.28 mmol) and sodium acetate (74.8 mg, 0.55 mmol) in methanol (5 rnL) was stirred at room temperature for 24 h. Solvent was evaporated at reduced pressure, the residue was mixed with dichioromethane (30 mL) and washed with water.
The dichioromethane solution was dried (sodium sulfate) and the solvent evaporated. The residue was purified by column chromatography on silica gel (chloroform:MeOH:2M ammonia in MeOH, 90:8:4) The first product to elute was Example 26, syn isomer with respect to oxime hydroxyl and piperidine (30 mg); [U]D +94.1 (c 0.528 g in 100 mL CHCl 3 The HCl salt was prepared by treatment with IN HCl in ether; m.p. 90-92 0 C; Anal. Calcd. for C 2
,H
3 4 N0F 2
C
2 .1.5 H 2 0.0.6 CH 2 Cl 2
C,
47.65; H, 5.35; N, 11.26. Found: C, 47.67; H; 5.56; N, 11.36.
The second product to elute was example 33, anti isomer with respect to oxime hydroxyl and piperidine (70 mg); [ot]D +104 (c 0.3 g in 100 mL CHCl 3 The HCl salt was prepared by treatment with IN HCl in ether; m.p.
103-105 OC; Anal. Calcd. for C 2
,H
3 4
N
6 0 6
F
2
C
2 .2.2 H 2 0-0.22
CH
2 Cl 2 C, 47.74; H, 5.51; N, 11.84. Found: C, 48.01; H, 5.72; N, 11.57.
Example 28 (+)-l,2,3,6-Tetrahydro-l-{N-(3-(4-(2-pyridyl)piperidine-l1-yl) (2 -methoximino) propyl] }carboxamido- -methoxycarbonyl-2-oxo-6- (3,4-difluoropheny.) -4-metho xymethylpyrimidine dihydrochioride A solution of (+)-1,2,3,6-tetrahydro-1-{N-[3- (2-pyridyl) -piperidine-1-yl) (2-oxo)propyl) }carbox WO 97/42956 PCT/US97/08335 -109amido-5-methoxycarbonyl-2-oxo-6- (3,4-difluorophenyl) 4-methoxymethylpyrimidine (30 mg, 0.047 mmol), 0methoxylamine hydrochloride (7.78 mg, 0.093 mmol), and sodium acetate (32 mg, 0.24 mmol) in methanol (5 mL) was stirred at room temperature for 24 h. Solvent was evaporated at reduced pressure, the residue was mixed with dichioromethane (30 mL) and washed with water.
The dichioromethane solution was dried (sodium sulfate) and the solvent evaporated. The residue was purified by column .chromatography on silica gel (chloroform:MeOH:2M ammonia in MeOH,90:8:4). Only one isomeric product was detected by this purification mg, 71%) [a 0 1D +98 (c 0. 4 g in 100 mL CHCl 3 The HCl salt was prepared by treatment with 1N HCl in ether; M.P. 109-112 0 C Anal. Calcd. for
C
29 11 3 6 6 0 6
F
2 C1 2 .2.3H 2 0.0.46 CH 2 Cl 2 C, 46.93; H, 5.55; N, 11.15. Found: C, 47.08; H, 5.66; N, 10.88.
Example 29 1 2 ,3 T et r ahy dr o-1- N- [3 (4 (2 -carboxamidopheny.) -piperazin-l1-yl) -propyl )carb oxamido 5-acetyl- 2 -oxo- 6- 4, 5 -tri fluorophenyl) 4-me thylpyrimidine dihydrochioride a) 3-{(3,4,5-Trifluorophenyl)methylene}-2,4pentanedione.
A mixture of 3,4,5-trifluorobenzaldehyde (4.2 g, 26.2 mmol) 2,4-pentanedione (2.62 g, 26.2 mmol) piperidine (0.430 g, 5 mmol)in benzene (150 mL) was stirred and ref luxed with a Dean-Stark trap for 8 hours. Benzene was evaporated, the yellow oily residue, 2-f{(3,4,5trifluorophenyl) methylene} 4-pentanedione, was used in the next step without any further purification..
b) 6- (3,4,5-Trifluorophenyl) -l,6-dihydro-2-methoxyacetyl -4-me thylpyrimidine.
A mixture of (3,4,5-trifluorophenyl)methylene}-2,4- WO 97/42956 PCTIS97/08335 -110pentanedione (26.2 mmol), O-methylisourea hydrogen sulfate (3.22 g, 39.3 mmol), and NaHCO 3 (6.6 g, 78.6 mmol) in EtOH (400 mL) was stirred and heated at 95-100 oC for 6 hours. The mixture was filtered, the solid residue was washed with ethanol (100 mL). Solvent was evaporated from the combined filtrate and the crude product was purified by flash column chromatography on silica gel using 10% through 25% EtOAc in hexane as the gradient eluent, to leave the product as an oil (2.80 g, 36%).
c) 6-(3,4,5-Trifluorophenyl)-1,6-dihydro-2-methoxy- 5-acetyl-4-methyl-l-[(4-nitrophenyloxy) carbonyl] pyrimidine To a solution of 6-(3,4,5-trifluorophenyl)- 1,6-dihydro-2-methoxy-5-acetyl-4-methylpyrimidine (2.8 g, 9.38 mmol) and pyridine (10 mL) in CH 2 Cl 2 (200 mL) at OC, 4-nitrophenyl chloroformate (1.886 g, 9.38 mmol) was added and the mixture was allowed to warm to room temperature. After 12 hours solvent was evaporated and the residue was purified by flash column chromatography (SiO 2 dichloromethane/EtOAc, 10%-15%)to obtain the product as a white powder (4.0 g, 92%).
d) 6-(3,4,5-Trifluorophenyl)-1,2,3,6-tetrahydro-2-oxo- 5-acetyl-4-methyl-l-[(4-nitrophenyloxy)carbonyl]pyrim idine.
To a well-stirred solution of 6-(3,4,5trifluorophenyl)-1,6-dihydro-2-methoxy- 5-acetyl-4-methyl-l-[(4-nitrophenyloxy)carbonyl]pyrim idine (4.0 g, 8.63 mmol) in THF (100 mL) at 0-5 OC, 6N aqueous HC1 (4 mL) was added and the mixture was allowed to warm to room temperature. After 2 h, solvent was evaporated and the product dried under vacuum. The product was obtained as a pure single component and no need for further purification (3.88 g, 100%).
WO 97/42956 PCT/US97/08335 -111e) -l,2,3,6-Tetrahydro-1-{N- [3- (2 -carboxamidophenyl) -piperazin-l-yl) -propyl] )carb oxamido -5 -ac etyl- 2 -oxo 6- 4, 5 -tri fluorophenyl) 4-me thylpyrimidine dihydrochioride A mixture of 6- 5-dif luorophenyl) 2,3, 6-tetra hydro-2-oxo-.5-acetyl-4 -methyl-i- (4 -nitrophenyloxy) carbonyllpyrimidine (44. 9 mg, 0.1 mmol) and 3- (2-carboxamidophenyl) -piperazin-1-yl] -propylamine (26.2 mg, 0.1 mmol) in THF (10 mL) was stirred at room temperature for 10 h and the solvent evaporated. it was redissolved in dichioromethane (10 mL) washed with ice-cold 0.5 N NaCH (2 X 5 mL) dried and solvent evaporated. The residue was purified by preparative thin layer chromatography on silica gel using chloroform -methanol -2M ammonia in methanol (100/2/1) as the eluent to afford the product as a white powder mg, 9301); The HC1 salt was prepared by treatment with 1N HCl in ether to give the product as a dihydrochloride salt. Anal. Calcd. for C 28
H
33
N
6 0 4 C1 2
F
3 0.4 1120: C, 51.52; H, 5.22; N, 12.88. Found: C, 51.70; H, 5.25; N, 12.53.
Example l,2,3,6-Tetrahydro-l-{N-[3-(4-(4-fluorobelzoyl) piperidin-1-yl) ethyl] )carboxamido-5-methoxycarbonyl-4 -methyl-6-(3,4-difluorophelyl)-2-oxopyrimidile hydrochloride a) 6-(3,4-Difluorophenyl)-l,2,3,6-tetrahydro-2-oxo-5methoxycarbonyl-4 -methyl-i -nitrophenoxy) carbonylpyrimidine.
A well stirred solution of 6-(3,4-difluorophenyl)-l,6dihydro-2-methoxy-5-methoxycarbony1-4-methy1-1- (4nit rophenoxy) carbonylpyrimi dine (10 g) in THF (200 mL) at room temperature, aqueous 6N hydrochloric acid mL) was added and the stirring was continued for 3 h.
WO 97/42956 PCT/US97/8335 -112- Solvent was evaporated and the residue was dried under vacuum to obtain the product as a white powder (9.7 g, 100%); m.p. 185-186 OC.
b) 6-(3,4-Difluorophenyl)-1,2,3,6-tetrahydro-2-oxo-5methoxycarbonyl-4-methyl-l-(2-bromoethylamino carbonyl)pyrimidine.
Amixture of 6-(3,4-difluorophenyl)-1,2,3,6-tetrahydro- 2-oxo-5-methoxycarbonyl-4-methyl-l-(4-nitrophenoxy) carbonylpyrimidine (0.5 g, 1.118 mmol), 2bromoethylamine hydrobromide (0.458 g, 2.237 mmol), and potassium carbonate (2.0 g) in THF/water (50 mL/5 mL) were stirred at room temperature for lh. Then most of the solvent was evaporated at reduced pressure. The residue was partitioned between dichloromethane and water (100 mL and 100 mL). The dichloromethane layer was separated, washed with ice-cold 0.5 N NaOH (2 X mL) and dried (sodium sulfate). Evaporation of the solvent gave the product as a single product (0.48 g, 100%) as a white powder; m.p. 159-160 OC.
c 1 2 3 6 Tetrahydro N- 2 (4-(4-fluorobenzoyl)piperidin--yl) ethyl] }carboxamido -5-methoxycarbonyl-4-methyl-6-(3,4-difluorophenyl)-2oxopyrimidine hydrochloride Amixture of 6-(3,4-difluorophenyl)-1,2,3,6-tetrahydro- 2-oxo-5-methoxycarbonyl-4-methyl-l-(2-bromoethylamino carbonyl)pyrimidine (43 mg, 0.1 mmol), 4-(4fluorobenzoyl)piperidine p-toluene sulfonate (57 mg, 0.15 mmol), potassium carbonate (300 mg), and potassium iodide (30 mg) in THF(10 mL) was stirred at room temperature for 20 h. The solid material was removed by filtration, the solvent from the filtrate was evaporated, and the residue was purified by preparative thin layer chromatography on silica gel using chloroform-methanol-2M ammonia in methanol (100/2/1) as WO 97/42956 PCTIUS97/08335 -113the eluent to afford the product as a viscous oil which was converted to the HCl salt by treatment with 1N HCl in ether; M. P. 159-160 Anal. Calcd. for
C
2 qH 2 qN 4 0 5
F
3 .1HCl.O.8Et 2 O: C, 57.27; H, 5.85; N, 8.56.
Found: C, 57.31; H; 5.75; N, 8.79.
Example 31 l,2,3,6-Tetrahydro-l-fN-[3-(4-(4-fluorophenyl)-4hydroxypiperidin-1-yl)propyl] rbonyl-4-methyl-6- 4-difluorophenyl) -2-oxopyrimidine hydrochloride a) 6-(3,4-Difluoropheziyl)-1,2,3,6-tetrahydro-2-oxo-5methoxycarbonyl -4-methyl -bromopropylamino carbonyl) pyrimidine.
Amixtureof 6-(3,4-difluorophenyl)-1,2,3,6-tetrahydro- 2-oxo-5-methoxycarbonyl-4-methyl-1- (4-nitrophenoxy) carbonylpyrimidine (1.0 g, 2.237 mmcl), 3bromopropylamine hydrobromide (0.979 g, 4.474 mmol), and potassium carbonate (4.0 g) in TI-F/water (100 rnL) were stirred at room temperature for lh. Then most of the solvent was evaporated at reduced pressure. The residue was partitioned between dichloromethane and water (100 mL and 100 mL). The dichioromethane layer was separated, washed with ice-cold 0.5 N NaOH (2 X rnL) and dried (sodium sulfate). Evaporation of the solvent gave the product as a single product (0.98.g, 100%) as a white powder and confirmed by 1
H-NMR.
b) 1,2,3,6-Tetrahydro-1-{N- (4-fluorophenyl) -4hydroxypiperidin- 1-yl) propyl] Icarboxamido- rbonyl -4 -methyl 6 4 -dif luorophenyl) 2 oxopyrimidine hydrochloride A mixture of 6- (3,4-difluorophenyl)-1,2,3,6-tetrahydro- 2-oxo-5-methoxycarbonyl-4-methyl-1- (3 -bromopropyl amino carbonyl)pyrimidine (44.6 mg, 0.1 mmol), 4-(4f luorophenyl) -4-hydroxypiperidine (28.7 mg, 0. 15 mmcl) potassium carbonate (300 mg) and potassium iodide mg) in THF(10 mL) was stirred at room temperature for WO 97/42956 PCTIUS97/08335 -114h. The solid material were removed by filtration, the solvent from the filtrate was evaporated, and the residue was purified by preparative thin layer chromatography on silica gel using chlorof orm- methanol 2M ammonia in methanol (100/2/1) as the eluent to afford the product as a viscous oil which was converted to the HC1 salt by treatment with IN HCl in ether; m.p.
160-164 OC; Anal. Calcd. for C 29
H
2 qN 5
F
3 .HCl.0.8Et 2 O: C, 57.27; H, 5.85; N, 8.56. Found: C, 57.31; H; 5.75; N, 8.79.
Example 32 a) 5- (Benzyloxycarbonyl) -4 ethyl 6 -dihydro -2 m et h oxy 3 ,4 -d if 1u or op he n y1 -m et h oxy carbonyl] pyrimidine.
To a well stirred solution of (benzyloxycarbonyl) 6-dihydro-2-methoxy-4-ethyl-6- (3,4-diflurophenyl)pyrimidine (0.6 g, 1.5 mmol) and 4- N -dimethyl amino) pyridine (0.32 g, 2.66 mmol) in
CH
2 C1 2 (6 mL) was added methyl chioroformate (0.2 mL, 2.66 mmol) at room temperature. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel with 3:1 Petroleum ether/EtOAC as the eluting system to obtain 0.45 g (78% yield) of (-)-5-(benzyloxycarbonyl)-4-ethyl-1,6dihydro-2-methoxy-6- (3,4-difluorophenyl) -1-[methoxycarbonylipyrimidine as a colorless oil.
b) (-)-l,2,3,6-Tetrahydro-4-ethyl-2-oxo-6-(3,4dif luorophenyl) 1- [methoxycarbonyll pyrimidine -5 carboxylic acid.
To a solution of (benzyloxycarbonyl) -4 -ethyl- 1,6-dihydro-2-methoxy-6-(3,4-difluorophenyl)-1- [methoxycarbonylllpyrimidine (0.45 g, 1.18 mmol) in mL of MeOH was added 0.05 g of 10% Pd on carbon and the resulting suspension was hydrogenated under 100 psi for 12 h. The catalyst was then filtered through a pad of WO 97/42956 PCT/US97/08335 -115celite and was washed thoroughly with MeOH. All the MeOH washings were collected and the solvent was removed in vacuo to obtain 0.42 g (99% yield) of 1,2,3,6-tetrahydro-4-ethyl-2-oxo-6-(3,4difluorophenyl)-1- carboxylic acid as a white solid which was used in the next reaction without further purification.
c) (-)1,2,3,6-Tetrahydro-5-{N-[3-(4-methoxycarbonyl)-4phenyl-piperidin-l-yl]propyl}-carboxamido-1methoxycarbonyl-4-ethyl-6-(3,4-difluorophenyl)-2-oxopyrimidine.
To a solution of (-)-1,2,3,6-tetrahydro-4-ethyl-2-oxo- 6-(3,4-difluorophenyl)-1-[methoxycarbonyl]pyrimidine-5carboxylic acid (1.18 mmol, 0.4 g) and 3-[4methoxycarbonyl-4-phenylpiperidin-1-yl)propylamine (1.23 mmol, 0.34 g) in 20 mL CH 2 C1 2 was added 4-(N,Ndimethylamino)-pyridine (1.16 mmol, 0.15 followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (1.84 mmol, 0.54 g) and the resulting solution was stirred at room temperature under argon for 2 days. The solution was then transferred into a separatory funnel, extracted with CH 2 C1 2 washed with sat. NH 4 Cl solution (2 X 20 mL) and then with brine (20 mL). The organic layer was separated and dried over Na 2 SO,, filtered and the solvent was evaporated in vacuo to obtain an offwhite solid. It was purified by column chromatography on silica gel with 10% MeOH in EtOAc as the solvent system to obtain (-)1,2,3,6-tetrahydro-5-{N-[3-(4methoxycarbonyl)-4-phenyl-piperidin-1-yl]propyl}carboxamido-1-methoxycarbonyl-4-ethyl-6-(3,4difluorophenyl)-2-oxo-pyrimidine as a white solid (0.55 g, 79% yield) M.P. 53-55 0 C; [arD -48.5 (c 0.43, CHC1 3 It was characterized as HC1 salt. Anal. Calcd.
For C 3
H
31
,N
4 0 6
F
2 C1.0.4 CHC13: C, 55.23; H, 5.52; N, 8.20.
Found: C, 55.29; H, 5.35; N, 7.99.
WO 97/42956 PCTfUS97/08335 Example 33 tetrahydro-4H- furo (3 -pyrimidine -3 carbonyl. amino}I acid methyl ester.
a) (3,4-Difluorophenyl) -1,6-dihydro-2-oxo-5methoxy-carbonyl-4-bromomethyl-l- ((4-nitrophenyloxy) carbonyl] pyrimidine.
To a well stirred solution of difluorophenyl) -l,6-dihydro-2-methoxy-5methoxycarbonyl-4-methyl-l.- -nitrophenyloxy) carbonyllpyrimidine (1.5 mmol, 0.66 g) in 5 mL of chloroform was added a solution of bromine (1.5 mmol, 0.09 mL) in 3 mL of chloroform at 0 0 C and the solution was allowed to attain room temperature over 1.5 h. The solvent was removed in vacua and the residue was again dissolved in CHC1, (20 mL) and washed with brine. The organic layer was separated, dried over Na 2
SO
4 filtered and the solvent was removed in vacuo to get 0.81 g of (+)-6-(3,4-difluorophenyl)-1,2,3,6-tetrahydro-2-oxo-5methoxycarbonyl-4-bromomethyl-1- [1(4-nitrophenyloxy) carbonyllpyrimidine as a yellow foam. It was used in the next step without any purification.
b) 4 4 -Di fluoropheriyl) 5 -di oxo 2,4, 5,6,7 hexahydro-cyclopentapyrimidine- 3-carboxylic acid-4 nitrophenyl ester.
(3,4-Dif luorophenyl) 6-dihydro-2-oxo-5-methoxycarbonyl -4 -bromomethyl -nitrophenyloxy) c arbonyl Ipyrimi dine (1.5 mmol, 0.81 g) was heated in oil bath for 3 h (bath temperature 130 0 C) The brown residue thus obtained was washed with CHC1 3 and (3,4-difluoro-phenyl) -2,5-dioxo-1,2,4,5,6,7-hexahydrocyclopenta pyrimidine-3-carboxylic acid- 4 -nitrophenyl ester was obtained as a pale brown solid which was used in the next step without further purification (crude wt. 0.51 g).
WO 97/42956 PCTIUS97/08335 -117- (3,4-Difluorophenyl) -2,5-dioxo-l,2, 5,7tetrahydro-4H-furo [3,4-di -pyrimidine-3-carbonyl] amino)acid methyl ester.
A solution of (+)-4-(3,4-difluorophenyl)-2,5-dioxo- 1,2,4,5,6,7-hexahydro-cyclopenta pyrimidine-3carboxylic acid- 4-nitrophenyl ester ((0.30 mmol, 0.13 g) and 3- [4-methoxycarbonyl-4-phenylpiperidin-lyl)propylamine (0.32 mmol, 0.09 g) in 10 rnL of anhydrous THF was stirred overnight at room temperature. The solvent was removed in vacua and the residue was purified by column chromatography (CI- 2 C1 2 followed by 9:1 CH 2 Cl 2 /MeOH) to obtain (3,4difluorophenyl) 5-dioxo-1, 2.5, 7-tetrahydro-4Hfurot3, 4-d] -pyrimidine-3-carbonyll amino) -propyl-4acid methyl ester as a pale yellow solid (0.12 g, 7.096). [011D 128.1 0.525, CHCl 3 -It was characterized as HCl salt. M.P.
142-145 0 C; Anal. Calcd. For C 2 9
H
3
,N
4 0 6
F
2 C1 0.23 CHC1 3
C,
55.55; H, 4.98; N, 8.87. Found: C, 55.25; H, 5.03; N, 8 .52.
Example 34 (3,4-Difluorophenyl) -2,5-dioxo-1,2,5,7tetrahydro-4H-furo [3,4-di -pyrimidine-3-carbonyl] amino)propyl -4 -phenyl-piperidine- 5-carboxylic acid methyl ester. In a similar way, difluorophenyl) 5-dioxo-1, 2, 5,7-tetrahydro-4Hfuro 4-d] -pyrimidine-3-carbonyll amino)}-propyl-4phenyl-piperidine-5-carboxylic acid methyl ester was prepared starting with 6- 4-dif luorophenyl) 1,6 dihydro-2-methoxy-5-methoxycarbonyl-4-methyl-l- (4nitrophenyloxy) carbonyl] pyrimidine (overall yield 270-).
M.P. 162-165 0 C. [ot) D -121.3 (c 0.52, CHC1 3 Example 6-Tetrahydro-l-{N- (2- WO 97/42956 PCT/US97/08335 -118carboxamidophenyl) piperazin-lyl]propyl} -carboxamido-4methyl-6-(3,4-difluorophenyl)-2-oxo-pyrimidine a)1-(2-Carboxamidophenyl)piperazine Concentrated sulfuric acid (15 mL) was added to 1-(2cyanophenyl)piperazine (1.5 g, 8.0 mmol) placed in a round bottom flask and the resulting slurry was stirred at room temperature for 48 h. The reaction mixture was poured on crushed ice very slowly and then basified (pH 9) with 50% solution of NaOH. The aqueous layer was extracted several times with EtOAc, dried over KCO 3 filtered and the solvent was evaporated. 1-(2carboxamidophenyl)piperazine was obtained as an offwhite solid (1.2 g, It was used in the next step without further purification. Mass spectrum 206 (M 1, 100%); Combustion analysis was obtained on its hydrochloride salt. Anal. Calcd. for C,,H, 7
N
3 0C. 0.3 CHC13: C, 43.23; H, 5.55; N, 13.30. Found: C, 43.58; H, 5.70; N, 12.79.
-1,2 6-Tetrahydro-- (2carboxamidophenyl)piperazin-lyl]propyl}-carboxamido-4methyl-6-(3,4-difluorophenyl)-2-oxo-pyrimidine.
To a solution of (+)-6-(3,4-difluorophenyl)-1,2,3,6tetrahydro-2-oxo-5-methoxycarbonyl-4-methyl-- (3bromopropylaminocarbonyl) pyrimidine (0.435 g, 1.0 mmol) and 1-(2-carboxamidophenyl)piperazine (0.4 g, 2.0 mmol) in 25 mL of anhydrous acetone was added powdered K 2
CO
3 (0.69 g, 5.0 mmol) and KI (0.17 g, 1.0 mmol) and the resulting suspension was heated to reflux for 10 h.
TLC indicated complete formation of the product (Rf 0.4, 3:0.5 EtOAc/MeOH). The solvent was evaporated and the residue was dissolved in water (10 mL). The aqueous layer was extracted in EtOAc (3 X 30 mL), the separated organic extract was dried over Na 2
SO
4 and the solvent was removed in vacuo. The residue thus obtained was purified by column chromatography on WO 97/42956 PCTIUS97/08335 -119silica gel with EtOAc/MeOH as the eluting system.
tetrahydro-l-{N-[4-(2-carboxanido phenyl)piperazin-lyllpropyl}-carboxamido-4-nethyl-6- 4-difluorophenyl) -2-oxo-pyrimidine was obtained as light yellow powder (0.48 g, 84% yield). The product was analyzed as its dihydrochloride salt. M.P. 190-193 0 C [oe]D 9 8.-8 (c =0 .3 1, MeOH) Anal calcd. f or
C,,H
34
N
6
F
2 0,C1 2 .0.35 EtOAc: C, 52.16; H, 5.50; N, 12.46.
Found: C, 51.84; H, 5.67; N, 12.05.
Examiple 36 1,2,3, 6-Tetrahydro-1{N- (N-benzimidazolyl) -piperidin- 1-yll propyll-carboxamido-4 -methyl (3 4 difluorophenyl) -2-oxo-pyrimidine.
To a solution of 6-(3,4-difluorophenyl)-1,2,3,6tetrahydro-2-oxo-5-methoxycarbonyl-4-methyl-1- (3bromopropylaminocarbonyl)pyrimidine (43 mg, 0.1 mmol) in 10 mL of anhydrous acetone was added 4- (Nbenzimidazolyl) -piperidine (32.6 mg, 0.15 mmol) followed by NaHCO 3 (41 mg, 0.3 mmol) and KI (16 mg, 0.1 mmol). The resulting suspension was heated to ref lux for 10 h and then cooled to room temperature. The solvent was removed in vacuo and the residue was purified by flash column chromatography on silica gel with EtOAc followed by 10%- MeOH in EtOAc to obtain 1,2,3, 6-tetrahydro-l{N- (N-benzimidazolyl) -piperidinl-yll propyl})-carboxamido-4 -methyl- 6- (3 ,4 difluorophenyl)-2-oxo-pyrimidine as an oil (15 mg, 26% yield) The product thus obtained was then dissolved in 2 mL of chloroform and 0.5 mL of HCl in Et 2 O (1 M) was added at room temperature. The solvent was removed in vacuo and the HCl salt was characterized by combustion analysis. M.P. 168-172 0 C. Anal calcd. for
C
29
H
33
N
6
F
2 0 5 C1 :0.75 CHCl 3 C, 50.43; H, 4.90; N, 11.86.
Found: C, 50.84; H, 5.44; N, 11.46.
Example 37 (-)-6-(Benzo[1,2,5joxadiazol-5-yl)-1-carboxanido-4-et WO 97/42956 PCTIUS97/08335 -120hyl-5-{N-[3-(4-methoxycarbonyl-4-phenylpiperidin-1-yl )propyl]}carboxamido-2- oxo-1,2,3,6-tetrahydro pyrimidine.
a) 4-Methyl-2-nitroaniline (100 g, 0.650 mol) was suspended in saturated alcoholic sodium hydroxide solution (1.50 To this suspension was added with cooling (5 OC) commercial aqueous sodium hypochlorite until the red color disappeared. The fluffy yellow precipitate formed was filtered, washed with cold water and recrystallized from ethanol to get methylbenzfuroxan (88.2 g, 89 yield) as a pale solid.
b) To 5-methylbenzfuroxan (88.2 g, 0.59 mol) in refluxing EtOH (75 ml) was added dropwise P(OEt) 3 (150 ml). When addition was complete, refluxing was continued for 1 more hour. The solvent was removed by rotary evaporation and the residue shaken with water (200 ml) and allowed to stand overnight at (0-5 0 The brown solid so obtained was filtered washed with water and chromatographed on silica gel to yield methylbenzofurazan (70 g, 87 as white needles.
c) (70 g, 0.52 mol), NBS (325 and benzoyl peroxide (0.5 g) were refluxed with stirring in carbon tetrachloride (1.5 1) with exclusion of moisture for 2 days. The reaction mixture was washed with water (2 X 0.5 brine, dried (Na 2 and the solvent removed in vacuo. The residue was chromatographed on silica (hexane/ EtOAc 150/1) to get 122 g of the title compound as a pink solid. Tribromomethylbenzofurazan (17 g, was also isolated as a pink solid.
d) WO 97/42956 PCTIS97/8335 -121- To a refluxing mixture of 5-dibromo methylbenzofurazan (122 g, 418 mmol) in EtOH (1 1) was added AgNO 3 (163 g) in 2 1 of water. When addition was complete, refluxing was continued for 2 hours. The mixture was cooled and the AgBr formed was removed by filtration.
The resulting solution was concentrated to a small volume and extracted with toluene (10 X 300 ml). The extract was concentrated and the residue collected was chromatographed on silica gel (3 kg), (EtOAc hexane 8/1000 to get the title compound (48.2 g, 78%) as a white solid.
e) 2-Cyanoethyl 3-benzo[l,2,5]oxadiazol-5-yl-2propionyl-acrylate.
A mixture of 5-formylbenzofurazan (25.0 g, 168.8 mmol), 2-cyanoethyl 3-oxo-pentanoate (31.4 g, 203 mmol), and piperidinium acetate (1.22 g, 8.40 mmol) in benzene (1.5 1 was refluxed with a Dean-Stark trap for 24 hours. Benzene was evaporated, and the residue was chromatographed on silica (200 g) (EtOAc CHC13 100) to get the title compound (32.36, 62.1 yield) as a orange oil.
f)2-Cyanoethyl 6-benzo[1,2,5]oxadiazol-5-yl-4-ethyl-2methoxy-1,6-dihydropyrimidine-5-carboxylate.
A mixture of 2-cyano-ethyl 3-benzo[1,2,5]oxadiazol-5yl-2-propionyl-acrylate (19 g, 63.48 mmol), 0methylisourea hydrogen sulfate (15.3 g, 88.9 mmol), and 4-dimethylaminopyridine (21.3 g, 175 mmol) in THF (200 ml) was stirred at 65 oC for 6 hours. The solvent was evaporated and the residue was chromatographed on silica gel (-300 g) (hexane EtOAc 2 1) to get 8 g of the title compound as an orange oily solid. This reaction was repeated for many times and the yields were between 5% and 38%.
g)6-Benzo[1,2,5]oxadiazol-5-yl-4-ethyl-2-methoxy-6H- WO 97/42956 PCTIUS97/08335 -122acid 5- (2-cyan-ethyl) ester 1- (4-nitro-phenyl) ester.
To a solution of 2-cyanoethyl 6-benzo 1, 2, 5]1 oxa d ia z o1- 5 -y1- 4- e t hy1- 2 -m et ho xy 1, 6 dihydropyrimidine-5-carboxylate (3.62 g, 10.19 mmol) and 4-dimethylaminopyridine (1.49 g, 12.2 mrnol) in
CH
2 Cl 2 (75 ml), at 0 0 C, was added 4nitrophenylchloroformate (2.46 g, 12.22 mmol) The reaction mixture was slowly warmed to r-t. at which it was stirred for 20 hours. Then, the solvent was evaporated and the residue was purified by flash column chromatography (-60 g of SiO 2 CHCl 3 EtOAc 100 3) to get the title compound (1.96 g, 37 O- yield) as a yellow solid.
h)2-Cyanoethyl ester. 6-benzo[2,2,51oxadiazol-5-yl-4ethyl-2-methoxy-1- (1-phenyl- ethyl carbamoyl) -1,6dihydro-pyrimidine- A solution of 6-benzo[1,2,5]oxadiazol-5-yl-4-ethyl-2methoxy-6H-pyrimidine-1,5-dicarboxylic acid 5- (2cyanoethyl) ester 1-(4-nitrophenyl) ester 2.2 g, 4.22 mmol and methylbenzylamine (1.36 ml, 10.6 mmol) in C11 2 C1 2 (30 ml) was stirred at room temperature f or 10 hours. The solvent was evaporated, and the residue was chromatographed on silica gel (100 g) (CHCd 3 EtOAc 30 1) to get the two diasteromers of the title compound (1.03 g in total, 49t).
i) (-)-2-Cyanoethyl 6-benzo[1,2,5]oxadiazol-5-yl-4ethyl-2-methoxy-l, A mixture of (-)-2-cyanoethyl ester 6benzo[1,2,5)oxadiazol-5-yl-4-ethyl-2-methoxy-l-(lphenyl- ethyl carbarnoyl) carboxylate (557 mg, 1.11 mmol) and 1,8diazabicyclo[5,4,0]undec-7-ene (82.5 ml, 0.55 mmol) in benzene (15 ml) was stirred at 50 ad for 1 hour. The solvent was evaporated, and the residue was WO 97/42956 PCTIUS97/08335 -123chrornatographed on silica gel (-30 g) (CHC., I EtOAc/ 2 N NH 3 in MeOH 40 10 1) to get the title compound (270 mg, 68.5 yield) as a yellow solid. No rotation was observed for this compound.
j) (-)-6-Benzo[1,2,5]oxadiazol-5-yl-4-ethyl-2-methoxy- 6H-pyrimidine-1, 5-dicarboxylic acid 5- (2-cyanoethyl) ester 1-(4-nitro-phenyl) ester.
To a solution of (-)-2-cyanoethyl 6benzo[(1,2, 51oxadiazol- 5-yl -4 -ethyl -2 -methoxy- 1,6 (220 mg, 0.62 mmol) and 4 -dime thyl aminopyri dine (99 mg, 0.81 mmol) in CH 2 C1 2 (12 ml), at 0 0 C, was added 4-nitrophenyichioroformate (164 mg, 0.81 mmol) The reaction mixture was slowly warmed to r.t. at which it was stirred for 24 hours.
The solvent was evaporated and the residue was purified by flash column chromatography (-30 g of SiO 2 CHC1 3 EtOAc 38/1) to get the title compound (301 mg, 93 01 yield) as a yellow solid.
k) (Benzo 2, 5]oxadiazol-5-yl) -1-carboxamido-4- (4-methoxycarbonyl-4-phenylpiperidin-1yl)propyl] carboxamido- 2- oxo- 1,6 -dihydropyrimidine.
To -6-benzo 2, 5]oxadiazol-5 -yl-4 -ethyl -2 -methoxy- 6H-pyrimnidine-1, 5-dicarboxylic acid 5- (2-cyanoethyl) ester 1-(4-nitrophenyl) ester (100 mg, 0.19 mmol) in dry THF (10 ml) ammonia (gas) was introduced with a balloon at room temperature. It was stirred at room temperature for 14 hours. TLC and 1H NMR of the reaction mixture showed that the reaction was complete.
NaOH (1 N, 3 ml) was added at room temperature. After it was stirred for 6 hours, HCl solution (6 N, 4 ml) was added. It was stirred at room temperature for 14 hours. The solvent was evaporated to get a white solid which was used directly in the next step.
WO 97/42956 PCTfS97/08335 -124- A mixture of the crude product from the above step, 4dimethyl aminopyridine (61mg, 0.5 mmol), 1-(3dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (96 mg, 0.5 mmol) in CH 2 C1 2 (15 ml) was stirred at room temperature for 4 hours. Methyl 1-(3-amino-propyl)-4phenyl-piperidine-4-carboxylate (140 mg, 0.5 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The solvent was evaporated and the residue was chromatographed on silica gel (5 g) (CHC13 MeOH 2 N NH3 in MeH 250 2 1) to get the title compound as a white solid (10.8 mg, 10 yield over 3 steps). [a]D -303.9. Hydrochloride of the title compound was made with HC1 in ether. M.P. of the salt: 140-143 C. Calculated for C 3
H
3 sN,,0 6 1.OHC1 0.6 ether: C, 58.03 H, 6.31 N, 14.62 Found: C, 58.07 H, 6.08 N,14.66 Example 38 6-(3,4-Difluoro-phenyl)-1-[3-(3',6'-dihydro-[2,4']bip yridinyl-1'-yl)-propylcarbamoyl]-4-methyl-5methoxycarbonyl-2-oxo-1,2,3,6-tetrahydropyrimidine hydrochloride.
a) 1-(3-Aminopropyl)-4-[pyrid-2-yl]pyridinium bromide hydrobromide.
A solution of 2,4'-dipyridyl (5.0 g, 32.0 mmol) and 3bromopropylamine hydrobromide (7.0 g, 32.0 mmol) in DMF (50.0 mL) and acetonitrile (50.0 mL) was heated at 0 C for 1 h. After cooling, the white solid that came out was filtered, washed with Et 2 O and dried. The mother liquor was concentrated to remove EtO2 and then heated to 90-95 0 C for 4 h. The solvent was evaporated and the white residue was triturated with Et2O (100.0 mL) and filtered. The combined weight of the salt was 11.6 g b) 3-(3',6'-Dihydro-2'-H-[2,4']bipyridinyl-1'-yl)propylamine.
WO 97/42956 PCTIUS97/08335 -125- To a solution of 1-(3-aminopropy]4-4-tpyrid-2yllpyridinium bromide hydrobromide (0.66 g, 1.75 mmol) in 20.0 mL MeOH was added NaBH 4 (0.101 g, 2.62 mmol) in small portions. The reaction mixture was stirred for 30 min and then quenched with 6M HC1 solution. The solution was concentrated to 20.0 mL and basified with 50%1 NaOH solution to pH 12. Extracted with CHCl 3 (5 x 30.0 mL), dried over MgSO 4 and the solvent was removed to give 3-(31,6' -dihydro-2' [2,4']1bipyridinyl-i1'-yl) propylamine as an oil (0.37 g, 96%0 yield) It is used in the next step immediately without purification.
c)6-(3,4-Difluoro-phenyl)-l-[3-(3',6'-dihydro-[2,4'Jb methoxycarbonyl-2-oxo-l,2,3, 6-tetrahydro-pyrimidine hydrochloride.
A solution of 6- (3,4-difluorophenyl) methoxycarbonyl-1- (4-nitrophenoxy) carbonyl- 2-oxo-1,2,3,6- tetrahydro-pyrimidine (20 mg, 0.045 mmol) and 6'-dihydro-2'H-[2,4']bipyridyl-1yl)propylamine (9.7 mg, 0.045 mmol) in CH 2 C1 2 (10 Ml) was stirred at room temperature for 3 days. The solvent was removed in vacuum. The residue was separated on preparative TLC (CHCl 3 MeOH 100 to get the title compound (21mg, 89 01 yield) as a yellow solid. Hydrochloride salt was made with HC1 in ether. M.P. of the salt: 242-244 0 C. Calcd for
C
2
,H
2 9
N
5 0 4
F
2 2.0 Nd1 1.05 CHC1 3 1.05 ether: C, 48.32 H, 5.35 N, 8.74 %.Found: C, 48.10 H, 5.13 N, 8.72 Example 39 6- 4-Difluorophenyl) (3-imidazol-l-yl-propylcarba moyl) -4 -=ethyl -2 -oxo-1, 2, 3, 6 -tetrahydro-pyrimidine- carboxylic acid methyl ester.
A solution of 6- (3,4-difluorophenyl) methoxycarbonyl-1- (4-nitrophenoxy) carbonyl-2-oxo- WO 97/42956 PCT/US97/08335 -126- 1,2,3,6-tetrahydro-pyrimidine (100 mg, 0.22 mmol) and 1-(3-aminopropyl)imidazole (40 ml, 0.34 mmol) in CH 2 Cl 2 ml) was stirred at room temperature for 3 hours.
The solvent was removed in vacuum. The residue was separated on preparative TLC (CHC13 MeOH 100 to get the title compound (80 mg, 84 yield) as a white solid. Hydrochloride of title compound was made with HC1 in ether. Calcd for C 20
H
2 1 NO0 4
F
2 0.3 HO: C, 54.74 H, 4.99 N, 15.89 Found: C, 54.92 4.65 N, 15.77 M.P. of the salt: 221-224 0
C.
E x a m p 1 e 4 0 6-(3,4-Difluorophenyl)-1-{N-[3-(2-phenylimidazol-1-yl )propyl] }carboxamido-4-methyl-5-methoxycarbonyl-2-oxo -1,2,3,6-tetrahydropyrimidine hydrochloride.
Amixture of 6-(3,4-difluorophenyl)-1,2,3,6-tetrahydro- 2-oxo-5-methoxycarbonyl-4-methyl-1- (3-bromopropylamino carbonyl)pyrimidine (100 mg, 0.22 mmol), 2phenylimidazole (32.3 mg, 0.22 mmol), and CsCO 3 (358 mg, 1.1 mmol) in DMF (10 ml) was stirred at room temperature for 2 days. The solid was filtered out.
The solution was concentrated and separated on preparative TLC (EtOAc hexane 3 1) to get the title compound (41 mg, 37 yield) as a white oily solid. Hydrochloride of title compound was made with HC1 in ether. M.P. of the salt: 278-282 0
C.
Calculated for CEH 2 sNsO 4
F
2 2.0 HC1 0.25 H 2 0: C, 52.23 H, 4.60 N, 11.60 Found: C, 52.21 H, 4.69 N, 11.11 Example 41 and Example 42 and (-)-3,6-Dihydro-l-(N-[4-(2-pyridyl)piperidine-1-yl] propyl)carboxamido-5- methoxy carbonyl-2-oxo-6-(3,4,5- trifluorophenyl)-4-methyl pyrimidine dihydrochloride.
a) Methyl2-acetyl-3-(3,4,5-trifluoro-phenyl) -acrylate.
WO 97/42956 PCTfUS97/08335 -127- A mixture of 3,4,5-trifluorobenzaldehyde (1.0 g, 6.3 mmol), methyl acetoacetate 0.81 ml, 7.5 mmol), and piperidinium acetate (45 mg, 0.31 mmol) in benzene ml) was refluxed with a Dean-Stark trap for 12 hours.
The solvent was evaporated, and the residue was chromatographed on silica gel (-50 g) (EtOAc hexane 1 6) to get the title compound (825 mg, 51 yield) as a mixture of cis and trans isomers (yellow oil).
b) Methyl 2-methoxy-4-methyl-6-(3,4,5-trifluorophenyl)-1,6-dihydro-pyrimidine-5-carboxylate.
A mixture of methyl 2-acetyl-3-(3,4,5-trifluorophenyl)-acrylate (670 mg, 2.60 mmol), O-methylisourea hydrogen hemisulfate (448 mg, 3.63 mmol), and 4dimethylaminopyridine (407 mg, 3.63 mmol) in ethanol ml) was stirred at 65 °C for 2 days. The solid formed was filtered out. The filtrate was concentrated and chromatographed on silica gel (30 g) (CH 2 Cl 2 EtOAc 9 1) to get the title compound (390 mg, 48 yield) as a pale yellow oil. Calculated for C 14
H
13
N
2 0 3
F
3
C,
53.50 H, 4.20 N, 8.90 Found: C, 53.24 H, 4.20 N, 8.60 c) 1,6-Dihydro- 5 -methoxycarbonyl 2 -methoxy- 4 -methyl-1 (4-nitro phenyloxy)carbonyl -6-(3,4,5-trifluorophenyl) -pyrimidine.
To a solution of methyl 1,6-dihydro-2-methoxy-4methyl-6-(3,4,5-trifluoro-phenyl)-pyrimidine-5carboxylate (385 mg, 1.23 mmol) and 4dimethylaminopyridine (195 mg, 1.60 mmol) in CH 2 Cl 2 ml), at room temperature, was added 4-nitrophenyl chloroformate (322 mg, 1.60 mmol). The reaction solution was stirred at room temperature for 2 days.
The white solid formed was filtered out. The filtrate was concentrated and chromatographed on silica gel g) (CHC13 CH 3 OH 9 1) to get the titled compound (206 mg, 35 yield) as a white solid. Calculated for WO 97/42956 PCT/US97/08335 -128-
C
21
H
1 6
N
3 0 7
F
3 1.0 H 2 0: C, 50.71 H, 3.65 N, 8.45 Found: C, 50.83%; H, 3.29 N, 8.33 d) 1,6-Dihydro-2-methoxy-5-methoxycarbonyl-4-methyl-l- (2-pyridyl) -piperidin-1-yl -propyl)carbamoyl-6- (3,4,5-trifluoro-phenyl)-pyrimidine.
A mixture of 1,6-dihydro-5- methoxycarbonyl -2-methoxy-(4-nitrophenyloxy)carbonyl 6- 5-trifluorophenyl) 4-methyl-pyrimidine (25 mg, 0.05 mmol) and 3-[4-(2-pyridyl)-piperidin-1-yllpropylamine (16 mg, 0.078 nmol) was stirred at room temperature for 12 hours. The solvent was evaporated and the residue chromatographed on silica gel g) (CHCl 3 EtOAc 30 1 to get the title compound (16 mg, 57 yield) as a pale solid.
e) 1,2,3,6-Tetrahydro-5-methoxycarbonyl-4-methyl- 2-oxo-1-{N-.(4-(2-pyridyl)-piperidine-1-ylpropyl)carboxamido-6-(3,4,5-trifluorophenyl)pyrimidine dihydrochlbride.
1,6-Dihydro-2-methoxy-S-methoxycarbonyl-4-methyl-1-{N- 14- (2-pyridyl)-piperidin-1-yl] -propyl carbamoyl-6- 5-trifluoro-phenyl) -pyrimidine from the previous step was dissolved in CH 2 Cl 2 (5 ml) and concentrated HCl solution (0.5 ml) was added. The reaction mixture was stirred at room temperature for 1 hour. NaOH solution (1 N) was added to neutralized the reaction mixture.
It was extracted with CH 2 Cl 2 The extractant was dried Na 2 SO.) and concentrated to get the title compound (16 mg, quantitative) as a pale solid. Hydrochloride of the title compound was made with HCl in ether.
Calculated for C 2
.H
29
N
5 0,F 3 2.0 HC1 4.0 THF 0.8
CH
2 Cl 2 C, 54.02 H, 6.69 N, 7.19 Found: C, 54.00 H, 6.48 N, 7.42 f) and (-)-3,6-Dihydro-l-{N-[4-(2-pyridyl)- WO 97/42956 PCTIUS97/8335 -129piperidine-1-yl] propyl)carboxamido-5- methoxy carbonyl-2-oxo-6-(3,4,5- trifluorophenyl)-4-methyl pyrimidine dihydrochioride.
The enantiomers were separated by chiral HPLC separation (column: chiralpak AS) of the racemic 1,2,3,6-tetrahydro-l-(N-[4-(2-pyridyl)-piperidine-1-y llpropyl~carboxamido-5-methoxycarbonyl-2-oxo-6- (3,4,5 -trifluorophenyl) -4-methylpyrimidine dihydrochioride which was synthesized in the previous step. The isomer: [cY]D +80.4 (c 0.2 g in 100 ml dichioromethane): The isomer: [c]D -82.2.
Hydrochloride salts of the title compounds was made with HCl in ether.
Example 43 (+)-1,2,3,6-Tetrahydro-5-methoxycarbonyl-4methoxymethyl-2-oxo-l-{N- 4-(2.-pyridyl) piperidine-1-ylJ-propyl carboxamido- 6-(3,4,5-trifluorophenyl) -pyrimidine dihydrochloride.
a) Methyl 2-methoxyacetyl-3- 5-trifluoro-phenyl) acrylate.
A mixture of 3,4,5-trifluoro benzaldehyde (10 g, 62.5 mmol), methyl 4-methoxyacetoacetate (9.7 ml, 75.0 mmol), and piperidinium acetate (450 mg, 3.1 mmol) in benzene (100 ml) was refluxed with a Dean-Stark trap for 8 hours. The white solid formed some side product) was filtered out. The solvent was evaporated, and the residue was chromatographed on silica gel 1 Kg) (toluene t-butyl methyl ether 8 1) to get the title compound (4.5 g, 25% yield) as a mixture of cis and trans isomers (white solid).
b) 1,6-Dihydro-2-methoxy-5-methoxycarbonyl-4methoxymethyl-6-(3,4,5-trifluoro-phenyl)-pyrimidine.
A mixture of methyl 2-methoxyacetyl-3-(3,4,5trifluoro-phenyl)-acrylate (6.0 g, 20.8 rmol), 0methylisourea hydrogen herisulfate (3.6 g, 29.2 mmol), WO 97/42956 PCT/US97/8335 -130and 4-dimethylaminopyridine (3.6 g, 29.2 mmol) in ethanol (20 ml) was stirred at 65 OC for 12 hours. The solid formed was filtered out. The filtrate was concentrated and chromatographed on silica gel kg) (hexane ether 2 1) to get the title compound g, 56 yield) as a pale colorless oily solid.
c) 1,6-Dihydro-2-methoxy-5-methoxycarbonyl-4methoxymethyl- 1-(4-nitrophenyloxy)carbonyl -6-(3,4,5-trifluorophenyl) -pyrimidine.
To a solution of 1,6-dihydro-2-methoxy-5methoxycarbonyl-4-methoxymethyl-6- (3,4,5-trifluorophenyl)-pyrimidine (3.24 g, 9.41 mmol) and 4dimethylaminopyridine (1.38 g, 11.3 mmol) in CH 2 Cl 2 ml) at room temperature, was added 4-nitrophenyl chloroformate (2.28 g, 11.3 mmol). The reaction solution was stirred at room temperature for 2 days.
The white solid formed was filtered out. The filtrate was concentrated and chromatographed on silica gel (hexane ether 1 1) to get the title compound (3.70 g, 77 yield) as a yellow solid.
d) and (-)-1,6-Dihydro-2-methoxy-5methoxycarbonyl-4-methoxymethyl-l- [N-(2-methylbenzyl carbamoyl-6-(3,4,5-trifluoro-phenyl)-pyrimidine.
A mixture of 1,6-dihydro-2-methoxy-5-methoxycarbonyl-4methoxymethyl-l-(4-nitrophenyloxy)carbonyl- 6-(3,4,5-trifluorophenyl)-pyrimidine (3.80 g, 7.46 mmol) and (+)--methylbenzylamine (2.02 mg, 16.4 mmol) in CH 2 C1, was stirred at room temperature for 2 days. The solvent was evaporated and the residue chromatographed on silica gel (toluene /t-butyl methyl ether 5 1) to get the title compound as yellow oil solids. For the less polar isomer (1.81 g, %yield) +164.3. For the more polar isomer (1.79 g, 50 yield) [a]D -86.2.
WO 97/42956 PCTIUS97/8335 -131e) 6-dihydro-2-methoxy-5-methoxycarbonyl-4methoxymethyl-6-(3,4,5-trifluoro-phenyl)-pyrimidine.
A mixture of (+)-1,6-dihydro-2-methoxy-5methoxycarbonyl-4-methoxymethyl-l-[N-(2-methylberzyl )]carbamoyl-6- (3,4,5-trifluoro-phenyl)-pyrimidine (1.81 g, 3.81 mmol) and 1,8-diazabicyclo[5,4, 0undec-7-ene (0.28 ml, 1.90 mmol) in benzene (10 ml) was stirred at room temperature for 4 days. The solvent was evaporated, and the residue was chromatographed on silica gel (-500 g) (hexane ether 2.5 1) to get the title compound (1.2 g, 91 yield) as a yellow oil.
No rotation was observed for this compound.
f) (+)-1,6-Dihydro-2-methoxy-S-methoxycarbonyl-4methoxymethyl-l-(4-nitrophenyloxy) carbonyl -6-(3,4,5-trifluorophenyl)-pyrimidine.
To a solution of 1,6-dihydro-2-methoxy-5methoxycarbonyl-4-methoxymethyl-6-(3,4,5-trifluorophenyl)-pyrimidine (1.20 g, 3.49 mmoi) and 4dimethylaminopyridine (0.51 g, 4.18 mmol) in CH 2 C1 2 ml), at room temperature, was added 4-nitrophenyl chioroformate (0.84 g, 11.3 mmol). The reaction solution was stirred at room temperature for 12 hours.
The white solid formed was filtered out. Trials to purify the crude product on silica gel only hydrolyzed the desired product to the start materials. The crude product was used in the next step without any further purification.
g) (+)-1,6-Dihydro-2-methoxy-5-methoxycarbonyl-4methoxymethyl-1-{N- (2-pyridyl) -piperidin-1-ylI propylcarbamoyl-6- (31415-trif luoro-phenyl) -pyrimidine.
A mixture of (+)-1,6-dihydro-2-methoxy--methoxy carbonyl-4-methoxymethyl-l-(4-nitrophenyloxy) carbonyl-6- (3,4,5-trifluorophenyl) -pyrimidine and 3- (2-pyridyl) -piperidin-1-yl) -propylamine (215 mg, WO 97/42956 PCTIU7S97/0335 -132- 1.05 mmol) was stirred at room temperature for 12 hours. The solvent was evaporated and the residue chromatographed on prep. TLC (CHCl 3 MeOH 100 to get the title compound (115 mg, 22 yield over 2 steps) as a yellow oil.
h) -4-methoxymethyl-2-oxo-l- {N-[4-(2-pyridyl)piperidine-l-yl] -propyl~carboxamido- 6- 5-trifluorophenyl) -pyrimidine dihydrochioride.
1,6-Dihydro-2-methoxy-5-methoxycarbonyl-4 methoxymethyl-l-(N-[4-(2-pyridyl)-piperiain-1-yl}propyl~carbamoyl-6- (3,4,5-trifluoro-phenyl) -pyrimidine from the previous step was dissolved in CH 2 C1 2 (5 ml) and HCl solution (6 N,0.5 ml) was added. The reaction mixture was stirred at room temperature for 4 hour.
KOH solution (1 N) was added to neutralize the reaction mixture. It was extracted with CH 2 C1 2 The extractant was dried Na 2 SO) and concentrated to get the title compound (106 mg, 94 yield) as a pale oily solid.
[(YID 78.6 (c 0.5 g in 100 ml dichloromethane) Hydrochloride of the title compound was made with HC1 in ether. Calculated for C 2
,H,
2
N
5
O,F
3 3.8 HC1+1.8 EtOAc: C, 48.44%; H, 5.80%; N, 8.02 Found: C, 48.19 H, 5.38 N, 8.32%.
Example 44 (-)-1,2,3,6-Tetrahydro-5-methoxycarbonyl-4methoxymethyl-2-oxo- -{N-[4-(2-pyridyl)piperidine-l-ylJ -propyl~carboxamido- 6-(3,4,5-trifluorophenyl)-pyrimidine dihydrochioride.
a) (-)-1,6-Dihydro-2-methoxy-5-methoxycarbonyl-4methoxymethyl-6-(3,4,5-trifluoro-phenyl)-pyrimidine.
A mixture of (-)-1,6-dihydro-2-methoxy-5methoxycarbonyl-4-methoxymethyl-l-[N-(2methylbenzyl) Icarbamoyl-6- (3,4,5-trifluoro-phenyl) WO 97/42956 PCT/US97/08335 -133pyrimidine (1.79 g, 3.80 mmol) and 1,8diazabicyclo[5,4,0]undec-7-ene (0.28 ml, 1.90 mmol) in benzene (10 ml) was stirred at room temperature for 4 days. The solvent was evaporated, and the residue was chromatographed on silica gel (-500 g) (hexane ether 2.5 1) to get the title compound (0.92 g,70 as a yellow oil. No rotation was observed for this compound.
b) (-)-1,6-Dihydro-2-methoxy-5-methoxycarbonyl-4methoxymethyl-1-(4-nitrophenyloxy)carbonyl -6-(3,4,5-trifluorophenyl)-pyrimidine.
To a solution of 1,6-dihydro-2-methoxy-5methoxycarbonyl-4-methoxymethyl-6-(3,4,5-trifluorophenyl)-pyrimidine (0.92 g, 2.67 mmol) and 4dimethylaminopyridine (0.46 g, 3.74 mmol) in CHCl 2 ml), at room temperature, was added 4-nitrophenyl chloroformate (0.75 g, 3.74 mmol). The reaction solution was stirred at room temperature for 2 days.
The white solid formed was filtered out. The filtrate was concentrated and chromatographed on silica gel (hexane ether 3 1) to get the title compound (1.01 g, 79 yield) as a yellow solid.
c) (-)-1,6-Dihydro-2-methoxy-5-methoxycarbonyl-4methoxymethyl-l-{N-[4-(2-pyridyl)-piperidin-1-yl]propyl}carbamoyl-6-(3,4,5-trifluorophenyl)-pyrimidine.
A m i x t u .r e o f 1,6-dihydro-2-methoxy-5-methoxycarbonyl-4methoxymethyl-1-(4-nitrophenyloxy)carbonyl- 6-(3,4,5-trifluorophenyl)-pyrimidine (300 mg, 0.59 mmol) and 3-[4-(2-pyridyl)-piperidin-l-yl]-propylamine (160 mg, 0.77 mmol) was stirred at room temperature for 12 hours. The solvent was evaporated and the residue chromatographed on prep. TLC (CHC13 MeOH 2 N NH 3 in MeOH 20 2 1) to get the title compound (290 mg, 83 yield) as a yellow oil.
WO 97/42956 PCTIUS97/08335 -134d) -1,2,3,6-Tetrahydro-5-methoxycarbonyl- 4-methoxymethyl-2-oxo-1-{N- (2-pyridyl) piperidine- l-ylJ -propylicarboxamido- 6- (3,4 ,5-trifluorophenyl) -pyriLmidine dihydrochioride.
(-)l,6-dihydro-2-methoxy-5-methoxycarbonyl-4methoxymethyl-l-{N-[4-(2-pyridyl) -piperidin-a.-yl] propyl Icarbamoyl -6 4, 5 -t ri fluoro -phenyl) pyrimi dine (290 mng, 0.49 mmol) was dissolved in CH 2 Cl 2 (5 ml) and HC1 solution (6 N, 2 ml) was added. The reaction mixture was stirred at room temperature for 10 hour.
KOH solution (1 N) was added to neutralized the reaction mixture. It was extracted with CH 2 C1 2 The extractant was dried Na 2
SO
4 and concentrated to get the title compound (180 mg, 64 yield) as a pale oily solid.[a] 31.4 (c 0.44 g in 100 ml dichloromethane). Hydrochloride of the title compound was made with HCl in ether. Calculated for C 2
,H
3 2 N.0 5
F
3 2.0 HC1 0.8 ether 0. 8 CH 2 Cl 2 C, 50.59 16; H, 5.78 N, 9.22 %.Found: C, 50.86 H, 5.82 N, 8.75 Example 1,2,3,6-Tetrahydro-5-methoxycarbonyl-4-methyl- 2-oxo-1-{N-[4-(2-pYridYl)- piperidine-1-ylJpropyl~carboxamido- 6- trifluorophenyl pyrimidine dihydrochioride.
a) Hethyl2-acetyl-3- (2,4,5-trifluoro-phenyl) -acrylate.
A mixture of 2,4,5-trifluorobenzaldehyde (1.0 g, '6.3 mmol), methyl acetoacetate 0.81 ml, 7.4 mmol), and piperidinium acetate(38 mg, 0.26 mmol) in benzene ml) was stirred at room temperature for 2 days. The solvent was evaporated, and the residue was chromatographed on silica gel (-50 g) hexane ether to get the title compound (1.60 g, quantitative as a mixture of cis and trans isomers (colorless oil).
WO 97/42956 PCT/US97/08335 -135b) 1, 6-Dihydro-2-methoxy-5-methoxycarbonyl-4-methyl-6- (2,4,5-trifluoro-phenyl)-pyrimidine.
A mixture of methyl 2-acetyl-3-(2,4,5-trifluorophenyl)-acrylate (1.60 g, 6.20 mmol), O-methylisourea hydrogen hemisulfate (1.07 g, 8.68 mmol), and 4dimethylaminopyridine (1.06 g, 8.68 mmol) in ethanol ml) was stirred at 65 oC for 2 days. The solid formed was filtered out. The filtrate was concentrated and chromatographed on silica gel (-50 g) (CH,C1, EtOAc 9 1) to get the title compound (982 mg, 50 yield) as a pale colorless oily solid.
c) 1,6-Dihydro-5-methoxycarbonyl-2-methoxy-4-methyl-l- (4-nitro phenyloxy)carbonyl -6-(2,4,5-trifluorophenyl) -pyrimidine.
To a solution of 1,6-dihydro-2-methoxy-5methoxycarbonyl-4-methyl-6-(2.,4,5-trifluoro-phenyl)pyrimidine (600 mg, 1.91 mmol) and 4dimethylaminopyridine (280 mg, 2.29 mmol) in CH 2 C1, (8 ml), at room temperature, was added 4-nitrophenyl chloroformate (462 mg, 2.29 mmol). The reaction solution was stirred at room temperature for 18 hours.
The white solid formed was filtered out. The filtrate was concentrated and chromatographed on silica gel g) (hexane ether 4 1) to get the title compound (143 mg, 16 yield) as a white solid.
d) 1,6-Dihydro-2-methoxy-5-methoxycarbonyl-4-methyl-l- {N-[4-(2-pyridyl)-piperidin-1-yl]-propyl}carbamoyl-6- (2,4,5-trifluoro-phenyl)-pyrimidine.
A mixture of 1,6-dihydro-5-methoxycarbonyl-2methoxy-4-methyl-l- (4-nitrophenyloxy)carbonyl- 6-(2,4,5-trifluorophenyl)-pyrimidine (70 mg, 0.146 mmol) and 3-[4-(2-pyridyl)-piperidin-1-yl]propylamine (46 mg, 0.220 mmol) was stirred at room temperature for 12 hours. The solvent was evaporated and the residue separated on preparative TLC (CHC13 MeOH 2 N NH3 in WO 97/42956 PCT/US97/08335 -136- MeOH 20 2 1) to get the title compound (59 mg, 72 yield as a yellow oil.
e) 1,2,3,6-Tetrahydro-5-methoxycarbonyl-4-methyl- 2-oxo-l-{N-[4-(2-pyridyl)- piperidine-l-yl]propyl}carboxamido-6-(2,4,5-trifluorophenyl- pyrimidine dihydrochloride.
1,6-Dihydro-2-methoxy-5methoxycarbonyl-4-methyl-l-{N- [4-(2-pyridyl)-piperidin-1-yl]-propyl}carbamoyl-6- (2,4,5-trifluoro-phenyl)-pyrimidine (59 mg, 0.11 mmol) was dissolved in THF (3 ml) and HC1 solution (6 N, 2 ml) was added. The reaction mixture was stirred at room temperature for 6 hour. KOH solution (1 N) was added to neutralized the reaction mixture. It was extracted with CH 2 Cl 2 The extractant was dried (Na 2
SO
4 and concentrated to get the title compound (50 mg, 87 yield) as a white solid. Hydrochloride of the title compound was made with HC1 in ether. Calculated for
C
2
,H
3 oNsO 4
F
2 2.0 HC1 1.0 C 6
H,
1 1.0 CHC13: C, 49.68 H, 5.52 N, 8.52 Found: C, 49.22 H, 6.11 N, 8.59 M.P. of the salt: 239-243 "C.
Example 46 4-(3,4-Difluorophenyl)-3-[3- (3-hydroxy-3-phenyl-8-aza bicyclo[3.2.1]oct-8-yl)propylcarbamoyl] -6-methyl-2-ox o-l,2,3,6-tetrahydro-pyrimidine-5-carboxylic acid methyl ester a) 8-Benzyl-3-phenyl-8-azabicyclo[3.2.1]octan-3-ol: N-benzyltropinone (14.4 g, 66.7 mmol) was added dropwise (neat) to a solution of phenyl magnesium bromide (100 mL, 0.1 M in THF) The addition was continued as such a rate to maintain a gentle reflux.
Once the addition was complete, the reaction mixture was heated at reflux temperature for 19 hours, cooled to room temperature, poured over 200 mL of crushed ice, saturated with ammonium chloride, and extracted with 3 X 100 mL of ethyl acetate. The combined organic WO 97/42956 PCT/US97/08335 -137extracts were dried (K 2 C0 3 I solvent removed in Vacuo, and the crude product was chromatographed on 500 g of silica packed with CHCl 3 The column was eluted with CHC1 3 (1 L) 5tEtOAc-CHCl 3 (1 L) 100- (1 L) 2001, (1 L), 30%0 (1 L) 50%V (1 L) 100%- EtOAc (1 L) and 10%; MeOH- EtOAc (2 L) to give 11.8 g of the desired product as a slightly yellow oily solid. Anal. Calc.
f or C 20
H
23
N
1 0 1 C, 81.87; H, 7.90; N, 4.77. Found: C, 81.63; H, 8.01; N, 4.70.
b) 3-Phenyl-8-azabicyclo[3.2.1]octan-3-ol: A mixture of 5.10 g of 8-benzyl-3-phenyl-8-azabicyclo [3.2.l1]octan-3-ol (17.4 mmol) 3.15 g of 10t Pd/C in mL of 959; ethanol was hydrogenated in a pressurized bomb (200 psi) at 60-70 0 C (bath temperature) for 16 hours. The reaction mixture was filtered through a pad of Celite, and the solids were washed with 5 X 30 mL of methanol. The combined organic extracts were concentrated, and the crude product was chromatographed on 300 g of silica packed with EtOAc-MeOH-isopropanol The column was eluted with EtOAc-MeOHisopropanol 25:2:1 (1 L) 20:2:1 (1 L) and 15:2:1 (1 L) to give 3. 16 g of the desired product as a slightly yellow oily solid. Anal. Calc. for C 13
H
171 1 C, 76.81; H, 8.43; N, 6.89. Found: C, 76.57; H, 8.53; N, 6.80.
c) 4-(3,4-Dif luorophenyl) [3 -(3-hydroxy-3-phenyl-8-a zabicyclo 1]oct-8-yl) propylcarbamoylj -6-methyl-2oxo-l,2, 3,6-tetrahydro-pyrimidine-5-carboxylic acid methyl ester.
A mixture of 243 mg of 3-phenyl-8-azabicyclo[3.2.11 octan-3-ol (1.2 mmol), 640 mg of 1,2,3,6-tetra hydro-1-{3- carbonyl-4-methyl-6-(3,4-difluorophenyl)-2-oxo pyrimidine (1.44 mmol) 197 mg of K 2 C0 3 44 mmol), catalytic amounts (a few crystals) of KI in 10 mL of WO 97/42956 PCT/US97/08335 -138ethanol were heated at reflux temperature for 4 hours.
The reaction mixture was cooled to room temperature, and the crude product was purified with preparative TLC (2000 microns, 10% MeOH-EtOAc) to give 290 mg of the desired product as a slightly yellow viscous oil.
Anal. Calc. For C 30
H
34
F
2
N
4 0 5 1.0 Methanol: C, 61.99; H, 6.38; N, 9.33. Found: C, 62.12; H, 6.02; N, 9.58. The hydrochloride salt was prepared by dissolving 150 mg of the free base in minimum EtOAc and excess IN HC1 in ether was added. The solvent was decanted and the separated oil was triturated with ether to give the hydrochloride as a slightly yellow powder: Anal. Calc.
for C 30
H
34
F
2
N
4 0s+ 1.0 HC1 1.2 H 2 0: C, 57.50; H, 6.01; N, 8.94. Found: C, 57.76; H, 5.82; N, 8.50.
Example 47 and Example 48 1,2,3,6-Tetrahydro- (3-(3-imidazol-1-yl)propyl)am ino)propylcarboxamido-5-methoxycarbonyl-2-oxo-6- (3,4difluorophenyl)-4-methylpyrimidine dihydrochloride and 1,2,3,6-Tetrahydro-1- (2-indol-3yl) ethyl)amino)propylcarboxamido-5-methoxycarbonyl-2 -oxo-6-(3,4-difluorophenyl)-4-methylpyrimidine hydrochloride In two separate reaction vessels, a mixture of 89 mg of 1,2,3,6-tetrahydro-l-{3-bromopropyl}carboxamido-5-met hoxy carbonyl-4-methyl-6-(3,4-difluorophenyl)-2-oxo pyrimidine (0.200 mmol), 0.200 mmol of the following nucleophiles (25.0 mg of 1-(3-aminopropyl)imidazole, mg of tryptamine), 89 mg of K 2
CO
3 in 1 mL of acetonitrile were heated at reflux temperature for days, applied to the preparative-TLC and eluted with CHC1 3 -MeOH-2N NH3 in MeOH (10:1:1) to give the title compounds. The hydrochlorides were prepared by dissolving the title compounds in minimum EtOAc, and excess 1N HC1 in ether was added until no more precipitate was apparent. The solids were filtered, washed with ether, and dried under high vacuum.
WO 97/42956 PCT/~S97/08335 -139- 1,2,3,6-Tetrahydro-l-(N-(3-(3-imidazol--yl)propyj)am ino)propylcarboxamido-5-methoxycarbonyl-2-oxo-6- (3,4difluorophenyl)-4-methylpyrimidine dihydrochioride (12 mg): Anal. Calc. for C 23
H
2
,F
2 N,0 4 2.0 HCl 0.6 ether 0.3 CH 2 C1 2 C, 49.31; H, 5.76; N, 13.12. Found: C, 49.07; H, 5.78; N, 13.28.
1,2,3,6-Tetrahydro-l-(N-(3-(2-indol-3yl)) ethyl) amino) propylcarboxamido-5-methoxycarbonyl-2 -oxo-6-(3,4-difluorophenyl)-4-methylpyrimidine hydrochloride (23 mg); Anal. Calc. for C 2 7
H
29
F
2
N
5 0 4 1.0 HCl 3.7 THF: C, 60.58; H, 7.25; N, 8.45. Found: C, 60.84; H, 7.21; N, 8.48.
Example 49 6-(3,4-Difluorophenyl)-1,6-dihydro-1-methoxycarbonyl-5- (3-(4-methoxycarbonyl-4-phenylpiperidin-l-yl)propylaminocarbonyl)-2,4-dimethylpyrimidine a) Benzyl 3-oxo-2-(3,4-difluorobenzylidenyl)butanoate.
A mixture of 3,4-difluorobenzaldehyde (7.1 g, mmol.), benzyl acetoacetate (12.48 g, 65 mmcl.), acetic acid (0.15 g, 2.5 mmol.) piperidine (0.212 g, mmol.) and benzene (300 mL) was refluxed under a deanstark trap overnight. After the removal of solvent, the residue was then dissolved in ethyl acetate and washed with saturated KHSO,, saturated NaHCO 3 water and then dried over Na 2 SO.. The solvent was evaporated, and the residue was flash chromatographed over silica gel (eluent: 1:1 v/v ethyl acetate-hexane) to give the product in 87% yield (13.7 g) as a yellow solid.
b) S-Benzyloxycarbonyl-6-(3,4-difluorophenyl)-1,6dihydro-2,4-dimethylpyrimidine.
To a stirred solution of acetamidine hydrochloride (1.42 g, 15 mmol.) in DMF (10 mL) were added a solution of potassium tert-butoxide (1.23 g, 11 mmol.) in DMF and a solution of the above yellow solid (3.16 WO 97/42956 PCT/US97/08335 -140g, 10 mmol.) in DMF (10 mL) at 0°C. After the mixture was stirred for 15 min at 0°C, p-toluenesulfonic acid monohydrate (3.8 g, 20 mmol.) was added. The mixture was heated at 100-110°C for 2 hrs. After cooling, it was quenched with 2N aqueous NaOH solution and extracted with ether. The organic layer was dried over Na 2 SO, and evaporated. The residue was flash chromatographed over silica gel (eluent: 100:5 v/v ethyl acetate-2M ammonia in methanol) to give the product in 42% yield (1.5 g) as an off-white solid.
c) 5-Benzyloxycarbonyl-6-(3,4-difluorophenyl)-1,6dihydro-l-methoxycarbonyl-2,4-dimethylpyrimidine.
To a stirred slurry of NaH (59 mg, 60% in mineral oil, 1.47mmol.) in THF (5 mL) was added a solution of the above off-white solid (0.5 g, 1.4 mmol.) in THF (10 mL) at 0°C. After 5 min, methyl chloroformate (0.16 g, 1.7 mmol.) was added at 0°C. Stirring was continued at room temperature for 30 min. The mixture was quenched with brine and extracted with ethyl acetate. The organic layer was dried over Na 2 SO, and evaporated to give a quantitative yield of the product as a yellow solid.
d) 5-Carboxy-6-(3,4-difluorophenyl)-1,6-dihydro-lmethoxycarbonyl-2,4-dimethylpyrimidine.
A solution of the above yellow solid (0.63 g, 1.52 mmol) in methonal (20 mL) was subjected to hydrogenation with a H 2 balloon in the presence of palladium (63 mg, 5% on The reaction was carried out at room temperature for 30 min. The catalyst was then filtered off and the solvent was removed in vacuo to give the product in 99% yield (0.487 g) as an offwhite solid.
e) 6-(3,4-Difluorophenyl)-1,6-dihydro-lmethoxycarbonyl-5-(3-(4-methoxycarbonyl-4phenylpiperidin-1-yl)-propylaminocarbonyl)-.2,4- WO 97/42956 PCT/US97/08335 -141dimethylpyrimidine.
A mixture of the above off-white solid (0.070 g, 0.22 mmol.), 4-dimethylaminopyridine (0.040 g, 0.33 mmol.), 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.060 g, 0.30 mmol.) and CH 2 C1 2 (5 mL) was stirred at room temperature for 0.5 hr. After the addition of 3-(4-methoxycarbonyl-4-phenylpiperidin-1yl)propylamine (0.075 g, 0.27 mmol.), the mixture was refluxed overnight. To the mixture was added another mL of CH 2 Cl1 and washed with saturated NH 4 C1 solution.
After the removal of the solvent, the residue was flash chromatographed over silica gel (eluent: 85:15 v/v ethyl acetate-methonal) to give the title compound in 42% yield (0.052 g) as a white solid: mp 55-57 0 C. Anal.
Calcd. for C 31
H
36
F
2
N
4 0s0.5CH 2 C1 2 C, 60.52; H, 5.97; N, 8.96. Found: C, 60.61; H, 6.09; N, 8.94.
Example 6-(3,4-Difluorophenyl)-1,6-dihydro-5-(3-(4methoxycarbonyl-4-phenylpiperidin- 1yl)propylaminocarbonyl)-l-methoxymethyl-2,4dimethylpyrimidine a) 5-Benzyloxycarbonyl-6-(3,4-difluorophenyl)-1,6dihydro-l-methoxymethyl-2,4-dimethylpyrimidine.
To a stirred slurry of NaH (24 mg, 60% in mineral oil, 0.6 mmol.) in THF (5 mL) was added a solution of benzyloxycarbonyl-6-(3,4-difluorophenyl)-1,6-dihydro- 2,4-dimethylpyrimidine (0.2 g, 0.56 mmol.) in THF mL) at 0°C. After 10 min, chloromethyl methyl ether (0.043 mL, 0.57 mmol.) was added at 0°C. Stirring was continued at room temperature for 3 hrs. The mixture was quenched with brine and extracted with ethyl acetate. The organic layer was dried over Na 2
SO
4 and evaporated to give the product in 44.5% yield as a yellow oil.
b) 5-Carboxy-6-(3,4-difluorophenyl)-1,6-dihydro-1- WO 97/42956 PCT/US97/08335 -142methoxymethyl-2,4-dimethylpyrimidine.
A solution of the above yellow oil (0.17 g, 0.43 mmol) in methanol (20 mL) was subjected to hydrogenation with a H 2 balloon in the presence of palladium (34 mg, 5% on The reaction was carried out at room temperature for 0.5 hr. The catalyst was then filtered off and the solvent was removed in vacuo to give the product in 100% yield (0.13 g) as an off-white solid.
c) 6-(3,4-Difluorophenyl)-1,6-dihydro-5-(3-(4methoxycarbonyl-4-phenylpiperidin-1 yl)propylaminocarbonyl)-l-methoxymethyl-2,4dimethylpyrimidine.
A mixture of 5-carboxy-6-(3,4-difluoro-phenyl)-1,6dihydro-1-methoxymethyl-2, 4-dimethylpyrimidine (0.13 g, 0.42 mmol.), 4-dimethylaminopyridine (0.1 g, 0.84 mmol.), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.16 g, 0.82 mmol.) and CHC1 2 (5 mL) was stirred at room temperature for 0.5 hr. After the addition of 3-(4-methoxycarbonyl-4-phenylpiperidin-lyl)propylamine (0.17 g, 0.62 mmol.), the mixture was refluxed overnight. To the mixture was added another mL of CH 2 C1 2 and washed with saturated NH 4 Cl solution.
After removal of the solvent, the residue was flash chramotographed over silica gel (eluent: 80:20 v/v ethyl acetate- methanol) to give the title compound in 32% yield (0.075 g) as a pale yellow solid: mp 53-57 0
C.
Anal. Calcd. for C 31
H
3
F
2
N
4 0 4 -0.25CHC1 3 C, 62.71; H, 6.44; N, 9.36. Found: C, 62.62; H, 6.79; N, 9.19.
Example 51 1, 6-Dihydro-5-methoxycarbonyl (4-methoxycarbonyl -4-phenylpiperidin -1 -yl pentyl) 4-methyl-6-(4-nitrophenyl)-pyrimidine a) 1,6-Dihydro-5-methoxycarbonyl-4-methyl-6-(4nitrophenyl)-pyrimidine.
Sodium (0.55 g, 23.9 mmol) was allowed to react with WO 97/42956 PCTIUS97/08335 -143anhydrous EtOH (100 mL). Then the solution was cooled by an ice water bath when formamidine acetate (2.29 g, 2 0 mmol) and methyl 2- 4nitrobenzylidenyl)acetoacetate (5.00 g, 20.1 mmol) were added. The mixture was stirred at room temperature for 3 h. The product was filtered off as a yellow powder (4.68 g, It was mixed with p-toluenesulfonic acid monohydrate (6.7 g, 35.2 mmol) in dry DMSO (125 mL) and heated at 110 0 C for 3 h. Ice water (450 mL) was added and the product as a tosylate was filtered off as an off-white solid (5.55 g, 78%).
b) 1-(5-Chloropentyl)-1,6-dihydro-5-methoxycarbonyl-4methyl-6-(4-nitrophenyl)pyrimidine.
The above solid (2.44 g, 5.45 mmol) was added to dry THF (50 mL) containing sodium hydride (60% oil dispersion, 480 mg, 12.0 mmol) and cooled by an ice water bath. Then l-bromo-5-chloropentane (3 mL, 22.8 mmol) was added. The mixture was stirred at room temperature for 7 h before ice water was added.
Extraction with EtOAc gave a dark oil (4.455 g) which was flash chromatographed over silica gel (120 g) eluting with EtOAc/hexane/Et 3 N (15:15:1) to afford a brown oil (1.43 g, 69%).
c) 1,6-Dihydro-5-methoxycarbonyl-l- (5-(4-methoxycarbon yl-4-phenyl-piperidin-l-yl)pentyl)-4-methyl-6- (4-nitrophenyl)-pyrimidine.
The above oil (220 mg, 0.58 mmol) was mixed with 4methoxy-carbonyl-4-phenylpiperidine (127 mg, 0.58 mmol) and potassium iodide (106 mg, 0.64 mmol) in dry glyme (4 mL) cooled by an ice water bath. Then sodium hydride (24 mg, 60% oil dispersion, 0.60 mmol) was added. The mixture was heated at reflux overnight and more KI (106 mg) was added. Reflux was continued for two more days. Ice water was added. Extraction with EtOAc (3 x 3 mL) gave a brown oil (158 mg) It was WO 97/42956 PCT/~S97/08335 -144dissolved in CHCl 3 /EtOAc and flash chromatographed over silica gel (16 g) eluting with EtOAc/MeOH/Et 3 N (20:1:1) to afford a yellow oil (89 mg, Anal. Calcd. for
C
3
H
38
,N
4 0 6 3/4H 2 0: C, 64.62; H, 6.91; N, 9.72. Found: C, 64.56; H, 6.84; N, 9.76.
Example 52 6-(2,4-Difluorophenyl) -1,6-dihydro-l- methoxycarbonyl-4-phenylpiperidin-l-yl)-pentyl)-2,4a) Benzyl 3-oxo-2-(2,4-difluorobenzylidenyl)butanoate.
A mixture of 2,4-difluorobenzaldehyde (7.1 g, mmol.), benzyl acetoacetate (12.48 g, 65 mmol.), acetic acid (0.15 g, 2.5 mmol.), piperidine (0.212 g, mmol.) and 2-propanol (300 mL) was stirred at room temperature for two days. After the removal of solvent, the residue was then dissolved in ethyl acetate and washed with saturated KHSO4, saturated NaHCO 3 water and then dried over Na 2
SO
4 The solvent was evaporated, and the residue was flash chromatographed over silica gel (eluent: 1:5 v/v ethyl acetate-hexane) to give the product in 91% yield (14.3 g) as a yellow solid.
b) 5-Benzyloxycarbonyl-6-(2,4-difluorophenyl)-1,6dihydro-2,4-dimethylpyrimidine. To a stirred solution of acetamidine hydrochloride (2.84 g, 30 mmol.) in DMF mL) were added a solution of potassium tertbutoxide (2.46 g, 22 mmol.) in DMF (20mL) and a solution of the above yellow solid (6.32 g, 20 mmol.) in DMF (20 mL) at 0°C. After the mixture was stirred for min at 0°C, p-toluenesulfonic acid monohydrate (7.6 g, 40 mmol.) was added. The mixture was heated at 100- 110 0 C for 2 hrs. After cooling, it was quenched with 2N aqueous NaOH solution and extracted with ether. The organic layer was dried over Na 2
SO
4 and evaporated, the residue was flash chromatographed over silica gel (eluent: 100:5 v/v ethyl acetate-2M ammonia in WO 97/42956 PCT/US97/08335 -145- Methanol) to give the product in 42% yield (1.5 g) as an off-white solid.
c) 5-Benzyloxycarbonyl-l-(5-bromopentyl)-6-(2,4difluorophenyl)-1,6-dihydro-2,4-dimethylpyrimidine. To a suspension of NaH (123 mg, 60% dispersion in mineral oil, 3.08 mmol.) in THF (5 mL) was added a solution of the above off-white solid (1.0 g, 2.8 mmol.) and HMPA g, 2.8 mmol.) in THF (5 mL) at 0°C. After 15 min, 1,5-dibromopentane (1.53 mL, 11.2 mmol.) was added.
The mixture was then refluxed for 30 min. The solid was filtered off. After the removal of the solvent, the residue was flash chromatographed over silica gel (eluent: ethyl acetate) to give the product in 78% yield (1.1 g) as a yellow oil.
d) 5-Benzyloxycarbonyl-6-(2,4-difluorophenyl)-1,6dihydro-1-(5-(4-methoxycarbonyl-4-phenylpiperidin-lyl)pentyl)-2,4-dimethyl-pyrimidine. A mixture of the above yellow oil (1.62 g, 3.2 mmol.), 4methoxycarbonyl-4-phenyl piperidine (1.4 g, 6.4 mmol.), potassium carbonate (1.76 g, 12.7 mmol.), sodium iodide (0.45 g, 3.0 mmol.) and 1,4-dioxane (15 mL) was refluxed overnight. The undissolved solid was then filtered off and the solvent was evaporated. The residue was flash chromatographed over silica gel (eluent: 80:20 v/v ethyl acetate-2M ammonia in methanol) to give the product in 66% yield (1.36 g) as a yellow oil.
e) 5-Carboxy-6-(2,4-difluorophenyl)-1,6-dihydro-l-(5- (4-methoxycarbonyl-4-phenylpiperidin-l-yl)pentyl)-2,4dimethyl-pyrimidine. A solution of the above yellow oil (0.36 g, 0.56 mmol) in methanol (20 mL) was subjected to hydrogenation with a H 2 balloon in the presence of palladium (36 mg, 5% on The reaction was carried out at room temperature for 30 min. The WO 97/42956 PCT/US97/8335 -146catalyst was then filtered off and the solvent was removed in vacuo to give the product in quantitative yield (0.31 g) as an off-white solid.
f) 6-(2,4-Difluorophenyl)-1,6-dihydro-l-(5-(4methoxycarbonyl-4-phenylpiperidin-l-yl)-pentyl)-2,4- A mixture of the above off-white solid (0.244 g, 0.44 mmol.), 4dimethylaminopyridine (0.26 g, 2.12 mmol.), 1-(3dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.13 g, 0.66 mmol.) and CH 2 Cl 2 (10 mL) was stirred at room temperature for 2 hrs. After the addition of methyl amine hydrogen chloride (0.089 g, 1.32 mmol.), the mixture was stirred at room temperature overnight.
To the mixture was added another 25 mL of CH 2 C1 2 and washed with saturated NH 4 Cl solution. After removal of the solvent, the residue was flash chramotographed over silica gel (eluent: 100:20 v/v ethyl acetate-2M ammonia in methanol) to give the title compound in 22% yield (0.055 g) as a yellow oil. Treatment of the free base with 2 equivalents of 1M HC1 in ether gave the HC1 salt as a pale yellow solid: mp 152-155 0 C. Anal. Calcd. for
C
32 ,HoF 2
N
4 0 3 -2HC1-1.6H 2 0-0.8CHC1 3 C, 51.57; H, 6.07; N, 7.33. Found: C, 51.38; H, 5.91; N, 7.27.
Example 53 (3,4-Difluorophenyl)-1,6-dihydro-5methoxycarbonyl-1-(5-(4-methoxycarbonyl-4phenylpiperidin-l-yl)-4(S)-methyl)pentyl-2,4dimethylpyrimidine a) (S)-(+)-3-Methylpiperidine. A mixture of mandelic acid (45.64 g, 0.3 mol) in ethyl acetate (300 mL) was heated to solution and treated with 3methylpiperidine (29.75 g, 0.3 mol) The mixture was allowed to come to room temperature before filtration.
The crystalline material was washed with 1:1 ethyl acetate-ether (400 mL). Two recrystallizations of this WO 97/42956 PCTfUS97/8335 -147salt from ethyl acetate gave the optically pure salt in 56% yield (21.7 g).
b) -N-Benzoyl-3-methylpiperidine. The above salt (21 g, 0.088 mol) was dissolved in sodium hydroxide solution (1.0 N, 200 mL). The solution was cooled to 3°C, and benzoyl chloride (12.5 g, 0.089 mol) was added dropwise over 10 min. After the addition was complete, the mixture was transferred to a separatory funnel and extracted with ether. The combined extracts were dried (Na 2
SO
4 and concentrated to give the pure amide in 98% yield 17.2 [l]D +45.9 (c 1.00, CHOH).
c) (S)-(-)-2-Methyl-1,5-dibromopentane. To the above amide powder was added phosphorus tribromide (7.81 mL, d 2.85, 0.082 mol) at 5 C over 20 min with vigorous stirring. After the addition, the mixture was warmed to room temperature, and Br 2 (4 mL, 0.082 mol) was added dropwise over 10 min. The mixture was then allowed to stand at room temperature overnight and distilled under vacuum (0.5-1 mm Hg) until the head temperature reached The distillate was dissolved in hexane (100 mL) and washed successively with water (20 mL), concentrated sulfuric acid (4x30 mL), water (20 mL), NaOH solution (IN, 2x40 mL), and water (20 mL). The hexane solution was then dried (Na 2
SO
4 and concentrated to give the product in 31% yield (6.4 g) as a light yellow liquid.
d) l-(5-Bromo-4(S)-methylpentyl)-6(R,S)-(3,4difluorophenyl)-1,6-dihydro-5-methoxycarbonyl-2,4dimethylpyrimidine. To a suspension of NaH (47mg, dispersion in mineral oil, 1.17 mmol.) in THF (3 mL) was added a solution of 6-(3,4-difluoro-phenyl)-1,6dihydro-5-methoxycarbonyl-2,4-dimethylpyrimidine (0.3 g, 1.07 mmol.) and HMPA (0.193 g, 1.07 mmol.) in THF (4 mL) at 0 C. After 10 min, a solution of (-)-2-methyl- WO 97/42956 PCT/US97/08335 -148- (0.86 g, 3.53 mmol.) in THF (5 mL) was added. The mixture was then refluxed for 10 min.
The solid formed was filtered off. After the removal of the solvent, the residue was flash chromatographed over silica gel (eluent: 100:5 v/v ethyl ammonia in methanol) to give the product in 36% yield (0.169 g) as a yellow oil.
e) 6(R,S)-(3,4-Difluorophenyl)-1,6-dihydro-5methoxycarbonyl-l-(5-(4-methoxycarbonyl-4phenylpiperidin-1-yl)-4(S)-methyl)pentyl-2,4dimethylpyrimidine. A mixture of the above yellow oil (0.169 g, 0.38 mmol.), 4-methoxycarbonyl-4-phenyl piperidine (0.167 g, 0.76 mmol.), potassium carbonate (0.21 g, 1.52 mmol.), sodium iodide (0.057 g, 0.38 mmol.) and 1,4-dioxane (8 mL) was refluxed overnight.
The undissolved solid was then filtered off and the solvent was evaporated. The residue was flash chromatographed over silica gel (eluent: 100:5 v/v ethyl acetate-2M ammonia in methanol) to give the title compound in 11% yield (0.025 g) as a yellow oil.
Treatment of the free base with 2 equivalents of 1M HC1 in ether gave the HC1 salt as a light yellow solid: mp 155-158 0 C. Anal. Calcd. for C 33
H
41
F
2
N
3 0 2HC1 0.5H 2 0: C, 59.72; H, 6.64; N, 6.33. Found: C, 59.47; H, 6.66; N, 6.10.
Example 54 6-(3,4-Difuorophenyl) -1,6-dihydro-5-methoxycarbonyl-1- (3-(4-methoxycarbonyl-4-phenylpiperidin-lyl)methyl)benzyl-2,4-dimethylpyrimidine a) 1-(3-Bromomethylbenzyl)-6-(3,4-difluorophenyl)-1,6dihydro-5-methoxycarbonyl-2,4-dimethylpyrimidine. To a suspension of NaH (31 mg, 60% dispersion in mineral oil, 0.77 mmol.) in THF (5 mL) was added a solution of 6-(3,4-difluorophenyl) -1,6-dihydro-5-methoxycarbonyl- 2,4-dimethylpyrimidine (0.3 g, 1.07 mmol.) and HMPA WO 97/42956 PCTIUS97/08335 -149- (0.193 g, 1.07 mmol.) in THEI (5 mL) at 0 0 C. After min, acya-dibromo-m-xylene (0.99 g, 3.75 mmol.-) was added. The mixture was then reflJuxed for 15 min. The solid was filtered off. After the removal of the solvent, the residue was flash chromatographed over silica gel (eluent: ethyl acetate) to give the product in 91% yield (0.45 g) as a yellow oil.
b) 6-(3,4-Difluorophenyl)-1,6-dihydro-5methoxycarbonyl-l- (4-methoxycarbonyl-4-phenyl-4phenylpiper idin 1-yl )me thyl) ben zyl 2 ,4 dime thylpyrimidine.
A mixture of the above yellow oil 45 g, 0. 97 mmol.), 4-methoxycarbonyl-4-phelyl piperidine (0.42 g, 1.9 mmol.) potassium carbonate (0.67 g, 4.86 mmol.) sodium iodide (0.14 g, 0.97 minol.) and 1,4-dioxane tnL) was ref luxed overnight. The undissolved solid was then filtered off and the solvent was evaporated. The residue was flash chromatographed over silica gel (eluent: 100:5 v/v ethyl acetate-2M ammonia in methanol) to give the title compound in 17% yield (0.10 g) as a yellow oil. Treatment of the free base with 2 equivalents of 1M HCl in ether gave the HC1 salt as an off-white solid: mp 181-183 0 C. Anal. Calcd. for
C
3
,H
3
,F
2
N
3 0 4 -2HC -1 .01H 2 0: C, 60.69; H, 5.97; N, 6.07.
Found: C, 60.73; H, 5.77; N, 5.94.
Example 6- 4-Difluorophenyl) 2,4-dimethyl-l-(5-(3-phenylpropylamino)pentyl)pyrimidine A mixture of 1 (5 -bromopentyl) 6- 4 -di fluorophenyl) 1, 6-dihydro-5-methoxycarbonyl-2 ,4-dimethylpyrimidine 186 g, 0. 433 mmcl. 3 -phenyl -1-propylamine 12 g, 0. 89 mmol.) potassium carbonate 3 g, 2.17 mmol.) sodium iodide (70 mg, 0.46 mmcl.) and 1,4-dioxane (8 mL) was ref luxed overnight. The undissolved solid was WO 97/42956 PCT/US97/08335 -150then filtered off and the solvent was evaporated. The residue was flash chromatographed over silica gel (eluent: 100:20:10 v/v/v CHCl 3 -methanol-2M ammonia in methanol) to give the product in 54% yield (0.114 g) as a yellow oil. Treatment of the free base with 2 equivalents of 1M HC1 in ether gave the HC1 salt as a white solid: mp 95-97 0 C. Anal. Calcd. for
C
28 ,HsF 2
N
3 0 2 2HC1-0.5CH 2 C1 2 C, 57.15; H, 6.39; N, 7.02.
Found: C, 57.09; H, 6.65; N, 6.85.
Example 56 (+)-6-(3,4-Difluorophenyl)-1,6-dihydro-l-(4-hydroxy-5- (2-pyridyl)piperidin-1-yl)pentyl)-5-methoxycarbonyl- 2,4-dimethylpyrimidine a) 3-Bromopropylepoxide.
To a solution of 5-bromo-l-pentene (2.15 g, 14.4 mmol.) in CH 2 Cl1 (40 mL) was added MCPBA (3.0 g, 17.3 mmol.) at 0°C slowly. After stirred at room temperature overnight, the mixture was poured into a mixture of ice and 2N NaOH solution. The separated aqueous layer was extracted with CHCl 2 The combined organic layer was then washed with water, brine and dried over Na 2
SO
4 The concentrated mixture was flash chromatographed over silica gel (eluent: CH 2 C1 2 to give the product in 92% yield (2.19 g) as a pale yellow liquid.
b) 1-(4,5-Epoxypentyl)-6-(3,4-difluorophenyl)-1,6dihydro-5-methoxycarbonyl-2,4-dimethylpyrimidine.
To a suspension of NaH (78 mg, 60% dispersion in mineral oil) in THF (10 mL) was added a solution of 6- (3,4-difluorophenyl)-1,6-dihydro-5-methoxycarbonyl-2,4dimethylpyrimidine (0.5 g, 1.78 mmol.) and HMPA (0.3 mL, 1.78 mmol.) in THF (5 mL) at 0°C. After 20 min, the above pale yellow liquid (0.6 g, 3.6 mmol.) was added.
The mixture was then refluxed 2hrs. After the removal of the solvent, the residue was flash chromatographed over silica gel (eluent:100:5 v/v ethyl WO 97/42956 PCTIUS97/08335 -151ammonia in methanol) to give the product in 62% yield (0.4 g) as a yellow oil.
c) 6-(3,4-Difluorophenyl)-1,6-dihydro-l-(4-hydroxy-5- (2 -pyridyl) piperidin-1 ylpentyl) 5 -methoxycarbonyl 2,4-dimethylpyrimidine.
A mixture of the above yellow oil (0.48 g, 1.32 mmol.) 4-(2-pyridyl)piperidine (0.32 g, 1.98 mmol.) and 1,4dioxane (10 mL) was refluxed overnight. The concentrated mixture was then flash chromatographed over silica gel (eluent: 80:20 v/v ethyl ammonia in methanol) to give all four diastereomers in 43% yield (0.3 Chiral HPLC separation gave the title enantiomer which was converted to a HC1 salt: 120.6 (c 0.7, MeOH); mp 163-165 0 C. Anal. Calcd. for
C
29
H
36
F
2 N403-3HC1-0.7CHC1, C, 49.57; H, 5.56; N, 7.79.
Found: C, 49.41; H, 5.96; N, 7.38.
Example 57 6- (3,4-Difluorophenyl) -1,6-dihydro-5-methoxycarbonyl- 2,4-dimethyl-l-(5-(4-(2-pyridyl)piperidin-1-yl)-4oxo)pentyl pyrimidine To a solution of oxalyl chloride (8 mg, 0.06 mmol.) in
CH
2 C1 2 (0.25 mL) was added a solution of DMSO (10 mg, 0.14 mmol.) in CH 2 Cl 2 (0.3 mL) at -78 0 C. After 3 min, a solution of 6-(3,4-difluorophenyl)-1,6-dihydro-l-(4hydroxy-5-(4-(2-pyridyl)-piperidin-1-yl)pentyl)-5methoxycarbonyl-2,4-dimethylpyrimidine (30 mg, 0.057 mmol.) in CH 2 C1 2 (1 mL) was added to the mixture which was stirred for another 15 min. The mixture was treated with triethylamine (0.04 mL) and stirred for another 5 min. Then it was allowed to warm up to room temperature. After the addition of water, it was washed with IN NaOH and water. The organic layer was dried over Na 2
SO
4 and concentrated. The residue was purified by preparative TLC (eluent: 100:20 v/v ethyl acetateammonia in methanol) to give the title compound in WO 97/42956 PCT/US97/08335 -152- 43-0 yield (13 mg) as a yellow oil. Treatment of the f ree base with 3 equivalents of 1M HCl in ether gave the HCl salt as a pale yellow solid: mp 135-137 0
C.
Anal. Calcd. for C 29
H
3 4
F
2
N
4 3 3HC12H 2 0-0.9CH 2 C1 2 C, 48.11; H, 5.78; N, 7.51. Found: C, 47.99; H, 6.08; N, 7.35.
Example 58 (3,4,5-Trifluorophenyl) -3,4-dihydro-5methoxycarbonyl-6-methyl-3- (2 -pyridyl)piperidinl-yl) -pentyl-2 (lH) -pyrimidone a) 3-(5-Bromopentyl)-4-(3,4,5- trifluorophenyl)-3,4dihydro- 5-methoxycarbonyl- 6-methyl -2 (lH) -pyrimidone.
To a suspension of NaH (0.23 g, 6001 dispersion in mineral oil, 5.8 mmol.) in THF (40 mL) was added a solution of 6-(3,4,5-trifluorophenyl-l,6-dihydro-2methoxy 5-methoxycarbonyl -4 -met hyl -pyrimidine (0.6 g, 1. 9 mmol.) and HMPA 33 mL, 1. 9 mmol.) in THF (10 mL) at OO 0 C. After 20 min, 1,5-dibromopentane (1.75 g, 9.4 mmol.) was added. The mixture was then ref luxed for 2 hrs and quenched by water. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, treated with 6N HC1 (10 mL) solution and stirred at room temperature for 1 hr. It was then separated and dried over Na 2
SO
4 After the removal of solvent, the residue was flash chromatographed over silica gel (eluent: 80:20 v/v hexane-ethyl acetate) to give the product in 73% yield (0 .62 g) as a yellow oil.
b) (+)-4-(3,4,5-Trifluorophenyl)-3,4-dihydro-5methoxycarbonyl-6-methyl-3- (2-pyridyl)piperidinl-yl) -pentyl-2 (lH-pyrimidone. A mixture of 3 (5 bromopentyl) (3,4,5-trifluorophenyl) -3,4-dihydro-5methoxycarbonyl-6-methyl-2 (11) -pyrimidone (0.3 g, 0.7 mmol.), 4-(2-pyridyl) piperidine (0.22 g, 1.4 mmol.), potassium carbonate (0.5 g, 3.6 mmol.), sodium iodide (0.1g, 0.7 mmol.) and acetone (20 mL) was refluxed overnight. The undissolved solid was then filtered off WO 97/42956 PCTIUS97/08335 -153and the solvent was evaporated. The residue was f lash chromatographed over silica gel (eluent: 80:20 v/v ethyl acetate-2.OM ammonia in Methanol) to give the racemic product in 85% yield (0.3 g) as a yellow oil.
Chiral HPLC separation afforded the title enantiomer which was converted to a HC1 salt: D 122 (c 4.1, MeOH); MP 125-127 0 C. Anal. Calcd. for
C
2 8
H
3 3
F
3
N
4 0 3 .2HCP2H 2 0-0.2Et 2 O C, 52.86; H, 6.32; N, 8.56.
Found: C, 52.66; H, 6.37; N, 8.15.
E X a m p 1 e 5 9 4- 5-Trifluorophenyl) -3,4-dihydro-5-methoxycarbon yl -6 -methyl 3- (3 (4 2 -pyridyl) piperidin- 1-yl) propylo xycarbonyl) -2 (11) -pyrimidone.
a) 1- (3-Hydroxypropyl) (2-pyridyl)piperidine.
A mixture of 4-C2-pyridyl)piperidine (200 mg, 1.23 mmol), 3-bromopropanol (135 mL, 1.49 mmcl), potassium carbonate (620 mg, 4.49 mmol) and a catalytic amount of sodium iodide in acetone (10 mL) was heated at ref lux overnight. Filtration followed by evaporation of the solvent gave a light brown oil (324 mg) which was dissolved in CHC1 3 and flash chromatographed over silica gel (20 g) eluting with EtOAc/MeOH/Et 3 N (20:1:1) to afford a light brown solid (166 mg, 610-).
b 4- (3,4,5-Trifluorophenyl) -3,4-dihydro-5-methoxycarbon yl 6-methyl 3- (3 (4 (2 -pyridyl) piperidin- 1-yl) propylo xycarbony1) -2 (1H) -pyrimidone.
A mixture of 1- (3-hydroxypropyl) (2-pyridyl) piperidine (72 mg, 0.33 mmol) and 4-(3,4,5trifluorophenyl) -3,4-dihydro-5-methoxycarbonyl-6methyl-3- (4-nitrophenoxycarbonyl) -2 (14) -pyrimidine (152 mg, 0.33 mmol) in dry THF (8 mL) was heated at ref lux overnight. The residue obtained after evaporation of the solvent was dissolved in EtOAc and flash chromatographed over silica gel (18 g) eluting with WO 97/42956 PCT/US97/08335 -154- EtOAc/MeOH/Et 3 N (100:3:3) to afford an off-white solid (133 mg, It was dissolved in CH 2 Cl and treated with 1M HC1 in ether (0.6 mL) to give an off-white solid: mp 154 0 C Anal. Calcd. for
C
27
H
29
F
3
N
4 0 5 -2HC1-2H 2 0: C, 49.47; H, 5.38; N, 8.55. Found: C, 49.48; H, 5.16; N, 8.35.
Example -1,2,3,6-Tetrahydro-l-{N- [4-cyano-4-(phenyl)cycloh ex-1-yl]ethyl}carboxamido-5-methoxy carbonyl-4-methoxy methyl-6-(3,4-difluorophenyl)-2-oxopyrimidine hydrochloride.
a) 2-[4-Cyano-4-(phenyl)cyclohex-l-yl]ethylamine.
A mixture of 4-phenyl-4-cyanocyclohexanone (5.00 g, 25.09 mmol) and ethylenediamine (5.58) and p-toluene sulfonic acid in benzene (200 mL) were refluxed for 4 h in a Dean-Stork set-up to remove the water formed.
Solvent was evaporated and the residue was redissolved in methanol and cooled to 0 oC. To this, sodium borohydride (1.5 g) was added in portions and the mixture was stirred at room temperature for 3 h.
Solvent was evaporated, the residue was dissolved in dichloromethane (300 mL), washed with brine (2 X 200 mL) and dried (sodium sulfate). Solvent was evaporated and the residue was dried under vacuum to leave the product as an oil 5.2 g) The 'H-NMR showed this product to be pure and found to contain the cis/trans isomers in the ratio of about 9:1. It was used as was in the next step.
b) -1,2,3,6-Tetrahydro-l-{N- [4-cyano-4-(phenyl)cycl ohex-1-yl] ethyl}carboxamido-5-methoxycarbonyl-4-methoxy methyl-6-(3,4-difluorophenyl)-2-oxopyrimidine hydrochloride.
Asolutionof (+)-6-(3,4-difluorophenyl)-1,6-dihydro-2methoxy-5-methoxycarbonyl-4-methoxymethyl-1- (4nitrophenoxy)carbonylpyrimidine (0.220 g, 0.448 WO 97/42956 PCTfUS97/08335 -155mmol),2-[4-cyano-4-(phenyl)cyclohex-1-yl]ethylamine (0.130 g, 0.538 mmol) in tetrahydrofuran (100 mL) was stirred at room temperature for 24 hours. The reaction mixture was stirred for another 1 hour after addition of 2 mL of 6N HC1. Solvent was evaporated at reduced pressure and the residue was basified by treatment with aqueous KOH solution, extracted with dichloromethane (3 x 10 mL). The combined extracts were dried over potassium carbonate, and solvent evaporated. The crude product was purified by preparative thinlayer chromatography (dichloromethane:MeOH:2M ammonia in MeOH,90:8:4). The two possible isomer were obtained in the order of less polar compound as the minor product and the more polar compound as the major component (yields: 16 mg minor and 160 mg major isomer). The HC1 salts were obtained by treatment with lN HC1 in ether. The minor isomer HC1 salt:m.p. 124-126 OC; [a]D +112 (c 0.21 g in 100 mL CHC1 3 Anal. Calcd. for C 30
H
34
N
5 sOF 2 C1.0.5 chloroform.
0.5 ether: C, 54.61; H, 5.57; N, 9.80. Found: C, 54.43; H, 5.29; N, 9.54. The major isomer HC1 salt: m.
p. 136-138 OC; [a]D +142 (c 0.21 g in 100 mL CHC1 3 Anal. Calcd. for C 3
,H
34 NsOF 2 ,C1.0.4 chloroform: C, 54.84; H, 5.21; N, 10.52. Found: C, 55.16; H, 5.39; N, 10.42.
WO 97/42956 PCT/US97/8335 -156- General Procedure for the Preparation of 4,4- Diarylpiperidines: A mixture of 0.5 g of 4-aryl-4-hydroxy piperidine, 3 mL of the aromatic substrate, and 1 g of aluminum chloride was stirred at room temperature for 3 days.
The reaction mixture was poured over 10 mL of ice, diluted with t-butyl-methyl ether, the resulting hydrochloride salt was filtered, washed with water and ether, dried, and used in the next step after spectral characterization.
4-Phenyl-4-(4-thiomethoxy-phenyl)-piperidine hydrochloride: From 4-phenyl-4-hydroxy-piperidine and thioanisole Anal. Calc. for C, 1
H
2 lN
I
S,+HC1+0.2H 2 0: C, 66.83; H, 6.98; N, 4.33. Found: C, 66.71; H, 6.81; N, 4.24.
4-(4-Fluorophenyl-4-(4-thiomethoxy-phenyl)-piperidine hydrochloride: From 4-(4-fluoro-phenyl-4-hydroxy-piperidine and thioanisole Anal. Calc. for
C
18
H
20 FNIS+HC1+0.35CH 2 Cl 2 C, 60.14; H, 5.56; N, 3.90.
Found: C, 59.96; H, 5.95; N, 3.81.
4-(4-Fluorophenyl-4-(2-methoxy-5-fluoro-phenyl)piperidine hydrochloride: From 4-(4-fluorophenyl)-4-hydroxy-piperidine and 4fluoroanisole Anal. Calc. for
C
1 ,HigNF 2 O0+HC1+0.2H 2 0: C, 62.96; H, 5.99; N, 4.08.
Found: C, 62.72; H, 6.06; N, 4.06.
Bis-4-(4-Chlorophenyl)-piperidine hydrochloride: From 4-(4-chlorophenyl)-4-hydroxy-piperidine and chlorobenzene Anal. Calc. for ClH 7 ,NiC1,+HC1: C, 59.58; H, 5.29; N, 3.90. Found: C, 59.58; H, 5.28; N, 3.90.
4-Phenyl-4-(4-Hydroxy-phenyl)-piperidine hydrochloride: From 4-phenyl-4-hydroxy-piperidine and phenol General Procedure for the preparation of 4,4-diaryl- N-(3-amino)-propylpiperidines: WO 97/42956 PCT/US97/8335 -157- A mixture of 4,4-diarylpiperidine hydrochloride (0.100 mmol), (3-bromopropyl)-carbamic acid tertbutyl ester (0.100 mmol), diisopropylethylamine (1 mL), and dioxane (2 mL) were heated at reflux temperature for 2 days, cooled, chromatographed (silica prep-TLC plates) to give the BOC protected 4,4-diaryl-N-aminopropylpiperidine.
The BOC protected amine was dissolved in 1:1 TFAdichloromethane, stirred for 6 hours, concentrated in vacuo, and the crude product was chromatographed (silica gel prep-TLC plates) to give 4,4-diaryl-N- (3-amino)propylpiperidines which were used after spectral characterization.
General Procedure for the Preparation of Dihydropyrimidinones: Method A: Reaction of piperidines with bromopropylcarbamoyl-dihydropyrimidinones: A mixture of the 3-{3-bromopropylcarbamoyl}- 4-(3,4-difluoro-phenyl)-6-methyl- 2-oxo-l,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid methyl ester (45 mg, 0.1 mmol) and 0.1 mmol of 4,4diarylpiperidine hydrochloride in a mixture of dioxane-diisopropylethylamine (2-0.5 mL) was heated at reflux temperature for 2 days, cooled, applied to a preparative-TLC plate and eluted with MeOH-EtOAc to give the dihydro-pyrimidine free base as the product. The free.base was dissolved in a minimum of EtOAc and excess 1 N HC1 in ether was added. The product was filtered, washed with ether, and dried.
Example 61: 3-{3-[(4-phenyl)-4-(4-thiomethoxy-phenyl)-piperidin-1 -yl]-propylcarbamoyl}-4-(3,4-difluoro-phenyl)-2-oxo-l,2,3,4-tetr ahydroacid methyl ester WO 97/42956 PCT/~S97/08335 -158hydrochloride.
Prepared by method A. 63% yield. Anal. Calc. for
C
3
,,H
38
N
4
F
2
O
4 S,+HC1+0 2CHC 3 C, 59.62; H, 5.57; N, 7.90.
Found: C, 60.07; H, 6.27; N, 7.40.
Example 62: [(4-phenyl) (4-thiomethoxy-phenyl) -piperidin-1 -ylJ propylcarbamoyl}-4-(3,4-difluorophenyl)-2-oxo-l,2,3,4 acid methyl ester hydrochloride.
Prepared by method A. 63% yield. Anal. Calc. for
C
3
,H,,N
4
F
3 0 4 S+HC1+ether: C, 60.26; H, 6.22; N, 7.21.
Found: C, 60.46; H, 6.58; N, 7.41.
Example 63: 3-{3-[4-(4-Fluorophenyl)-4-(2-methoxy-5-methyl-phenyl )piperidin- 1-yl-propylcarbamoyl)-4-(3,4-difluoro-phenyl)-2-oxo-l ,2,3,4tetrahydropyrimidine- 5-carboxylic acid methyl ester hydrochloride.
Prepared by method A. 63% yield. Anal. Calc. for
C
3 5H 36
N
4
F
4 O+HCl+H 2 O: C, 58.13; H, 5.44; N, 7.75. Found: C, 57.97; H, 5.55; N, 7.31.
Example 64: 3-{3-[Bis-4-(4- Chiorophenyl)piperidin--yl-propylcarbamoyl}- 4-(3,4-difluorophenyl)-2-oxo-1,2,3,4-tetrahydro-pyrim idineacid methyl ester hydrochloride.
Prepared by method A. 71% yield. Anal. Calc. for
C
34
H
34 C1 2
N
4
F
2 0 4 +HCl+ether: C, 58.35; H, 5.80; N, 7.16.
Found: C, 58.23; H, 5.71; N, 7.39.
Example (4-phenyl)-4-(4-hydroxyphenyl)piperidin-l-yllpr opyl-carbamoyl)-4-(3,4-difluorophenyl)-2-oxo-1,2,3,4acid methyl ester hydrochloride.
WO 97/42956 PCTfUS97/08335 -159- Prepared by method A. 63% yield. Anal. Calc. for
C
34
H
3
N
4
F
2 0 1 +HCl+1.4ethanol: C, 61.08; HI, 6.61; N, 7.75. Found: C, 60.86; H, 6.77; N, 7.32.
Method B. Reaction of 4,4-diaryl-J- (3aminopropyl)piperidines with pni trophenylcarbamoyldihydropyrimidinones: Example 66: 3,6 -Dihydro- 5-methoxycarbonyl-4 -methoxymethyl 2-oxo-l-{N- (4,4bis- (4-f luorophenyl) -piperidine-1-yl] propyl )carboxamido 6- (2,3,6 -trifluorophenyl) -pyrimidine dihydrochioride.
a) Methyl 2-methoxyacetyl-3- 3,6trifluorophenyl)acrylate. A mixture of 2,3,6trifluorobenzaldehyde (5.2 g, 33 mmol methyl 4methoxyacetoacetate 5.7 ml, 39 mmcl), and piperidinium acetate (catalytic amount) in benzene ml) was stirred at room temperature for 3 days.
The solvent was evaporated, and the residue was chromatographed on silica gel (hexane/ether 7/1) to yield the title compound (3.4 g, 36%) as a mixture of cis and trans isomers as a colorless oil.
b) 1, 6-dihydro-2-methoxy-5-methoxycarbonyl-4methoxymethyl-6- 6-trifluorophenyl)pyrimidine.
A mixture of methyl 2-methoxyacetyl-3-(2,3,6trifluorophenyl)-acrylate (3,4 g, 11.8 mmcl), 0methylisourea hydrogen hemisulf ate (2.3 g, 16.5 mmcl), and 4-dimethylarninopyridine (32.0 g, 16.5 mmcl) in ethanol (10 ml) was stirred at 65 0 C for 24 hours, cooled and filtered The filtrate was concentrated and chrornatographed on silica gel (hexane/ether to yield the title compound (0.78 g, 20 yield) as a colorless oil.
c) 1, 6-Dihydro-2-methoxy-5-methoxycarbonyl-4methoxymethyl-l- (4-nitrophenyloxy) carbonyl-6- 6-trifluorophenyl) pyrimidine.
WO 97/42956 PCT/US97/08335 -160- To a solution of 1,6-dihydro-2-methoxy-5methoxycarbonyl-4-methoxymethyl-6-(2,3,6-trifluorophenyl)-pyrimidine (0.76 g, 2.2 mmol) and 4dimethylaminopyridine (0.33 g, 2.7 mmol) in CH,C1, ml), at room temperature, was added 4-nitrophenyl chloroformate (0.54 g, 2.7 mmol). The reaction solution was stirred at room temperature for 24 hours. It was filtered. The filtrate was concentrated and chromatographed on silica gel (hexane/ether 2/1) to give the title compound (0.98 g, 87 yield) as a pale yellow solid.
d) 3,6-Dihydro-5-methoxycarbonyl-4-methoxymethyl- 2-oxo-1-{N-[4,4-bis-(4-fluorophenyl)-piperidine-1-yl]-propyl}carboxamido- 6-(2,3,6-trifluorophenyl)-pyrimidine dihydrochloride.
A mixture of 1,6-Dihydro-2-methoxy-5-methoxycarbonyl-4-methoxymethyl-1-(4-nitrophenyloxy)carbonyl-6- (2,3,6-trifluoro-phenyl)pyrimidine (25 mg, 0.05 mmol) and 3-[4,4-bis-(4-fluoro-phenyl)-piperidin-lyl]-propylamine (20 mg, 0.06 mmol) in CH1C1 3 ml was stirred at room temperature for 12 hours. HC1 solution (6 N, 2 ml) was added. The reaction mixture was stirred at room temperature for 6 hour. KOH solution (1 N) was added to neutralize the reaction mixture, and was extracted with CH, 2 C1. The extracts were dried (Na 2 concentrated and the product was chromatographed on prep. TLC (CH 2 C1 2 CH3OH 2 N NH 3 in CH 3 OH 40:2:1) to obtain the title compound (18 mg, 53%) as a colorless oil. The hydrochloride of the title compound was synthesized using HC1 in ether. Calculated for C 3 5H 3 sN04Fs 2.0 HC1: C,55.06%; H,4.63%; N, 7.16%. Found: C,55.34%; H,4.91%; N,7.38%.
Example 67: 3,6 -Dihydro- 5 -methoxycarbonyl-4-methoxymethyl- 2-oxo-l-{N-[4-(4-chloro-phenyl)-4-(5-fluoro-2- WO 97/42956 PCT/US97/08335 -161methoxy-phenyl) -piperidine-1 -yl -propyl}carboxamido- 6-(3,5-difluorophenyl)-pyrimidine dihydrochloride.
a) Methyl 2-methoxyacetyl-3-(3,5-difluoro-phenyl)acrylate.
A mixture of 3,5-difluorobenzaldehyde (10.g, 70 mmol methyl 4-methoxyacetoacetate 11 ml, 80 mmol), and piperidinium acetate (catalytical amount) in benzene (100 ml) was stirred at room temperature for 3 days. The solvent was evaporated, and the residue was chromatographed on silica gel (hexane/ether 5/1) to give the cis and trans mixture of the title compound (3.7 g, 20% yield) as a yellow oil b) 1,6-dihydro-2-methoxy-5-methoxycarbonyl-4methoxymethyl-6-(3,5-difluoro-phenyl)-pyrimidine.
A mixture of methyl 2-methoxyacetyl-3-(3,5difluoro-phenyl)-acrylate (3.74 g, 13.8 mmol), 0methylisourea hydrogen hemisulfate (2.68 g, 19.4 mmol), and 4-dimethylaminopyridine (2.37 g, 19.4 mmol) in ethanol (30 ml) was stirred at 65 oC for 2 days, cooled and filtered The filtrate was concentrated and chromatographed on silica gel (hexane/ether 3/1) to get the title compound (1.7 g, 38 yield) as a yellow solid.
c) 1,6-Dihydro-2-methoxy-5-methoxycarbonyl-4methoxymethyl-1- (4-nitrophenyloxy)carbonyl-6-(3,5-difluorophenyl)-pyr imidine.
To a solution of 1,6-dihydro-2-methoxy-5methoxycarbonyl-4-methoxymethyl-6-(3,5difluorophenyl)pyrimidine (1.67 g, 5.10 mmol) and 4dimethylaminopyridine (0.75 g, 6.1 mmol) in CH2Cl 2 ml), at room temperature, was added 4-nitrophenyl chloroformate (1.24 g, 6.1 mmol). The reaction solution was stirred at room temperature for 24 hours, and filtered. The filtrate was concentrated and chromatographed on silica gel (hexane/ether 2/1) to yield the title compound (1.82 g, 72 yield) WO 97/42956 PCTIUS97/8335 -162as a white solid.
d) 3,6 -Dihydro- 5-methoxycarbonyl -4 -methoxymethyl- 2-oxo-1-{N-[4-(4-chioro-phenyl)-4-(5-fluoro-2methoxy-phenyl)-piperidine-l-ylJ-propyl)carboxamido- 6-(3,5-difluorophenyl)-pyrimidine dihydrochioride.
A mixture of 1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-methoxymethyl-l-(4-nitrophenyloxy)carbonyl-6-(3,5-difluorophenyl)pyrimidine (25 mg, 0.050 mmol) and chioro-phenyl)-4-(5-fJuoro-2-methoxy-phenyl)piperidin-1-yl)-propylamine (23 mg, 0.060 mmcl) in
CH
2 C1 2 3 ml was stirred at room temperature for 12 hours. HCl solution (6 N, 2 ml) was added. The reaction mixture was stirred at room temperature for 6 hour. KOH solution (1 N) was added to neutralize the reaction mixture, and extracted with CH 2 Cl 2 The extracts were dried (Na 2
SO
4 concentrated and chromatographed on prep. TLC CH 2 C1 2
CH
3 OH 2 N NH3 in CH 3 OH 40:2:1) to give the title compound (18 mg, 50%) as a colorless oil. The hydrochloride of the title compound was synthesized using HCl in ether.
Anal. Calculated for C 36
H
3 ,C1N 4 0,F 3 1.0 HC1 CHCl 3 C, 54.45%; H,4.68%; N,6.36%. Found: C, 54.04%; H, 4.91%; N, 6.91%.
Example 68: (+)-1-(5-(4-Cyano-4-phenylpiperidin-1-yl)-4(S)methyl)pentyl-6-(3,4-difluorophenyl)-1,6-dihydro-5- (methoxycarbonyl)-4-methyl-2-pyrimidine.
a) -l-(5-Bromo-4 -methyl)pentyl-6-(3,4difluorophenyl)-1,6-dihydro-5-methoxycarbonyl-4methyl-2-pyrimidone.
To a suspension of NaH (18 mg, 60% dispersion in mineral oil, 0.45 mmcl.) in TEF (5 mL) was added a solution of (+)-6-(3,4-difluorophenyl-l,6-dihydro-2methoxy-5-methoxycarbonyl-4-methyl-pyrimidine (0.12 g, 0.4 mmcl.) and HMPA (0.07 mL, 0.4 mmcl.) in THF mL) at 0 0 C. After 20 min, 2(S)-methyl-1,5- WO 97/42956 PCT/US97/08335 -163dibromopentane (0.2 mg, 0.82 mmol.) was added. The reaction mixture was then refluxed for 2 h and quenched by water. It was partitioned bewteen ethyl acetate and water. The organic layer was separated, treated with 6N HC1 (5 mL) solution and stirred at room temperature for 1 h. The organic layer was then separated and dried over Na 2
SO
4 After the removal of solvent, the residue was flash chromatographed over silica gel (eluent: 1:1 hexane/ethyl acetate) to give the product in 81% yield (0.15 g) as a yellow oil.
b) (+)-1-(5-(4-Cyano-4-phenylpiperidin-l-yl)-4(S)methyl)pentyl-6-(3,4-difluorophenyl)-1,6-dihydro-5- (methoxycarbonyl)-4-methyl-2-pyrimidone.
A mixture of (+)-l-(5-Bromo-4(S)-methyl)pentyl-6- (3,4-difluorophenyl)-1,6-dihydro-5-methoxycarbonyl-4methyl-2-pyrimidone (0.138g, 0.31 mmol.), 4-cyano-4phenylpiperidine hydrochloride (0.138 g, 0.62 mmol.), potassium carbonate (0.22 g, 1.6 mmol.), sodium iodide (47 mg, 0.31 mmol.) and dioxane (8 mL) was refluxed overnight. The undissolved solid was then filtered off and the solvent was evaparated. The residue was purified by flash chromatographed over silica gel (eluent: ethyl acetate) to give the product in 18% yield (0.030 g) as a yellow oil.
Treatment of the free base with one equivalent of 1M HC1 in ether gave the HC1 salt as a light yellow solid: mp 133-135 0 C; [a]D 87.4 (1.75 mg/mL, MeOH) Anal. Calc. for Cz 3
H
36
F
2
N
4 0 3 .HCl.0.3CHC 3 1: C, 60.35; H, 6.04; N, 8.99. Found: C, 60.26; H, 6.29; N, 8.67.
Example 69: (+)-1-(5-(4-(2-Aminocarbonyl)phenylpiperazin-1-yl) 4(S)-methyl)pentyl-6-(3,4-difluorophenyl) -1,6dihydro-5-methoxy-carbonyl-4-methyl-2-pyrimidone.
A mixture 1-(5-bromo-4(S)-methyl)pentyl-6-(3,4difluorophenyl)-1,6-dihydro-5-methoxycarbonyl-4methyl-2-pyrimidone (0.lg, 0.22 mmol.), 4-(2aminocarbonylphenyl)piperazine (0.070 g, 0.34 mmol.), WO 97/42956 PCTIUS97/08335 -164potassium carbonate (0.16 g, 1.2 mmol.), sodium iodide (33 mg, 0.22 mmol.) and dioxane (8 mL) was refluxed overnight. The undissolved solid was then filtered off and the solvent was evaparated. The residue was purified by flash chromatographed over silica gel (eluent: 20:1 ethyl acetate/2M ammonia in methanol) to give the product in 41% yield (0.052 g) as a yellow oil. Treatment of the free base with one equivalent of IM HC1 in ether gave the HC1 salt as a pale yellow solid: mp 168-171°C; 83.5 (2 mg/mL, MeOH). Anal. Calc. for C 30
H
3
,F
2
N
5 sO42HC1-0.5CH 2 C12: C, 53.48; H, 5.89; N, 10.22. Found: C, 53.74; H, 5.94; N, 9.99.
Example 1-(5-(4-Cyano-4-phenyl)piperidin-1-yl)pentyl-6-(3,4difluoro-phenyl) -1,6-dihydro-5-methoxycarbonyl-2methoxymethyl-4-methyl-pyrimidine.
a) 6-(3,4-Difluorophenyl)-1,6-dihydro-5methoxycarbonyl-2-methoxy-methyl-4-methylpyrimidine.
To a solution of 2-methoxyacetamidine hydrochloride (1.4 g, 11.2 mmol.) in DMF (6 mL) were added a solution of potassium tert-butoxide (0.69 g, 6.1 mmol.) in DMF (6 mL) and a solution of methyl {2- (3,4-difluorophenyl) methylene}-3-oxobutanoate (1.4 g, 5.8 mmol.) in DMF (6 mL) at 0°C. After the mixture was stirred for 0.5 hr at 0°C, p-toluenesulfonic acid monohydrate (2.2 g, 11.6 mmol.) was added. The mixture was heated at 100-120 0 C for 2.5 hrs. The mixture was cooled to room temperature, quenched with aqueous NaOH solution (2N, 30 mL), and extracted with ether. The organic layer was dried over Na 2 SO, and evaporated. The residue was flash chromatographed over silica gel (eluent: ethyl acetate) to give the product in 44% yield (0.8 g) as a yellow oil.
b) l-(5-Bromopentyl)-6-(3,4-difluorophenyl)-1,6dihydro- 5 -methoxycarbonyl- 2 -methoxymethyl -4methylpyrimidine.
WO 97/42956 PCT/US97/08335 -165- To a suspension of NaH (0.11 g, 60% dispersion in mineral oil, 2.8 mmol.) in THF (20 mL) was added a solution of 6-(3,4-difluorophenyl)-1,6-dihydro-5methoxycarbonyl-2-methoxymethyl-4-methylpyrimidine (0.8 g, 2.6 mmol.) in THF (5 mL) at 0C. After 20 min, (0.7 mL, 5.2 mmol.) was added. The mixture was then refluxed overnight. After the removal of solvent, the residue was flash chromatographed over silica gel (eluent: ethyl acetate) to give the product in quantitative yield (1.2 g) as a yellow oil.
c) 1-(5-(4-Cyano-4-phenyl)piperidin-1-yl)pentyl-6- (3,4-difluorophenyl)-1,6-dihydro-5-methoxycarbonyl-2methoxymethyl-4-methylpyrimidine.
A mixture of 1-(5-bromopentyl)-6-(3,4difluorophenyl)-1,6-dihydro-5-methoxycarbonyl-2methoxymethyl-4-methylpyrimidine (0.15 g, 0.33 mmol.), 4-cyano-4-phenylpiperidine hydrochloride (0.15 g, 0.67 mmol.), potassium carbonate (0.23 g, 1.7 mmol.), sodium iodide (50 mg, 0.33 mmol.) and acetone (6 mL) was refluxed overnight. The undissolved solid was then filtered off and the solvent was evaporated. The residue was flash chromatographed over silica gel (eluent: 10:1 ethyl acetate/2M ammonia in methanol) to give the title compound in 44% yield (0.080 g) as a yellow oil.
Treatment of the free base with 2 equivalents of 1M HC1 in ether gave the HC1 salt as an off-white solid: mp 98-101°C. Anal. Calc. for C 32
H
38
F
2
N
4 0 3 -2HC1 1.1CHC1 3 C, 51.70; H, 5.39; N, 7.29. Found: C, 51.56; H, 5.52; N, 7.27.
Example 71: (+)-6-(3,4-Difluorophenyl)-16-dihydro-5methoxycarbonyl-2,4-dimethyl-l- (4(S)-methyl-5-(4- (2methylphenyl)-4-(4-methyl-phenyl)piperidin-1yl)pentyl)pyrimidine.
a) (+)--(5-Bromo-4(S)-methylpentyl)-6-(3,4- WO 97/42956 PCT/US97/08335 -166difluorophenyl)-1,6-dihydro-5-methoxycarbonyl-2,4dimethylpyrimidine.
To a suspension of NaH (47 mg, 60% dispersion in mineral oil, 1.17 mmol.) in THF (3 mL) was added a solution of 6-(3,4-difluorophenyl)-l,6-dihydro-5methoxycarbonyl-2,4-dimethyl-pyrimidine (0.3 g, 1.07 mmol.) and HMPA (0.193 g, 1.07 mmol.) in THF (4 mL) at 0°C. After 10 min, a solution of (-)-2-methyl-1,5dibromopentane (0.86 g, 3.53 mmol.) in THF (5 mL) was added. The reaction mixture was then refluxed for min. The solid formed was filtered off. After the removal of solvent, the residue was flash chromatographed over silica gel (eluent: 20:1 ethyl acetate/2M ammonia in methanol) to give the product in 36% yield (0.169 g) as a yellow oil. Chiral HPLC separation of the above diastereomers (Column: Chiralcel OD 20 x 250 mm. Eluent: 2propanol/hexane/diethylamine 10:90:0.1) gave the desired enantiomer: 200.9 (25.5 mg/mL, CH 2 C1 2 b) (+)-6-(3,4-Difluorophenyl)-1,6-dihydro-5methoxycarbonyl-2,4-dimethyl-l-(4(S)-methyl-5-(4-(2methylphenyl)-4-(4-methyl-phenyl)piperidin-lyl)pentyl)pyrimidine.
A mixture of (+)-1-(5-bromo-4(S)-methylpentyl)-6- (3,4-difluorophenyl)-1,6-dihydro-5-methoxycarbonyl- 2,4-dimethyl-pyrimidine (0.1 g, 0.23 mmol.), 4-(2methylphenyl)-4-(4-methylphenyl)piperidine hydrochloride (0.08 g, 0.26 mmol.), potassium carbonate (0.18 g, 1.3 mmol.), sodium iodide (0.033 g, 0.26 mmol.) and acetone (8 mL) was refluxed overnight. The undissolved solid was then filtered off and the solvent was evaporated. The residue was flash chromatographed over silica gel (eluent: 10:1 ethyl acetate/2M ammonia in methanol) to give the title compound in 64% yield (0.090 g) as a yellow oil. Treatment of the free base with 2 equivalents of 1M HC1 in ether gave the HC1 salt as a light WO 97/42956 PCT/US97/08335 -167yellow solid: rnp 130-133 0 C; D 62.4 (1.85 mg/mL, MeOH) Anal. Caic. for C 39
H
4
F
2
N
3 0 2 2HC12H 2 0-0.65CHCl 3 C, 58.48; H, 6.64; N, 5.16. Found: C, 58.27; H, 6.46; N, 5.40.
Examnple 72: (3,4-Difluorophenyl) -1,6-dihydro-5methoxycarbonyl-2-methoxymethyl-4-methyl-l- (2methyiphenyl) (4-methyl -phenyl) piperidin- 1yl) pentyl) pyrimidine.
a) (+)-1-(5-Bromopentyl)-6-(3,4-difJuorophenyl)-1,6dihydro- 5-methoxycarbonyl -2 -methoxymethyl -4methylpyrimidine.
To a suspension of NaH (0.11 g, 60% dispersion in mineral oil, 2.8 mmol.) in THF (20 mL) was added a solution of 6- (3,4-difluorophenyl) methoxycarbonyl -2 -methoxymethyl -4 -methylpyrimidine (0.8 g, 2.6 mmol.) in THF (5 niL) at 0 0 C. After min., 1,5-dibromopentane (0.7 rnL, 5.2 mmcl.) was added. The mixture was then ref luxed overnight. After the removal of the solvent, the residue was flash chromatographed over silica gel (eluent: ethyl acetate) to give the product in quantitative yield (1.2 g) as a yellow oil. Chiral HPLC separation (Column: Chiralcel OD 20 x 250 mm. Eluent: 2propanol/hexane/diethylamine 10:90:0.1) gave the title enantiomer: [a]ID 190.5 (55 mg/mL, CH 2 Cl 2 b) (3,4-Difluorophenyl) methoxycarbonyl-2-methoxymethyj.-4-methyl-1- (2methyiphenyl) (4-methyl -phenyl) piperidin-1 yl) pentyl)pyrimidine.
A mixture of (+)-l-(5-bromopentyl)-6-(3,4difluorophenyl) 6-dihydro-5-methoxycarbonyl-2methoxymethyl-4-methylpyrimidine (0.08 g, 0.17 mmol.), 4-(2-methylphenyl)-4-(4methylphenyl)piperidine hydrochloride (0.063 g, 0.21 mmcl.), potassium carbonate (0.14 g, 1.0 mmcl.), sodium iodide (26 mg, 0.17 mmol.) and acetone (6 mL) WO 97/42956 PCT/US97/08335 -168was refluxed overnight. The undissolved solid was then filtered off and the solvent was evaporated.
The residue was flash chromatographed over silica gel (eluent:.10:1 ethyl acetate/2M ammonia in methanol) to give the title compound in 89% yield (0.1 g) as a yellow oil. Treatment of the free base with 2 equivalents of 1M HC1 in ether gave the HC1 salt as a pale yellow solid: mp 137-140°C; [a]D 56.5 (1.65 mg/mL, MeOH). Anal. Calc. for
C
39
H
4
,F
2
N
3 0 3 -2HC1-2H 2 0-0.75CHC13: C, 56.68; H, 6.43; N, 4.99. Found: C, 56.55; H, 6.19; N, 5.02.
Example 73: (+)-1,2,3,6-Tetrahydro-l-{N-[3-(4,4diphenylpiperidin-l-yl)propyl] }carboxamido-5-methoxycarbonyl-2-oxo-6-(3,4difluoro-phenyl)-4-methoxymethylpyrimidine hydrochloride.
A solution of (+)-6-(3,4-difluorophenyl)-1,2,3,6tetrahydro-2-oxo-5-methoxycarbonyl-4-methoxymethyl-1- (4-nitrophenoxy)-carbonylpyrimidine (0.160 g) and 3- (4,4-diphenyl-piperidin-1-yl)propylamine(0.150 g) in tetrahydrofuran (10 mL) was stirred at room temperature for 14 hours. The product was purified by preparative thin layer chromatography on silica gel using ethyl aceate as eluent to give 0.22 g of the product as a syrup, which was converted to the hydrochloride salt by treatment with IN HC1 in ether; m.p. 178-181 oC; [a]D +99.6 (c 0.24, MeOH) Anal.
Calcd. for C 35
H
39 C1F 2
N
4 0s.0.2CH 2 C1 2 C, 60.93; H, 5.74; N, 8.06. Found: C, 60.73; H, 5.89; N, 7.92.
Example 74: (±)-1,2,3,6-Tetrahydro-l-(N-[3-(4,4diphenylpiperidinl-yl) propyl]}carboxamido-5-acetyl-2-oxo-6-(3, 4 5 trifluorophenyl)-4-methylpyrimidine dihydrochloride.
A mixture of 6-(3,4,5-difluorophenyl)- 1,2,3,6-tetrahydro-2-oxo- WO 97/42956 PCT/tJS97/08335 -169- 5-acetyl-4-methyl-l-[(4-nitrophenyloxy)carbonyl]pyrim idine (0.150 g)-and 3-(4,4diphenylpiperidin-l-yl)propylamine(0.180 g) in THF mL) was stirred at room temperature for 14 h. The product was purified by preparative thin layer chromatography on silica gel using ethyl aceate as eluent to give 0.23 g of the product as a syrup, which was converted to the hydrochloride salt by treatment with 1N HCl in ether; n.p. 180-182 OC.
Anal. Calcd. for C 34
H
36 C1F 3 N,0 3 .1CH 2 Cl 2 C, 57.90; H, 5.28; N, 7.72. Found: C, 57.54; H, 5.10; N, 7.79.
Example (±)-1,2,3,6-Tetrahydro-l-{N-[3- (4-(2-methyiphenyl) -4- (4methyiphenyl)piperidin-l-yl)-propyl] etyl-2-oxo-6- (3,4,5-trifluorophenyl)-4-methylpyrimidine hydrochloride.
A mixture of 6- (3,4,5-difluorophenyl) 1,2,3,6-tetrahydro-2-oxo- 5-acetyl-4-methyl-l-[(4-nitrophenyloxy)carbonyllpyrim idine (0.02 g) and 3-[4-(2-methylphenyl)-4-(4methylphenyl)-piperidin-1-yll-propylamine(0.02 g) in THF (1 mL) was stirred at room temperature for 14 h.
The product was purified by preparative thinlayer chromatography on silica gel using ethyl aceate as eluent to give 0.03 g of the product as a syrup, which was converted tothe hydrochloride salt by treatment with 1N HCl in ether; m.p. 180-184 OC.
Anal. Calcd. for C 36 H,C1F 3 N 0 3 .0.4CH 2 C1 2 C, 62.18; H, 5.85; N, 7.97. Found: C, 62.42; H, 6.00; N, 7.88.
Example 76: (3,4-Difluorophenyl-l- [4-cyano-4-phenylpiperidin-l-yl- 2,2-difluoropropylcarboxamido 4-methoxymethyl-2-oxo-l,2,3,6-tetrahydro-pyrimidine.
a) 3- [4-Cyano-4-phenyl-piperidin-l-ylJ (2- WO 97/42956 PCT/US97/08335 -170hydroxypropyl)-phthalimide.
A mixture of 4-cyano-4-phenylpiperidine (10 g, 44.9 mmol) and 2,3-epoxypropylphthalimide (10.94 g, 53.9 mmol) in DMF (100 mL) was stirred and heated at 70 °C for 72 h. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using chloroformmethanol-2M ammonia in methanol (1000/28/14) as the eluent, to obtain the desired product as a viscous oil (16.45 g, 86%).
b) 3-[4-Cyano-4-phenyl-piperidin-l-yl](2oxopropyl)phthalimide.
To a stirred solution of DMSO (3.6 mL, 51.07 mmol) in dichloromethane (100 mL) at -78 oC, oxalyl chloride (2.18 mL, 24.5 mmol) in dichloromethane (15 mL) was added and the mixture was stirred for 3 min. To this, a solution of 3-[4-cyano-4-phenylpiperidin-1-yl](2-hydroxypropyl)phthalimide (8.70 g, 20.42 mmol) in dichloromethane (25 mL) was added and the stirring was continued for 15 min. It was warmed to room temperature and added 5 mL of water.
The pH of the mixture was adjusted to 10-11 by adding IN NaOH and the dichloromethane layer was separated.
The aqueous layer was extracted with more dichloromethane (3 X 100 mL). The combined dichloromethane extracts were dried (magnesium sulfate), solvents evaporated, and the residue was purified by flash chromatography on silica gel using ethyl acetate/hexane as eluent (6.05 g, c) 3-[4-Cyano-4-phenyl-piperidin-l-yl](2,2difluoropropyl)-phthalimide.
To a well stirred solution of 3-[4-cyano-4-phenylpiperidin-l-yl]-(2-oxopropyl)phthalimide (0.22 g, 0.52 mmol) in anhydrous dichloromethane (25 mL) at 78 0 C, under argon atmosphere was added diethyaminosulfur trifluoride (DAST) (0.251 mg, 1.56 mmol) and the mixture was allowed to warm to room WO 97/42956 PCT/US97/08335 -171temperature. After 36 h, the reaction mixture was cooled to 0-5 oC and to this saturated sodium bicarbonate solution (20 mL) was added cautiously.
The dichloromethane layer was separated, dried (sodium sulfate), and the solvent was evaporated.
The product was purified by flash column chromatography on silica gel using 30% ethyl acetate in hexanes as eluent (80 mg, 'H-NMR was in agreement with the product.
d) 3- [4-Cyano-4-phenylpiperidin-1-yl] (2,2difluoro)propylamine.
A mixture of 3-[4-cyano-4-phenyl-piperidin-l-yl] (2,2difluoro-propyl)phthalimide (120 mg, 0.29 mmol) and hydrazine (0.5 mL g) in methanol (15 mL) was stirred and refluxed for 4.5 h. It was cooled, filtered, and the solid was washed with methanol (30 mL).
Evaporation of solvent from the filtrate gave the product as a viscous oil (60 mg, 73%) which was used in the next step without any further purification.
e) (+)-6-(3,4-Difluorophenyl-l-[{N-[4-cyano-4-phenylpiperidin-1-yl] -2,2-difluoropropyl}-carboxamido]- -methoxycarbonyl-4-methoxymethyl-2-oxo- 1,2,3,6-tetrahydro-pyrimidine.
A solution of (+)-5-methoxycarbonyl-4-methoxymethyl- 1,2,3,6-tetrahydro-2-oxo-6-(3,4-difluorophenyl)-1- [(4-nitrophenyloxy)-carbonyl]pyrimidine (38 mg, 0.077 mmol) and 3-[4-cyano-4-phenyl-piperidin-l-yl] (2,2difluoropropyl)propylamine (30 mg, 0.107 mmol) in dichloromethane (3 mL) was stirred at room temperature for 12 hours. The mixture was purified by preparative tlc on silica gel (60% ethyl acetate in hexanes) to give 38 mg as a white powder.
The HC1 salt was prepared by treatment of a solution of the free base in ether with lN HC1 in ether. The white powder was dried and recrystallized from anhydrous 2-propanol. M.P. 184-186 OC; [a]D +96.36 (c 0.55, dichloromethane). Anal. Calcd. for WO 97/42956 PCT/US97/08335 -172-
C
3 oH 32 NsOF 4 Cl:C, 55.12; H, 4.87; N, 9.95. Found: C, 55.09; H; 4.93; N, 9.71.
Example 77: (+)-l,2,3,6-Tetrahydro-l-{N- [4-(4-methoxycarbonyl-4phenylyl-2oxo-6-(3,4,5-trifluorophenyl)-4-methoxymethylpyrimidi ne hydrochloride.
a) l-Benzyl-4-(4-Methoxycarbonyl-4phenylpiperidinl-yl)-piperidine.
A mixture of 4-methoxycarbonyl-4-phenylpiperidine (6.50 g, 0.0296 mol), N-benzyl-4-piperidone (5.62 g), and p-toluenesulfonic acid (100 mg) in benzene (100 mL) was heated at 110 oC for 14 h with a Dean-Stark trap to remove the water that formed. Solvent was evaporated and the residue was redissolved in methanol (20 mL). To this, sodium cyanoborohydride (1.86 g) was added in portions and the mixture was stirred at room temperature for 6 h. Solvent was evaporated, the residue was mixed with 1N NaOH mL) and the resultant mixture was extracted with ether (4 X 20 mL). The combined extracts were washed with brine (20 mL), dried (sodium sulfate), and the solvent evaporated. The residue was purified by column chromatography on silica gel using dichloromethane/methanol/2M ammonia in methanol (50/20/10) as eluent. The product was obtained as a viscous oil which on trituration with hexane became a white powder.
b) 4-(4-Methoxycarbonyl-4phenylpiperidin-1-yl)-piperidine.
A mixture of 1-benzyl-4-(4-Methoxycarbonyl-4phenylpiperidin-1-yl)piperidine (3.92 g) and 10% Pd-C (0.4 g) in ethanol (200 mL) was hydrogenated at psi for 12h. The catalyst was removed by filtration and the solvent was evaporated from the filtrate to WO 97/42956 PCTIUS97/08335 -173leave the product (2.9 g, 96%) as a white powder.
c) (+)-l,2,3,6-Tetrahydro-l-{N- (4-methoxycarbonyl- 4 -phenyl piperidin-l-yl) -piperidinyll)}carbonyl- yl-2-oxo-6trifluorophenyl) -4-methoxymethylpyrimidine hydrochloride.
A solution of (+)-6-(3,4,5-trifluorophenyl)-l,2,3,6tetrahydro-2-oxo-5-methoxycarbonyl-4 -methoxymethyl- 1- (4-nitrophenoxy)-carbonylpyrimidine (50 mg, prepared similarly to (+)-6-(3,4-difluorophenyl)-l,2,3,6tetrahydro-2-oxo-5-rnethoxycarbonyl-4 -methoxy-methyl- 1- (4 -nitrophenoxy) carbonylpyrimidine) and 4- (4methoxycarbonyl-4-phenylpiperidin-l-yl) piperidine mg) in THF (2 mL) was stirred at room temperature for 14 hours. The product was purified by preparative thin layer chromatography on silica gel using ethyl aceate as eluent to give 70 mg of the product as a syrup, which was converted to the hydrochloride salt by treatment with 1N HCl in ether; rn.p. 178-181 OC; IUD= +135 (c 0.65, MeOl) Anal. Calcd. for
C
35
H
38 C1F 3
N
4 07.0.4CH 2 C1 2 C, 55.02; H, 5.36; N, 7.68.
Found: C, 55.22; H, 5.48; N, 7.56.
Example 78: -l,2,3,6-Tetrahydro-l-{N- 12- (4-phenyl-4methoxycarbonyl) -piperidin- l-yl) ethyl] )acetamido- me thoxycarbonyl -2 -oxo -6 (3,4 -difluorophenyl) -4 -methylpyrimidine hydrochloride.
a) 6-Tetrahydro-l-{bezyJ.oxycarbonylmethyl) methoxycarbonyl-2-oxo-6- 4-difluorophenyl) -4-methylpyrimid mne.
A mixture of (+)-1,6-dihydro-5methoxycarbonyl -2 -methoxy- 6- (3,4-difluorophenyl) -4-methylpyritnidine (0.296 g), WO 97/42956 PCT/U~S97/08335 -174benzyl bromoacetate (0.229 potassium carbonate (0.600 and potassium iodide (30 mg) in acetone mL) was heated under reflux for 14 h. It was filtered, washed with acetone (15 mL). To the combined filtrates 6N HC1 (0.5 mL) was added and stirred for 4 h. Solvent was evaporated and the product was purified by preparative thin layer chromatography on silica gel using hexane/ethyl acetate to give the product as a foam (0.20 g) which was used in the next step without further characterization.
b) (+)-l,2,3,6-Tetrahydro-5-methoxycarbonyl-2-oxo- 6-(3,4-difluorophenyl)-4-methylpyrimidine-l-acetic acid.
To a suspension of 10% Pd-C (20 mg) in MeOH (10 mL) and H 2 0 (2 mL) was added a solution of (+)-1,2,3,6-tetrahydro-l-(benzyloxy-carbonylmethyl)- 5-methoxycarbonyl-2-oxo-6-(3,4-difluorophenyl)- 4-methylpyrimidine (200 mg) in methanol (1 mL) and the mixture was hydrogenated at 80 psi for 4 h. The black suspension was filtered through a pad of Celite and washed thoroughly with MeOH (100 mL). Solvent was evaporated from the combined filtrate to yield the product (+)-1,2,3,6-tetrahydro-1-5methoxycarbonyl-2-oxo-6- (3,4-difluorophenyl)-4-methylpyrimidine-l-acetic acid as a white solid (0.15 It was used in the next step without further purification.
c) (+)-l,2,3,6-Tetrahydro-1-{N-[2-(4-phenyl-4methoxycarbonyl-2-oxo- 6-(3,4-difluorophenyl)-4-methylpyrimidine hydrochloride.
A mixture of (+)-1,2,3,6-tetrahydro-l-5methoxycarbonyl-2-oxo- 6-(3,4-difluorophenyl)-4-methylpyrimidine-l-acetic acid (20 mg), 2-(4-phenyl-4- WO 97/42956 PCT/US97/08335 -175methoxycarbonyl)piperidin-l-yl)ethylamine (20 mg), 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (20 mg), and 4-(N,Ndimethylamino)pyridine (20 mg) in anhydrous dichloromethane (4 mL) was stirred at room temperature for 12 h. The reaction mixture was purified by preparative thin layer chromatography on silica gel using ethyl acetate as the eluent. The product was dissolved in ether (0.5 mL), cooled to 0- 5 oC and treated with IN HCI in ether (10 mL) and the solvents evaporated to leave the product as a white powder (25 mg); mp 247-250OC; [o]D +108.2 (c 0.50, MeOH). Anal. Calcd. for C 30
H
3 5N 4 0 6
F
2 C1: C, 58.02; H, 5.68; N, 9.02. Found: C, 58.21; H; 5.70; N, 8.92.
Example 79: 1,6-Dihydro-l-{N-[2-(4-phenyl-4methoxycarbonyl)piperidin-l-yl) -ethyl] methoxycarbonyl-6-(3,4,5-trifluorophenyl)- 2,4-dimethylpyrimidine dihydrochloride.
a) 6-(3,4,5-trifluorophenyl)-1,6-dihydro-5methoxycarbonyl-2,4-dimethylpyrimidine.
To a solution of acetamidine hydrochloride (1.41 g, 14.9 mmol.) In DMF (10 mL) was added a solution of potassium tert-butoxide (12 mL, 1.0 M in THF at 0°C.
After stirred for 10 minutes, a solution of methyl {2-(3,4,5-trifluorophenyl)methylene}-3-oxobutanoate (2.10 g, 10.0 mmol) in DMF (10 mL) was added and the mixture was stirred for 2 hours while warmed up to room temperature. p-Toluenesulfonic acid monohydrate (4.50 g, 23.6 mmol) was added to the solution and the reaction mixture was heated at 110-120 OC for 2 hours.
The mixture was cooled to room temperature and poured into ice (100 g) and aqueous NaOH solution (3 N, 200 mL), and extracted with ether (3x100 mL). The organic layers were combined, dried (K 2
CO
3 and evaporated.
The residue was purified by flash chromatography over silica gel (eluent: 10-15% MeOH in methylene WO 97/42956 PCT/US97/08335 -176chloride) to afford the product in 47% yield 1.4 g )as an oil.
b) 1,6-Dihydro-l-{bezyloxycarbonylmethyl)-5methoxycarbonyl- 6-(3,4,5-trifluorophenyl)-2,4-dimethylpyrimidine. A mixture of 1,6-dihydro-5methoxycarbonyl-6-(3,4,5-trifluorophenyl)- 2,4-dimethylpyrimidine (0.298 benzyl bromoacetate (0.229 potassium carbonate (0.600 and potassium iodide (30 mg) in acetone (20 mL) was heated under reflux for 14 h. It was filtered, washed with acetone (15 mL). Solvent was evaporated and the product was purified by preparative thin layer chromatography on silica gel using hexane/ethyl acetate to give the product as a foam (0.34 g).
NMR confirmed it to be the desired product which was used in the next step without any further characterization.
c) 1,6-Dihydro-5methoxycarbonyl-6-(3,4,5-trifluorophenyl)- 2,4-dimethylpyrimidine-l-acetic acid. To a suspension of 10% Pd-C .(30 mg) in MeOH (10 mL) and H 2 0 (2 mL) was added a solution of 1,6-dihydro-l-{bezyloxycarbonylmethyl)-5methoxycarbonyl- 6-(3,4,5-trifluorophenyl)-2,4-dimethylpyrimidine (300 mg) in methanol (1 mL) and the mixture was hydrogenated at 80 psi for 4 h. The black suspension was filtered through a pad of Celite and washed thoroughly with MeOH (100 mL). Solvent was evaporated from the combined filtrate to leave the product 1,6-dihydro-5methoxycarbonyl-6-(3,4,5-trifluorophenyl)-2,4-dimethy lpyrimidine-l-acetic acid as a white solid (0.225 g).
It was used in the next step without further purification.
d) 1,6-Dihydro-l-{N-[2-(4-phenyl-4- WO 97/42956 PCT/US97/08335 -177methoxycarbonyl)piperidin-l-yl) methoxycarbonyl-6-(3,4,5-trifluoro-phenyl)- 2,4-dimethylpyrimidine dihydrochloride.
A mixture of 1,6-dihydro-5methoxycarbonyl-6-(3,4,5-trifluoro-phenyl)- 2,4-dimethylpyrimidine-l-acetic acid (20 mg), 2-(4phenyl-4-methoxycarbonyl)piperidin-1-yl)ethylamine mg), 1-(3-dimethyl-aminopropyl)-3ethylcarbodiimide hydrochloride (20 mg), and 4-(N,Ndimethylamino)pyridine (20 mg) in anhydrous dichloromethane (4 mL) was stirred at room temperature for 12 h. The reaction mixture was purified by preparative thin layer chromatography on silica gel using ethyl acetate as the eluent. The product was dissolved in ether (0.5 mL), cooled to 0oC and treated with 1N HC1 in ether (10 mL) and the solvents evaporated to leave the product as a white powder (25 mg); m.p. 187-190 OC; Anal. Calcd. for
C
31
H
37
N
4 0 5
F
3 C12: C, 55.28; H, 5.54; N, 8.32. Found: C, 55.36; H; 5.80; N, 8.41.
Example (+)l,2,3,6-Tetrahydro-l-{N-[4-(2nitrophenyl)piperazin-1-yl]-propyl}-carboxamido-4methyl-6-(3,4-difluorophenyl)-2-oxo-pyrimidine.
a) 1-(2-nitrophenyl)-piperazine.
A heterogenous reaction mixture containing 2-bromo-1nitrobenzene (2.02 g, 10.0 mmol) and piperazine (4.3 g, 50.0 mmol) was heated at 100 0 C for 10 h. The orange-red solid was extracted with ethyl acetate and washed thoroughly with 3 N NaOH solution followed by brine. The organic layer was separated and dried over Na 2
SO
4 filtered and the solvent was removed in vacuo. The resulting red oil was purified by column chromatography on silica gel (1:1 hexane/EtOAc followed by 4:1 EtOAc/MeOH) to yield 1-(2-nitrophenyl)-piperazine as an orange-red oil (1.90 g, It was converted to its hydrochloride salt.
WO 97/42956 PCT/US97/08335 -178- Anal. calcd. for CoHH 14
N
3 0 2 C10.10 CHC13: C, 47.46; H, 5.56; N, 16.44. Found: C, 47.63; H, 5.69; N, 16.42.
b) (+)-1,2,3,6-Tetrahydro-l-{N-[4-(2nitrophenyl)piperazin-1-yl]propyl}-carboxamido-4methyl-6-(3,4-difluorophenyl)-2-oxo-pyrimidine.
To a solution of (+)-1-(3-bromo-propylcarbamoyl)-6- (3,4-difluoro-phenyl)-4-methyl-2-oxo-l,6-dihydroacid methyl ester (0.22 g, mmol) and 1-(2-nitro-phenyl)-piperazine (0.15 g, 0.75 mmol) in 20 mL of anhydrous acetone was added powdered K 2
CO
3 (0.34 g, 3.5 mmol) and KI (0.07 g, mmol) and the resulting suspension was heated to reflux for 10 h. The suspension was cooled, filtered and the solvent was evaporated and the residue was purified by column chromatography on silica gel with EtOAc/MeOH as the eluting system. tetrahydro-l-{N-4-(2-nitrophenyl)piperazin-lyl]propyl}-carboxamido-4-methyl-6-(3,4difluorophenyl)-2-oxo-pyrimidine was obtained as a yellow oil (0.08 g, 29% yield). The product was analyzed as its hydrochloride salt. M.P. 133-136 0
C;
+56.7 (c 0.11, MeOH). Anal. calcd. for
C
2
,H
31
N
6
F
2 0 6 C1 0.20 CH 2 C1,: C, 51.62; H, 4.97; N, 13.28.
Found: C, 51.35; H, 5.18; N, 11.99.
Example 81: (+)-1,2,3,6-Tetrahydro-l-{N-[4-(2-aminophenyl)piperazin-1-yl]propyl}-carboxamido-4-methyl-6- (3,4-difluorophenyl)-2-oxo-pyrimidine.
To a cooled suspension of 10% palladium on carbon mg) in methanol (25 mL) was added a solution of 1,2,3,6-tetrahydro-l-{N-4-(2-nitrophenyl)piperazinlyl]propyl}-carboxamido-4-methyl-6-(3,4difluorophenyl)-2-oxo-pyrimidine (50 mg, 0.09 mmol) in methanol (5 mL) and the resulting suspension was hydrogenated at 100 psi at room temperature for 3 h.
The suspension was filtered through a pad of celite and washed with 50 mL of methanol. The solvent was WO 97/42956 PCT/US97/08335 -179removed in vacuo from the combined filtrate to get 0.03 g of (+)-1,2,3,6-tetrahydro-1-{N-[4-(2amino-phenyl)-piperazin-1-yl]propyl)-carboxamido-4methyl-6-(3,4-difluoro-phenyl)-2-oxo-pyrimidine as a yellow oil. No purification was performed on this material and it was characterized as its dihydrochloride salt. Mass spectrum (low res.) 543 100%); [ay] 75.1 (c 0.41, MeOH); Anal calcd. for C 27
H
34
N
6
F
2 0 4 C1, 2 0.03 CHC13: C, 52.48; H, 5.54; N, 13.59. Found: C, 52.35; H, 5.83; N, 12.50.
Example 82: 1,2,3,6-Tetrahydro-l-{N-[4-(6-(nitro)pyrid-2yl)piperazin-1-yl]propyl}-carboxamido-4-methyl-6- (3,4 -di f luorophenyl) -2 -oxo-pyrimidine.
a) 1-[6-(nitro)pyrid-2-yl]piperazine.
To a solution of 2-chloro-3-nitropyridine (1.58 g, 10.0 mmol) in 1,4-dioxane (50 mL) was added piperazine (4.3 g, 50.0 mmol) and powdered K 2
CO
3 (50.0 mmol, 6.9 g) and the resulting suspension was heated at reflux for 10 h. After the suspension was cooled, it was extracted with ethyl acetate (2 X 50 mL) and washed successively with 3 N NaOH (20 mL) and water mL). The organic layer was dried over Na 2
SO
4 filtered and the solvent was removed in vacuo. The resulting residue was purified by column chromatography on silica gel (1:1 hexane/EtOAc followed by 4:1 EtOAc/MeOH) to yield 1-[6- (nitro)pyrid-2-yl]piperazine as a yellow solid. It was charcterized as a hydrochloride salt.
Anal calcd. for CH 12
N
4 0Cl .0.25 CHC13: C, 40.47; H, 4.86; N, 20.41. Found: C, 40.72; H, 4.97; N, 20.50.
b) 1,2,3,6-Tetrahydro-l-{N-[4-(6-(nitro)pyrid-2yl)piperazin-1-yl]propyl}-carboxamido-4-methyl-6- (3,4-difluorophenyl)-2-oxo-pyrimidine.
To a solution of 1-(3-bromo-propylcarbamoyl)-6-(3,4difluoro-phenyl)-4-methyl-2-oxo-1,6-dihydroacid methyl ester (0.04 g, WO 97/42956 PCT/US97/08335 -180- 0.1 mmol) and 1-[6-(nitro)pyrid-2-yl]-piperazine (0.03 g, 0.15 mmol) in 10 mL of anhydrous acetone was added powdered KCO 3 (0.06 g, 0.6 mmol) and KI (0.01 g, 0.10 mmol) and the resulting suspension was heated to reflux for 10 h. The suspension was cooled, filtered and the solvent was evaporated in vacuo. The residue was purified by column chromatography on silica gel with EtOAc/MeOH as the eluting system. 1,2,3,6-tetrahydro-1-{N- [4-(6-(nitro)pyrid-2yl)-piperazin-1-yl]propyl}-carboxamido-4-methyl-6- (3,4-difluoro-phenyl)-2-oxo-pyrimidine was obtained as a yellow oil (0.04 g, 70% yield). The product was analyzed as its hydrochloride salt. M.P. 142-145 0
C;
Anal calcd. for C 26
H
30
N
7
F
2 0 6 C1 0.30 CHC1 2 C, 48.91; H, 4.74; N, 15.18. Found: C, 48.94; H, 4.94; N, 13.29.
Example 83: (+)-1,2,3,6-Tetrahydro-l-{N-[2-(S)-methyl)-4-(2nitrophenyl)-piperazin-1-yl]propyl}-carboxamido-4methyl-6-(3,4-difluoro-phenyl)-2-oxo-pyrimidine.
a) (2-nitrophenyl)piperazine.
To a solution of 2-bromo-1-nitrobenzene (0.6 g, mmol) in 1,4-dioxane (15 mL) was added methylpiperazine (0.5 g, 0.5 mmol) and powdered K 2
CO
3 (15.0 mmol, 1.5 g) and the resulting suspension was heated at reflux for 10 h. After the suspension was cooled, it was filtered through a sintered glass funnel and the solvent was evaporated in vacuo. The resulting residue was purified by column chromatography on silica gel (1:1 hexane/EtOAc followed by 4:1 EtOAc/MeOH) to yield methyl-l-(2-nitrophenyl)-piperazine as an orange oil (0.53 g, b) (+)-1,2,3,6-Tetrahydro-l-{N-[2-(S)-methyl)-4-(2nitrophenyl)-piperazin-1-yl]propyl} -carboxamido-4methyl-6-(3,4-difluoro)-phenyl-2-oxo-pyrimidine.
To a solution of (+)-1-(3-bromopropylcarbamoyl)-6- (3,4-difluorophenyl)-4-methyl-2-oxo-1,6-dihydro- WO 97/42956 PCT/US97/08335 -181acid methyl ester (0.2 g, mmol) and nitrophenyl)piperazine (0.17 g, 0.75 mmol) in 20 mL of anhydrous acetone was added powdered K 2 CO (0.34 g, 3.5 mmol) and KI (0.07 g, 0.5 mmol) and the resulting suspension was heated to reflux for 10 h. TLC indicated a new spot for the product (Rf 0.3, 3:0.5 EtOAc/MeOH) and mostly the starting material. The suspension was cooled, filtered and the solvent was evaporated and the residue was purified by column chromatography on silica gel with EtOAc/MeOH as the eluting system. (+)-1,2,3,6-Tetrahydro-l-{N-[2- (S)-methyl)-4-(2-nitrophenyl)piperazin-1-yl]propyl}carboxamido-4-methyl- 6 -(3,4-difluorophenyl)-2-oxopyrimidine was obtained as yellow oil (0.03 g, yield). The product was analyzed as its hydrochloride salt. M.P. 150-153 0 C; [alc 58.3 (c 0.3, MeOH); Anal calcd. for C 2
,H
33
N
6
F
2 0OC1.0.20 CH 2 C1 2 C, 52.92; H, 5.26; N, 13.13. Found: C, 52.84; H, 5.68; N, 12.94.
Example 84: A) -1,2,3,6-Tetrahydro-5-methoxycarbonyl-4-methyl- 2-oxo-1-{N-[2- (R)-methyl)-4- (2-nitrophenyl)piperazin- 1-yl]propyl}-6-(3,4-difluorophenyl)pyrimidine.
a) (2-nitrophenyl)piperazine.
To a solution of 2-bromo-nitrobenzene (0.4 g, mmol) in 1,4-dioxane (10 mL) was added methylpiperazine (0.25.g, 0.25 mmol) and powdered
K
2
CO
3 (7.5 mmol, 0.8 g) and the resulting suspension was heated at reflux for 10 h. After the suspension was cooled, it was filtered through a sintered glass funnel and the solvent was evaporated in vacuo. The resulting residue was purified by column chromatography on silica gel (1:1 hexane/EtOAc followed by 4:1 EtOAc/MeOH) to yield methyl-l-(2-nitrophenyl)-piperazine as an orange-red oil (0.26 g, 78%).
WO 97/42956 PCTIUS97/8335 -182b) (+)-1,2,3,6-Tetrahydro-5-methoxycarbonyl-4-methyl- 2-oxo-l-{N-[2-(R)-methyl)-4-(2-nitrophezyl)piperazin- 1-yl]propyl}-6-(3,4-difluorophenyl)pyrimidine.
To a solution of (+)-l-(3-bromo-propylcarbamoyl)-6- (3,4-difluorophenyl)-4-methyl-2-oxo-1,6-dihydroacid methyl ester (0.11 g, 0.25 mmol) and (R)-(+)-3-methyl-l-(2-itrophenyl)piperazine (0.11 g, 0.50 mmol) in 20 mL of anhydrous acetone was added powdered K 2
CO
3 (0.34 g, 3.5 mmol) and KI (0.07 g, 0.5 mmol) and the resulting suspension was heated to reflux for 10 h. TLC indicated a new spot for the product (Rf 0.3, 3:0.5 EtOAc/MeOH) and mostly the starting material. The suspension was cooled, filtered and the solvent was evaporated and the residue was purified by column chromatography on silica gel with EtOAc/MeOH as the eluting system.(+)-l,2,3,6-Tetrahydro-5methoxycarbonyl-4-methyl-2-oxo-l-(N-[2-(R)-methyl)-4- (2-nitrophenyl)piperazin-1-yl]propyl)-6-(3,4difluorophenyl)-pyrimidine was obtained as yellow oil (0.02 g, 14% yield). The product was analyzed as its hydrochloride salt. M.P. 135-138 0 C; [ar]D 63.5 (c 0.2, MeOH) Anal calcd. for C 2
,H
3 N,F2F 2 C1 1. 0 CHC1 3 C, 46.92; H, 4.62; N, 11.32. Found: C, 46.94; H, 4.97; N, 11.47.
Example (+)-1,2,3,6-Tetrahydro-5-methoxycarbonyl-4methoxymethyl-2-oxo-l-{N-[4-(2-methoxy-5methyl)phenyl-4-phenyl-piperidif-l-y1]propyl}-6-(3,4difluorophenyl) pyrimidine.
a) 4-(2-Methoxy-5-methyl)phenyl-4-pheylpiperidie hydrochloride.
To a 100 mL round bottom flask equipped with a rubber septum and a stirring bar was added 4-hydroxy-4phenyl-piperidine (1.25 g, 7.0 mmol) followed by mL of 4-methylanisole. The resulting solution was stirred at room temperature under argon atmosphere WO 97/42956 PCT/US97/08335 -183and then A1C13 (2.82 g, 21.0 mmol) was added in one portion. An exotherm was observed. The reaction mixture was stirred for 8 h and then poured carefully over 150 ml of ice-water. The white solid that precipitated out was filtered and washed thoroughly with water followed by diethyl ether to obtain 4-(2methoxy-5-methyl)-phenyl-4-phenyl-piperidine hydrochloride (1.59 g, 50%) as a white solid. Mass spectrum: 282 100%). Anal calcd. for
C,
9
H
24 NOC1.0.15 CH 2 C12: C, 69.57; H, 7.41; N, 4.24.
Found: C, 69.62; H, 7.31; N, 4.36.
b) 3-[4-(2-methoxy-5-methyl)phenyl-4-phenylpiperidin-1-yl]-propylamine.
To a solution of 4-(2-methoxy-5-methyl)-phenyl-4phenyl-piperidine (0.6 g, 2.1 mmol) in 30 mL dioxane was added 3-bromo-N-tert-butoxycarbonyl-propylamine (0.6 g, 2.5 mmol) and K 2
CO
3 (0.6 g, 6.0 mmol) and the resulting suspension was heated to reflux for 10 h.
The suspension was allowed to cool, filtered and the solvent was evaporated to obtain yellow residue which was purified by column chromatography (Rf 0.4, 3:1 EtOAc/MeOH) to obtain 3-[4-(2-methoxy-5methyl)phenyl-4-phenyl-piperidin-1-yl]-N-tertbutoxycarbonyl-propylamine as a yellow oil (0.35 g).
It was dissolved in 15 mL of CHC1, and 3.0 mL of trifluoroacetic acid was added with stirring at room temperature under argon atmosphere for 1 h. The solvent was evaporated in vacuo and the residue was basified to pH 10 by adding minimum amount of 1 N KOH solution. The product was extracted with CHCl 2 (3 X mL), dried over MgS04, filtered and the solvent was removed in vacuo to obtain 3-[4-(2-methoxy-5methyl)phenyl-4-phenyl-piperidin-1-yl]propylamine as a yellow oil (0.25 g, 35% for two steps). It was used in the next step without further purification.
c) (+)-1,2,3,6-Tetrahydro-5-methoxycarbonyl-4methoxymethyl-2-oxo--{N- WO 97/42956 PCT/US97/08335 -184methyl)phenyl-4-phenyl-piperidin-l-yl]propyl}-6-(3,4difluorophenyl) pyrimidine.
To a solution of 3-[4-(2-methoxy-5-methyl)phenyl-4phenyl-piperidin-1-yl]propylamine (0.12 g, 0.36 mmol) in 5.0 mL THF was added (+)1,6-dihydro-5methoxycarbonyl-4-methoxymethyl-2-oxo-1- (4nitrophenyloxy)carbonyl-6 (3,4difluorophenyl)pyrimidine (0.12 g, 0.33 mmol) at room temperature and the resulting yellow solution was stirred for 6 h. The solvent was removed in vacuo and the resulting residue was subjected to column chromatography over silica gel (1:1 hexane/EtOAc to EtOAc to 9:1 EtOAC/MeOH) to obtain tetrahydro-5-methoxycarbonyl-4-methoxymethyl-2-oxo-1- {N-[4-(2-methoxy-5-methyl)phenyl-4-phenyl-piperidin- 1-yl]propyl}-6- (3,4-difluorophenyl)pyrimidine (0.12 g, 65%) as a yellow oil. It was converted into its HC1 salt (pale yellow powder). M.P. 102-105 0 C. [a]D 49.4 (c 0.65, MeOH) Anal calcd. for
C
32
H
36
N
3 0 4
F
2 C1 1.5 CH 2 C1 2 C, 55.31; H, 5.40; N, 5.78.
Found: C, 55.55; H, 5.06; N, 6.08.
Example 86: (+)-1,2,3,6-Tetrahydro-5-methoxycarbonyl- 4 methoxymethyl-2-oxo-l-{N-[4-(4-methyl)-phenyl-4-(2methyl)phenyl piperidin-l-yl]-propyl}-6-(3,4difluorophenyl) pyrimidine.
a) 4-(4-methyl)phenyl-4-(2-methyl)phenylpiperidine hydrochloride.
To a 100 mL round bottom flask equipped with a rubber septum and a stirring bar was added 4-hydroxy-4-(4methyl)phenyl-piperidine (1.25 g, 6.54 mmol) followed by 20 mL of anhydrous toluene. The resulting solution was stirred at room temperature under argon atmosphere and then A1C1 3 (1.4 g, 10.2 mmol) was added in one portion. An exotherm was observed. The reaction mixture was stiired for 10 h and then poured carefully over 100 ml of ice-water. The white solid WO 97/42956 PCT/US97/08335 -185that precipitated out was filtered and washed thoroughly with water followed by diethyl ether to obtain 4-(4-methyl)phenyl-4-(2methyl)phenylpiperidine hydrochloride (1.95 g, 99%) as a white solid. .Mass spectrum: 266 100%).
Anal calcd. for C 1
,H
24 NC1.0.15 CH 2 Cl 2 C, 73.11; H, 7.79; N, 4.45. Found: C, 73.33; H, 7.82; N, 3.92.
b) 3-[4-(4-methyl)phenyl-4-(2-methyl)phenylpiperidin- 1-yl]-propylamine.
To a solution of 4-(4-methyl)-phenyl-4-(2methyl)phenyl piperidine hydrochloride (2.6 g, 9.8 mmol) in 100 mL dioxane was added 3-bromo-N-tertbutoxycarbonyl-propylamine (2.57 g, 10.8 mmol) and
K
2 C0 3 (4.06 g, 29.4 mmol) and the resulting suspension was heated to reflux for 10 h. The suspension was allowed to cool, filtered and the solvent was evaporated to obtain a yellow residue which was purified by column chromatography over silica gel (Rf 0.4, 3:1 EtOAc/MeOH) to give 3-[4-(4-methyl)phenyl- 4-(2-methyl)phenylpiperidin-1-yl]-N-tertbutoxycarbonyl-propylamine as a yellow oil (2.30 g).
It was dissolved in 60 mL of CH 2 C1, and 10.0 mL of trifluoroacetic acid was added with stirring at room temperature under argon atmosphere for 1 h. The solvent was evaporated in vacuo and the residue was basified to pH 10 by adding minimum amount of 1 N KOH solution. The product was extracted with CH 2 Cl1 (3 X mL), dried over MgS04, filtered and the solvent was removed in vacuo to obtain 3-[4-(4-methyl)phenyl-4-(2-methyl)phenyl piperidin-1-yl]propylamine as a yellow oil (1.39 g, 44% for two steps). It was used in the next step without further purification.
c) (+)-1,2,3,6-Tetrahydro-5-methoxycarbonyl-4methoxymethyl-2-oxo-l-{N-[4-(4-methyl)-phenyl-4-(2methyl)phenylpiperidin-l-yl]-propyl}-6-(3,4difluorophenyl)pyrimidine.
To a solution of 3-[4-(4-methyl)phenyl-4-(2- WO 97/42956 PCTIUS97/08335 -186methyl)phenyl- piperidin-l-yl~propylamiie (0.10 g, 0.31 mmol) in 10.0 mL THF was added (+)-l,6-Dihydro- 5-methoxcarbolyl-4-mfethoxymethyl 2 -0ool-(4nitrophenyloxy) carbonyl-6- (3,4difluorophenyl)pyrimfidine (0.10 g, 0.28 mmol) at room temperature and the resulting yellow solution was stirred for 8 h. The solvent was removed in vacuo and the resulting residue was subjected to column chromatography over silica gel (1:1 hexane/EtOAc to EtOAc to 9:1 EtOAC/MeOH) to obtain Tetrahydro-5-methoxycarboflyl-4-methoxymethyl- 2 -oxo-l- (4-methyl)phenyl-4-( methyl) phenylpiperidin-1-yl) propyl} (3,4difluorophenyl)pyrimidine (0.11 g, 70%) as a yellow oil. It was converted into its HCl salt (pale yellow powder). M.P. 103-107(C. [atID 104.8 (c 0.31, MeOH) Anal calcd. for C 38
H
6 N0 5
F
2 C10 .66 CH 2 Cl 2
C,
60.44; H, 6.32; N, 6.71. Found: C, 60.44; H, 6.21; N, 7 .19.
Example 87: -l,2,3,6-Tetrahydro-5-methoxycarboflyl-4-methyl- 2 oxo-1-{N- (4-methyl)pheflyl-4- (2methyl)phenylpiperidif-llpropyl}-6- (3,4difluorophenyl) pyrimidine.
To a solution of 3-[4-(4-methyl)phelyl-4-(2methyl)phenyl-piperidin-l-ylpropylamile (0.25 g, 0.78 mmol) in 10.0 mL THF was added (+)-l,6-dihydro- 5-methoxycarbonyl-.4-methyl- 2 -oxo-l- (4nitrophenyloxy) carbonyl -6 dif].uorophenyl)pyrimlidine (0.22 g, 0.67 mmol) at room temperature and the resulting yellow solution was stirred for 8 h. The solvent was removed in vacuo and the resulting residue was subjected to column chromatography over silica gel (1:1 hexane/EtOAc to EtOAc to 9:1 EtOAC/MeOH) to obtain Tetrahydro-5-methoxycarbonyl4methyl2oxol-{N-[3- (4-methyl)phenyl-4- (2-methyl)phenylpiperidin-1- WO 97/42956 PCT/US97/08335 -187yl]-propyl}-6-(3,4-difluorophenyl)pyrimidine (0.19 g, 64%) as a yellow oil. It was converted into its HC1 salt (pale yellow powder). M.P. 143-147 0 C. [a]D 79.8 (c 0.25, MeOH). Anal. calcd. for
C,
3
H
44
N
4 0 4
F
2 C1.0.50 CH 2 C1 2 C, 62.19; H, 6.26; N, 7.73.
Found: C, 62.15; H, 5.92; N, 7.21.
Example 88: 1,2,3,6-Tetrahydro-l-{ [4-benzamido-piperidin-1yl]propyl}-carboxamido-4-methyl-6-(3,4difluorophenyl)-2-oxo-pyrimidine.
a) 4-Amino-l-benzylpiperidine.
To a solution of hydroxylamine hydrochloride (3.67 g, 52.8 mmol) in water (10 mL) and ethyl alcohol (80 mL) was added 1-benzyl piperidone (10.0 g, 52.8 mmol) at room temperature. The reaction mixture was heated to reflux for 4 h and then stirred at room temperature overnight. The resulting white solid was filtered, washed with ether and dried (8.4 g, It was added in small portions to a suspension of lithium aluminum hydride (2.3 g, 60.0 mmol) in diethyl ether (150 mL) at room temperature and the suspension was heated to reflux for 8 h. The reaction mixture was cooled to 0 C and quenched with successive addition of water (3 mL), 3 N NaOH (3 mL) and water (9 mL). The white suspension was filtered and the filtrate was dried over MgSO,. The solvent was removed in vacuo after filtration. 4-Amino-l-benzyl-piperidine was obtained as a colorless oil (6.0 It was used in the next step without purification.
b) 1-Benzyl-4-benzamidopiperidine.
To a biphasic solution of 4-amino-l-benzylpiperidine g, 31.6 mmol), KCO 3 (8.71 g, 63.1 mmol) in CH,C1 2 (200 mL) and water (100 mL) was added benzoyl chloride (4.86 g, 34.7 mmol) in 20 mL of CHC1, at 0 C with stirring. After stirring for 4 h at room temperature, the layers were separated. The organic layer was washed with water, dried over MgSO, and WO 97/42956 PCT/US97/08335 -188filtered. The solvent was removed in vacuo to obtain 1.benzyl-4-benzamidopiperidile (8.16 g, 87% yield) as a white solid. It was used in the next step without purification.
c) 4-Benzamido-piperidile.
To a suspension of 10t palladium on carbon (0.2 g) in mL of ethyl alcohol was added a solution of 1benzyl-4-benzamido- piperidine (0.5 g, 1.79 mmcl) in ethyl alcohol (10 mL). The resulting suspension was hydrogenated at 100 psi at 50 0 C for 30 h after which it was filtered through a pad of celite and the solvent was removed in vacuo to obtain 0.34 g (100%) of 4-benzamidopiperidine as a white solid. It was used in the next step without purification.
d) 1,2,3, 6-Tetrahydro-l-{ [4-benzanmido-piperidin-1yllpropyl)-carboxamido-4-methyl- 6 (3,4difluorophenyl) -2 -oxo-pyrimidine.
To a solution of 1- (3-bromopropylcarbamoyl) (3,4difluoro-phenyl) -4-methyl-2-oxo-l,6dihydropyrimidine-5-carboxylic acid methyl ester (0.04 g, 0.10 mmcl) and 4-benzamidopiperidine (0.03 g, 0.15 mmcl) in 15 ML of anhydrous THF was added triethylamine (2 mL) and the resulting solution was heated to ref lux for 10 h. The suspension was cooled, filtered and the solvent was evaporated. The residue was purified by column chromatography on silica gel with EtOAc/MeOH as the eluting system. 1,2,3, 6-tetrahydro-l-{ [4-benzamidopiperidinl-yllpropyl~carboxamido-4-methYl-6- (3,4difluorophenyl)-2-oxo-pyrimidile was obtained as a yellow oil (0.02 g, 37% yield). The product was analyzed as its hydrochloride salt. M.P. 121-125 0
C.
Anal calcd. for C 29
H
34 NsF 2 OSCl 0.53 CHCl 3 C, 53.03; H, 5.20; N, 10.37. Found: C, 52.90; H, 5.61; N, 9.97.
Example 89: 4- (3,4-Difluorophenyl) -6-methoxymethyl-2-oxo-3- 13- (4phenyl-4- (thiophen-2-yl)piperidil-1-y1) WO 97/42956 PCT/S97/08335 -189propylcarbamoyl -1,2,3,4-tetrahydropyrimidine- carboxylic acid methyl ester.
a) 4-Phenyl-4-(thiophen-2-yl)piperidine.
To a solution of 4-hydroxy-4-phenylpiperidine (1.0 g, 5.6 mmol) and thiophene (0.88 ml, 11 mmol) in 20 ml of CH 2 C1 was added AlCI 3 (0.75 g, 5.6 mmol) at -78 °C and the resulting reaction mixture was stirred for 1 h. The reaction mixture was basified with sat'd aqueous NaHCO 3 and extracted with EtOAc. The organic layer was dried over Na 2
CO
3 and concentrated in vacuo to provide the product as a colorless oil which was subjected to the following reaction without further purification.
b) 3-(4-Phenyl-4-(thiophen-2-yl)piperidin-lyl)propylamine.
A solution of 4-phenyl-4-(thiophen-2-yl)piperidine and 3-Boc-aminopropylbromide (1.0 g, 4.4 mmol) with 1 g of K 2
CO
3 in 20 ml of dioxane was stirred at reflux for 12 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic solution was dried over NaSO, and concentrated in vacuo to yield an oil which was subjected to column chromatography over silica gel (EtOAc) to provide 0.43 g (1.1 mmol, 20% for two steps) of 3-(4-phenyl- 4-(thiophene-2-yl)piperidin-1-yl)-propylcarbamic acid tert-butyl ester as colorless oil. The ester in 5 ml of CH 2 C1 2 was added with 1 ml of CF 3
CO
2 H and resulting solution was stirred for 1 h at 25 OC. The reaction mixture was concentrated in vacuo to yield oily mixture, which was dissolved in EtOAc and washed with aqueous NaHCO 3 Concentration of the reaction mixture provided the desired product as an oil (0.29 g, 0.96 mmol, 88%) which was used in the next step without further purification.
c) 4-(3,4-Difluorophenyl)-6-methoxymethyl-2-oxo-3- [3-(4-phenyl-4-(thiophen-2-yl)piperidin-lyl)propylcarbamoyl}-1,2,3,4-tetrahydropyrimidine- WO 97/42956 PCTS97/08335 -190carboxylic acid methyl ester.
To a solution of 6-(3,4-difluorophenyl)-4methoxymethyl-2-oxo-3,6-dihydro-2H-pyrimidine-1,5dicarboxylic acid 5-methyl ester 1-(4nitrophenyl)ester (29 mg, 0.06 mmol) in 2 ml of CH,C1l was added 3-(4-phenyl-4-thiophen-2-yl-piperidin-lyl)propylamine (20 mg, 0.07 mmol) and the resulting solution was stirred for 2 h at 25 OC. The reaction mixture was concentrated in vacuo to provide an oil which was subjected to column chromatography over silica gel MeOH/CHC1 3 to yield 25 mg of the desired product which was converted to a HC1 salt and recrystallized from EtOAC-Et 2 O to afford 22 mg of the product as a white solid: mp 157-159°C; Anal. Calc.
For C 33
H
36
F
2
N
4 0sS requires C, 58.6; H, 5.33; N, 8.29.
Found: C, 57.3; H, 5.45; 7.90.
Example 4-(3,4-Difluorophenyl)-6-methoxymethyl-2-oxo-3-[3-(4phenyl-4-(furan-2-yl)piperidin-1-yl)propyl]carbamoyl- 1,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester.
a) 4-Phenyl-4-(furan-2-yl)piperidine.
To a solution of 4-hydroxy-4-phenyl-piperidine (0.3 g, 1.7 mmol) and furan (0.50 ml, 6.8 mmol) in 20 ml of CH 2 Cl1 was added A1C1 3 (0.50 g, 3.7 mmol) at 25 °C and the resulting reaction mixture was stirred for 1 h. The reaction mixture was basified with sat'd aqueous NaHCO 3 and extracted with EtOAc. The organic layer was dried over Na 2
CO
3 and concentrated in vacuo to provide a colorless oil which was identified as the desired product by NMR analysis and subjected to the following reaction without further purification.
b) 3-(4-Phenyl-4-(furan-2-yl)piperidin-lyl)propylamine.
A solution of 4-phenyl-4-furan-2-yl-piperidine and 3- Boc-aminopropylbromide (0.30 g, 1.3 mmol) with 0.5 g of K 2
CO
3 in 20 ml of dioxane was stirred at reflux for WO 97/42956 PCT/S97/08335 -191- 12 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic solution was dried over Na 2
SO
4 and concentrated in vacuo to yield an oil which was subjected to column chromatography over silica gel (EtOAc) to provide 0.21 g (0.54 mmol, 32% for two steps) of 3-(4-phenyl-4-(furan-2yl)piperidin-l-yl)propylcarbamic acid tert-butyl ester as a colorless oil. The ester in 5 ml of CH 2 C1 2 was added with 1 ml of CF 3
CO
2 H and resulting solution was stirred for 1 h at 25 OC. The reaction mixture was concentrated in vacuo to yield oily mixture, which was dissolved in EtOAc and washed with aqueous NaHCO 3 Concentration of the reaction mixture provided the desired product as an oil (0.13 g, 0.45 mmol, 84%).
c) 4-(3,4-Difluorophenyl)-6-methoxymethyl-2-oxo-3- (4-phenyl-4-(furan-2-yl)piperidin-lyl)propylcarbamoyl}-1,2,3,4-tetrahydropyrimidine-5carboxylic acid methyl ester.
To a solution of 6-(3,4-difluorophenyl)-4methoxymethyl-2-oxo-3,6-dihydro-2H-pyrimidine-1,5dicarboxylic acid 5-methyl ester 1-(4nitrophenyl)ester (20 mg, 0.04 mmol) in 2 ml of CH 2 C1 2 was added 3-(4-phenyl-4-furan-2-yl-piperidin-1-yl)propylamine (12 mg, 0.04 mmol) and resulting solution was stirred for 2 h at 25 oC. The reaction mixture was concentrated in vacuo to provide an oil which was subjected to column chromatography over silica gel MeOH/CHC1 3 to yield 22 mg of the desired product, which was converted to HC1 salt and recrystallized from EtOAC-Et 2 O to afford 18 mg of the product as a white solid: mp 153-155 OC; Anal. Calc.
For C 33
H
36
F
2
N
4 0 6 requires C, 60.1; H, 5.46; N, 8.49.
Found: C, 58.9; H, 5.53; 8.45.
Example 91: 4-(3,4-Difluorophenyl)-6-methoxymethyl-2-oxo-3-{3-[4phenyl-4- (l-methylpyrrol-2-yl)-piperidin-1-yl WO 97/42956 PCT/US97/08335 -192propylcarbamoyl-1,2,3,4 carboxylic acid methyl ester.
a) 4-Phenyl-4- (l-methylpyrrol-2-yl)piperidine.
To a solution of 4-hydroxy-4-phenylpiperidine (0.5 g, 2.8 mmol) and 1-methylpyrrole (0.50 ml, 5.6 mmol) in ml of CH 2 C1, was added A1C1 3 (0.75 g, 5.6 mmol) at OC and the resulting reaction mixture was stirred for 1 h. The reaction mixture was basified with sat'd aqueous NaHCO 3 and extracted with EtOAc. The organic layer was dried over Na 2
CO
3 and concentrated in vacuo to provide the desired product as a colorless oil.
b) 3-[4-Phenyl-4- (l-methylpyrrol-2-yl)piperidin-lyl]-propylamine.
A solution of 4-phenyl-4-(1-methylpyrrol-2-yl)piperidine and 3-Boc-aminopropylbromide (1.0 g, mmol) with 1.5 g of K 2
CO
3 in 20 ml of dioxane was stirred at reflux for 12 h. The reaction mixture was diluted with water and extracted with EtOAc. Organic solution was dried over Na 2 SO, and concentrated in vacuo to yield an oil which was subjected to column chromatography over silica gel (EtOAc) to provide 0.44 g (1.1 mmol, 20% for two steps) of 3-[4-phenyl- 4-(l-methylpyrrol-2-yl)-piperidin-1-y] propylcarbamic acid tert-butyl ester as a colorless oil. The ester in 10 ml of CH 2
C
2 was added with 1 ml of CF 3 C02H and resulting solution was stirred for 1 h at 25 OC. The reaction mixture was concentrated in vacuo to yield an oily mixture, which was dissolved in EtOAc and washed with aqueous NaHCO 3 Concentration of the reaction mixture provided an oil (0.26 g, 0.87 mmol, 79%) which was identified as the desired product.
c) 4- (3,4-Difluorophenyl)-6-methoxymethyl-2-oxo-3- (3-[4-phenyl-4-(1-methylpyrrol-2-yl)-piperidin-lyl]propylcarbamoyl-1,2,3,4 tetrahydropyrimidine- carboxylic acid methyl ester.
WO 97/42956 PCT[US97/08335 -193- To a solution of 6-(3,4-difluorophenyl)-4methoxymethyl-2-oxo- 3 ,6-dihydro-2H-pyrimidine-1,5dicarboxylic acid 5-methyl ester 1-(4nitrophenyl)ester (24 mg, 0.05 mmol) in 2 ml of CH,C1, was added 3-[4-phenyl-4-(1-methylpyrrol-2-yl)piperidin-1-yl]-propylamine (15 mg, 0.05 mmol) and resulting solution was stirred for 2 h at 25 OC.
Reaction mixture was concentrated in vacuo to provide an oil which was subjected to column chromatography over silica gel MeOH/CHC13) to yield 22 mg (69%) of the desired product, which was converted to HC1 salt and recrystallized from EtOAC-EtzO to afford 16 mg of the product as a white solid: mp 139-142 0
C.
Example 92 As a specific embodiment of an oral composition of a compound of this invention, 100mg of one of the compounds described herein is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size 0 hard gel capsule.
WO 97/42956 PCTfUS97/8335 -194- Pharmacoloqical Profiles of the Compounds in Cloned Human Adreneric Receptors.
Binding affinities were measured for selected compounds of the invention at six cloned human alpha-1 and alpha- 2 receptor subtypes, as well as at the L-type calcium channel. The protocols for these experiments are given below.
Protocol for the Determination of the Potency of ac Antagonists The activity of compounds at the different human receptors was determined in vitro using cultured cell lines that selectively express the receptor of interest. These cell lines were prepared by transfecting the cloned cDNA or cloned genomic DNA or constructs containing both genomic DNA and cDNA encoding the human a-adrenergic receptors as follows: a, Human Adrenergic Receptor: The entire coding region of oaD (1719 bp), including 150 base pairs of untranslated sequence UT) and 300 bp of 3' untranslated sequence UT), was cloned into the BamHI and Clal sites of the polylinker-modified eukaryotic expression vector pCEXV-3, called EXJ.HR.
The construct involved the ligation of partial overlapping human lymphocyte genomic and hippocampal cDNA clones: 5' sequence were contained on a 1.2 kb SmaI-XhoI genomic fragment (the vector-derived BamHI site was used for subcloning instead of the internal insert-derived SmaI site) and 3' sequences were contained on an 1.3 kb XhoI-ClaI cDNA fragment (the Clal site was from the vector polylinker). Stable cell lines were obtained by cotransfection with the plasmid alA/EXJ (expression vector containing the alA receptor gene (old nomenclature)) and the plasmid pGCcos3neo (plasmid containing the aminoglycoside transferase WO 97/42956 PCTIUS97/08335 -195gene) into LM(tk-) cells using calcium phosphate technique. The cells were grown, in a controlled environment (370C., 5% CO) as monolayers in Dulbecco's modified Eagle's Medium (GIBCO, Grand Island, NY) containing 25mM glucose and supplemented with bovine calf serum, 100 units/ml penicillin g, and 100 Ag/ml streptomycin sulfate. Stable clones were then selected for resistance to the antibiotic G-418 (1 mg/ml), and membranes were harvested and assayed for their ability to bind [HIprazosin as described below (see "Radioligand Binding assays").
The cell line expressing the human a 1 receptor used herein was designated L-alA (old nomenclature) and was deposited with the American Type Culture Collection, 12301 Parklawn Drive, Rockville, Maryland 20852, U.S.A.
under the provisions of the Budapest Treaty for the International Recognition of the Deposit of Microorganisms for the Purposes of Patent Procedure.
The cell line expressing the human receptor, was accorded ATCC Accession No. CRL 11138, and was deposited on September 25, 1992.
Human Adrenergic Receptor: The entire coding region of alB (1563 bp), including 200 base pairs and untranslated sequence UT) and 600 bp of 3' untranslated sequence UT), was cloned into the EcoRI site of pCEXV-3 eukaryotic expression vector.
The construct involved ligating the full-length containing EcoRI brainstem cDNA fragment from X ZapII into the expression vector. Stable cell lines were selected as described above. The cell line used herein was designated L-ae and was deposited with the American Type Culture Collection, 12301 Parklawn Drive, Rockville, Maryland 20852, U.S.A. under the provisions of the Budapest Treaty for the International Recognition of the Deposit of Microorganisms for the -196- Purposes of Patent Procedure. The cell line L-a- was accorded ATCC Accession No. CRL 11139, on September 1992.
0a, Human Adrenergic Receptor: The entire coding region of a- (1401 bp), including 400 base pairs of untranslated sequence UT) and 200 bp of 3' untranslated sequence UT), was cloned into the KpnI site of the polylinker-modified pCEXV-3-derived eukaryotic expression vector, EXJ.RH. The construct involved ligating three partial overlapping fragments: a 5' 0.6kb HincII genomic clone, a central 1.8 EcoRI hippocampal cDNA clone, and 3' 0.6Kb PstI genomic clone. The hippocampal cDNA fragment overlaps with the 5' and 3' genomic clones so that the HincII and PstI sites at the 5' and 3' ends of the cDNA clone, respectively, were utilized for ligation. This fulllength clone was cloned into the KpnI site of the expressed vector, using the 5' and 3' KpnI sites of the fragment, derived from vector pBluescript) :and 3'-untranslated sequences, respectively. Stable cell lines were selected as described above. The stable cell line expressing the human a, receptor used herein was designated L-a- (old nomenclature) and was 25 deposited with the American Type Culture Collection, 12301 Parklawn Drive, Rockville, Maryland 20852, U.S.A.
under the provisions of the Budapest Treaty for the International Recognition of the Deposit of SMicroorganisms for the Purposes of Patent Procedure.
30 The cell line expressing the human U1A receptor was accorded Accession No. CRL 11140 on September 25, 1992.
Radioligand Binding Assays: Transfected cells from culture flasks were scraped into 5ml of 5mM Tris-HCl, 5mM EDTA, pH 7.5, and lysed by sonication. The cell TQ, lysates were centrifuged at 1000 rpm for 5 min at 4 0
C,
K 'and the supernatant was centrifuged at 30,000 x g for WO 97/42956 PCT/US97/08335 -197min at 4 0 C. The pellet was suspended in 50mM Tris- HC1, imM MgC,, and 0.1% ascorbic acid at pH Binding of the al antagonist 3 H]prazosin (0.5 nM, specific activity 76.2 Ci/mmol) to membrane preparations of LM(tk-) cells was done in a final volume of 0.25 ml and incubated at 37°C for 20 min.
Nonspecific binding was determined in the presence of AM phentolamine. The reaction was stopped by filtration through GF/B filters using a cell harvester.
Inhibition experiments, routinely consisting of 7 concentrations of the tested compounds, were analyzed using a non-linear regression curve-fitting computer program to obtain Ki values.
2, Human Adrenergic Receptors: To determine the potency of al antagonists at the a 2 receptors, LM(tk-) cell lines stably transfected with the genes encoding the a 2 A, a2B, and a 2 c receptors were used. The cell line expressing the a 2 A receptor is designated L- 2 A, and was deposited on November 6, 1992 under ATCC Accession No.
CRL 11180. The cell line expressing the u 2 B receptor is designated L-NGC-2B, and was deposited on October 1989 under ATCC Accession No. CRL10275. The cell'line expressing the a 2 c receptor is designated L-o2c, and was deposited on November 6, 1992 under ATCC Accession No.
CRL-11181. All the cell lines were deposited with the American Type Culture Collection, 12301 Parklawn Drive, Rockville, Maryland 20852, U.S.A. under the provisions of the Budapest Treaty for the International Recognition of the Deposit of Microorganisms for the Purposes of Patent Procedure. Cell lysates were prepared as described above (see Radioligand Binding Assays), and suspended in 25mM glycylglycine buffer (pH 7.6 at room temperature). Equilibrium competition binding assay were performed using [3H]rauwolscine and nonspecific binding was determined by incubation with 10,/M phentolamine. The bound WO 97/42956 PCT/US97/8335 -198radioligand was separated by filtration through GF/B filters using a cell harvester.
Determination of the Activity of eo Antagonists at Calcium Channels The potency of a, antagonists at calcium channels may be determined in competition binding assays of [3H]nitrendipine to membrane fragments of rat cardiac muscle, essentially as described by Glossman and Ferry (Methods in Enzymology 109:513-550, 1985). Briefly, the tissue is minced and homogenized in 50mM Tris-HC1 (pH 7.4) containing 0.1mM phenylmethylsulfonyl fluoride. The homogenates are centrifuged at 1000 g for 15 minutes, and the resulting supernatant centrifuged at 45,000 g for 15 minutes. The 45,000 g pellet is suspended in buffer and centrifuged a second time. Aliquots of membrane protein are then incubated for 30 minutes at 37°C in the presence of [3H]nitrendipine (InM), and nonspecific binding determined in the presence of 10~M nifedipine. The bound radioligand is separated by filtration through GF/B filters using a cell harvester.
The compounds described above were assayed using cloned human alpha adrenergic receptors. The preferred compounds were found to be selective arc antagonists.
The binding affinities of compounds 13-17 are illustrated in the following table.
WO 97/42956 PCT/US97/08335 -199- Binding affinities of compounds 13-17 at cloned human aid, alb and ala receptors.
Example hald halb hala pKi SEM n pKi SEM n pKi SEM n 13 6.14 0.02 3 6.21 0.09 3 9.74 0.02 3 14 6.46 0.04 3 6.59 0.08 3 9.68 0.05 3 6.01 0.03 3 6.33 0.06 3 9.41 0.09 3 16 6.24 0.06 3 6.37 0.06 3 9.54 0.09 3 17 6.17 0.04 4 6.32 0.06 4 8.99 0.12 4 h human SUBSTITUTE SHEET (RULE 26) WO 97/42956 WO 9742956PCT/US97/08335 -200-
N
BEH
3 R= R, 4-NeO-Ph Ph RZ!S204 R T he, rt R Dr RE2 -HBr K2O'K! A-Dianne R 0H, COOKe. COOEt
OCH
IM1 Scheme 1. General synthetic schemes for the synthesis of the piperidine sidechains.
HR
I
0
R
2 0 N RI N XR 1
NO
3 4
R
2 0 1. NaOAc, DMF.
2. 4-Nitrophenyl chioroformate, NaHCO 3
CH
2 Cl 2 H120- 3.
4. HC1/THF or EtSH/TFA.
Scheme 1 (continued). General synthetic scherne for examp'les 1-12.
NH
2 Y02
I
102 0 IleO
NH
lie N Olie 102 0111: 0a lie N Otte 3 CO 2 e
CO
2 fte 1. NaQAC, DMF.
2. 4-Nitrophelyl chioroformate, NaHCO 3 1 CH 2 C1 2
H
2 0.
3. 3 4 -Methoxycarbonyl4pheny)piperidineylJprpylai
THF.
4. 6N HC1/THF.
Scheme 2. Synthetic schemne for example 11.
N102 0 0 NO2 tleO 0 Hie N -IOlle lie H.,1 N
THF
to0: O tie 0
H
Ohe diastereorner I L Separated by chromatography 2.
DBIJ
N K-j CO h11e N102 lleO
NH
Hie N IkO~e isomer isomer -4 14a 14b( Scheme 3. Synthetic scheme for examples lla and 11b.
WO 97/42956 WO 9742956PCTIUS97/08335 -204-
~QCHO
0,CH 3 0 AO CY~ CIT 021 0 0 0 0 Piperidine. lOkc Isopropanol NR- 102 I9HCOS so C 0 zt O R0 ItOH II Ole 102 00 0 00 N 0 0 0 1. 4-Nitrophenyl chioroformate, NaHC 3 C4 2 C1, 14 2 0.
2. 3- [(4-Methoxycarbonyl-4-phenyl)piperidin-lyl] propylamine.
3. 6N Ndl.
4. NaQH, Acetone.
DMAPECD, DMAP, NH31 CH 2 C1 2 Scheme 4. synthetic scheme for example 13.
WO 97/42956 PCT/US97/08335 -205-
H
F 0 01 0 0C 0 Piperidine. HOAc 0 0 Benzene
NH
2 HN Ofte NaHCO 3 DN1F
I.
ci
NH
N Otte 2. 3 0~~
F
NT
0 -0 2
H
H
4.
1. 4-Nitrophenyl chioroformate, DMAP, THF 2. 3- ((4-Methoxycarbonyl-4-phenyl)piperidin-1ylJ propylamnine.
3. 6N HC1.
4. H 2 Pd-C, MeOH.
DMAPECD, DMAP, NHI 4 OH, CH 2 C1 2 Scheme 5. Synthetic scheme for example 14.
SUBSTITUTE SHEET (RULE 26) WO 97/42956 WO 9742956PCT/US97/08335 -206- HO IfOH
H
1) Na 2 CO 3 8li No 2) SOd 2 IeOH 81% C 1 fC
I
Bn
NN
f-(C 4
H
9 )N HSO 4 KaOK, Toluene 650 C N. N
NN
En Conc. H 2 S0 4
RT
2) tKeOH, H.
44X
I.
N
N
BN
1) H 2 Pd(OH) 2 200 PSi 2) Br,'NHBOC KC0 3 Dioxane, reflux 3) TFA. CH12 C12. 98%
I.
N
NHZ
Scheme 6. Synthetic scheme for the preparation of 3-14- (2-Pyridyl) -piperidin-1-ylJ propylamine (Example 21 part d).
SUBSTITUTE SHEET (RULE 26) WO 97/42956 WO 9742956PCTIUS97/08335 -2 07-
NH
2 +HN J
OCH
3 1
F
0 CH 30 N N
OH
2 0 N02 kyllfNO 3
CH
3 0
H
OCH 3 4
N..
I. NaQAc, DMF.
2. 4-Nitrophenyl chioroformate, NaHCO 3
CH
2 Cl 2
H
2 0.
3. 3- [(4-Pyridyl) -piperidin-1-yllpropylamine,
CH
2 Cl 2 4. 6N HC1/THF.
Scheme 7. Synthetic scheme for example SUBSTITUTE SHEET (RULE 26) WO 97/42956 WO 9742956PCTIUS97/08335 -208-
NH
2 H1 OCH 3 2
CH
3 0 0 NO0 0
CH
3 0,
H
4 s 1. NaOAc, DMF.
2. 4-NitrophelYl chloroformfate, NaHCO 3
CH
2 C1 2
H
2 0.
3. (2-PyridYl) -piperidin1-yl)propylamine,
CH
2 ,C1 2 4. 6N HC1/THF.
Scheme 8. synthetic scheme for example 16.
WO 97/42956 WO 9742956PCT/US97/08335 -209o Ar eO 0 o Ar lieC-I Y' N1jI
I
2 3 0Ole 1. t-BuOY, DMF, OOC; TSOH.H.0, DMF, 100-120-C.
2. NaH, THF, reflux.
3. 4 -Methoxycarbolyl -4 -phelylp ipe ridinle, K 2 C0 3 Nal, 1,4dioxane, ref lux.
Scheme 9. Synthetic scheme for example 17.
0 0 0 0
H
0
R
NH
2 OR HN I0IMe Do- R 1-1' N OMe ClL11 NO 2 Ref. Sch.3 for resolution
R
0 1 NO 2 RO N 0 R N O Me for racemi compounds H2
N,
2. HCl1 for pure enantiomers Scheme 10. General synthetic scheme for examples 18, 41, 42, 43, 44, and 0 0 ~rr 1 N OMe F F 0 NO 2 <1 0N 0 'I N O 1 H C 1 f H N N OMe
N
NH 2 Scheme 11. Preparation of example 29.
MeO 1. HC1
H
MeO, 1 42.
HC1 0
H
MeO MeO
H
Scheme 12. General synthetic scheme for 0 examples 30, 31, 35, 37, 39, 40, 47 and 48.
Nil 2 Yt N 2 113 NaOC1 NaOlH, EtOH- 0-
H
3 P (QE t) 3 EtOl N-0 Ik y 3 N -Ow AgNO 3
H
2 0 CC1 4 IE tOH N -0 O H 0 0 Piperidinium Acetate
NH
,CN 2jO" DMAP, EtOAc N-0 Gil 0-\O
O
-a-Methylbenzylamine Ph :1-K
CH
2 C1 2 DMAP, CH 2 C1 2 N- -0-W N Scheme 13. Preparation of example 37 part-i N-0 Cl 'T 0
O
2 Ammonia DMAP, CH 2 C1 2 N-0 0 0 N NH:l 1. 1 N NaOH, THF 2. 6 NHCl
'NILO
DMAP, DMAPECD, C1- Cl 2 Scheme 13 (continued) Preparation of example 37 part-2 Br
K
2 00 3
KI
DMF
Hydrazine MeOH Scheme 14. Preparation of example 22 (part-i) WO 97/42956 WO 9742956PCT/US97/08335 -2 16- 0 0 o 0 OBn 2, 4-difluorobenzaldehyde, Piperidine, HOAc OMe H 2N" NH NaHCO 3 EtOH, A 1. p-Nitrophenylchloroformate 2. R (+)-Phenethylamine 3. Separate diastereomers 4. DBU BnO 1. p-Nitrophenylchioroformate 2. a. R'NH 2
THF
b. aq. HC1
H
1. H 2 Pd-C 2. NH 3
EDC
DMAP
3. HCl Et 2 o HC1 R
CN
Scheme 14 (cont.) Preparation of example 22 (part-2) SUBSTITUTE SHEET (RULE 26) ,"NO 2
NC
1. a. R'NH 2
THF
b. aq. HCl
P
1 .NaQH 2.NH 3 ,or MeOH EDC, DMAP 3.HCl Et2O 0 0 1-110 1-11 0 HC1 -4
H
Example 29: Example 30: Rt=
NH
2 OMe Scheme 15. Preparation of examples 23 and 24.
-NO 2 HND
/N-
F
F
0 0 MeO 0
N~
0 1.DMF,heat H 2 N No 2.Hydraziie OH
F
F
D A S M e O N
Y
Scheme 16. Preparation of examples 19, 20 and 21.
MeO,
+H
2 N NR 2 1. THF O.MO 2. HCl
OH
Ox alyl chloride DMSO Me( MeO,r 1-1~0 v '2 H 2
NOH
0 -0 MeO
N-OH
HO 1-11 0 11-10 NR 2 N Me Scheme 17. Preparation of examples 25, 26,- 27 and 28.
1 2 3 1. Br 2 CHC1 3 0 OC 2. Neat 130 OC Scheme 18. Preparation of examples 33 and 34.
1 2 2 No 3 1. CiCOOMe, DMAP, C hC1 2 2. 10% Pd-C, MeOH(99%) Ph 3. EDC, DMAP, C'K~1 2 H, dCOOMe Scheme 19. Preparation of example 32.
NH
2. NaBH 4 MeC H 2 N ND MeO 2. HC1 PhN 1. Ph~gBr 2 .H- 2 /Pd-C O9 H HN _Ph HG3 0 3 0 HG3 N 0
H
Scheme 20. Preparation of examples 38 and 46.
WO 97/42956 WO 9742956PCTIUS97/08335 -223- 0 At Bno -0 0 0 Ar R n~J R H.AWk 0 At o At o Ar 0 1. KtBuO, DMF; TsOHii 2 O, DMF, 100-110*C.
2. NaH, THY, 1,5-dibromopentane; 4-Methoxycarbonyl-4phenylpiper idine, K,,CO 3 dioxane.
3. Pd/C, MeOH. CH.
3
NH
2 DMAPECD, CH 2 ,C1 2 4. NaH, ClC0 2 Me, THF.
H21 Pd/C, MeOH. 3-(4-Methoxycarboflyl-4phenylpiperidin-1-y.) propylamine, DMAPECD, CH 2 C1 2 Scheme 21 (part-2). S ynthetic scheme for examples 49, 50 and 51.
md r H
H
Scheme 21 (part-i). Synthesis of (S)-(-)-2-methyl-1,5dibromopentane (Thurkauf et al. J. Org. Chem. 1987, 52, 5466- 5467).
WO 97/42956 WO 9742956PCTIUS97/08335 -224- R OH Y.R&N,0 1. -MCPBA, CH 2 C1 2 2. 4- (2-Pyridyl)piperidile, dioxane.
3. Oxalyl chloride, DMSO, CH 2 C1 2 Scheme 22. Synthetic scheme for examples 56 and 57 WO 97/42956 WO 9742956PCT/US97/08335 -225- N r 0 Ar A1 H Moo0 Scheme 23. Synthetic scheme for example 59 WO 97/42956 WO 9742956PCTIUS97/08335 -226-
R
1
OH
N
R
2 AIC13 Br RI H, F, C1, CH3 R2 =4-fluoro- I -rnethoxy, CH3 4-methyl-I -methoxy, thiomethoxy, CI, F
H
R3 methyl, methoxymethyl R4 =CH3, OCH3 multifluoro
NO
2 1 BrCH 2
CH
2
CH
2
NHBOC
2. TEA Scheme for the synthesis of examples 61-67.
SUBSTITUTE SHEET (RULE 26) WO 97/42956 WO 9742956PCTIUS97/08335 -227- F F F F IBr ,-Br
R
NH MeQN R Me R H H
F
FIIQK Ar
F
MeO I N or HN NAr R~
H
X C-CN Synthetic scheme for examples 68 and 69.
WO 97/42956 WO 9742956PCT/US97/08335 -228- Br -*-Br
R
R Me X Me, CH 2 OMe QAr Y =CN, Arl Synthetic scheme for examples 70-72.
0
DMF
N (COC) 2
DMF
0
DAST
CH2C12
F
F F
NO
2 0 u
H
THF O
N
F
F
F- -I -F Scheme for the synthesis of example 76.
0 (N N 1. PTSA. Benzene. Heat 2. NaCNBH3, MeOH H2, Pd-C N N
H
THF H3C. C F- ~F
N
'C
Scheme for the synthesis of example 77. -4 0 00
U'
Scheme for the synthesis of example 78 Br' "Bn K 2 C0 3 0 F-1C.
2. HCI
F
H
2 Pd-C DMAPECD. DMAP, CHI 2 01 2 0 0
F
Scheme for the synthesis of example 79 F F -oC.
NH
ar~'~en K 2 C03 1. 0 2. HCI F F IOH H2. Pd-C DMAPECO. DMAP. CHI 2C02
H
2
N
0 0
NO
2 X CH, N N K2C03. Dioxane
H
RI H. R2 =H Ri= H. R2 CH3 XjANO 2
N
RI
0 t 0 X-jeL- N02
N
H
K2C03, acetone Reflux Scheme for the synthesis of examples 80, 82, 83 and 84.
H2. 10% Pd-C MeOH Scheme for the synthesis of example 81.- 0$
(N
H2NOH.HCI EtQH LiAH4 P20O
N
1. PhCOCI, K2C03 2. H2, Pd-C, EtOH H C0
H
U)
C
w
U)
C:
-4
U)
X
in m
N
0)
F
F
0 0
H
3
C
0
O-B
Nio
H
H
F 2O THF, Et3N Reflux 'NkOH Scheme for the synthesis of example 88.
AIC13 CH-2CI2 1. Br "Nff X= 0, S, W~e CH-2C12 Synthetic scheme for examples -89-91.
Claims (33)
1. A compound having the structure: A x N R 1 2 R 3 0 A x 0 rn N X wherein A is YY Y 4 N YT 3 wherein each independently of -H; Y 1 Y 2 Y 3 Y 4 and Y 5 is straight chained or branched SUBSTITUTE SHEET (RULE 26) WO 97/42956 WO 9742956PCTIUS97/08335 -236- alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, mono fluorocycl1oalkyl, polyfluorocycloalkyl or cycloalkenyl; -Cl, -Br, or -NO 2 -N 3 -CN; -OR 3 -OCOR 3 -COR 3 -CONHR 3 1 CON(R 3 2 or -COOR 3 or any two of Y It Y 2 Y 3 1 Y, and Y 5 present on adj acent carbon atoms can constitute a methylenedioxy group; wherein X is S; 0; or NR 3 wherein R, is -NO 2 -CN; straight chained or branched C 1 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C7 alkenyl or alkynyl; C 3 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 wherein R. is straight chained or branched C 1 -C7 alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or. branched C 2 alkenyl or ailkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; C 3 -C 10 cycloalkyl-Cl-C 1 0 -alkyl, 0 cycloalkyl-Cl-Cl 0 monofluoroalkyl or C 3 -C 10 cycloalkyl-C,-C, 0 polyfluoroalkyl; -CN; CH 2 XR 3 CH 2 X (CH 2 P NHR 3 1 (CH 2 nNHR 3 1 CH 2 X (CH 2 PN (R 3 2' -CH 2 X (CH 2 P N 3 1 or CH 2 X (CH 2 PNHCXR7; or -OR 3 wherein each p is independently an integer from 1 to 7; wherein each n is independently an integer from 0 to wherein each R 3 is independently straight chained or branched C 1 alkyl, monofluoroalkyl or WO 97/42956 PCTfUS97/8335 -237- polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; wherein R 4 is R nN V R I R v R7 R6 wherein Z' is CO, (CH 2 )oCO, or CO(CH 2 wherein each V is independently 0; S; CH 2 CRR C(R 7 2 or NR 7 wherein each m is independently an integer from 0 to 3; wherein o is an integer from 1 to 3; wherein each R is independently 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 -NO 2 -CN; -C0 2 R 3 or -OR 3 wherein R, and R 7 each independently may be F; Cl; Br; I; -COR 3 -C0 2 R 3 -CON(R 3 2 -CN; -NO 2 -N(R 3 2 -OR 3 -(CH 2 )pOR 3 -(CH 2 )pSR 3 straight chained or branched CI-C 7 alkyl, aminoalkyl, carboxamidoalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl, or C 3 -C 7 cycloalkyl or cycloalkenyl; wherein the alkyl, aminoalkyl, carboxamidoalkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl may be substituted with one or more aryl or heteroaryl, wherein the aryl or heteroaryl may be substituted with -Cl, -Br, -NO 2 SUBSTITUTE SHEET (RULE 26) WO 97/42956 PCTIUS97/08335 -238- CN, -OR 3 -SR 3 C,-C 3 alkyl, or carboxamido; aryl or heteroaryl, wherein the aryl or heteroaryl may be substituted with one or more -Cl, -Br, COR 3 C0 2 R 3 -CON(R 3 2 -CN, -NO 2 -N(R 3 2 -OR 3 -SR 3 (CH 2 )oOR 3 (CH 2 )oSR 3 straight chained or branched alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; and wherein each R 6 is independently straight chained or branched C,-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; or -OR 3 or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1, wherein the compound comprises the enantiomer.
3. The compound of claim 1, wherein the compound comprises the enantiomer.
4. The compound of claim 1 having the structure: N Z' N V 8 T, 5 I IMm 6 2 N x M v R 7 R 6 The compound of claim 4, wherein Z' is CO and n is 0. SUBSTITUTE SHEET (RULE 26) -239-
6. The compound of claim 5 having the structure: F
7. A compound selected from the. group consisting of: F F 0 0 N 0H F 0 N)II N 0 i A -240- and a -241-
8. A compound having the structure: o r c) X RR wherein A is Y "'2 H Y' Y 3 N YIY Y, N YI 0 N or Y -242- wherein each of Y 1 Y 2 Y 3 Y 4 and Y, is independently -H; straight chained or branched C,-C alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C,-C. aikenyl or alkynyl; cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -C1, -Br, or -N 3 -CN; -OR3, -OCOR3, -COR 3 -CONHR3, -CON(R3), or -COOR 3 or any two of Y 2 Y 3 Y 4 and Y 5 present on adjacent carbon atoms can constitute a methylenedioxy group; wherein X is S, O, or NR3, provided that X is not NR- when R. is (viii) below; wherein R 1 is -NO; -CN; straight chained or branched CO-C- alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched alkenyl or alkynyl; C3-C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R 3 -OR 3 -(CH 2 OR 3 -COR 3 -CO 2 R 3 or e. -CON (R 3 2; wherein R 2 is straight chained or branched C1-C, alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C, cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; C3-C0o cycloalkyl-C 1 -Clo-alkyl, cycloalkyl-C-Clo-monofluoroalkyl or C3-Co0 cycloalkyl-C l Clo-polyfluoroalkyl; -CN; -CH 2 XR 3 -CH 2 X (CH 2 )pNHR 3 (CH 2 )nNHR 3 -CH 2 X(CH 2 )pN(R 3 -CH 2 X(CH 2 N 3 or -CHX (CH 2 pNHCXR, or -OR 3 wherein each p is independently an integer from 1 to 7; wherein each n is independently an integer from 0 to -243- wherein each R, is independently straight chained or branched C,-C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; szraight chained or branched C-.-C 7 alkenyl or alkynyl; or '--cycloalkyl, monofluorocycloalkyl, Polyfluorocycloalkyl or cycloalkenyl; wherein R 4 is ZtPN V R R 6 N z m R6 mR R *0 0 -244- (i V) R R 6 R m -N _R R R R6j~>. RR RV R 6m :R R R~m 6 R7 *Y I R R4 (vii) N m R Wrm 10 Y 3 a D -245- (Viii) All L~ 1 8 R R R R f\\R -Z r i rN V (ix) Lfl W R6 v .v R6 oR7 -246- wherein Z is C 2 -C 7 alkenyl or alkynyl; CH2; O; CONR 3 S; SO; SO,; or NR 3 wherein Z' is CO, or CO(CH2)o; wherein each D is independently CH,; O; S; NR 3 CO; or CS; wherein W is C=O; C=NOR 3 substituted or unsubstituted phenyl, pyridyl, thienyl, furanyl, pyrazinyl, pyrrolyl, naphthyl, indolyl, imidazolyl, benzfurazanyl, benzfuranyl or benzimidazolyl, wherein the phenyl, pyridyl, thienyl, furanyl, pyrazinyl, pyrrolyl, naphthyl, indolyl, imidazolyl, benzfurazanyl, benzfuranyl or benzimidazoly 1 is substituted with -Cl, -Br, -NO 2 -CN, straight chained or branched CI-C alkyl, straight chained or branched C 1 -C 7 monofluoroalkyl, straight chained or branched C 1 -C 7 polyfluoroalkyl, straight chained or branched C 2 -C 7 alkenyl, straight chained or branched C 2 -C 7 alkynyl, C 3 cycloalkyl, C 3 monofluorocycloalkyl, C 3 polyfluorocycloalkyl, C 3 -C 7 cycloalkenyl, -N(R3) -OR 3 -COR 3 -C0 2 R 3 or -CON(R 3 2; wherein each V is independently O; S; CH 2 CR 5 R 7 C(R 7 or NR,; wherein each m is independently an integer from 0 to 3; wherein o is an integer from 1 to 3; o wherein each R 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; -N(R 3 2 -NO 2 -CN; -C0 2 R 3 or -OR 3 wherein R 5 is aryl or heteroaryl, substituted with one or -247- more Cl; Br; I; COR 3 C0 2 ,R 3 -CON(R 3 2 ON; -NO,; -OR 3 -SR 3 (CH 2 ),0R 3 (CH,),SR 3 straight chained or branched C,-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C9)-C7 alkenyl, C,-C7 alkynyl; or 03-07 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; wherein each R 6 is independently straight chained or branched 01-07 alkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; 03-07 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; or -OR 3 wherein R 7 is aryl or heteroaryl, substituted with one or more 01; Br; I; C0R 3 ;C 2 3 -CON(R); ON; -N (R 3 2 -OR 3 -SR 3 (CH 2 0 0R 3 (CH 2 SR 3 straight chained or branched CI-C 7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched 02-07 alkenyl, 02-07 alkynyl; or 03-07 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; with the proviso that when the compound has formula (a) above and R 4 is Ci,(v) or (ix) R 7 is heteroaryl; wherein R 8 is substituted or unsubstituted benzyl, benzoyl, phenyl, pyridyl, thienyl, furanyl, pyrazinyl, pyrrolyl, naphthyl, indolyl, imidazolyl, benzfurazanyl, benzfuranyl, benzimidazolyl or 2-keto-l-benzimidazolinyl, wherein the benzyl, benzoyl, phenyl, pyridyl, thienyl, furanyl, pyrazinyl, pyrrolyl, naphthyl, indolyl, imidazolyl, benzfurazanyl, benzfuranyl, benzimidazolyl or -248- 2-keto-1-benzimidazolinyl is substituted with -F, -Cl, -Br, -CN, straight chained or branched alkyl, straight chained or branched CI-C-7 monofluoroalkyl, straight chained or branched Cl-C, polyfluoroalkyl, straight chained or branched C 2 -C, aikenyl, straight chained or branched Cq__C 7 alkynyl, C-,C- cycloalkyl, C 3 -C_ 7 monofluorocycloalkyl, C 3 -C'7 polyfluorocycloalkyl, C 3 cycloalkenyl, -N -COR!, or -CON(R 3 substituted or unsubstituted straight chained or branched C 1 alkyl, monofluoroalkyl or polyfluoroalkyl; substituted or unsubstituted straight chained or branched C.2-C 7 alkenyl or alkynyl; 0 3 -C- cycloalkyl or cycloalkenyl, wherein the alkyl, monofluoroalkyl, polyfluoroalkyl, alkenyl, aikynyl, cycloalkyl or cycloalkenyl is substituted with -H, phenyl, pyridyl, thienyl, furanyl, pyrazinyl, pyrrolyl, naphthyl, indolyl, imidazolyl, benzfurazanyi, benzfuranyl, benzirnidazolyi, -N(R 3 2 -NO 2 -CN, -C0 2 R 3 -OR 3 -249- w R R5 or R7 or a pharmaceutically acceptable salt thereof.
9. The compound of claim 8 having the structure: 0 A N V R3 N R 6 .0 R RO R7 2,I 9~ 0 0 0690 s o S S 4 e oooo ,0 oooo S sao B .5.5 9 S B S e4 The compound of claim 9 having the structure: N V P mR6 R7 -250-
11. A compound having the structure: B N R wherein A is Y 2 Y N 13 Y2 Y Y.1-N Y 3 *Goo 0 3. 0 0 0 000 a s o 0 wherein each of Y 1 Y 2 Y 3 Y 4 and Y, isr independently straight chained or branched CI-C 7 alkyl, monof luoroalkyl or polyf luoroalkyl; straight chained or branched C 2 -C7 alkenyl or alkcynyl; C 3 -C 7 cycloalkyl monof luorocycloalkyl, 1- po2.yfluorocycloalcyl or cycloalkenyl; -Cl, -Bor -1 N2' -N3 -CN; -OR, -OCOR4,-O. -CONHR 4 or -COOR.; or any two of Y 1 Y 2 Y 3 Y. and Y, present on adjacent carbon~ atoms can constitute a methylenedioxy group; wherein X is S; 0; or NR,; wherein B is straight chained or branched Cl-c, alkyl, monof luoroalkyl, polyf luoroalkyl, aikoxy or thioalkyl; straight chained or branched C 2 -C, alkenyl; -SCH 2 C 6 H 4 OR.; (CH' 2 ,C6H; -CH 2 X (CH 2 ,NR.; -(CH 2 ).NHR 4 or -OR 4 iswherein R, is -NO 2 7; -CN; straight chained or branched C2 alkyl, ronofluoroalkyl or pojlyfluoroalkyl; straight chained or branched C.-C, alkenyl or alkynyl; C3-C, cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or 0 2 o clorel -CN (R4) 2 -OR 4 OR,; -COR,; wherein R 2 is straight chained or branched alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, monofluoroalkyl or polyfluoroalkyl; straight 000000chained or branched alkenyl or alkynyl; C 3 -C, 00000cycloalkyl, monof'luorocycloalkyl, oeeooo polyfluorocycloalkyl or cycloalkenyl; C 3 -CIO .0.0 cycloalkyl C 1 CIO -alkyl, C 3 -C2 0 cycloalkyl -C ;L6 monofluoroalkyl or C 3 -C 10 cyclo'alkyl-C,-C 0 o o* oo polyfluoroalkyl; -CN; CH. 2 XR4, -CH 2 X (CH 2 PNHR4, o (CH 2 ),NMR 4 CH 2 X (CH 2 )pN (R 4 2 -CH 2 X (CH 2 pN 3 or -CH 2 X(CH 2 )pNHCXR.; or -OR 4 wherein each p is independently an integer from 1 ~TF~ to 7; wherein each n is independently an integer -~from 0 to -252- wherein 3 is R I R 9* 9 9 9 9 99 9 9 9 9 9. 9. 99 9 9 9 9 9 9 9 .9.9 *999 9 9 999*99 9 99 *9 30 99 9. I-'z R i R6 Rv N -253- -Z R RI R R R R P R R -254- R R hff -z w4 NbAAR 6 R 7 or R R m m1R R 7 R 6 wherein Z is C 2 -C7 alkenyl or alkynyl; CH 2 0; CO; C0 2 CNIR4; S; SO; S0 2 or N&R; wherein Z' is (CH 2 CO, (CH 2 or CO(CH 2 wherein each D is independently CH 2 0; S; NR1; CO; or CS; wherein W is C-0; C--NOR; substituted or unsubstituted phenyl, pyridyl, thiophenyl, furanyl, pyrazinyl, pyrryl, naphthyl, indolyl, imidazolyl, benzfurazanyl, berzfuranyl or benzyimidazolyl, wherein the phenyl, pyridyl, thiophenyl, furanyl, pyrazinyl, pyrryl, naphthyl, *i indolyl, imidazolyl, benzfurazayl, benzfuranyl or benzyimidazolyl is substituted with -Cl, Br, -NO 2 -C1, straight chained or branched C,-C 7 alkyl, straight chained or branched C,-C 7 monofluoroalkYl, straight chained or branched C,-C 7 polyfluoroalkyli straight chained or branched C 2 -C 7 -255- aJlkenyl, straight chained or branched C, C' alkny.,cycloalkyl, C 3 C_ monofluorocycloalkyl, C C, polyfluorocycloalkyl, C 3 cycloalkenyl, -N(R 4 2 OR 4 COR, -C0 2 R, or -CON 2 wherein each V is independently 0; S; CH 2 CRsR,; C (R 7 or NR,; wherein each m is independently an integer from 0 to 3; wherein o is an integer from i-to 3; wherein each R is independently straight chained or branched C C, alkyl, monof luoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C, alkenyl or alkynyl; -N(F4) 2 -CN; -CO 2 R;,or wherein each R, is independently straight chained or branched C, alkyl, monof luoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C, alkenyl or alkynyl; C cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; wherein R. is aryl or heteroaryl substituted with one or more of F; Cl; Br; 1; COR 3 -C0 2 R 3 CON 2 CN; -NO 2 -N(R 3 2 -OR 3 ,I -SR 3 (CH 2 ).OR 3 (CH 2 )cSR3; straight chained or branched C, C.7 alkyl, 30 monofluoroalkyl., polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C 2 -C7 alkenyl, C 2 alkynyl, C 3 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; Rj wherein each R, is independently straight chained or branched C 1 alkyl, hydroXyalkyl, -256- aminoalkyl, alk-oxyalkyJ., monofluoroalkyl or polyf luoroalkyl; straight chained or branched c2-c, alkenyl or alkynyl; C3-C, cycloalkyl, monof2uorocycloalkyl, polyf2.uorocycloalkyl or cycloalkenyl; or -OR.; wherein is aryl or heteroaryl substituted with one or more of F; Cl; Br; 1; COR3; CO. 2 -CONCR 3 2 CN; -NO 2 -N(R3) 2 -OR3, -SR3; (CH, 2 0 0R3; (CH, 2 0 SR,; straight chained or branched Cl-C7 alkyl, mono fluoroalkyl, po2.yfluoroalkyl, arninoalkyl, or carboxamidoalkyl; straight chained or branched alkenyl, C 2 alkynyl, cycloalkyl, ronofluorocycloalkyl, polyfluorocycloalkyl or cycloalkelYl; and wherein Re is substituted or unsubstituted benzyl, benzoyl, phenyl, pyridyl, thiophenyl, furanyl,. pyrazinyl, pyrryl, naphthyl, indolyl. imidazolyl, benzfurazanyl, benzfuranyl, benzimidazo2lyl or 2-keto-1i-benzimidazolinyl, wherein the benzyl, benzoyl, phenyl, pyridyl, thiophenyl, furanyl, pyrazinyl, pyrryl, naphthyl, indolyl, imidazolyl, benzfurazanyl, benzfuranyl, 25 k~enzimidazolyl or 2- keto-1-b~enzimidazolinyl is substituted with -Cl, -Br, -NO 2 -CN, straight chained- or branched alkyl, straight chained or branched C C, monofluoroalkyl, straight chained or branched C, polyf luoroalkyl, straight chained or branched C-C, alkenyl, straight chained or branched C 2 alkynYl, C3-C., cycloalkyl, C,-C, monofluorocycloalkyl, C3 C,7 polyfluorocycloalkyl, cycloalkenyl, -NCR)I 2 -COR 4 -C0 2 or -CON(R 4 2 substituted or umeubstituted. straight 4~T 3 1 5 chained or branched C C, alkyl, monof luoroalkyl or polyfluoroalkyl; substituted or unsubstituted 1straight chained or branched C 2 alkenyl or -257- alkynyl; q-C 7 cycloalkyl or cycloalkenyl, wherein the alkyl, monofluoroalkyl, polyfluoroalkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl is substituted with phenyl, pyridyl, thiophenyl, furanyl, pyrazinyl, pyrryl, naphthyl, indolyl, imidazolyl, benzfurazanyl, benzfuranyl, benzimidazolyl, -NO, -C?4 -COA, R7? a or a pharmaceutically acceptable salt thereof.
12. The compound of claim 11 wherein the compound comprises the enantiomer.
13. The compound of claim 11 wherein the compound comprises enantiomer.
14. The compound of claim 11 having the structure: R 0 A B2IRS RqR Na R -258- The compound of claim 14 having the structure: R
16. The compounld of claim 15, wherein the compound is selected from the group consisting of: and -259-
17.- A compound having the structure: A R 1 NR R 2 LB A iR 3 o R R of N R 2 R wherein A is ,Y 3 1Y 3 Y N 20 S S S S S S S *5 S S S =N ~0 N wherein each of yi, Y2 Y3, Y4 and Y 5 is independently straight chained or branched C,-c 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C,-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -Cl, -Br, or -NO2; -N3; -CN; -OR4, -OCO.ly -CO&, -CONHR 4 -CON(R4) 2 or -COO&; or any two of Y 2 Y 4 and Y, present on adjacent carbon atoms can -260- constitute a methylenedioxy group; wherein X is S; 0; or NR,; wherein B is straight chained or branched c. -C. alkyl, ronofluoroalkyl, po2.yfluoroalky., alkoxy or thioal.Jyl; straight chained or branched c 2 alkenyl; -SCH 2 C 6 H4OR4; 2 CH)flE -C (C 2 ,NHR 4 (CH 2 or -OM,; wherein is -NO 2 -CN; straight chained or branched CI-C, al.kyl, monofluoroalkyl or polyf2.uoroalky.; straight chained or branched c 2 -c, alkeny. or alkynyl; C3 -C7 cycloalkyl, isnonofluorocycloalkyl, polyfluorocycloa.kyl or cycloalkenyl; -N POR,; -COR,; CO 2 R4; or -CON(R4) 2 wherein R 2 is straight chained or branched alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, :monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 alkenyl or alkynyl.: C,-c, cycloalkyl, Tonofluorocycloalkyl, **polyf2.uorocycloalkyl or cycloalkenyl; C 3 -C2 0 cycloalkyl -C CIO -alkyl, C.-CO cycloalkyl-C-C 0 ronofluoroalkyl or C3 -CIO cycloalkyl-C,-C 0 ::polyfluoroalkyl; -CN; -CH 2 XR4, -HX (CH 2 PNHR,, -(CH 2 INHR,, -CH 2 X (CH 2 PN (R4) 2' -CH2X (CH 2 ,N 3 or -CHX(CH 2 ),NHCXR,; or -OR,; wherein each p is independently an integer from I. to 7; wherein each n is independently an integer fromn 0 to wherein R3 iS -26 1- R 7 6 is 30 9 wherein Z' is (CH 2 CO, (CH 2 or CO(CH 2 wherein each V is independently 0i; S; CH2; CL4R7; C(R 7 2 or NR 7 wherein each is independently an integer from 0 to 3; wherein o is an integer f rom 1 to 3; wherein each R is independently straight chained or branched C,-C 7 alkyl, monof luoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; -N(R 4 2 -NO 2 -Cii; -COjR&; or wherein each fl~is independently H; straight chained or branched C,-C7 alkyl, monof luoroalkyl or polyfluoroalkyl; straight chained or branched C 2 C 7 alkenyl or alkynyl; C3-C7 cycloalkyl, ionofluorocycloalkyl, polyfluorocyCloalkyl or cycloalkeflyl; wherein P.3 and R7 each independently may be F; Cl; Br; 1; -COR3; -C0 2 R 3 -CON(R3) 2 -CII; -NO 2 -N(R 3 -OR 3 -SR 3 -(CH 2 ),0R 3 -(CH 2 ),SR 3 straight chained or branched C 1 -C 7 alkyl, aminoalkyl, carboXaflidoalkyl; straight chained or branched c 2 -c 7 alkenyl or alkynyl, or C3-C 7 cycloalkyl or cycloalkenyl; wherein the alkyl, aminoalkyl, carboxamidoalkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl may be suibstituted with one or more aryl or heteroaryl, wherein the aryl or heteroaryl -262- may be substituted with -Cl, -Br, NO 2 CN, -SR3, C,-C3 alkyl, or carboxamido; aryl or heteroaryl, wherein the aryl or heteroaryl may be substituted with one or more -Cl, -Br, COR,, CO 2 R3, -CON(R3,), -CN, -NO 2 -NCR3) 2 -OR 3 -SR3, (CH 2 0R31 (C 2 0 SR3; straight chained or branched C2 alkyl, monof2.uoroalkyl or polyfluoroalkyl; -straight chained or branched C 2 -C. alkenyl, C 2 -C-7 alkynyl, C 3 cycloalkyl, monofluorocycloalkyl, polyf luorocycloalkyl or cyc2.oalkenyl; and wherein each R. is independently straight chained or branched C C, alkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C-_C, alkenyl or alkynyl; C3-C, cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkelyl; or -OR&; or a pharmaceuticaJlly acceptable salt thereof. *18. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 1 and a pharmaceutically acceptable carrier.
19. The pharmaceutical composition of claim 18 wherein the amount of the compound is an amount from about 30 0.01 mg to about 500 mg. The pharmaceutical composition of claim 19 !wherein the amount of the compound is f rom about 0. 1 mg to about 60 mg.
21. The pharmaceutical composition of claim 20 wherein the amount of the compound is f rom about 1 mg to about 20 mg. -263-
22. The pharmaceutical composition of claim 18 wherein the carrier is a liquid and the composition is a solution. 23 The pharmaceutical composition of claim 18 wherein the carrier is a solid and the composition is a tablet. S** 20 o. a a 25 a a a a o
24. The pharmaceutical composition of claim 18 wherein the carrier is a gel and the composition is a suppository. The pharmaceutical composition of claim 18, wherein the compound additionally does not cause a fall in blood pressure at dosages effective to alleviate benign prostatic hyperplasia. 26 A method of treating a subject suffering from benign prostatic hyperplasia which comprises administering to the subject an amount of the compound of claim 1 effective to treat benign prostatic hyperplasia.
27. A method of claim 26, wherein the compound additionally does not cause a fall in blood pressure at dosages effective to alleviate benign prostatic hyperplasia.
28. The method of claim 27, wherein the compound effects treatment of benign prostatic hyperplasia by relaxing lower urinary tract tissue.
29. The method of claim 28, wherein lower urinary tract tissue is prostatic smooth muscle. A method of treating a subject suffering from high intraocular pressure which comprises administering to the subject an amount of the compound of claim 1 effective to lower intraocular pressure. -264-
31. A method of treating a subject suffering from a disorder associated with high cholesterol which comprises administering to the subject an amount of the compound of claim 1 effective to inhibit cholesterol synthesis. 32 A method of treating a disease which is susceptible to treatment by antagonism of the a. receptor which comprises administering to the subject an amount of the compound of claim 1 effective to treat the disease.
33. A method of treating a subject suffering from impotency which comprises administering to the subject an amount of the compound of claim 1 effective to treat impotency. 34 A method of treating a subject suffering from sympathetically mediated pain which comprises 20 administering to the subject an amount of the compound of claim 1 effective to treat o sympathetically mediated pain. A method of treating a subject suffering from 25 cardiac arrhythmia which comprises administering to the subject an amount of the compound of claim 1 effective to treat cardiac arrhythmia.
36. A method of treating a subject suffering from 0* 30 benign prostatic hyperplasia which comprises S. administering to the subject an amount of the compound of claim 1 effective to treat benign prostatic hyperplasia.
37. The method of claim 36 wherein the compound effects treatment of benign prostatic hyperplasia by relaxing lower urinary tract tissue.
38. The method of claim 37 wherein lower urinary -265- tract tissue is prostatic smooth muscle.
39. A method of treating a subject suffering from benign prostatic hyperplasia which comprises administering to the subject an amount of the compound of claim 1 in combination with a 5 alpha- reductase inhibitor effective to treat benign prostatic hyperplasia.
40. The method of claim 39 wherein the reductase inhibitor is finasteride.
41. A method of treating a subject suffering from benign prostatic hyperplasia which comprises administering to the subject an amount of the compound of claim 1 in combination with a 5 alpha- reductase inhibitor effective to treat benign prostatic hyperplasia. S* S 20 42. The method of claim 41, wherein the reductase inhibitor is finasteride. 43 A pharmaceutical composition comprising a therapeutically effective amount of the compound 25 of claim 1 in combination with a therapeutically effective amount of finasteride and a pharmaceutically acceptable carrier. S
44. The pharmaceutical composition of claim 43 wherein 30 the compound is present in an amount from about 0.01 mg to about 500 mg and the therapeutically effective amount of the finasteride is about 5 mg. The pharmaceutical composition of claim 44 wherein the compound is present in an amount from about T 0.1 mg to about 60 mg and the therapeutically effective amount of finasteride is about 5 mg.
46. The pharmaceutical composition of claim 45 wherein -266- the compound is present in an amount from about 1 mg to about 20 mg and the therapeutically effective amount of finasteride is about 5 mg.
47. A method of relaxing lower urinary tract tissue which comprises contacting the lower urinary tract tissue with an amount of the compound of claim 1 effective to relax lower urinary tract tissue. 48 The method of claim 47 wherein the lower urinary tract tissue is prostatic smooth muscle.
49. A method of relaxing lower urinary tract tissue in a subject which comprises administering to the subject an amount of the compound of claim 1 effective to relax lower urinary tract tissue. The method of claim 49, wherein the lower urinary tract tissue is prostatic smooth muscle. e 6O S 4000 c 0 S 0 O **OO *O O S O O
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| US1780196P | 1996-05-16 | 1996-05-16 | |
| US08/648768 | 1996-05-16 | ||
| US60/017801 | 1996-05-16 | ||
| PCT/US1997/008335 WO1997042956A1 (en) | 1996-05-16 | 1997-05-16 | Didhydropyrimidines and uses thereof |
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| AU727972B2 true AU727972B2 (en) | 2001-01-04 |
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| JP (1) | JP2000506904A (en) |
| AU (1) | AU727972B2 (en) |
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| US6228861B1 (en) | 1995-11-16 | 2001-05-08 | Synaptic Pharmaceutical Corporation | Dihydropyrimidines and uses thereof |
| US6245773B1 (en) | 1996-05-16 | 2001-06-12 | Synaptic Pharmaceutical Corporation | 5-(heterocyclic alkyl)-6-aryl-dihydropyrimidines |
| US6172066B1 (en) | 1996-05-16 | 2001-01-09 | Synaptic Pharmaceutical Corporation | Dihydropyrimidines and uses thereof |
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| US6080760A (en) * | 1997-06-18 | 2000-06-27 | Merck & Co., Inc. | Alpha 1A adrenergic receptor antagonists |
| US6057350A (en) * | 1997-06-18 | 2000-05-02 | Merck & Co., Inc. | Alpha 1a adrenergic receptor antagonists |
| US6143750A (en) * | 1997-06-18 | 2000-11-07 | Merck & Co., Inc. | Alpha 1a adrenergic receptor antagonists |
| US6214832B1 (en) | 1997-06-18 | 2001-04-10 | Merck & Co., Inc. | Bis-piperidinyl-pyrimidin-2-ones as alpha 1a adrenergic receptor antagonists |
| US6376503B1 (en) | 1997-06-18 | 2002-04-23 | Merck & Co., Inc | Alpha 1a adrenergic receptor antagonists |
| SG72827A1 (en) * | 1997-06-23 | 2000-05-23 | Hoffmann La Roche | Phenyl-and aminophenyl-alkylsulfonamide and urea derivatives |
| WO1999032486A1 (en) * | 1997-12-23 | 1999-07-01 | Alcon Laboratories, Inc. | Muscarinic agents and use thereof to treat glaucoma, myopia and various other conditions |
| CA2327543A1 (en) | 1998-05-06 | 1999-11-11 | Duke University | Method of treating bladder and lower urinary tract syndromes |
| WO2000006565A1 (en) * | 1998-07-30 | 2000-02-10 | Merck & Co., Inc. | ALPHA 1a ADRENERGIC RECEPTOR ANTAGONISTS |
| HN1999000149A (en) | 1998-09-09 | 2000-01-12 | Pfizer Prod Inc | DERIVATIVES OF 4,4-BIARILPIPERIDINA |
| WO2000025782A1 (en) | 1998-10-29 | 2000-05-11 | Merck & Co., Inc. | Dihydropyridinones and pyrrolinones useful as alpha 1a adrenoceptor antagonists |
| US6228870B1 (en) | 1998-11-10 | 2001-05-08 | Merck & Co., Inc. | Oxazolidinones useful as alpha 1a adrenoceptor antagonists |
| US6319932B1 (en) | 1998-11-10 | 2001-11-20 | Merck & Co., Inc. | Oxazolidinones useful as alpha 1A adrenoceptor antagonists |
| AU1345600A (en) | 1998-11-12 | 2000-06-05 | Merck & Co., Inc. | Pyrimidinedione derivatives useful as alpha 1a adrenoceptor antagonists |
| GB2344821A (en) | 1998-12-17 | 2000-06-21 | Merck & Co Inc | Crystalline pharmaceutically acceptable salt of an oxazolidinone derivative |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5202330A (en) * | 1985-06-03 | 1993-04-13 | E. R. Squibb & Sons, Inc. | 2-thio or oxo-4-aryl or heterocyclo-1,5(2H)-pyrimidinedicarboxylic acid diesters and 3-acyl-5-pyrimidinecarboxylic acids and esters |
| US4855301A (en) * | 1986-10-09 | 1989-08-08 | E. R. Squibb & Sons, Inc. | 1,2,3,4-Tetrahydro-6-substituted-4-aryl(or heterocyclo)-3-((substituted amino)carbonyl)-2-thioxo (or oxo)-5-pyrimidinecarboxylic acids and esters |
| US5403847A (en) * | 1992-11-13 | 1995-04-04 | Synaptic Pharmaceutical Corporation | Use of α1C specific compounds to treat benign prostatic hyperlasia |
| PL320263A1 (en) * | 1994-11-16 | 1997-09-15 | Synaptic Pharma Corp | Dihydropyrimidines and their application |
-
1997
- 1997-05-16 CA CA002253862A patent/CA2253862A1/en not_active Abandoned
- 1997-05-16 WO PCT/US1997/008335 patent/WO1997042956A1/en not_active Application Discontinuation
- 1997-05-16 EP EP97924745A patent/EP1021185A4/en not_active Withdrawn
- 1997-05-16 JP JP9541146A patent/JP2000506904A/en not_active Withdrawn
- 1997-05-16 AU AU30082/97A patent/AU727972B2/en not_active Ceased
Also Published As
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|---|---|
| EP1021185A4 (en) | 2005-09-07 |
| JP2000506904A (en) | 2000-06-06 |
| WO1997042956A1 (en) | 1997-11-20 |
| EP1021185A1 (en) | 2000-07-26 |
| CA2253862A1 (en) | 1997-11-20 |
| AU3008297A (en) | 1997-12-05 |
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