MAO-B INHIBITORS USEFUL FOR TREATING OBESITY
The invention provides novel compounds of formulae I and II: that are monoamine oxidase-B inhibitors, which can be useful in treating obesity, diabetes, and/or cardiometabolic disorders (e.g., hypertension, dyslipidemias, high blood pressure, and insulin resistance).
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This application claims the priority benefit of U.S. Provisional Application No. 60/696,067 filed Jul. 1, 2005, now pending, which is incorporated herein by reference.
FIELD OF THE INVENTIONThe present invention provides compounds and pharmaceutical compositions thereof and methods of using the same for treating obesity, diabetes, and/or cardiometabolic disorders (e.g., hypertension, dyslipidemias, high blood pressure, and insulin resistance).
BACKGROUND OF THE INVENTIONL-Selegiline is a monoamine oxidase (MAO) inhibitor that was developed for the treatment of neurological disorders and is primarily used to treat Parkinson's disease. MAO is an enzyme responsible for metabolizing biogenic monoamines including serotonin, dopamine, histamine, and phenylethylamine. By inhibiting MAO located in the central nervous system (CNS), MAO inhibitors and their analogues increase the concentration of monoamines present within the brain synapses. This enhances monoamine-mediated neurotransmission, effectively treating neurological disorders such as Parkinson's disease and depression.
MAO enzymes are also located in a number of peripheral (non-CNS) tissues, including adipose tissue, muscle, and liver. The function of MAO enzymes in these tissues has not been established. Currently, the only approved clinical use of L-selegiline and other MAO inhibitors is for the treatment of neurological disorders such as Parkinson's disease and depression.
Obesity is associated with an increase in the overall amount of adipose tissue (i.e., body fat), especially adipose tissue localized in the abdominal area. Obesity has reached epidemic proportions in the United States. The prevalence of obesity has steadily increased over the years among all racial and ethnic groups. According to the United States Surgeon General, 61% of the adult population and 14% of children are obese or overweight. Forty four million Americans are obese, with an additional eighty million deemed medically overweight. Obesity is responsible for more than 300,000 deaths annually, and will soon overtake tobacco usage as the primary cause of preventable death in the United States. Obesity is a chronic disease that contributes directly to numerous dangerous co-morbidities, including type 2 diabetes, cardiovascular disease, inflammatory diseases, premature aging, and some forms of cancer. Type 2 diabetes, a serious and life-threatening disorder with growing prevalence in both adult and childhood populations, is currently the 7th leading cause of death in the United States. Since more than 80% of patients with type 2 diabetes are overweight, obesity is the greatest risk factor for developing type 2 diabetes. Increasing clinical evidence indicates that the best way to control type 2 diabetes is to reduce weight.
The most popular over-the counter drugs for the treatment of obesity, phenylpropanolamine and ephedrine, and the most popular prescription drug, fenfluramine, were removed from the marketplace as a result of safety concerns. Drugs currently approved for the long-term treatment of obesity fall into two categories: (a) CNS appetite suppressants such as sibutramine and (b) gut lipase inhibitors such as orlistat. CNS appetite suppressants reduce eating behavior through activation of the ‘satiety center’ in the brain and/or by inhibition of the ‘hunger center’ in the brain. Gut lipase inhibitors reduce the absorption of dietary fat from the gastrointestinal (GI) tract. Although sibutramine and orlistat work through very different mechanisms, they share in common the same overall goal of reducing body weight secondary to reducing the amount of calories that reach the systemic circulation. Unfortunately, these indirect therapies produce only a modest initial weight loss (approximately 5% compared to placebo) that is usually not maintained. After one or two years of treatment, most patients return to or exceed their starting weight. In addition, most approved anti-obesity therapeutics produce undesirable and often dangerous side effects that can complicate treatment and interfere with a patient's quality of life.
The lack of therapeutic effectiveness, coupled with the spiraling obesity epidemic, positions the ‘treatment of obesity’ as one of the largest and most urgent unmet medical needs. There is, therefore, a real and continuing need for the development of improved medications that treat obesity.
MAO-B inhibitors such as selegiline have been clinically useful in the treatment of CNS disorders. They have now unexpectedly been discovered to also have anti-obesity activity. Even more surprising is that the anti-obesity activity effects of MAO-B inhibitors are mediated via a peripheral (i.e., non-CNS) mechanism. This new discovery provides a novel approach for the treatment of obesity. Moreover, if the CNS effects of these compounds can be reduced, their peripherally mediated anti-obesity properties should provide therapeutic agents with greater safety. It has, as a result, become highly desirable to find MAO-B inhibitors with limited or no CNS effects. Compounds of this sort are expected to be useful in treating obesity and the variety of co-morbidities to which it contributes.
SUMMARY OF THE INVENTIONAccordingly, in an aspect, the present invention provides novel MAO-B inhibitors or stereoisomers or pharmaceutically acceptable salts that are useful to treat obesity, diabetes, and/or cardiometabolic disorders (e.g., hypertension, dyslipidemias, high blood pressure, and insulin resistance).
In another aspect, the present invention provides novel pharmaceutical compositions, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a stereoisomer or pharmaceutically acceptable salt thereof.
In another aspect, the present invention provides novel methods for treating obesity, diabetes, and/or cardiometabolic disorders (e.g., hypertension, dyslipidemias, high blood pressure, and insulin resistance), comprising: administering to a patient in need thereof a therapeutically effective amount of at least one of the compounds of the present invention or a stereoisomer or pharmaceutically acceptable salt thereof.
In another aspect, the present invention provides novel methods for treating CNS disorders, comprising: administering to a patient in need thereof a therapeutically effective amount of at least one of the compounds of the present invention or a stereoisomer or pharmaceutically acceptable salt thereof.
In another aspect, the present invention provides processes for preparing novel compounds.
In another aspect, the present invention provides novel compounds or stereoisomers or pharmaceutically acceptable salts for use in therapy.
In another aspect, the present invention provides the use of novel compounds for the manufacture of a medicament for the treatment of obesity, diabetes, and/or cardiometabolic disorders.
In another aspect, the present invention provides the use of novel compounds for the manufacture of a medicament for the treatment of CNS disorders.
These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors' discovery that the presently claimed compounds or stereoisomers or pharmaceutically acceptable salts thereof are expected to be effective MAO-B inhibitors.
DETAILED DESCRIPTION OF THE INVENTIONThe present invention is based on the unexpected finding that an MAO-B inhibitor is capable of reducing the amount of adipose tissue (i.e., body fat) in a warm-blooded mammal. This finding was unexpected because body fat can be reduced despite little, if any, concomitant reduction in food intake.
[1] In an embodiment, the present invention provides novel compound A or a stereoisomer or pharmaceutically acceptable salt thereof:
wherein: Y is O or H2 and R, R1, R2, X, X1, and Z are all independently selected from H, C1-6 alkyl, and a group capable of reducing or limiting the CNS activity of compound A; and,
provided that at least one of R, R1, R2, X, X1, and Z is other than H.
[2] In another embodiment, the present invention provides a novel compound of formula I or II, or a stereoisomer or a pharmaceutically acceptable salt thereof:
wherein:
R, at each occurrence, is independently selected from H, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl;
R1 is selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, (CH2)mCO2R, C2-6 alkenyl-CO2R, CH2CH(NHAc)CO2R, CH2CH(NHR)CO2R, and, (CH2)nPO(OR)2;
R2 is selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, (CH2)mCO2R, C2-6 alkenyl-CO2R, (CH2)nCON(R)2, (CH2)nPO(OR)2, and (CH2)n-tetrazole;
X and X1 are independently selected from H, OR, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, CF3, nitro, N(R)2, (CH2)m-tetrazole, (CH2)mCO2R, (CH2)mCONR2, (CH2)mCN, O(CH2)nCN, O(CH2)n-tetrazole, O(CH2)nCO2R, O(CH2)mCON(R)2, O—C2-6 alkenyl-CO2R, O(CH2)nPO(OR)2, NR—C2-4 alkenyl, NRSO2CH3, NR(CH2)nCO2R, NR(CH2)nCON(R)2, NR—C2-4 alkenyl-CO2R, NR(CH2)nPO(OR)2, NR(CH2)nSO2OR, NR(CH2)n-tetrazole, NRCO(CH2)nCO2R, NRCO(CH2)nCON(R)2, SO2NRCH3, OCH2CHMCONRCH2CO2R, CH2-aryl, O(CH2)nPO(OR)2, O(CH2)nSO2OR, (CH2)nN+(R)3A−, OCH2(CH2)nN+(R)3A−, O(CH2)n-biphenyl, O(CH2)n-biphenyl-(CH2)mCO2R, O(CH2)n-biphenyl-(CH2)mtetrazole, O(CH2)n-biphenyl-(CH2)mCN, O(CH2)n-biphenyl-(CH2)mCON(R)2, NR(CH2)n-biphenyl, NR(CH2)n-biphenyl-(CH2)mCO2R, NR(CH2)n-biphenyl-(CH2)mtetrazole, NR(CH2)n-biphenyl-(CH2)mCN, NR(CH2)n-biphenyl-(CH2)mCON(R)2, O(CH2)n-aryl, O(CH2)n-heteroaryl, NR(CH2)n-aryl, NR(CH2)n-heteroaryl, O(CH2)n-aryl(CH2)mCO2R, O(CH2)n-aryl-C2-6 alkenyl-CO2R, O(CH2)n-aryl(CH2)m-tetrazole, O(CH2)n-aryl(CH2)mCN, O(CH2)n-aryl(CH2)mCON(R)2, O(CH2)n-aryl(CH2)m—PO(OR)2, O(CH2)n-aryl-O(CH2)nCO2R, O(CH2)n-aryl-O—C2-6 alkenyl-CO2R, O(CH2)n-arylO(CH2)n-tetrazole, O(CH2)n-arylO(CH2)nCN, O(CH2)n-arylO(CH2)nCON(R)2, O(CH2)n-arylO(CH2)n—PO(OR)2, O(CH2)n-aryl-NR(CH2)nCO2R, O(CH2)n-aryl-NRC2-6 alkenyl-CO2R, O(CH2)n-aryl-NR(CH2)n-tetrazole, O(CH2)n-aryl-NR(CH2)nCN, O(CH2)n-aryl-NR(CH2)nCON(R)2, O(CH2)n-aryl-NR(CH2)n—PO(OR)2, NR(CH2)n-aryl(CH2)mCO2R, NR(CH2)n-aryl-C2-6 alkenyl-CO2R, NR(CH2)n-aryl(CH2)m-tetrazole, NR(CH2)n-aryl(CH2)mCN, NR(CH2)n-aryl(CH2)mCON(R)2, NR(CH2)n-aryl(CH2)m—PO(OR)2, NR(CH2)n-aryl-NR(CH2)nCO2R, NR(CH2)n-aryl-NR—C2-6 alkenyl-CO2R, NR(CH2)n-aryl-NR(CH2)n-tetrazole, NR(CH2)n-aryl-NR(CH2)nCN, NR(CH2)n-aryl-NR(CH2)nCON(R)2, NR(CH2)n-aryl-NR(CH2)nPO(OR)2, NR(CH2)n-arylO(CH2)nCO2R, NR(CH2)n-aryl-O—C2-6 alkenyl-CO2R, NR(CH2)n-aryl-O(CH2)n-tetrazole, NR(CH2)n-arylO(CH2)nCN, NR(CH2)n-aryl-O(CH2)nCON(R)2, NR(CH2)n-arylO(CH2)nPO(OR)2, O(CH2)n-heteroaryl(CH2)mCO2R, O(CH2)n-heteroaryl-C2-6 alkenyl-CO2R, O(CH2)n-heteroaryl(CH2)m-tetrazole, O(CH2)n-heteroaryl-(CH2)mCN, O(CH2)n-heteroaryl(CH2)mCON(R)2, O(CH2)n-heteroaryl(CH2)m—PO(OR)2, O(CH2)n-heteroaryl-O(CH2)nCO2R, O(CH2)n-heteroaryl-O—C2-6 alkenyl-CO2R, O(CH2)n-heteroarylO(CH2)n-tetrazole, O(CH2)n-heteroaryl O(CH2)nCN, O(CH2)n-heteroarylO(CH2)nCON(R)2, O(CH2)n-heteroarylO(CH2)n—PO(OR)2, O(CH2)n-heteroaryl-NR(CH2)nCO2R, O(CH2)n-heteroaryl-NR—C2-6 alkenyl-CO2R, O(CH2)n-heteroaryl-NR(CH2)n-tetrazole, O(CH2)n-heteroaryl-NR(CH2)nCN, O(CH2)n-heteroaryl-NR(CH2)nCON(R)2, O(CH2)n-heteroaryl-NR(CH2)n—PO(OR)2, NR(CH2)n-heteroaryl(CH2)mCO2R, NR(CH2)n-heteroaryl-C2-6 alkenyl-CO2R, NR(CH2)n-heteroaryl(CH2)m-tetrazole, NR(CH2)n-heteroaryl(CH2)mCN, NR(CH2)n-heteroaryl(CH2)mCON(R)2, NR(CH2)n-heteroaryl(CH2)m—PO(OR)2, NR(CH2)n-heteroaryl-NR(CH2)nCO2R, NR(CH2)n-heteroaryl-NR—C2-6 alkenyl-CO2R, NR(CH2)n-heteroaryl-NR(CH2)n-tetrazole, NR(CH2)n heteroaryl-NR(CH2)nCN, NR(CH2)n-heteroaryl-NR(CH2)nCON(R)2, NR(CH2)n-heteroaryl-NR(CH2)nPO(OR)2, NR(CH2)n-heteroaryl-O(CH2)nCO2R, NR(CH2)n-heteroaryl-O—C2-6 alkenyl-CO2R, NR(CH2)n-heteroaryl-O(CH2)n-tetrazole, NR(CH2)n-heteroaryl-O(CH2)nCN, NR(CH2)n-heteroaryl-O(CH2)nCON(R)2, NR(CH2)n-heteroarylO(CH2)nPO(OR)2, and O(CH2CH2O)pCH2CH2OR3, where heteroaryl is a 5-12 membered ring system consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S, and wherein aryl, biphenyl, and heteroaryl are substituted with 1-2 X2 and tetrazole is substituted with 0-1 R;
R3 is selected from H, C1-6 alkyl, and aryl-C1-6 alkyl-;
X2, at each occurrence, is independently selected from H, OR, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, halogen, CF3, nitro, —CN, C(O)NR2, NRSO2CH3, and SO2N(R)C1-4alkyl;
A−, at each occurrence, is a counterion;
Y is selected from O and H2;
Z is selected from H, OR, O(CH2)nCO2R, O(CH2)nCONH2, OCH2CHMCONRCH2CO2R, OCH2CH(NHC(O)CH3)CO2R, OCH2CH(NHR)CO2R, O(CH2)nPO(OR)2, O(CH2)nSO2OR, O(CH2)n-tetrazole, O—C2-6 alkenyl, O(CH2)n-aryl, OCH2CH2CONRCH(OR)CO2R, OCH2CH2CONRC(R)2CH2SO2OR, NRR, NR(CH2)nCO2R, NR(CH2)nCONH2, NRCH2CHMCONRCH2CO2R, NRSO2R, NRCH2CH(NHC(O)CH3)CO2R, NRCH2CH(NHR)CO2R, NR(CH2)nPO(OR)2, NR(CH2)nSO2OR, NR(CH2)n-tetrazole, NR—C2-6 alkenyl, NR(CH2)n-aryl, NRCH2CH2CONRCH(OR)CO2R, NRCH2CH2CONRC(R)2CH2SO2OR, and NRCO(CH2)nCO2R, O(CH2)n-aryl-CO2R, O(CH2)n-aryl-tetrazole, O(CH2)n-aryl-CON(R)2, O(CH2)n-aryl-PO(OR)2, NR(CH2)n-aryl-CO2R, NR(CH2)n-aryl-tetrazole, NR(CH2)n-aryl-CON(R)2, and NR(CH2)n-aryl-PO(OR)2, wherein aryl is substituted with 1-2 X2 and tetrazole is substituted with 0-1 R;
when Y is H2, Z1 is selected from H, OR, O(CH2)nCO2R, O(CH2)nCONH2, OCH2CHMCONRCH2CO2R, OCH2CH(NHC(O)CH3)CO2R, OCH2CH(NHR)CO2R, O(CH2)nPO(OR)2, O(CH2)nSO2OR, O—C2-6 alkenyl, O(CH2)n-aryl, NR(CH2)n-aryl, OCH2CH2CONRCH(OR)CO2R, OCH2CH2CONRC(R)2CH2SO2OR, and NRCO(CH2)nCO2R, wherein aryl is substituted with 1-2 X2;
when Y is O, Z1 is selected from OR, NRR, NR(CH2)nCONH2, NR—C2-6 alkyl O(CH2)n-aryl, and NR(CH2)n-aryl, wherein aryl is substituted with 1-2 X2;
M is selected from H, C1-6 alkyl, C3-8 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, 5-12 membered heteroaryl consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S, (CH2)n-aryl, and (CH2)n-5-12 membered heteroaryl consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S, wherein aryl and heteroaryl are substituted with 1-2 X2;
Q is selected from O−, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, (CH2)n-aryl, and (CH2)n-5-12 membered heteroaryl consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S, wherein aryl and heteroaryl are substituted with 1-2 X2;
provided that when Q is other than O−, then A− is present;
m is selected from 0, 1, 2, 3, and 4;
n is selected from 1, 2, 3, and 4;
p is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and 11; and,
provided that in formula I:
(a) R is other than H and CH3,
(b) C(═Y)Z is other than CH3; and/or
(c) at least one of R1, R2, X, and X1 is other than H;
further provided that at least one of X and X1 is other than H, alkyl, alkoxy, hydroxy, and halo.
In another variant, the compounds of the present invention have no more than one acid functionality.
[3] In another embodiment, the present invention provides a novel compound of formula Ia, or a stereoisomer or a pharmaceutically acceptable salt thereof:
wherein:
R, at each occurrence, is independently selected from H and C1-4 alkyl;
R1 is selected from H and C1-4 alkyl;
X and X1 are independently selected from H, OR, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, halogen, CF3, nitro, O(CH2)nCON(R)2, O—C2-4 alkenyl, N(R)2, (CH2)mCONR2, (CH2)mCN, NRSO2CH3, NRCO(CH2)nCON(R)2, SO2NRCH3, CH2N(C1-4 alkyl)2, CH2-aryl, CH2-heteroaryl, O(CH2)n-aryl, O(CH2)n-heteroaryl, NR(CH2)n-aryl, NR(CH2)n-heteroaryl, O(CH2)n-aryl-(CH2)mCON(R)2, O(CH2)n-aryl-O(CH2)nCON(R)2, O(CH2)n-aryl-NR(CH2)nCON(R)2, O(CH2)n-heteroaryl-(CH2)mCON(R)2, O(CH2)n-heteroaryl-O(CH2)nCON(R)2, O(CH2)n-heteroaryl-NR(CH2)nCON(R)2, NR(CH2)n-aryl-(CH2)mCON(R)2, NR(CH2)n-aryl-O(CH2)nCON(R)2, NR(CH2)n-aryl-NR(CH2)nCON(R)2, NR(CH2)n-heteroaryl-O(CH2)nCON(R)2, NR(CH2)n-heteroaryl-(CH2)mCON(R)2, NR(CH2)n-heteroaryl-NR(CH2)nCON(R)2, O(CH2)n-biphenyl, O(CH2)n-biphenyl-CN, O(CH2)n-biphenyl-CON(R)2, NR(CH2)n-biphenyl, NR(CH2)n-biphenyl-CN, and NR(CH2)n-biphenyl-CONH2, and O(CH2CH2O)pCH2CH2OR3, where heteroaryl is a 5-10 membered ring system consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S; and wherein aryl, biphenyl, and heteroaryl are substituted with 1-2 X2,
R3 is selected from H, C1-4 alkyl, and aryl-C1-4 alkyl-;
X2, at each occurrence, is independently selected from H, OR, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, halogen, CF3, nitro, —CN, C(O)NR2, NRSO2CH3, and SO2N(R)C1-4alkyl; and,
provided that at least one of X and X1 is other than H, alkyl, alkoxy, hydroxy, and halo.
[3a] In another embodiment, the present invention provides a novel compound of formula Ia, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein:
one of X and X1 is H and the other selected from C2-4 alkenyl, C2-4 alkynyl, CF3, nitro, O(CH2)nCON(R)2, O—C2-4 alkenyl, N(R)2, (CH2)mCONR2, (CH2)mCN, NRCO(CH2)nCON(R)2, NRSO2CH3, SO2NRCH3, CH2N(C1-4 alkyl)2, CH2-aryl, CH2-heteroaryl, O(CH2)n-aryl, O(CH2)n-heteroaryl, NR(CH2)n-aryl, NR(CH2)n-heteroaryl, O(CH2)n-aryl-(CH2)mCON(R)2, O(CH2)n-aryl-O(CH2)mCON(R)2, O(CH2)n-aryl-NR(CH2)nCON(R)2, O(CH2)n-heteroaryl-(CH2)mCON(R)2, O(CH2)n-heteroaryl-O(CH2)nCON(R)2, O(CH2)n-heteroaryl-NR(CH2)nCON(R)2, NR(CH2)n-aryl-(CH2)mCON(R)2, NR(CH2)n-aryl-O(CH2)nCON(R)2, NR(CH2)n-aryl-NR(CH2)nCON(R)2, NR(CH2)n-heteroaryl-O(CH2)nCON(R)2, NR(CH2)n-heteroaryl-(CH2)mCON(R)2, NR(CH2)n-heteroaryl-NR(CH2)nCON(R)2, O(CH2)n-biphenyl, O(CH2)n-biphenyl-CN, O(CH2)n-biphenyl-CON(R)2, NR(CH2)n-biphenyl, NR(CH2)n-biphenyl-CN, and NR(CH2)n-biphenyl-CONH2, and O(CH2CH2O)pCH2CH2OR3, where heteroaryl is a 5-10 membered ring system consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S; and wherein aryl, biphenyl, and heteroaryl are substituted with 1-2 X2.
[4] In another embodiment, the present invention provides a novel compound of formula Ib, or a stereoisomer or a pharmaceutically acceptable salt thereof:
wherein:
R, at each occurrence, is independently selected from H and C1-4 alkyl;
R1 is selected from (CH2)mCO2R, C2-4 alkenyl-CO2R, CH2CH(NHAc)CO2R, CH2CH(NHR)CO2R, and, (CH2)nPO(OR)2;
X and X1 are independently selected from H, OR, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, halogen, CF3, nitro, O(CH2)nCON(R)2, O—C2-4 alkenyl, N(R)2, (CH2)mCONR2, (CH2)mCN, NRCO(CH2)nCON(R)2, NRSO2CH3, SO2NRCH3, CH2N(C1-4 alkyl)2, CH2-aryl, CH2-heteroaryl, O(CH2)n-aryl, O(CH2)n-heteroaryl, NR(CH2)n-aryl, NR(CH2)n-heteroaryl, O(CH2)n-aryl-(CH2)mCON(R)2, O(CH2)n-aryl-O(CH2)nCON(R)2, O(CH2)n-aryl-NR(CH2)nCON(R)2, O(CH2)n-heteroaryl-(CH2)mCON(R)2, O(CH2)n-heteroaryl-O(CH2)nCON(R)2, O(CH2)n-heteroaryl-NR(CH2)nCON(R)2, NR(CH2)n-aryl-(CH2)mCON(R)2, NR(CH2)n-aryl-O(CH2)nCON(R)2, NR(CH2)n-aryl-NR(CH2)nCON(R)2, NR(CH2)n-heteroaryl-O(CH2)nCON(R)2, NR(CH2)n-heteroaryl-(CH2)mCON(R)2, NR(CH2)n-heteroaryl-NR(CH2)nCON(R)2, O(CH2)n-biphenyl, O(CH2)n-biphenyl-CN, O(CH2)n-biphenyl-CONH2, NR(CH2)n-biphenyl, NR(CH2)n-biphenyl-CN, NR(CH2)n-biphenyl-CONH2, and O(CH2CH2O)pCH2CH2OR3, where heteroaryl is a 5-10 membered ring system consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S, and wherein aryl, biphenyl, and heteroaryl are substituted with 1-2 X2;
R3 is selected from H, C1-4 alkyl, and aryl-C1-4 alkyl-;
X2, at each occurrence, is independently selected from H, OR, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, halogen, CF3, nitro, —CN, C(O)NR2, NRSO2CH3, and SO2N(R)C1-4alkyl;
M is selected from H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, (CH2)n-aryl, and (CH2)n-5-10 membered heteroaryl consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S, wherein aryl and heteroaryl are substituted with 1-2 X2; and,
provided that in formula Ib:
(a) R is other than H and CH3, and/or
(b) at least one of R1, X, and X1 is other than H;
further provided that at least one of X and X1 is other than H, alkyl, alkoxy, hydroxy, and halo.
[4a] In another embodiment, the present invention provides a novel compound of formula Ib, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein:
one of X and X1 is H and the other selected from C2-4 alkenyl, C2-4 alkynyl, CF3, nitro, O(CH2)nCON(R)2, O—C2-4 alkenyl, N(R)2, (CH2)mCONR2, (CH2)mCN, NRCO(CH2)nCON(R)2, NRSO2CH3, SO2NRCH3, CH2N(C1-4 alkyl)2, CH2-aryl, CH2-heteroaryl, O(CH2)n-aryl, O(CH2)n-heteroaryl, NR(CH2)n-aryl, NR(CH2)n-heteroaryl, O(CH2)n-aryl-(CH2)mCON(R)2, O(CH2)n-aryl-O(CH2)nCON(R)2, O(CH2)n-aryl-NR(CH2)nCON(R)2, O(CH2)n-heteroaryl-(CH2)mCON(R)2, O(CH2)n-heteroaryl-O(CH2)nCON(R)2, O(CH2)n-heteroaryl-NR(CH2)nCON(R)2, NR(CH2)n-aryl-(CH2)mCON(R)2, NR(CH2)n-aryl-O(CH2)nCON(R)2, NR(CH2)n-aryl-NR(CH2)nCON(R)2, NR(CH2)n-heteroaryl-O(CH2)nCON(R)2, NR(CH2)n-heteroaryl-(CH2)mCON(R)2, NR(CH2)n-heteroaryl-NR(CH2)nCON(R)2, O(CH2)n-biphenyl, O(CH2)n-biphenyl-CN, O(CH2)n-biphenyl-CONH2, NR(CH2)n-biphenyl, NR(CH2)n-biphenyl-CN, NR(CH2)n-biphenyl-CONH2, and O(CH2CH2O)pCH2CH2OR3, where heteroaryl is a 5-10 membered ring system consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S, and wherein aryl, biphenyl, and heteroaryl are substituted with 1-2 X2.
[5] In another embodiment, the present invention provides a novel compound of formula Ic, or a stereoisomer or a pharmaceutically acceptable salt thereof:
wherein:
R, at each occurrence, is independently selected from H and C1-4 alkyl;
R1 is selected from H and C1-4 alkyl;
X and X1 are independently selected from H, OR, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, halogen, CF3, nitro, O(CH2)nCON(R)2, O—C2-4 alkenyl, N(R)2, (CH2)mCONR2, (CH2)mCN, NRCO(CH2)nCON(R)2, NRSO2CH3, SO2NRCH3, CH2N(C1-4 alkyl)2, CH2-aryl, CH2-heteroaryl, O(CH2)n-aryl, O(CH2)n-heteroaryl, NR(CH2)n-aryl, NR(CH2)n-heteroaryl, O(CH2)n-aryl-(CH2)mCON(R)2, O(CH2)n-aryl-O(CH2)nCON(R)2, O(CH2)n-aryl-NR(CH2)nCON(R)2, O(CH2)n-heteroaryl-(CH2)mCON(R)2, O(CH2)n-heteroaryl-O(CH2)nCON(R)2, O(CH2)n-heteroaryl-NR(CH2)nCON(R)2, NR(CH2)n-aryl-(CH2)mCON(R)2, NR(CH2)n-aryl-O(CH2)nCON(R)2, NR(CH2)n-aryl-NR(CH2)nCON(R)2, NR(CH2)n-heteroaryl-O(CH2)nCON(R)2, NR(CH2)n-heteroaryl-(CH2)mCON(R)2, NR(CH2)n-heteroaryl-NR(CH2)nCON(R)2, O(CH2)n-biphenyl, O(CH2)n-biphenyl-CN, O(CH2)n-biphenyl-CONH2, NR(CH2)n-biphenyl, NR(CH2)n-biphenyl-CN, NR(CH2)n-biphenyl-CONH2, and O(CH2CH2O)pCH2CH2OR3, where heteroaryl is a 5-10 membered ring system consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S, and wherein aryl, biphenyl, and heteroaryl are substituted with 1-2 X2;
R3 is selected from H, C1-4 alkyl, and aryl-C1-4 alkyl-;
X2, at each occurrence, is independently selected from H, OR, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, halogen, CF3, nitro, —CN, C(O)NR2, NRSO2CH3, and SO2N(R)C1-4alkyl;
A− is selected from Cl− and Br−;
Z is selected from O(CH2)nCO2R, O(CH2)nCONH2, O(CH2)nPO(OR)2, O(CH2)nSO2OR, O(CH2)n-tetrazole, NR(CH2)nCO2R, NR(CH2)nCONH2, NRCH2CHMCONRCH2CO2R, NRSO2R, NR(CH2)nPO(OR)2, NR(CH2)nSO2OR, NR(CH2)n-tetrazole, NRCO(CH2)nCO2R, O(CH2)n-phenyl-CO2R, O(CH2)n-phenyl-tetrazole, O(CH2)n-phenyl-CON(R)2, O(CH2)n-phenyl-PO3(R)2, NR(CH2)n-phenyl-CO2R, NR(CH2)n-phenyl-tetrazole, NR(CH2)n-phenyl-CON(R)2, and NR(CH2)n-phenyl-PO3(R)2, wherein phenyl is substituted with 1-2 X2 and tetrazole is substituted with 0-1 R; and,
M is selected from H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, (CH2)n-aryl, and (CH2)n-5-10 membered heteroaryl consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S, wherein aryl and heteroaryl are substituted with 1-2 X2; and,
provided that at least one of X and X1 is other than H, alkyl, alkoxy, hydroxy, and halo.
[5a] In another embodiment, the present invention provides a novel compound of formula Ic, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein:
one of X and X1 is H and the other selected from C2-4 alkenyl, C2-4 alkynyl, CF3, nitro, O(CH2)nCON(R)2, O—C2-4 alkenyl, N(R)2, (CH2)mCONR2, (CH2)mCN, NRCO(CH2)nCON(R)2, NRSO2CH3, SO2NRCH3, CH2N(C1-4 alkyl)2, CH2-aryl, CH2-heteroaryl, O(CH2)n-aryl, O(CH2)n-heteroaryl, NR(CH2)n-aryl, NR(CH2)n-heteroaryl, O(CH2)n-aryl-(CH2)mCON(R)2, O(CH2)n-aryl-O(CH2)nCON(R)2, O(CH2)n-aryl-NR(CH2)nCON(R)2, O(CH2)n-heteroaryl-(CH2)mCON(R)2, O(CH2)n-heteroaryl-O(CH2)nCON(R)2, O(CH2)n-heteroaryl-NR(CH2)nCON(R)2, NR(CH2)n-aryl-(CH2)mCON(R)2, NR(CH2)n-aryl-O(CH2)nCON(R)2, NR(CH2)n-aryl-NR(CH2)nCON(R)2, NR(CH2)n-heteroaryl-O(CH2)nCON(R)2, NR(CH2)n-heteroaryl-(CH2)mCON(R)2, NR(CH2)n-heteroaryl-NR(CH2)nCON(R)2, O(CH2)n-biphenyl, O(CH2)n-biphenyl-CN, O(CH2)n-biphenyl-CONH2, NR(CH2)n-biphenyl, NR(CH2)n-biphenyl-CN, NR(CH2)n-biphenyl-CONH2, and O(CH2CH2O)pCH2CH2OR3, where heteroaryl is a 5-10 membered ring system consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S, and wherein aryl, biphenyl, and heteroaryl are substituted with 1-2 X2.
[6] In another embodiment, the present invention provides a novel compound of formula Ic, or a stereoisomer or a pharmaceutically acceptable salt thereof:
wherein:
R, at each occurrence, is independently selected from H and C1-4 alkyl;
R1 is selected from H, C1-4 alkyl, (CH2)mCO2R, C2-4 alkenyl-CO2R, CH2CH(NHAc)CO2R, CH2CH(NHR)CO2R, and, (CH2)nPO(OR)2;
X and X1 are independently selected from H, OR, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, halogen, CF3, nitro, N(R)2, (CH2)m-tetrazole, (CH2)mCO2R, (CH2)mCONR2, (CH2)mCN, O(CH2)nCN, O(CH2)n-tetrazole, O(CH2)nCO2R, O(CH2)nCON(R)2, O—C2-4 alkenyl-CO2R, O(CH2)nPO(OR)2, NR—C2-4 alkenyl, NRSO2CH3, NR(CH2)nCO2R, NR(CH2)nCON(R)2, NR—C2-4 alkenyl-CO2R, NR(CH2)nPO(OR)2, NR(CH2)nSO2OR, NR(CH2)n-tetrazole, NRCO(CH2)nCO2R, NRCO(CH2)nCON(R)2, SO2NRCH3, OCH2CHMCONRCH2CO2R, CH2-aryl, O(CH2)nPO(OR)2, O(CH2)nSO2OR, (CH2)nN+(R)3A−, OCH2(CH2)nN+(R)3A−, O(CH2)n-biphenyl, O(CH2)n-biphenyl-(CH2)mCO2R, O(CH2)n-biphenyl-(CH2)mtetrazole, O(CH2)n-biphenyl-(CH2)mCN, O(CH2)n-biphenyl-(CH2)mCON(R)2, NR(CH2)n-biphenyl, NR(CH2)n-biphenyl-(CH2)mCO2R, NR(CH2)n-biphenyl-(CH2)mtetrazole, NR(CH2)n-biphenyl-(CH2)mCN, NR(CH2)n-biphenyl-(CH2)mCON(R)2, O(CH2)n-aryl, O(CH2)n-heteroaryl, NR(CH2)n-aryl, NR(CH2)n-heteroaryl, O(CH2)n-aryl(CH2)mCO2R, O(CH2)n-aryl-C2-4 alkenyl-CO2R, O(CH2)n-aryl(CH2)m-tetrazole, O(CH2)n-aryl(CH2)mCN, O(CH2)n-aryl(CH2)mCON(R)2, O(CH2)n-aryl(CH2)m—PO(OR)2, O(CH2)n-aryl-O(CH2)nCO2R, O(CH2)n-aryl-O—C2-4 alkenyl-CO2R, O(CH2)n-arylO(CH2)n-tetrazole, O(CH2)n-arylO(CH2)nCN, O(CH2)n-arylO(CH2)nCON(R)2, O(CH2)n-arylO(CH2)n—PO(OR)2, O(CH2)n-aryl-NR(CH2)nCO2R, O(CH2)n-aryl-NRC2-4 alkenyl-CO2R, O(CH2)n-aryl-NR(CH2)n-tetrazole, O(CH2)n-aryl-NR(CH2)nCN, O(CH2)n-aryl-NR(CH2)nCON(R)2, O(CH2)n-aryl-NR(CH2)n—PO(OR)2, NR(CH2)n-aryl(CH2)mCO2R, NR(CH2)n-aryl-C2-4 alkenyl-CO2R, NR(CH2)n-aryl(CH2)n-tetrazole, NR(CH2)n-aryl(CH2)mCN, NR(CH2)n-aryl(CH2)mCON(R)2, NR(CH2)n-aryl(CH2)m—PO(OR)2, NR(CH2)n-aryl-NR(CH2)nCO2R, NR(CH2)n-aryl-NR—C2-4 alkenyl-CO2R, NR(CH2)n-aryl-NR(CH2)n-tetrazole, NR(CH2)n-aryl-NR(CH2)nCN, NR(CH2)n-aryl-NR(CH2)nCON(R)2, NR(CH2)n-aryl-NR(CH2)nPO(OR)2, NR(CH2)n-arylO(CH2)nCO2R, NR(CH2)n-aryl-O—C2-4 alkenyl-CO2R, NR(CH2)n-aryl-O(CH2)m-tetrazole, NR(CH2)n-arylO(CH2)nCN, NR(CH2)n-aryl-O(CH2)nCON(R)2, NR(CH2)n-arylO(CH2)nPO(OR)2, O(CH2)n-heteroaryl(CH2)mCO2R, O(CH2)n-heteroaryl-C2-4 alkenyl-CO2R, O(CH2)n-heteroaryl(CH2)m-tetrazole, O(CH2)n-heteroaryl-(CH2)mCN, O(CH2)n-heteroaryl(CH2)mCON(R)2, O(CH2)n-heteroaryl(CH2)m—PO(OR)2, O(CH2)n-heteroaryl-O(CH2)nCO2R, O(CH2)n-heteroaryl-O—C2-4 alkenyl-CO2R, O(CH2)n-heteroarylO(CH2)n-tetrazole, O(CH2)n-heteroaryl O(CH2)nCN, O(CH2)n-heteroarylO(CH2)nCON(R)2, O(CH2)n-heteroarylO(CH2)n—PO(OR)2, O(CH2)n-heteroaryl-NR(CH2)nCO2R, O(CH2)n-heteroaryl-NR—C2-4 alkenyl-CO2R, O(CH2)n-heteroaryl-NR(CH2)n-tetrazole, O(CH2)n-heteroaryl-NR(CH2)nCN, O(CH2)n-heteroaryl-NR(CH2)nCON(R)2, O(CH2)n-heteroaryl-NR(CH2)n—PO(OR)2, NR(CH2)n-heteroaryl(CH2)mCO2R, NR(CH2)n-heteroaryl-C2-4 alkenyl-CO2R, NR(CH2)n-heteroaryl(CH2)m-tetrazole, NR(CH2)n-heteroaryl(CH2)mCN, NR(CH2)n-heteroaryl(CH2)mCON(R)2, NR(CH2)n-heteroaryl(CH2)m—PO(OR)2, NR(CH2)n-heteroaryl-NR(CH2)nCO2R, NR(CH2)n-heteroaryl-NR—C2-4 alkenyl-CO2R, NR(CH2)n-heteroaryl-NR(CH2)n-tetrazole, NR(CH2)n heteroaryl-NR(CH2)nCN, NR(CH2)n-heteroaryl-NR(CH2)nCON(R)2, NR(CH2)n-heteroaryl-NR(CH2)nPO(OR)2, NR(CH2)n-heteroaryl-O(CH2)nCO2R, NR(CH2)n-heteroaryl-O—C2-4 alkenyl-CO2R, NR(CH2)n-heteroaryl-O(CH2)n-tetrazole, NR(CH2)n-heteroaryl-O(CH2)nCN, NR(CH2)n-heteroaryl-O(CH2)nCON(R)2, NR(CH2)n-heteroarylO(CH2)nPO(OR)2, and O(CH2CH2O)pCH2CH2OR3, where heteroaryl is a 5-12 membered ring system consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S, and wherein aryl, biphenyl, and heteroaryl are substituted with 1-2 X2 and tetrazole is substituted with 0-1 R;
R3 is selected from H, C1-4 alkyl, and aryl-C1-4 alkyl-;
X2, at each occurrence, is independently selected from H, OR, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, halogen, CF3, nitro, —CN, C(O)NR2, NRSO2CH3, and SO2N(R)C1-4alkyl;
A−, at each occurrence, is selected from Cl− and Br−;
Z is selected from H, OH, halogen, CF3, C1-4 alkoxy, O—C2-4 alkenyl, O(CH2)nCONH2, OCH2-aryl, NRR, NR—C2-4 alkenyl, NR(CH2)nCONH2, NR(CH2)n-aryl, and NRCO(CH2)nCO2R, wherein aryl is substituted with 1-2 X2;
M is selected from H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, (CH2)n-aryl, and (CH2)n-5-10 membered heteroaryl consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S; and, wherein aryl and heteroaryl are substituted with 1-2 X2; and,
provided that in formula Ic:
(a) R is other than H and CH3,
(b) Z is other than H; and/or
(c) at least one of R1, X, and X1 is other than H;
further provided that at least one of X and X1 is other than H, alkyl, alkoxy, hydroxy, and halo.
[6a] In another embodiment, the present invention provides a novel compound of formula Ic, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein:
one of X and X1 is H and the other selected from C2-4 alkenyl, C2-4 alkynyl, CF3, nitro, N(R)2, (CH2)m-tetrazole, (CH2)mCO2R, (CH2)mCONR2, (CH2)mCN, O(CH2)nCN, O(CH2)n-tetrazole, O(CH2)nCO2R, O(CH2)nCON(R)2, O—C2-4 alkenyl-CO2R, O(CH2)nPO(OR)2, NR—C2-4 alkenyl, NRSO2CH3, NR(CH2)nCO2R, NR(CH2)nCON(R)2, NR—C2-4 alkenyl-CO2R, NR(CH2)nPO(OR)2, NR(CH2)nSO2OR, NR(CH2)n-tetrazole, NRCO(CH2)nCO2R, NRCO(CH2)nCON(R)2, SO2NRCH3, OCH2CHMCONRCH2CO2R, CH2-aryl, O(CH2)nPO(OR)2, O(CH2)nSO2OR, (CH2)nN+(CH3)3A−, OCH2(CH2)nN+(CH3)3A−, O(CH2)n-biphenyl, O(CH2)n-biphenyl-(CH2)mCO2R, O(CH2)n-biphenyl-(CH2)mtetrazole, O(CH2)n-biphenyl-(CH2)mCN, O(CH2)n-biphenyl-(CH2)mCON(R)2, NR(CH2)n-biphenyl, NR(CH2)n-biphenyl-(CH2)mCO2R, NR(CH2)n-biphenyl-(CH2)mtetrazole, NR(CH2)n-biphenyl-(CH2)mCN, NR(CH2)n-biphenyl-(CH2)mCON(R)2, O(CH2)n-aryl, O(CH2)n-heteroaryl, NR(CH2)n-aryl, NR(CH2)n-heteroaryl, O(CH2)n-aryl(CH2)mCO2R, O(CH2)n-aryl-C2-4 alkenyl-CO2R, O(CH2)n-aryl(CH2)m-tetrazole, O(CH2)n-aryl(CH2)mCN, O(CH2)n-aryl(CH2)mCON(R)2, O(CH2)n-aryl(CH2)m—PO(OR)2, O(CH2)n-aryl-O(CH2)nCO2R, O(CH2)n-aryl-O—C2-4 alkenyl-CO2R, O(CH2)n-arylO(CH2)n-tetrazole, O(CH2)n-arylO(CH2)nCN, O(CH2)n-arylO(CH2)nCON(R)2, O(CH2)n-arylO(CH2)n—PO(OR)2, O(CH2)n-aryl-NR(CH2)nCO2R, O(CH2)n-aryl-NRC2-4 alkenyl-CO2R, O(CH2)n-aryl-NR(CH2)n-tetrazole, O(CH2)n-aryl-NR(CH2)nCN, O(CH2)n-aryl-NR(CH2)nCON(R)2, O(CH2)n-aryl-NR(CH2)n—PO(OR)2, NR(CH2)n-aryl(CH2)mCO2R, NR(CH2)n-aryl-C2-4 alkenyl-CO2R, NR(CH2)n-aryl(CH2)m-tetrazole, NR(CH2)n-aryl(CH2)mCN, NR(CH2)n-aryl(CH2)mCON(R)2, NR(CH2)n-aryl(CH2)m—PO(OR)2, NR(CH2)n-aryl-NR(CH2)nCO2R, NR(CH2)n-aryl-NR—C2-4 alkenyl-CO2R, NR(CH2)n-aryl-NR(CH2)n-tetrazole, NR(CH2)n-aryl-NR(CH2)nCN, NR(CH2)n-aryl-NR(CH2)nCON(R)2, NR(CH2)n-aryl-NR(CH2)nPO(OR)2, NR(CH2)n-arylO(CH2)nCO2R, NR(CH2)n-aryl-O—C2-4 alkenyl-CO2R, NR(CH2)n-aryl-O(CH2)n-tetrazole, NR(CH2)n-arylO(CH2)nCN, NR(CH2)n-aryl-O(CH2)nCON(R)2, NR(CH2)n-arylO(CH2)nPO(OR)2, O(CH2)n-heteroaryl(CH2)mCO2R, O(CH2)n-heteroaryl-C2-4 alkenyl-CO2R, O(CH2)n-heteroaryl(CH2)m-tetrazole, O(CH2)n-heteroaryl-(CH2)mCN, O(CH2)n-heteroaryl(CH2)mCON(R)2, O(CH2)n-heteroaryl(CH2)m—PO(OR)2, O(CH2)n-heteroaryl-O(CH2)nCO2R, O(CH2)n-heteroaryl-O—C2-4 alkenyl-CO2R, O(CH2)n-heteroarylO(CH2)n-tetrazole, O(CH2)n-heteroaryl O(CH2)nCN, O(CH2)n-heteroarylO(CH2)nCON(R)2, O(CH2)n-heteroarylO(CH2)n—PO(OR)2, O(CH2)n-heteroaryl-NR(CH2)nCO2R, O(CH2)n-heteroaryl-NR—C2-4 alkenyl-CO2R, O(CH2)n-heteroaryl-NR(CH2)n-tetrazole, O(CH2)n-heteroaryl-NR(CH2)nCN, O(CH2)n-heteroaryl-NR(CH2)nCON(R)2, O(CH2)n-heteroaryl-NR(CH2)n—PO(OR)2, NR(CH2)n-heteroaryl(CH2)mCO2R, NR(CH2)n-heteroaryl-C2-4 alkenyl-CO2R, NR(CH2)n-heteroaryl(CH2)m-tetrazole, NR(CH2)n-heteroaryl(CH2)mCN, NR(CH2)n-heteroaryl(CH2)mCON(R)2, NR(CH2)n-heteroaryl(CH2)m—PO(OR)2, NR(CH2)n-heteroaryl-NR(CH2)nCO2R, NR(CH2)n-heteroaryl-NR—C2-4 alkenyl-CO2R, NR(CH2)n-heteroaryl-NR(CH2)n-tetrazole, NR(CH2)n heteroaryl-NR(CH2)nCN, NR(CH2)n-heteroaryl-NR(CH2)nCON(R)2, NR(CH2)n-heteroaryl-NR(CH2)nPO(OR)2, NR(CH2)n-heteroaryl-O(CH2)nCO2R, NR(CH2)n-heteroaryl-O—C2-4 alkenyl-CO2R, NR(CH2)n-heteroaryl-O(CH2)n-tetrazole, NR(CH2)n-heteroaryl-O(CH2)nCN, NR(CH2)n-heteroaryl-O(CH2)nCON(R)2, NR(CH2)n-heteroarylO(CH2)nPO(OR)2, and O(CH2CH2O)pCH2CH2OR3, where heteroaryl is a 5-12 membered ring system consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S, and wherein aryl, biphenyl, and heteroaryl are substituted with 1-2 X2 and tetrazole is substituted with 0-1 R.
[7] In another embodiment, the present invention provides a novel compound of formula Ic, or a stereoisomer or a pharmaceutically acceptable salt thereof:
wherein:
R, at each occurrence, is independently selected from H and C1-4 alkyl;
R1 is selected from H and C1-4 alkyl;
X and X1 are independently selected from H, OR, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, halogen, CF3, nitro, O(CH2)nCON(R)2, O—C2-4 alkenyl, N(R)2, (CH2)mCONR2, (CH2)mCN, NRCO(CH2)nCON(R)2, NRSO2CH3, SO2NRCH3, CH2N(C1-4 alkyl)2, CH2-aryl, CH2-heteroaryl, O(CH2)n-aryl, O(CH2)n-heteroaryl, NR(CH2)n-aryl, NR(CH2)n-heteroaryl, O(CH2)n-aryl-(CH2)mCON(R)2, O(CH2)n-aryl-O(CH2)nCON(R)2, O(CH2)n-aryl-NR(CH2)nCON(R)2, O(CH2)n-heteroaryl-(CH2)mCON(R)2, O(CH2)n-heteroaryl-O(CH2)nCON(R)2, O(CH2)n-heteroaryl-NR(CH2)nCON(R)2, NR(CH2)n-aryl-(CH2)mCON(R)2, NR(CH2)n-aryl-O(CH2)nCON(R)2, NR(CH2)n-aryl-NR(CH2)nCON(R)2, NR(CH2)n-heteroaryl-O(CH2)nCON(R)2, NR(CH2)n-heteroaryl-(CH2)mCON(R)2, NR(CH2)n-heteroaryl-NR(CH2)nCON(R)2, O(CH2)n-biphenyl, O(CH2)n-biphenyl-CN, O(CH2)n-biphenyl-CONH2, NR(CH2)n-biphenyl, NR(CH2)n-biphenyl-CN, NR(CH2)n-biphenyl-CONH2, and O(CH2CH2O)pCH2CH2OR3, where heteroaryl is a 5-10 membered ring system consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S, and wherein aryl, biphenyl, and heteroaryl are substituted with 1-2 X2;
R3 is selected from H, C1-4 alkyl, and aryl-C1-4 alkyl-;
X2, at each occurrence, is independently selected from H, OR, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, halogen, CF3, nitro, —CN, C(O)NR2, NRSO2CH3, and SO2N(R)C1-4alkyl; and,
Z is selected from H, OH, C1-4 alkoxy, O—C2-4 alkenyl, O(CH2)nCONH2, OCH2-aryl, NRR, NR—C2-4 alkenyl, NR(CH2)nCONH2, and NRCH2-aryl, wherein aryl is substituted with 1-2 X2; and,
provided that at least one of X and X1 is other than H, alkyl, alkoxy, hydroxy, and halo.
[7a] In another embodiment, the present invention provides a novel compound of formula Ic, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein:
one of X and X1 is H and the other selected from C2-4 alkenyl, C2-4 alkynyl, CF3, nitro, O(CH2)nCON(R)2, O—C2-4 alkenyl, N(R)2, (CH2)mCONR2, (CH2)mCN, NRCO(CH2)nCON(R)2, NRSO2CH3, SO2NRCH3, CH2N(C1-4 alkyl)2, CH2-aryl, CH2-heteroaryl, O(CH2)n-aryl, O(CH2)n-heteroaryl, NR(CH2)n-aryl, NR(CH2)n-heteroaryl, O(CH2)n-aryl-(CH2)mCON(R)2, O(CH2)n-aryl-O(CH2)nCON(R)2, O(CH2)n-aryl-NR(CH2)nCON(R)2, O(CH2)n-heteroaryl-(CH2)mCON(R)2, O(CH2)n-heteroaryl-O(CH2)nCON(R)2, O(CH2)n-heteroaryl-NR(CH2)nCON(R)2, NR(CH2)n-aryl-(CH2)mCON(R)2, NR(CH2)n-aryl-O(CH2)nCON(R)2, NR(CH2)n-aryl-NR(CH2)nCON(R)2, NR(CH2)n-heteroaryl-O(CH2)nCON(R)2, NR(CH2)n-heteroaryl-(CH2)mCON(R)2, NR(CH2)n-heteroaryl-NR(CH2)nCON(R)2, O(CH2)n-biphenyl, O(CH2)n-biphenyl-CN, O(CH2)n-biphenyl-CONH2, NR(CH2)n-biphenyl, NR(CH2)n-biphenyl-CN, NR(CH2)n-biphenyl-CONH2, and O(CH2CH2O)pCH2CH2OR3, where heteroaryl is a 5-10 membered ring system consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S, and wherein aryl, biphenyl, and heteroaryl are substituted with 1-2 X2.
[8] In another embodiment, the present invention provides a novel compound of formula IIa, or a stereoisomer or a pharmaceutically acceptable salt thereof:
wherein:
R, at each occurrence, is independently selected from H and C1-6 alkyl;
R1 is selected from H and C1-4 alkyl;
R2 is selected from H and C1-4 alkyl;
X and X1 are independently selected from H, OR, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, halogen, CF3, nitro, O(CH2)nCON(R)2, O—C2-4 alkenyl, (CH2)mCONR2, (CH2)mCN, NRCO(CH2)nCON(R)2, NRSO2CH3, SO2NRCH3, CH2-aryl, CH2-heteroaryl, O(CH2)n-aryl, O(CH2)n-heteroaryl, NR(CH2)n-aryl, NR(CH2)n-heteroaryl, O(CH2)n-aryl-(CH2)mCON(R)2, O(CH2)n-aryl-O(CH2)nCON(R)2, O(CH2)n-aryl; O(CH2)n-heteroaryl-(CH2)mCON(R)2, O(CH2)n-heteroaryl-O(CH2)nCON(R)2, O(CH2)n-biphenyl, O(CH2)n-biphenyl-CN, O(CH2)n-biphenyl-CONH2, NR(CH2)n-biphenyl, NR(CH2)n-biphenyl-CN, and NR(CH2)n-biphenyl-CONH2, and O(CH2CH2O)pCH2CH2OR3, where heteroaryl is a 5-10 membered ring system consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S, and wherein aryl, biphenyl, and heteroaryl are substituted with 1-2 X2;
R3 is selected from H, C1-4 alkyl, and aryl-C1-4 alkyl-;
X2, at each occurrence, is independently selected from H, OR, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, halogen, CF3, nitro, —CN, C(O)NR2, NRSO2CH3, and SO2N(R)C1-4alkyl;
Y is selected from O and H2;
when Y is H2, Z1 is selected from H and OR;
when Y is O, Z1 is selected from NRR, NR(CH2)nCONH2, NR—C2-4 alkenyl, and NR(CH2)n-aryl, wherein aryl is substituted with 1-2 X2;
Q is selected from O−, C1-4 alkyl, C3-4 alkenyl, and C3-4 alkynyl; and,
provided that when Q is other than O−, A− is present and is selected from Cl and Br;
further provided that at least one of X and X1 is other than H, alkyl, alkoxy, hydroxy, and halo.
[8a] In another embodiment, the present invention provides a novel compound of formula IIa, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein:
one of X and X1 is H and the other selected from C2-4 alkenyl, C2-4 alkynyl, CF3, nitro, O(CH2)nCON(R)2, O—C2-4 alkenyl, (CH2)mCONR2, (CH2)mCN, NRCO(CH2)nCON(R)2, NRSO2CH3, SO2NRCH3, CH2-aryl, CH2-heteroaryl, O(CH2)n-aryl, O(CH2)n-heteroaryl, NR(CH2)n-aryl, NR(CH2)n-heteroaryl, O(CH2)n-aryl-(CH2)mCON(R)2, O(CH2)n-aryl-O(CH2)nCON(R)2, O(CH2)n-aryl, O(CH2)n-heteroaryl-(CH2)mCON(R)2, O(CH2)n-heteroaryl-O(CH2)nCON(R)2, O(CH2)n-biphenyl, O(CH2)n-biphenyl-CN, O(CH2)n-biphenyl-CONH2, NR(CH2)n-biphenyl, NR(CH2)n-biphenyl-CN, and NR(CH2)n-biphenyl-CONH2, and O(CH2CH2O)pCH2CH2OR3, where heteroaryl is a 5-10 membered ring system consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S, and wherein aryl, biphenyl, and heteroaryl are substituted with 1-2 X2.
In another embodiment, the present invention provides novel pharmaceutical compositions, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of the present invention or a stereoisomer or pharmaceutically acceptable salt thereof.
In another embodiment, the present invention provides a novel method for treating a disease, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention or a stereoisomer or pharmaceutically acceptable salt thereof, wherein the disease is selected from obesity, diabetes, cardiometabolic disorders, and a combination thereof.
In another embodiment, the cardiometabolic disorder is selected from hypertension, dyslipidemias (e.g., undesirable blood lipid levels, elevated cholesterol levels, and lowered LDL levels), high blood pressure, and insulin resistance.
In another embodiment, the present invention provides a novel method for treating a co-morbidity of obesity, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention or a stereoisomer or pharmaceutically acceptable salt thereof.
In another embodiment, the present invention provides a novel method for treating a co-morbidity of obesity, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention or a stereoisomer or pharmaceutically acceptable salt thereof.
In another embodiment, the co-morbidity is selected from diabetes, Metabolic Syndrome, dementia, and heart disease.
In another embodiment, the co-morbidity is selected from hypertension; gallbladder disease; gastrointestinal disorders; menstrual irregularities; degenerative arthritis; venous statis ulcers; pulmonary hypoventilation syndrome; sleep apnea; snoring; coronary artery disease; arterial sclerotic disease; pseudotumor cerebri; accident proneness; increased risks with surgeries; osteoarthritis; high cholesterol; and, increased incidence of malignancies of the ovaries, cervix, uterus, breasts, prostrate, and gallbladder.
In another embodiment, the present invention provides a novel method for treating a CNS disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention or a stereoisomer or pharmaceutically acceptable salt thereof.
In another embodiment, the CNS disorder is selected from acute and chronic neurological disorders, cognitive disorders, and memory deficits. Examples of these disorders include chronic or traumatic degenerative processes of the nervous system, which include Alzheimer's disease, other types of dementia, minimal cognitive impairment, and Parkinson's disease. Other examples of CNS disorders include psychiatric diseases, which include depression, anxiety, panic attack, social phobia, schizophrenia, and anorexia. Further examples of CNS disorders include withdrawal syndromes induced by alcohol, nicotine and other addictive drugs. Additional examples of CNS disorders include neuropathic pain and neuroinflamatory diseases (e.g., multiple sclerosis).
In another embodiment, the present invention also provides a method of preventing or reversing the deposition of adipose tissue in a mammal by the administration of a MAO-B inhibitor. By preventing or reversing the deposition of adipose tissue, MAO-B inhibitors are expected to reduce the incidence or severity of obesity, thereby reducing the incidence or severity of associated co-morbidities.
In another embodiment, the present invention provides a compound of the present invention for use in therapy.
In another embodiment, the present invention provides the use of compounds of the present invention for the manufacture of a medicament for the treatment of obesity, diabetes, cardiometabolic disorders, and a combination thereof.
In another embodiment, the present invention provides the use of novel compounds for the manufacture of a medicament for the treatment of CNS disorders.
The present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof. This invention encompasses all combinations of preferred aspects of the invention noted herein. It is understood that any and all embodiments of the present invention may be taken in conjunction with any other embodiment or embodiments to describe additional more preferred embodiments. It is also to be understood that each individual element of the preferred embodiments is intended to be taken individually as its own independent preferred embodiment. Furthermore, any element of an embodiment is meant to be combined with any and all other elements from any embodiment to describe an additional embodiment.
DEFINITIONSThe examples provided in the definitions present in this application are non-inclusive unless otherwise stated. They include but are not limited to the recited examples.
The compounds herein described may have asymmetric centers, geometric centers (e.g., double bond), or both. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms, by synthesis from optically active starting materials, or through use of chiral auxiliaries. Geometric isomers of olefins, C═N double bonds, or other types of double bonds may be present in the compounds described herein, and all such stable isomers are included in the present invention. Specifically, cis and trans geometric isomers of the compounds of the present invention may also exist and may be isolated as a mixture of isomers or as separated isomeric forms. All processes used to prepare compounds of the present invention and intermediates made therein are considered to be part of the present invention. All tautomers of shown or described compounds are also considered to be part of the present invention.
The present invention includes all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C-13 and C-14.
Examples of the molecular weight of the compounds of the present invention include (a) less than about 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 grams per mole; (b) less than about 950 grams per mole; (c) less than about 850 grams per mole; and, (d) less than about 750 grams per mole.
“Alkyl” includes both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. C1-6 alkyl, for example, includes C1, C2, C3, C4, C5, and C6 alkyl groups. Examples of alkyl include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, and s-pentyl.
“Alkenyl” includes the specified number of hydrocarbon atoms in either straight or branched configuration with one or more unsaturated carbon-carbon bonds that may occur in any stable point along the chain, such as ethenyl and propenyl. C2-6 alkenyl includes C2, C3, C4, C5, and C6 alkenyl groups.
“Alkynyl” includes the specified number of hydrocarbon atoms in either straight or branched configuration with one or more triple carbon-carbon bonds that may occur in any stable point along the chain, such as ethynyl and propynyl. C2-6 Alkynyl includes C2, C3, C4, C5, and C6 alkynyl groups.
“Cycloalkyl” includes the specified number of hydrocarbon atoms in a saturated ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. C3-8 cycloalkyl includes C3, C4, C5, C6, C7, and C8 cycloalkyl groups.
“Alkoxy” represents an alkyl group as defined above with the indicated number of hydrocarbon atoms attached through an oxygen bridge. C1-6 alkoxy, includes C1, C2, C3, C4, C5, and C6 alkoxy groups. Examples of alkoxy include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy.
“Halo” or “halogen” refers to fluoro, chloro, bromo, and iodo.
“Counterion” is used to represent a small, negatively charged species, such as chloride, bromide, hydroxide, acetate, and sulfate.
“Aryl” refers to any stable 6, 7, 8, 9, 10, 11, 12, or 13 membered monocyclic, bicyclic, or tricyclic ring, wherein at least one ring, if more than one is present, is aromatic. Examples of aryl include fluorenyl, phenyl, naphthyl, indanyl, adamantyl, and tetrahydronaphthyl.
“Heteroaryl” refers to any stable 5, 6, 7, 8, 9, 10, 11, or 12 membered monocyclic, bicyclic, or tricyclic heterocyclic ring that is aromatic, and which consists of carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, and S. If the heteroaryl group is bicyclic or tricyclic, then at least one of the two or three rings must contain a heteroatom, though both or all three may each contain one or more heteroatoms. If the heteroaryl group is bicyclic or tricyclic, then only one of the rings must be aromatic. The N group may be N, NH, or N-substituent, depending on the chosen ring and if substituents are recited. The nitrogen and sulfur heteroatoms may optionally be oxidized (e.g., S, S(O), S(O)2, and N—O). The heteroaryl ring may be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. The heteroaryl rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable.
Examples of heteroaryl includes acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl, pteridinyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl.
Preventing the deposition of adipose tissue covers methods of treating wherein the levels of adipose tissue of a subject remain about the same as prior to being treated in accordance with the present invention (i.e., its pre-administration level) or not more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10% greater than pre-administration level (particularly when the subject is pre-disposed to increasing adipose tissue levels).
Reversing the deposition of adipose tissue covers methods of treating wherein the levels of adipose tissue of a subject are lower than those prior to being treated in accordance with the present invention (i.e., its pre-administration level). Examples of lower include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20% or more lower than pre-administration level.
Mammal and patient covers warm blooded mammals that are typically under medical care (e.g., humans and domesticated animals). Examples of mammals include (a) feline, canine, equine, bovine, and human and (b) human.
“Treating” or “treatment” covers the treatment of a disease-state in a mammal, and includes: (a) preventing the disease-state from occurring in a mammal, in particular, when such mammal is predisposed to the disease-state but has not yet been diagnosed as having it; (b) inhibiting the disease-state, e.g., arresting it development; and/or (c) relieving the disease-state, e.g., causing regression of the disease state until a desired endpoint is reached. Treating also includes the amelioration of a symptom of a disease (e.g., lessen the pain or discomfort), wherein such amelioration may or may not be directly affecting the disease (e.g., cause, transmission, expression, etc.).
“Pharmaceutically acceptable salts” refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 1,2-ethanedisulfonic, 2-acetoxybenzoic, 2-hydroxyethanesulfonic, acetic, ascorbic, benzenesulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic, ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodide, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methanesulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic, salicyclic, stearic, subacetic, succinic, sulfamic, sulfanilic, sulfuric, tannic, tartaric, and toluenesulfonic.
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, Pa., 1990, p 1445, the disclosure of which is hereby incorporated by reference.
“Therapeutically effective amount” includes an amount of a compound of the present invention that is effective when administered alone or in combination to treat obesity or another indication listed herein. “Therapeutically effective amount” also includes an amount of the combination of compounds claimed that is effective to treat the desired indication. The combination of compounds is preferably a synergistic combination. Synergy, as described, for example, by Chou and Talalay, Adv. Enzyme Regul. 1984, 22:27-55, occurs when the effect of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent. In general, a synergistic effect is most clearly demonstrated at sub-optimal concentrations of the compounds. Synergy can be in terms of lower cytotoxicity, increased effect, or some other beneficial effect of the combination compared with the individual components.
Utility
Obesity is defined as having a body mass index (BMI) of 30 or above. The index is a measure of an individual's body weight relative to height. BMI is calculated by dividing body weight (in kilograms) by height (in meters) squared. Normal and healthy body weight is defined as having a BMI between 20 and 24.9. Overweight is defined as having a BMI of 25 or above. Obesity has reached epidemic proportions in the U.S., with 44 million obese Americans, and an additional eighty million deemed medically overweight.
Obesity is a disease characterized as a condition resulting from the excess accumulation of adipose tissue, especially adipose tissue localized in the abdominal area. It is desirable to treat overweight or obese patients by reducing their amount of adipose tissue, and thereby reducing their overall body weight to within the normal range for their sex and height. In this way, their risk for co-morbidities such as diabetes and cardiovascular disease will be reduced. It is also desirable to prevent normal weight individuals from accumulating additional, excess adipose tissue, effectively maintaining their body weights at a BMI <25, and preventing the development of co-morbidities. It is also desirable to control obesity, effectively preventing overweight and obese individuals from accumulating additional, excess adipose tissue, reducing the risk of further exacerbating their co-morbidities.
There exist two forms of MAO, designated MAO-A and MAO-B. The two forms differ with respect to substrate and inhibitor specificities and amino acid number and sequence. A preferred substrate for MAO-B is beta-phenylethylamine. In contrast, a preferred substrate for MAO-A is serotonin. Some MAO inhibitors show selectivity for MAO-A or for MAO-B, whereas other MAO inhibitors show little, if any selectivity. For example, the MAO inhibitor clorgyline preferentially inhibits MAO-A; the MAO inhibitor L-selegiline preferentially inhibits MAO-B; and, the MAO inhibitor iproniazid is non-selective (i.e., has a similar affinity for both). Examples of selectivity include a compound having about 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, or more fold higher affinity for one form of MAO than for the other form. One of ordinary skill in the art recognizes that there can be some difficulty in classifying MAO inhibitors. Some compounds may selectively inhibit one form of MAO in vitro and then lose their selectivity in vivo. Also, selectivity of a compound may vary from species to species or from tissue to tissue. In the context of the present invention, it is desirable to inhibit MAO-B activity in vivo in a mammal. Thus, selectivity and affinity are based on the in vivo activity of the MAO inhibitor and the mammalian species to which it is being or to be administered. Examples of the selectivity of a MAO-B inhibitor of the present invention include (a) at least a 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, to 100-fold greater affinity for MAO-B than MAO-A in the mammalian species (e.g., human) to be treated and (b) at least 100-fold greater affinity for MAO-B than MAO-A in the mammalian species (e.g., human) to be treated.
Some of the compounds of the present invention have been designed to have reduced CNS exposure by virtue of their inability or limited ability to penetrate the blood-brain barrier (e.g., quaternary salts or acid substituents) or by their participation in active transport systems, thus reducing centrally mediated side-effects, a potential problem with many anti-obesity agents.
Other compounds of the present invention are expected to penetrate the blood-brain barrier and therefore also be useful to treat CNS disorders (e.g., Parkinson's disease, depression, and Alzheimer's disease).
MAO enzymes are also located in a number of peripheral (non-CNS) tissues, including adipose tissue, muscle and liver. In order to treat non-CNS disorders (e.g., obesity, diabetes, and/or cardiometabolic disorders), it is necessary to administer enough of a drug sufficient to inhibit MAO in peripheral tissues. MAO inhibitors in use today to treat various psychiatric and neurological diseases, regardless of route of administration, enter the CNS from the systemic circulation. While present in the systemic circulation, such drugs have access to peripheral tissues, including adipose tissue, liver, and muscle. One of skill in the art recognizes that MAO inhibitors intended to enter the CNS from the systemic circulation in order to treat psychiatric and neurological diseases also have access to MAO in peripheral tissues, including adipose tissue, liver, and muscle. Thus, an MAO inhibitor useful for treating non-CNS disorders may have some access to the CNS from the systemic circulation.
Drugs enter the CNS from the systemic circulation by crossing the blood-brain barrier (BBB). The BBB is a highly specialized ‘gate-keeper’ that protects the brain by preventing the entry of many potentially harmful substances into the CNS from the systemic circulation. Much is known about the BBB, and of the physical-chemical properties required for compounds transported across it.
Drugs that do not cross the BBB into the CNS or that are readily eliminated through transport mechanisms (J Clin Invest. 97, 2517 (1996)) are known in the literature and have low CNS activity due to their inability to develop brain levels necessary for pharmacological action. The BBB has at least one mechanism to remove drugs prior to their accumulation in the CNS. P-Glycoproteins (P-gp) localized in plasma membrane of the BBB can influence the brain penetration and pharmacological activity of many drugs through translocation across membranes. The lack of accumulation into the brain by some drugs can be explained by their active removal from the brain by P-gp residing in the BBB. For example, the typical opioid drug loperamide, clinically used as an antidiarrheal, is actively removed from the brain by P-gp, thus explaining its lack of opiate-like CNS effects. Another example is domperidone, a dopamine receptor blocker that participates in the P-gp transport (J Clin Invest. 97, 2517 (1996)). Whereas dopamine receptor blockers that cross the BBB can be used to treat schizophrenia, the readily-eliminated domperidone can be used to prevent emesis, without the likelihood of producing adverse CNS effects.
In addition to the above compounds, agents possessing structural characteristics that retard or prevent BBB penetration or contribute to participation in active elimination processes have been identified in various classes of therapeutics. These include antihistamines (Drug Metab. Dispos. 31, 312 (2003)), beta-adrenergic receptor antagonists (B-blockers) (Eur. J. Clin. Pharmacol. 28, Suppl: 21-3 (1985); Br. J. Clin. Pharmacol., 11 (6), 549-553 (1981)), non-nucleoside reverse transcriptase inhibitors (NNRTIs) (J. Pharm Sci., 88(10) 950-954 (1999)), and opioid antagonists. This latter group has been tested in relation to their activity in the GI tract. These peripherally selective opioid antagonists are described in various US patents as being useful in the treatment of non-CNS pathologies in mammals, in particular those of the GI tract (see U.S. Pat. No. 5,260,542; U.S. Pat. No. 5,434,171; U.S. Pat. No. 5,159,081; and U.S. Pat. No. 5,270,238).
Other types of non-brain penetrant compounds can be prepared through the creation of a charge within the molecule. Thus, the addition of a methyl group to the tertiary amine functionality of the drugs scopolamine or atropine, unlike the parent molecules, prevents their passage across the BBB through the presence of a positive charge. However, the new molecules (methyl-scopolamine and methyl-atropine) retain their full anticholinergic pharmacological properties. As such, these drugs can also be used to treat peripheral diseases, without the concern of adverse CNS effects. The quaternary ammonium compound methylnaltrexone is also used for the prevention and/or treatment of opioid and non-opioid induced side effects associated with opioid administration.
MAO-B inhibitors such as selegiline have been useful in the treatment of CNS disorders. The unexpected discovery that the anti-obesity activity mediated by these agents is mediated by a non-CNS mechanism may make it desirable that the compounds of the present invention be peripherally restricted, i.e., have an inability or limited ability to cross the BBB or be readily eliminated from the brain through active transport systems, when a non-CNS disorder is to be treated. It may be desirable for the compounds of the present invention to be peripherally restricted, which in turn will result in no or very limited CNS effects. Compounds that provide peripherally mediated anti-obesity properties should result in therapeutic agents with greater safety, as previously demonstrated in earlier classes of peripherally restricted agents. It can be desirable that the compounds of the present invention, when administered in a therapeutically effective amount, have no or very limited CNS effects. It can also be desirable that the lack of CNS effects is a result of the compounds of the present invention having minimal brain concentrations when administered in therapeutically effective amounts. In this context, minimal brain concentrations means levels that are too low to be therapeutically effective for the treatment of a CNS indication or too low to cause significant or measurable deleterious or undesired side effects. It is noted that CNS activity is desirable when seeking to treat a CNS disorder.
Compound A is Selegiline when Y is O and R, R1, R2, X, X1, and Z are all H. Selegiline is a drug that crosses the BBB and is indicated for the treatment of Parkinson's disease. In compound A, one of R, R1, R2, X, X1, and Z is a group capable of reducing or limiting the CNS activity of compound A. This reduced or limited CNS activity occurs via at least one of R, R1, R2, X, X1, and Z being a group that either limits compound A's ability to cross the BBB relative to that of Selegiline or enables it to be actively removed at a rate greater than that of Selegiline. Examples of brain levels of compound A include levels that are (a) from 50, 55, 60, 65, 70, 75, 80, 85, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, to 100% lower than Selegiline, when administered at the same dosage; (b) from 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, to 100% lower than Selegiline, when administered at the same dosage; and, (c) from 98, 99, to 100% lower than Selegiline, when administered at the same dosage.
Most methods of treating obesity are dependent on a significant reduction in energy intake, either by a decrease in food intake (e.g., sibutramine) or by inhibition of fat absorption (e.g., orlistat). In the present invention, it can be desirable for adipose tissue to be significantly reduced in the absence of a significant reduction in food intake. The weight loss, as a result of the present invention, comes from the treatment with an MAO-B inhibitor, largely independent of appetite and food intake. Examples of the level of food intake during adipose tissue loss include (a) food intake is maintained, increased or about 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20% below the normal range of the subject prior to being treated in accordance with the present invention (i.e., its pre-administration level); (b) food intake is maintained, increased, or about 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15% below its pre-administration level; (c) food intake is maintained, increased or about 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10% below its pre-administration level; and (d) food intake level is maintained, increased or about 0, 1, 2, 3, 4, or 5% below its pre-administration level.
In some cases, loss of adipose tissue can be accompanied by a concomitant loss of lean muscle mass. This is particularly evident in cancer patients who show a wasting of all body tissue components, including adipose tissue and lean muscle mass. In the present invention, however, it can be desirable for body fat to be significantly reduced in the absence of a significant reduction in lean body mass. Adipose tissue loss comes from treatment with an MAO-B inhibitor, independent of a significant change in lean body mass. Examples of the level of lean body mass during adipose tissue loss include (a) lean body mass is maintained, increased, or is no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30% below the normal range of the subject prior to being treated in accordance with the present invention (i.e., its pre-administration level); (b) lean body mass is maintained, increased, or is no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15% below pre-administration levels; (c) lean body mass is maintained, increased, or is no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10% below pre-administration levels; and (d) lean body mass is maintained, increased, or is no more than about 1, 2, 3, 4, or 5% below pre-administration levels.
In some cases, loss of adipose tissue can be accompanied by a concomitant loss of water mass. This is particularly evident with diet regimens that promote dehydration. In the present invention, it can be desirable for body fat to be significantly reduced in the absence of a significant reduction in water mass. In other words, adipose tissue loss comes from treatment with an MAO-B inhibitor, independent of a significant change in water mass. Examples of the level of water mass during adipose tissue loss include (a) water mass is maintained, increased, or is no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30% below the normal range of the subject prior to being treated in accordance with the present invention (i.e., its pre-administration level); (b) water mass is maintained, increased, or is no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15% below pre-administration levels; (c) water mass is maintained, increased, or is no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10% below pre-administration levels; and (d) water mass is maintained, increased, or is no more than about 1, 2, 3, 4, or 5% below pre-administration levels.
Sibutramine and orlistat are currently marketed for use in the treatment of obesity. These two compounds achieve weight loss through entirely different mechanisms. Sibutramine, a CNS appetite suppressant, inhibits the neuronal reuptake of serotonin and noradrenaline. Orlistat inhibits gut lipase enzymes that are responsible for breaking down ingested fat.
The mechanism of action of MAO-B inhibitors is believed to be entirely different from appetite suppressants, gut lipase inhibitors, and other agents with similar indications (e.g., serotonin agonists, leptin, and fatty acid synthase inhibitors). Co-administration of a MAO-B inhibitor together with one or more other agents that are useful for treating the indications described above (e.g., obesity, diabetes, cardiometabolic disorders, and a combination thereof) is expected to be beneficial, by producing, for example, either additive or synergistic effects. Examples of additional agents include an appetite suppressant and a lipase inhibitor. Therefore, the present invention provides a method of treating obesity, diabetes, and/or cardiometabolic disorders, comprising administering a therapeutically effective amount of a compound of the present invention and a second component selected from an appetite suppressant (e.g., sibutramine, phentermine, fenfluramine) and a gut lipase inhibitor (e.g., orlistat).
MAO-B inhibitors are expected to promote weight loss without appreciably reducing caloric intake. Co-administration of an MAO-B inhibitor together with an appetite suppressant is expected to produce either additive or synergistic effects on weight loss. Similarly, co-administration of an MAO-B inhibitor together with a lipase inhibitor is expected to produce either additive or synergistic effects on weight loss.
The ability of compounds to inhibit MAOs can be determined using the method of R. Uebelhack et al., Pharmacopsychiatry 31, 187-192 (1988) (as described below).
Preparation of Platelet-Rich Plasma and Platelets. Venous Blood from healthy subjects was collected between 8 and 8.30 a.m. after an overnight fast into EDTA-containing vacutainer tubes (11.6 mg EDTA/ml blood). After centrifugation of the blood at 250×g for 15 minutes at 20° C., the supernatant platelet-rich plasma (PRP) was collected and the number of platelets in PRP counted with a cell counter (MOIAB, Hilden, Germany). 2 ml of PRP was spun at 1500×g for 10 min to yield a platelet pellet. The pellet was washed three times with ice-cold saline, resuspended in 2 ml Soerensen phosphate buffer, pH 7.4 and stored at −18° C. for one day.
MAO assay. Fresh PRP or frozen platelet suspension (100 μL) was generally preincubated for 10 min in the absence or presence of drugs at 37° C. in 100 uL of 0.9% NaCl solution or phosphate buffer pH 7.4, respectively, at 37° C. 50 μL of 2-phenylethylamine-[ethyl-1-14C]hydrochloride (P EA) solution (specific activity 56 Ci/mol, Amersham) was then added in a final concentration of 5 μM, and the incubation was continued for 30 min. The reaction was terminated by the addition of 50 μL of 4M HClO4. The reaction product of MAO, phenylacetaldehyde, was extracted into 2 mL of n-hexane. An aliquot of the organic phase was added to scintillator cocktail and the radioactivity was determined using a liquid scintillation counter. Product formation was linear with time for at least 60 min with appropriate platelet numbers. Blank values were obtained by including 2 mM pargyline in the incubation mixtures. All assays were performed in duplicate.
The ability of compounds to inhibit MAO activity can also be determined using the following method. cDNA's encoding human MAO-B can be transiently transfected into EBNA cells using the procedure described by E.-J. Schlaeger and K. Christensen (Transient Gene Expression in Mammalian Cells Grown in Serum-free Suspension Culture; Cytotechnology, 15: 1-13, 1998). After transfection, cells are homogeneized by means of a Polytron homogeneiser in 20 mM Tris HCl buffer, pH 8.0, containing 0.5 mM EGTA and 0.5 mM phenylmethanesulfonyl fluoride. Cell membranes are obtained by centrifugation at 45,000×g and, after two rinsing steps with 20 mM Tris HCl buffer, pH 8.0, containing 0.5 mM EGTA, membranes are eventually re-suspended in buffer and aliquots stored at −80° C. until use.
MAO-B enzymatic activity can be assayed using a spectrophotometric assay adapted from the method described by M. Zhou and N. Panchuk-Voloshina (A One-Step Fluorometric Method for the Continuous Measurement of Monoamine Oxidase Activity, Analytical Biochemistry, 253: 169-174, 1997). Briefly, membrane aliquots are incubated in 0.1 M potassium phosphate buffer, pH 7.4, for 30 min at 37° C. with or without various concentrations of the compounds. After incubation, the enzymatic reaction is started by the addition of the MAO substrate tyramine together with 1 U/ml horse-radish peroxidase (Roche Biochemicals) and 80 μM N-acetyl-3,7-dihydroxyphenoxazine (Amplex Red, Molecular Probes). The samples are further incubated for 30 min at 37° C. in a final volume of 200 μl and absorbance is determined at a wavelength of 570 nm using a SpectraMax plate reader (Molecular Devices). Background (non-specific) absorbance is determined in the presence of 10 μM L-deprenyl for MAO-B. IC50 values are determined from inhibition curves obtained using nine inhibitor concentrations in duplicate, by fitting data to a four parameter logistic equation.
Compounds of the present invention are expected to be MAO-B inhibitors. Representative compounds have been tested, as measured in the assay described herein, and have been shown to be active as their IC50 values were found to be in the range of ≦10 μM. Compounds of the present invention are considered to be MAO-B inhibitors if they have an IC50 value less than or equal to 10 μM. Additional examples of desirable activity levels of MAO-B inhibitors useful in the present invention include (a) an IC50 value of 1 μM or lower, (b) an IC50 value of 0.1 μM or lower, (c) an IC50 value of 0.01 μM or lower, (d) an IC50 value of 0.001 μM or lower, and (e) an IC50 value of 0.0001 μM or lower.
In the present invention, MAO-B inhibitor(s) can be administered enterally, parenterally, orally, and transdermally. One skilled in this art is aware that the routes of administering the compounds of the present invention may vary significantly. In addition to other oral administrations, sustained release compositions may be favored. Other examples of routes include injections (e.g., intravenous, intramuscular, and intraperitoneal); subcutaneous; subdermal implants; buccal, sublingual, topical (e.g., a dermal patch), rectal, vaginal, and intranasal administrations. Bioerodible, non-bioerodible, biodegradable, and non-biodegradable systems of administration may also be used.
If a solid composition in the form of tablets is prepared, the main active ingredient can be mixed with a pharmaceutical vehicle, examples of which include silica, starch, lactose, magnesium stearate, and talc. The tablets can be coated with sucrose or another appropriate substance or they can be treated so as to have a sustained or delayed activity and so as to release a predetermined amount of active ingredient continuously. Gelatin capsules can be obtained by mixing the active ingredient with a diluent and incorporating the resulting mixture into soft or hard gelatin capsules. A syrup or elixir can contain the active ingredient in conjunction with a sweetener, which is preferably calorie-free, an antiseptic (e.g., methylparaben and/or propylparaben), a flavoring, and an appropriate color. Water-dispersible powders or granules can contain the active ingredient mixed with dispersants or wetting agents or with suspending agents such as polyvinylpyrrolidone, as well as with sweeteners or taste correctors. Rectal administration can be effected using suppositories, which are prepared with binders melting at the rectal temperature (e.g., cocoa butter and/or polyethylene glycols). Parenteral administration can be effected using aqueous suspensions, isotonic saline solutions, or injectable sterile solutions, which contain pharmacologically compatible dispersants and/or wetting agents (e.g., propylene glycol and/or polyethylene glycol). The active ingredient can also be formulated as microcapsules or microspheres, optionally with one or more carriers or additives. The active ingredient can also be presented in the form of a complex with a cyclodextrin, for example α-, β-, or γ-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, and/or methyl-β-cyclodextrin.
The dose of the MAO-B inhibitor administered daily will vary on an individual basis and to some extent may be determined by the severity of the disease being treated (e.g., obesity). The dose of the MAO-B inhibitor will also vary depending on the MAO-B inhibitor administered. An example of a range of dosages of an MAO-B inhibitor is about from 0.001, 0.002, 0.003, 0.004, 0.005, 0.006, 0.007, 0.008, 0.009, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 76, 80, 85, 90, 95, to 100 mg/kg of mammal body weight. The MAO-B inhibitor can be administered in a single dose or in a number of smaller doses over a period of time. The length of time during which the MAO-B inhibitor is administered varies on an individual basis, and can continue until the desired results are achieved (i.e., reduction of body fat, or prevention of a gain in body fat). Therapy could, therefore, last from 1 day to weeks, months, or even years depending upon the subject being treated, the desired results, and how quickly the subject responds to treatment in accordance with the present invention.
A possible example of a tablet of the present invention is as follows.
A possible example of a capsule of the present invention is as follows.
In the above capsule, the active ingredient has a suitable particle size. The crystalline lactose and the microcrystalline cellulose are homogeneously mixed with one another, sieved, and thereafter the talc and magnesium stearate are admixed. The final mixture is filled into hard gelatin capsules of suitable size.
A possible example of an injection solution of the present invention is as follows.
The compounds of the present invention can be prepared in a number of ways known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or by variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. The reactions are performed in a solvent appropriate to the reagents and materials employed and suitable for the transformations being effected. It will be understood by those skilled in the art of organic synthesis that the functionality present on the molecule should be consistent with the transformations proposed. This will sometimes require a judgment to modify the order of the synthetic steps or to select one particular process scheme over another in order to obtain a desired compound of the invention. It will also be recognized that another major consideration in the planning of any synthetic route in this field is the judicious choice of the protecting group used for protection of the reactive functional groups present in the compounds described in this invention. An authoritative account describing the many alternatives to the trained practitioner is Greene and Wuts (Protective Groups In Organic Synthesis, Wiley and Sons, 1991). All references cited herein are hereby incorporated in their entirety herein by reference.
Scheme 1 provides access to one of a series of compounds that are part of the present invention. An amino acid ester, such as phenylalanine (X═H) or O-benzyltyrosine (X═O-benzyl), can be N-alkylated using formalin and sodium cyanoborohydride in the presence of acetic acid to provide an N-methylated ester (step a). Alternatively, alkylation of the amino ester with propargyl bromide in DMF at about 50° C. in the presence potassium carbonate should give the monopropargyl amino ester which can be converted to the des-methyl acid of the compound described in step e, below. When the secondary amine is treated with propargyl bromide in DMF in the presence of potassium carbonate at about 50° C., the tertiary amino ester will be produced (step b). Hydrolysis of the ester using aqueous LiOH solution in a co-solvent should afford the desired amino acid (step c). If the tertiary amino ester has a benzyloxy group on its phenyl ring, the benzyl group can be removed using trifluoroacetic acid (step d) prior to hydrolysis of the ester (step e).
Alternatively, if the tertiary amino ester is reduced with lithium aluminum hydride (LAH), the primary alcohol will be produced (step f). Deprotonation of the alcohol with sodium hydride followed by alkylation with ethyl bromopropionate will afford the amino alkoxyester (step g). Treatment of this ester as in step c will yield the tertiary amino acid (step h). If the tertiary amino alkoxyester has a benzyloxy group on its phenyl ring, the benzyl group can be removed using trifluoroacetic acid prior to hydrolysis of the ester.
Scheme 2 illustrates how one could make substituted propargyl compounds of the present invention. A starting propargyl amine can be deprotonated with n-butyl lithium at low temperature in a solvent such as THF, and the resulting anion alkylated with methylchloroformate or ethyl bromoacetate to afford an aminoester (step a). Hydrolysis of the ester using aqueous LiOH in a co-solvent can afford an amino acid (step b). Alternatively, if the tertiary amino ester has a benzyloxy group on its phenyl ring, the benzyl group can be removed using trifluoroacetic acid prior to hydrolysis of the ester.
Scheme 3 shows how to prepare hydroxy-phenyl and substituted hydroxy-phenyl compounds of the present invention. A starting p-hydroxyphenethylamine can be treated with sodium hydide and the resulting phenoxide anion can be alkylated with ethyl bromoacetate to provide an ester (step a). The carboxylic acid can then be formed by the previously described hydrolysis (step b). If the alkoxide anion was alkylated with 1,3-dibromopropane, then a bromoalkylether should be produced (step c). This halide, in turn, could be treated with trimethyl amine to give the propyloxy-trimethyl ammonium salt (step d). Treatment of the hydroxyphenyl compound with formalin and dimethyl amine followed by further reaction with acetic anhydride and concentrated hydrochloric acid should yield the intermediate chloromethylated phenol (step e). Subsequent reaction with excess trimethylamine should afford the trimethylammonium salt (step f).
Scheme 4 describes the synthesis of optionally substituted benzyloxy compounds. This reaction scheme as well as the procedures found in J. Org. Chem. 1991, 56, 2395 can also be utilized to prepare substituted-biphenylmethyl analogs of this and the anilino compounds of Scheme 5 by utilizing commercially available 4′-bromomethyl-biphenyl-2-carbonitrile, or for unsubstituted compounds commercially available 4-phenylbenzyl bromide, to alkylate the phenol of Scheme 4 and the anilines of Scheme 5, respectively. Treatment of the phenol with an optionally substituted benzyl bromide in a solvent such as acetone in the presence of a base such as potassium carbonate upon heating should afford the benzyl ether (step a). If the substituent on the benzyloxy group is an ester or a carbon-chain linked ester, the acid can be produced via hydrolysis using lithium hydroxide in aqueous THF (step b). If the benzyl bromide contains a nitrile substituent or a alkyl-chain linked substituent with a nitrile group or an oxyalkyl-chain linked substituent with a nitrile group, the alkylation product (step c) can be treated with 30% hydrogen peroxide and potassium carbonate in DMSO to produce the amides (step d). Alternatively, if these nitriles are reacted with sodium azide in the presence of zinc chloride in aqueous solution or treated with trialkyltin chloride and sodium azide in refluxing toluene or xylene, followed by removal of the trialkyl tin group with anhydrous HCl in THF/toluene, the tetrazoles should be formed (step e).
Scheme 5 describes the general synthesis of achiral compounds starting from substituted phenylacetones. If one uses commercially available 4-nitophenyl acetone, an anilino compound of step e that can also be used as a starting material for the reactions of Scheme 4, can be produced. Treatment of a nitro-phenyl acetone with benzylamine in the presence of sodium triacetoxyborohydride in dichloroethane (DCE) and acetic acid at 25-30° C. will yield the secondary amine (step a). Alkylation of the amine using formalin and sodium triacetoxyborohydride in DCE and HOAc at about 30° C. will provide the tertiary amine (step b). Reduction of the nitro group using Fe and ammonium formate in methanol at reflux will afford the anilino compound that has also been debenzylated (step c). Alkylation of the secondary amine with propargylbromide in the presence of potassium carbonate in acetonitrile at room temperature can give the tertiary amine (step d). Treatment of this aniline with benzaldehydes in the presence of triacetoxyborohydride in DCE and HOAc will yield benzylated anilines with optionally selected substituents that can be used further for the transformations described in Scheme 4 (step e). Reaction of this aniline with methanesulfonyl chloride in the presence of a base will provide the sulfonamide derivative (step f). In addition, reaction of this aniline with acid chlorides such as ethyl malonyl chloride or 3-cyanobenzenesulfonyl chloride will produce the acetanilide or the sulfonamide, respectively.
Scheme 6 describes how one can form quarternary ammonium salts or N-oxides of the present invention. When a starting tertiary propargyl amine is treated with an alkyl halide such as propargyl bromide in a solvent such as methanol or ethanol the quaternary ammonium salt can result (step a). Alternatively, a tertiary propargyl amine treated with an oxidizing agent such as 2-phenylsulfonyl-3-phenyloxaziridine (Davis reagent) in the presence of potassium carbonate in methylene chloride should give the amine N-oxides (step b).
Scheme 7 illustrates a route to another series of compounds that are part of the present invention. An amino acid ester, optionally substituted on the aromatic ring, can be N-alkylated using formalin and sodium cyanoborohydride under slightly acidic conditions to provide an N-methylated ester (step a). The secondary amine can then be alkylated with propargyl bromide to give a tertiary amino ester (step b). If the tertiary amino ester is reduced with lithium aluminum hydride (LAH), the primary alcohol should be produced (step c). Deprotonation of the alcohol with sodium hydride followed by alkylation with benzyl bromide should afford the amino benzyl ether (step d). Treatment of this ether with butyl lithium followed by ethyl bromoacetate should produce the acetylenic ester (step e). Hydrolysis of the ester using aqueous LiOH in a co-solvent will afford an amino acid (step f). The benzyl group can be removed using trifluoroacetic acid to give the amino acid alcohol (step g).
As shown in Scheme 8, the previously described amino alcohol (Scheme 1, step f) can be oxidized to the aldehyde using the Dess-Martin periodinane[1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one] in wet dichlormethane at about room temperature (step a). Treatment of the amino aldehyde with aqueous ammonia in the presence of sodium cyanoborohydride or with hydroxylamine followed by lithium aluminum hydride reduction should give the primary amine (step b). Reaction of the primary amine with methane sulfonyl chloride will afford the sulfonamide derivative (step c). The primary amine can also be reacted with ethyl 4-bromocrotonate in DMF in the presence of potassium carbonate to give the diaminoester (step d). Subsequent hydrolysis using lithium hydroxide in aqueous THF solution will provide the diamino acid (step e). The primary amine can also be treated with ethyl malonyl chloride in the presence of pyridine to give the amide ester (step f). Subsequent treatment with lithium hydroxide in aqueous THF solution will provide the acid (step g).
Scheme 9 shows the synthesis of chiral analogs of selegiline starting from L-tyrosine methyl ester. Treatment of the ester with di-t-butyl-dicarbonate (t-Boc anhydride) in methanol in the presence of triethylamine at 40-50° C. will provide the N-t-BOC-protected ester (step a). The phenol can be alkylated with benzyl bromide or a substituted version thereof, in acetone at 50-60° C. for about 4 hours to yield the O-benzyl ether analogs (step b). The t-BOC group will then be removed with TFA in methylene chloride at room temperature for 18-20 hours (step c), and the ester can be reduced with LAH at about 60 degrees C. for 6-8 hours to afford the alcohol (step d). Protection of the amine with t-Boc anhydride in methanol in the presence of triethylamine at 40-50° C. provides the N-t-BOC-protected ester (step e). The alcohol can be converted to the iodide with iodine in the presence of triphenylphosphine and imidazole in dichloromethane at about 40-50° C. for 4-6 hours (step f). Reduction of the iodide is carried out using sodium borohydride in DMSO at about 90° C. for about 1 hour (step g). Removal of the t-BOC group with TFA in methylene chloride at room temperature for about 15-20 hours will give the amine (step h), and reductive amination using formalin, sodium triacetoxyborohydride, HOAc in dichloromethane for about 24 hours will afford the methylated amine (step i). Subsequent alkylation with propargyl bromide in the presence of potassium carbonate in acetone for about 20 hours will produce the tertiary amine (step j). In Scheme 9, Bn is benzyl or benzyl optionally substituted with substituents that are compatible with LAH reduction. To produce substituted benzyl compounds with groups that are not compatible with LAH reduction, the product of step j (unsubstituted benzyl) can be de-benzylated with TFA, and the resulting phenol can be re-alkylated with benzyl halides containing various substituents on the phenyl ring.
As shown in Scheme 10, hydroxy-selegiline can be coupled with a polyethylene glycol (PEG), with one protected hydroxyl group (e.g., with a t-butyldimethylsilyl (TBDMS), alkyl, benzyl or aralkyl group), under Mitsunobu conditions using diethylazodicarboxylate (DEAD) and triphenylphosphine in a solvent (e.g., THF) to produce phenolethers (step a). The compounds with a terminal alkyl or aryl-alkyl group can be quaternized with an alkyl or propargyl halide in a variety of solvents (e.g., ether, ethanol, or toluene) to produce the quaternary ammonium salts (step b). The TBDMS-protected PEG pendants can be treated with tetrabutylammonium fluoride in THF to give the PEG pendants with terminal hydroxyl groups (step c). These alcohols can also be converted to the quaternary salts as described above (step d). The various mono-terminally substituted PEG-halides can be prepared by procedures described in Nuclear Medicine and Biology, 32, 799 (2005) or are commercially available.
Alternatively, as shown in Scheme 11, a hydroxyphenylacetic acid ester can be coupled with a halo-polyethylene glycol (PEG), optionally terminally substituted (e.g., TBDMS, alkyl, benzyl, or aryl-alkyl group), in DMF in the presence of potassium carbonate at about 100° C. with stirring for 12-16 hours to afford the PEG ether ester (step a). After hydrolysis of the ester with lithium hydroxide in aqueous THF, the resultant acid can converted to the acid chloride upon heating in oxalyl chloride (step b). Treatment of the acid chloride with 2,2-dimethyl-1,3-dioxane-4,6-dione (Meldrum's acid) should produce the acylated anhydride (step c), and subsequent hydrolysis in aqueous acetic acid will provide the methyl ketone (step d). Reductive amination of the ketone with methylpropargylamine in the presence of sodium triacetoxyborohydride in dichloroethane and acetic acid should afford the amine (step e). The compounds with a terminal alkyl or aryl-alkyl group can be quaternized with alkyl or propargyl halides in a variety of solvents such as ether, ethanol, or toluene to produce the quaternary ammonium salts (step f). The TBDMS-protected PEG pendants can be treated with tetrabutylammonium fluoride in THF to give the PEG pendants with terminal hydroxyl groups (step g). These alcohols can also be converted to the quaternary salts as described above (step h).
One stereoisomer of a compound of the present invention may be a more potent MAO-B inhibitor than its counterpart(s). Thus, stereoisomers are included in the present invention. Some of these stereoisomers are shown below in Scheme 12. When required, separation of the racemic material can be achieved by HPLC using a chiral column or by a resolution using a resolving agent such as described in Wilen, S. H. Tables of Resolving Agents and Optical Resolutions 1972, 308 or using enantiomerically pure acids and bases. A chiral compound of the present invention may also be directly synthesized using a chiral catalyst or a chiral ligand, e.g., Jacobsen, E. Acc. Chem. Res. 2000, 33, 421-431 or using other enantio- and diastereo-selective reactions and reagents known to one skilled in the art of asymmetric synthesis.
Other features of the invention will become apparent in the course of the following descriptions of exemplary embodiments that are given for illustration of the invention and are not intended to be limiting thereof.
ExamplesTables A and B below describe examples of the present invention that have been prepared. The examples can be prepared according to the methods of the scheme numbers provided for each example.
For X, the number in the parentheses indicates the substituent's position on phenyl ring in the X group.
Tables I-Xb show representative examples of the compounds of the present invention. Each example in each table represents an individual species of the present invention.
Numerous modifications and variations of the present invention are possible in light of the above teachings. It is therefore to be understood that within the scope of the appended claims, the invention may be practiced otherwise that as specifically described herein.
Claims
1-13. (canceled)
14. A method of treating a disease, comprising: administering to a mammal in need thereof a therapeutically effective amount of a compound selected from Tables A, I, IIa, IIb, IIIa, IIIb, IVa, IVb, IVc, IVd, V, VIIIa, VIIIb, VIIIc, VIIId, IXa, and IXb, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein the disease is selected from disease sets (a), (b), and (c): TABLE A Ex # X Y Z 1 OCH2C6H5 H2 H 2 OCH2C6H4—CO2CH3 (3) H2 H 3 OCH2C6H4—CONH2 (4) H2 H 4 OCH2C6H4—CONH2 (3) H2 H 5 OCH2CH═CH—CO2CH2CH3 H2 H 6 OCH2C6H5 O OCH3 7 OCH2C6H4—OCH2CONH2 (3) H2 H 8 OCH2C6H4—CH2CONH2 (3) H2 H 9 H H2 OH 10 OCH2C6H5 H2 OH 11 OCH2C6H5 O OCH3 13 OCH2C6H4CH3 (3) H2 H 14 OCH2C6H4CF3 (3) H2 H 15 OCH2C6H4CH3 (4) H2 H 16 OCH2C6H4CN (4) H2 H 17 NHCH2C6H4CN (4) H2 H 18 NHCH2C6H4OH (4) H2 H 19 NHCH2C6H4OH (3) H2 H TABLE I Ex. # X X1 R R1 1 H H CH3 H 2 H H H H 3 H H CH3 CH3 4 H H H CH3 5 OH H CH3 H 6 OH H H H 7 OH H CH3 CH3 8 OH H H CH3 9 OCH3 H CH3 H 10 OCH3 H H H 11 OCH3 H CH3 CH3 12 OCH3 H H CH3 13 OCH2C6H5 H CH3 H 14 OCH2C6H5 H H H 15 OCH2C6H5 H CH3 CH3 16 OCH2C6H5 H H CH3 17 OCH2CH2C6H5 H CH3 H 18 OCH2CH2C6H5 H H H 19 OCH2CH2C6H5 H CH3 CH3 20 OCH2CH2C6H5 H H CH3 21 OCH2CH═CH2 H CH3 H 22 OCH2CH═CH2 H H H 23 OCH2CH═CH2 H CH3 CH3 24 OCH2CH═CH2 H H CH3 25 OCH2CONH2 H CH3 H 26 OCH2CONH2 H H H 27 OCH2CONH2 H CH3 CH3 28 OCH2CONH2 H H CH3 29 Cl H CH3 H 30 Cl H H H 31 Cl H CH3 CH3 32 Cl H H CH3 33 NO2 H CH3 H 34 NO2 H H H 35 NO2 H CH3 CH3 36 NO2 H H CH3 41 NHSO2CH3 H CH3 H 42 NHSO2CH3 H H H 43 NHSO2CH3 H CH3 CH3 44 NHSO2CH3 H H CH3 45 OH CH2N(CH3)2 CH3 H 46 OH CH2N(CH3)2 H H 47 OH CH2N(CH3)2 CH3 CH3 48 OH CH2N(CH3)2 H CH3 49 OH CH2N+(CH3)3Cl− CH3 H 50 OH CH2N+(CH3)3Cl− H H 51 OH CH2N+(CH3)3Cl− CH3 CH3 52 OH CH2N+(CH3)3Cl− H CH3 53 OCH3 CH2N(CH3)2 CH3 H 54 OCH3 CH2N(CH3)2 H H 55 OCH3 CH2N(CH3)2 CH3 CH3 56 OCH3 CH2N(CH3)2 H CH3 57 OCH3 CH2N+(CH3)3Cl− CH3 H 58 OCH3 CH2N+(CH3)3Cl− H H 59 OCH3 CH2N+(CH3)3Cl− CH3 CH3 60 OCH3 CH2N+(CH3)3Cl− H CH3 TABLE II Ex. # X X1 R1 1 H H CO2CH2CH3 2 H H CO2H 3 OH H CO2CH2CH3 4 OH H CO2H 5 OCH3 H CO2CH2CH3 6 OCH3 H CO2H 7 OCH2CH═CH2 H CO2CH2CH3 8 OCH2CH═CH2 H CO2H 9 OCH2C6H5 H CO2CH2CH3 10 OCH2C6H5 H CO2H 11 OCH2CH2C6H5 H CO2CH2CH3 12 OCH2CH2C6H5 H CO2H 13 OCH2CONH2 H CO2CH2CH3 14 OCH2CONH2 H CO2H 15 Cl H CO2CH2CH3 16 Cl H CO2H 17 NO2 H CO2CH2CH3 18 NO2 H CO2H 21 NHSO2CH3 H CO2CH2CH3 22 NHSO2CH3 H CO2H 23 OH CH2N(CH3)2 CO2CH2CH3 24 OH CH2N(CH3)2 CO2H 25 OCH3 CH2N(CH3)2 CO2CH2CH3 26 OCH3 CH2N(CH3)2 CO2H 27 OCH2C6H5 CH2N(CH3)2 CO2CH2CH3 28 OCH2C6H5 CH2N(CH3)2 CO2H 29 OH CH2N+(CH3)3Cl− CO2CH2CH3 30 OH CH2N+(CH3)3Cl− CO2H 31 OCH3 CH2N+(CH3)3Cl− CO2CH2CH3 32 OCH3 CH2N+(CH3)3Cl− CO2H 33 OCH2C6H5 CH2N+(CH3)3Cl− CO2CH2CH3 34 OCH2C6H5 CH2N+(CH3)3Cl− CO2H 35 H H CH2CO2CH2CH3 36 H H CH2CO2H 37 OH H CH2CO2CH2CH3 38 OH H CH2CO2H 39 OCH3 H CH2CO2CH2CH3 40 OCH3 H CH2CO2H 41 OCH2CH═CH2 H CH2CO2CH2CH3 42 OCH2CH═CH2 H CH2CO2H 43 OCH2C6H5 H CH2CO2CH2CH3 44 OCH2C6H5 H CH2CO2H 45 OCH2CH2C6H5 H CH2CO2CH2CH3 46 OCH2CH2C6H5 H CH2CO2H 47 OCH2CONH2 H CH2CO2CH2CH3 48 OCH2CONH2 H CH2CO2H 49 Cl H CH2CO2CH2CH3 50 Cl H CH2CO2H 51 NO2 H CH2CO2CH2CH3 52 NO2 H CH2CO2H 55 NHSO2CH3 H CH2CO2CH2CH3 56 NHSO2CH3 H CH2CO2H 57 OH CH2N(CH3)2 CH2CO2CH2CH3 58 OH CH2N(CH3)2 CH2CO2H 59 OCH3 CH2N(CH3)2 CH2CO2CH2CH3 60 OCH3 CH2N(CH3)2 CH2CO2H 61 OCH2C6H5 CH2N(CH3)2 CH2CO2CH2CH3 62 OCH2C6H5 CH2N(CH3)2 CH2CO2H 63 OH CH2N+(CH3)3Cl− CH2CO2CH2CH3 64 OH CH2N+(CH3)3Cl− CH2CO2H 65 OCH3 CH2N+(CH3)3Cl− CH2CO2CH2CH3 66 OCH3 CH2N+(CH3)3Cl− CH2CO2H 67 OCH2C6H5 CH2N+(CH3)3Cl− CH2CO2CH2CH3 68 OCH2C6H5 CH2N+(CH3)3Cl− CH2CO2H 69 H H CH2CH2CO2CH2CH3 70 H H CH2CH2CO2H 71 OH H CH2CH2CO2CH2CH3 72 OH H CH2CH2CO2H 73 OCH3 H CH2CH2CO2CH2CH3 74 OCH3 H CH2CH2CO2H 75 OCH2CH═CH2 H CH2CH2CO2CH2CH3 76 OCH2CH═CH2 H CH2CH2CO2H 77 OCH2C6H5 H CH2CH2CO2CH2CH3 78 OCH2C6H5 H CH2CH2CO2H 79 OCH2CH2C6H5 H CH2CH2CO2CH2CH3 80 OCH2CH2C6H5 H CH2CH2CO2H 81 OCH2CONH2 H CH2CH2CO2CH2CH3 82 OCH2CONH2 H CH2CH2CO2H 83 Cl H CH2CH2CO2CH2CH3 84 Cl H CH2CH2CO2H 85 NO2 H CH2CH2CO2CH2CH3 86 NO2 H CH2CH2CO2H 89 NHSO2CH3 H CH2CH2CO2CH2CH3 90 NHSO2CH3 H CH2CH2CO2H 91 OH CH2N(CH3)2 CH2CH2CO2CH2CH3 92 OH CH2N(CH3)2 CH2CH2CO2H 93 OCH3 CH2N(CH3)2 CH2CH2CO2CH2CH3 94 OCH3 CH2N(CH3)2 CH2CH2CO2H 95 OCH2C6H5 CH2N(CH3)2 CH2CH2CO2CH2CH3 96 OCH2C6H5 CH2N(CH3)2 CH2CH2CO2H 97 OH CH2N+(CH3)3Cl− CH2CH2CO2CH2CH3 98 OH CH2N+(CH3)3Cl− CH2CH2CO2H 99 OCH3 CH2N+(CH3)3Cl− CH2CH2CO2CH2CH3 100 OCH3 CH2N+(CH3)3Cl− CH2CH2CO2H 101 OCH2C6H5 CH2N+(CH3)3Cl− CH2CH2CO2CH2CH3 102 OCH2C6H5 CH2N+(CH3)3Cl− CH2CH2CO2H 103 H H CH2CH═CHCO2CH2CH3 104 H H CH2CH═CHCO2H 105 OH H CH2CH═CHCO2CH2CH3 106 OH H CH2CH═CHCO2H 107 OCH3 H CH2CH═CHCO2CH2CH3 108 OCH3 H CH2CH═CHCO2H 109 OCH2CH═CH2 H CH2CH═CHCO2CH2CH3 110 OCH2CH═CH2 H CH2CH═CHCO2H 111 OCH2C6H5 H CH2CH═CHCO2CH2CH3 112 OCH2C6H5 H CH2CH═CHCO2H 113 OCH2CH2C6H5 H CH2CH═CHCO2CH2CH3 114 OCH2CH2C6H5 H CH2CH═CHCO2H 115 OCH2CONH2 H CH2CH═CHCO2CH2CH3 116 OCH2CONH2 H CH2CH═CHCO2H 117 Cl H CH2CH═CHCO2CH2CH3 118 Cl H CH2CH═CHCO2H 119 NO2 H CH2CH═CHCO2CH2CH3 120 NO2 H CH2CH═CHCO2H 123 NHSO2CH3 H CH2CH═CHCO2CH2CH3 124 NHSO2CH3 H CH2CH═CHCO2H 125 OH CH2N(CH3)2 CH2CH═CHCO2CH2CH3 126 OH CH2N(CH3)2 CH2CH═CHCO2H 127 OCH3 CH2N(CH3)2 CH2CH═CHCO2CH2CH3 128 OCH3 CH2N(CH3)2 CH2CH═CHCO2H 129 OCH2C6H5 CH2N(CH3)2 CH2CH═CHCO2CH2CH3 130 OCH2C6H5 CH2N(CH3)2 CH2CH═CHCO2H 131 OH CH2N+(CH3)3Cl− CH2CH═CHCO2CH2CH3 132 OH CH2N+(CH3)3Cl− CH2CH═CHCO2H 133 OCH3 CH2N+(CH3)3Cl− CH2CH═CHCO2CH2CH3 134 OCH3 CH2N+(CH3)3Cl− CH2CH═CHCO2H 135 OCH2C6H5 CH2N+(CH3)3Cl− CH2CH═CHCO2CH2CH3 136 OCH2C6H5 CH2N+(CH3)3Cl− CH2CH═CHCO2H 137 H H CH2CH2PO(OCH2CH3)2 138 H H CH2CH2PO(OH)2 139 OH H CH2CH2PO(OCH2CH3)2 140 OH H CH2CH2PO(OH)2 141 OCH3 H CH2CH2PO(OCH2CH3)2 142 OCH3 H CH2CH2PO(OH)2 143 OCH2CH═CH2 H CH2CH2PO(OCH2CH3)2 144 OCH2CH═CH2 H CH2CH2PO(OH)2 145 OCH2C6H5 H CH2CH2PO(OCH2CH3)2 146 OCH2C6H5 H CH2CH2PO(OH)2 147 OCH2CH2C6H5 H CH2CH2PO(OCH2CH3)2 148 OCH2CH2C6H5 H CH2CH2PO(OH)2 149 OCH2CONH2 H CH2CH2PO(OCH2CH3)2 150 OCH2CONH2 H CH2CH2PO(OH)2 151 Cl H CH2CH2PO(OCH2CH3)2 152 Cl H CH2CH2PO(OH)2 153 NO2 H CH2CH2PO(OCH2CH3)2 154 NO2 H CH2CH2PO(OH)2 157 NHSO2CH3 H CH2CH2PO(OCH2CH3)2 158 NHSO2CH3 H CH2CH2PO(OH)2 159 OH CH2N(CH3)2 CH2CH2PO(OCH2CH3)2 160 OH CH2N(CH3)2 CH2CH2PO(OH)2 161 OCH3 CH2N(CH3)2 CH2CH2PO(OCH2CH3)2 162 OCH3 CH2N(CH3)2 CH2CH2PO(OH)2 163 OCH2C6H5 CH2N(CH3)2 CH2CH2PO(OCH2CH3)2 164 OCH2C6H5 CH2N(CH3)2 CH2CH2PO(OH)2 165 OH CH2N+(CH3)3Cl− CH2CH2PO(OCH2CH3)2 166 OH CH2N+(CH3)3Cl− CH2CH2PO(OH)2 167 OCH3 CH2N+(CH3)3Cl− CH2CH2PO(OCH2CH3)2 168 OCH3 CH2N+(CH3)3Cl− CH2CH2PO(OH)2 169 OCH2C6H5 CH2N+(CH3)3Cl− CH2CH2PO(OCH2CH3)2 170 OCH2C6H5 CH2N+(CH3)3Cl− CH2CH2PO(OH)2 TABLE IIIa Ex. # X X1 Z1 R1 1 H H CH2CO2CH2CH3 H 2 H H CH2CO2H H 3 H H CH2CO2CH2CH3 CH3 4 H H CH2CO2H CH3 5 OH H CH2CO2CH2CH3 H 6 OH H CH2CO2H H 7 OH H CH2CO2CH2CH3 CH3 8 OH H CH2CO2H CH3 9 OCH3 H CH2CO2CH2CH3 H 10 OCH3 H CH2CO2H H 11 OCH3 H CH2CO2CH2CH3 CH3 12 OCH3 H CH2CO2H CH3 13 OCH2C6H5 H CH2CO2CH2CH3 H 14 OCH2C6H5 H CH2CO2H H 15 OCH2C6H5 H CH2CO2CH2CH3 CH3 16 OCH2C6H5 H CH2CO2H CH3 17 OCH2CH2C6H5 H CH2CO2CH2CH3 H 18 OCH2CH2C6H5 H CH2CO2H H 19 OCH2CH2C6H5 H CH2CO2CH2CH3 CH3 20 OCH2CH2C6H5 H CH2CO2H CH3 21 OCH2CH═CH2 H CH2CO2CH2CH3 H 22 OCH2CH═CH2 H CH2CO2H H 23 OCH2CH═CH2 H CH2CO2CH2CH3 CH3 24 OCH2CH═CH2 H CH2CO2H CH3 25 OCH2CONH2 H CH2CO2CH2CH3 H 26 OCH2CONH2 H CH2CO2H H 27 OCH2CONH2 H CH2CO2CH2CH3 CH3 28 OCH2CONH2 H CH2CO2H CH3 29 Cl H CH2CO2CH2CH3 H 30 Cl H CH2CO2H H 31 Cl H CH2CO2CH2CH3 CH3 32 Cl H CH2CO2H CH3 33 NO2 H CH2CO2CH2CH3 H 34 NO2 H CH2CO2H H 35 NO2 H CH2CO2CH2CH3 CH3 36 NO2 H CH2CO2H CH3 41 NHSO2CH3 H CH2CO2CH2CH3 H 42 NHSO2CH3 H CH2CO2H H 43 NHSO2CH3 H CH2CO2CH2CH3 CH3 44 NHSO2CH3 H CH2CO2H CH3 45 OH CH2N(CH3)2 CH2CO2CH2CH3 H 46 OH CH2N(CH3)2 CH2CO2H H 47 OH CH2N(CH3)2 CH2CO2CH2CH3 CH3 48 OH CH2N(CH3)2 CH2CO2H CH3 49 OH CH2N+(CH3)3Cl− CH2CO2CH2CH3 H 50 OH CH2N+(CH3)3Cl− CH2CO2H H 51 OH CH2N+(CH3)3Cl− CH2CO2CH2CH3 CH3 52 OH CH2N+(CH3)3Cl− CH2CO2H CH3 53 OCH3 CH2N(CH3)2 CH2CO2CH2CH3 H 54 OCH3 CH2N(CH3)2 CH2CO2H H 55 OCH3 CH2N(CH3)2 CH2CO2CH2CH3 CH3 56 OCH3 CH2N(CH3)2 CH2CO2H CH3 57 OCH3 CH2N+(CH3)3Cl− CH2CO2CH2CH3 H 58 OCH3 CH2N+(CH3)3Cl− CH2CO2H H 59 OCH3 CH2N+(CH3)3Cl− CH2CO2CH2CH3 CH3 60 OCH3 CH2N+(CH3)3Cl− CH2CO2H CH3 61 H H CH2CH2CO2CH2CH3 H 62 H H CH2CH2CO2H H 63 H H CH2CH2CO2CH2CH3 CH3 64 H H CH2CH2CO2H CH3 65 OH H CH2CH2CO2CH2CH3 H 66 OH H CH2CH2CO2H H 67 OH H CH2CH2CO2CH2CH3 CH3 68 OH H CH2CH2CO2H CH3 69 OCH3 H CH2CH2CO2CH2CH3 H 70 OCH3 H CH2CH2CO2H H 71 OCH3 H CH2CH2CO2CH2CH3 CH3 72 OCH3 H CH2CH2CO2H CH3 73 OCH2C6H5 H CH2CH2CO2CH2CH3 H 74 OCH2C6H5 H CH2CH2CO2H H 75 OCH2C6H5 H CH2CH2CO2CH2CH3 CH3 76 OCH2C6H5 H CH2CH2CO2H CH3 77 OCH2CH2C6H5 H CH2CH2CO2CH2CH3 H 78 OCH2CH2C6H5 H CH2CH2CO2H H 79 OCH2CH2C6H5 H CH2CH2CO2CH2CH3 CH3 80 OCH2CH2C6H5 H CH2CH2CO2H CH3 81 OCH2CH═CH2 H CH2CH2CO2CH2CH3 H 82 OCH2CH═CH2 H CH2CH2CO2H H 83 OCH2CH═CH2 H CH2CH2CO2CH2CH3 CH3 84 OCH2CH═CH2 H CH2CH2CO2H CH3 85 OCH2CONH2 H CH2CH2CO2CH2CH3 H 86 OCH2CONH2 H CH2CH2CO2H H 87 OCH2CONH2 H CH2CH2CO2CH2CH3 CH3 88 OCH2CONH2 H CH2CH2CO2H CH3 89 Cl H CH2CH2CO2CH2CH3 H 90 Cl H CH2CH2CO2H H 91 Cl H CH2CH2CO2CH2CH3 CH3 92 Cl H CH2CH2CO2H CH3 93 NO2 H CH2CH2CO2CH2CH3 H 94 NO2 H CH2CH2CO2H H 95 NO2 H CH2CH2CO2CH2CH3 CH3 96 NO2 H CH2CH2CO2H CH3 101 NHSO2CH3 H CH2CH2CO2CH2CH3 H 102 NHSO2CH3 H CH2CH2CO2H H 103 NHSO2CH3 H CH2CH2CO2CH2CH3 CH3 104 NHSO2CH3 H CH2CH2CO2H CH3 105 OH CH2N(CH3)2 CH2CH2CO2CH2CH3 H 106 OH CH2N(CH3)2 CH2CH2CO2H H 107 OH CH2N(CH3)2 CH2CH2CO2CH2CH3 CH3 108 OH CH2N(CH3)2 CH2CH2CO2H CH3 109 OH CH2N+(CH3)3Cl− CH2CH2CO2CH2CH3 H 110 OH CH2N+(CH3)3Cl− CH2CH2CO2H H 111 OH CH2N+(CH3)3Cl− CH2CH2CO2CH2CH3 CH3 112 OH CH2N+(CH3)3Cl− CH2CH2CO2H CH3 113 OCH3 CH2N(CH3)2 CH2CH2CO2CH2CH3 H 114 OCH3 CH2N(CH3)2 CH2CH2CO2H H 115 OCH3 CH2N(CH3)2 CH2CH2CO2CH2CH3 CH3 116 OCH3 CH2N(CH3)2 CH2CH2CO2H CH3 117 OCH3 CH2N+(CH3)3Cl− CH2CH2CO2CH2CH3 H 118 OCH3 CH2N+(CH3)3Cl− CH2CH2CO2H H 119 OCH3 CH2N+(CH3)3Cl− CH2CH2CO2CH2CH3 CH3 120 OCH3 CH2N+(CH3)3Cl− CH2CH2CO2H CH3 121 H H CH2CH2PO—(OCH2CH3)2 H 122 H H CH2CH2PO—(OH)2 H 123 H H CH2CH2PO—(OCH2CH3)2 CH3 124 H H CH2CH2PO—(OH)2 CH3 125 OH H CH2CH2PO—(OCH2CH3)2 H 126 OH H CH2CH2PO—(OH)2 H 127 OH H CH2CH2PO—(OCH2CH3)2 CH3 128 OH H CH2CH2PO—(OH)2 CH3 129 OCH3 H CH2CH2PO—(OCH2CH3)2 H 130 OCH3 H CH2CH2PO—(OH)2 H 131 OCH3 H CH2CH2PO—(OCH2CH3)2 CH3 132 OCH3 H CH2CH2PO—(OH)2 CH3 133 OCH2C6H5 H CH2CH2PO—(OCH2CH3)2 H 134 OCH2C6H5 H CH2CH2PO—(OH)2 H 135 OCH2C6H5 H CH2CH2PO—(OCH2CH3)2 CH3 136 OCH2C6H5 H CH2CH2PO—(OH)2 CH3 137 OCH2CH2C6H5 H CH2CH2PO—(OCH2CH3)2 H 138 OCH2CH2C6H5 H CH2CH2PO—(OH)2 H 139 OCH2CH2C6H5 H CH2CH2PO—(OCH2CH3)2 CH3 140 OCH2CH2C6H5 H CH2CH2PO—(OH)2 CH3 141 OCH2CH═CH2 H CH2CH2PO—(OCH2CH3)2 H 142 OCH2CH═CH2 H CH2CH2PO—(OH)2 H 143 OCH2CH═CH2 H CH2CH2PO—(OCH2CH3)2 CH3 144 OCH2CH═CH2 H CH2CH2PO—(OH)2 CH3 145 OCH2CONH2 H CH2CH2PO—(OCH2CH3)2 H 146 OCH2CONH2 H CH2CH2PO—(OH)2 H 147 OCH2CONH2 H CH2CH2PO—(OCH2CH3)2 CH3 148 OCH2CONH2 H CH2CH2PO—(OH)2 CH3 149 Cl H CH2CH2PO—(OCH2CH3)2 H 150 Cl H CH2CH2PO—(OH)2 H 151 Cl H CH2CH2PO—(OCH2CH3)2 CH3 152 Cl H CH2CH2PO—(OH)2 CH3 153 NO2 H CH2CH2PO—(OCH2CH3)2 H 154 NO2 H CH2CH2PO—(OH)2 H 155 NO2 H CH2CH2PO—(OCH2CH3)2 CH3 156 NO2 H CH2CH2PO—(OH)2 CH3 161 NHSO2CH3 H CH2CH2PO—(OCH2CH3)2 H 162 NHSO2CH3 H CH2CH2PO—(OH)2 H 163 NHSO2CH3 H CH2CH2PO—(OCH2CH3)2 CH3 164 NHSO2CH3 H CH2CH2PO—(OH)2 CH3 165 OH CH2N(CH3)2 CH2CH2PO—(OCH2CH3)2 H 166 OH CH2N(CH3)2 CH2CH2PO—(OH)2 H 167 OH CH2N(CH3)2 CH2CH2PO—(OCH2CH3)2 CH3 168 OH CH2N(CH3)2 CH2CH2PO—(OH)2 CH3 169 OH CH2N+(CH3)3Cl− CH2CH2PO—(OCH2CH3)2 H 170 OH CH2N+(CH3)3Cl− CH2CH2PO—(OH)2 H 171 OH CH2N+(CH3)3Cl− CH2CH2PO—(OCH2CH3)2 CH3 172 OH CH2N+(CH3)3Cl− CH2CH2PO—(OH)2 CH3 173 OCH3 CH2N(CH3)2 CH2CH2PO—(OCH2CH3)2 H 174 OCH3 CH2N(CH3)2 CH2CH2PO—(OH)2 H 175 OCH3 CH2N(CH3)2 CH2CH2PO—(OCH2CH3)2 CH3 176 OCH3 CH2N(CH3)2 CH2CH2PO—(OH)2 CH3 177 OCH3 CH2N+(CH3)3Cl− CH2CH2PO—(OCH2CH3)2 H 178 OCH3 CH2N+(CH3)3Cl− CH2CH2PO—(OH)2 H 179 OCH3 CH2N+(CH3)3Cl− CH2CH2PO—(OCH2CH3)2 CH3 180 OCH3 CH2N+(CH3)3Cl− CH2CH2PO—(OH)2 CH3 181 H H CH2CH2CONH—CH(OH)CO2H H 182 H H CH2CH2CONH—CH(OH)CO2H CH3 183 OH H CH2CH2CONH—CH(OH)CO2H H 184 OH H CH2CH2CONH—CH(OH)CO2H CH3 185 OCH3 H CH2CH2CONH—CH(OH)CO2H H 186 OCH3 H CH2CH2CONH—CH(OH)CO2H CH3 187 OCH2C6H5 H CH2CH2CONH—CH(OH)CO2H H 188 OCH2C6H5 H CH2CH2CONH—CH(OH)CO2H CH3 189 OCH2CH2C6H5 H CH2CH2CONH—CH(OH)CO2H H 190 OCH2CH2C6H5 H CH2CH2CONH—CH(OH)CO2H CH3 191 OCH2CH═CH2 H CH2CH2CONH—CH(OH)CO2H H 192 OCH2CH═CH2 H CH2CH2CONH—CH(OH)CO2H CH3 193 OCH2CONH2 H CH2CH2CONH—CH(OH)CO2H H 194 OCH2CONH2 H CH2CH2CONH—CH(OH)CO2H CH3 195 Cl H CH2CH2CONH—CH(OH)CO2H H 196 Cl H CH2CH2CONH—CH(OH)CO2H CH3 197 NO2 H CH2CH2CONH—CH(OH)CO2H H 198 NO2 H CH2CH2CONH—CH(OH)CO2H CH3 201 NHSO2CH3 H CH2CH2CONH—CH(OH)CO2H H 202 NHSO2CH3 H CH2CH2CONH—CH(OH)CO2H CH3 203 OH CH2N(CH3)2 CH2CH2CONH—CH(OH)CO2H H 204 OH CH2N(CH3)2 CH2CH2CONH—CH(OH)CO2H CH3 205 OH CH2N+(CH3)3Cl− CH2CH2CONH—CH(OH)CO2H H 206 OH CH2N+(CH3)3Cl− CH2CH2CONH—CH(OH)CO2H CH3 207 OCH3 CH2N(CH3)2 CH2CH2CONH—CH(OH)CO2H H 208 OCH3 CH2N(CH3)2 CH2CH2CONH—CH(OH)CO2H CH3 209 OCH3 CH2N+(CH3)3Cl− CH2CH2CONH—CH(OH)CO2H H 210 OCH3 CH2N+(CH3)3Cl− CH2CH2CONH—CH(OH)CO2H CH3 211 H H CH2CH2CONH—C(CH3)2CH2SO3H H 212 H H CH2CH2CONH—C(CH3)2CH2SO3H CH3 213 OH H CH2CH2CONH—C(CH3)2CH2SO3H H 214 OH H CH2CH2CONH—C(CH3)2CH2SO3H CH3 215 OCH3 H CH2CH2CONH—C(CH3)2CH2SO3H H 216 OCH3 H CH2CH2CONH—C(CH3)2CH2SO3H CH3 217 OCH2C6H5 H CH2CH2CONH—C(CH3)2CH2SO3H H 218 OCH2C6H5 H CH2CH2CONH—C(CH3)2CH2SO3H CH3 219 OCH2CH2C6H5 H CH2CH2CONH—C(CH3)2CH2SO3H H 220 OCH2CH2C6H5 H CH2CH2CONH—C(CH3)2CH2SO3H CH3 221 OCH2CH═CH2 H CH2CH2CONH—C(CH3)2CH2SO3H H 222 OCH2CH═CH2 H CH2CH2CONH—C(CH3)2CH2SO3H CH3 223 OCH2CONH2 H CH2CH2CONH—C(CH3)2CH2SO3H H 224 OCH2CONH2 H CH2CH2CONH—C(CH3)2CH2SO3H CH3 225 Cl H CH2CH2CONH—C(CH3)2CH2SO3H H 226 Cl H CH2CH2CONH—C(CH3)2CH2SO3H CH3 227 NO2 H CH2CH2CONH—C(CH3)2CH2SO3H H 228 NO2 H CH2CH2CONH—C(CH3)2CH2SO3H CH3 229 NHSO2CH3 H CH2CH2CONH—C(CH3)2CH2SO3H H 232 NHSO2CH3 H CH2CH2CONH—C(CH3)2CH2SO3H CH3 233 OH CH2N(CH3)2 CH2CH2CONH—C(CH3)2CH2SO3H H 234 OH CH2N(CH3)2 CH2CH2CONH—C(CH3)2CH2SO3H CH3 235 OH CH2N+(CH3)3Cl− CH2CH2CONH—C(CH3)2CH2SO3H H 236 OH CH2N+(CH3)3Cl− CH2CH2CONH—C(CH3)2CH2SO3H CH3 237 OCH3 CH2N(CH3)2 CH2CH2CONH—C(CH3)2CH2SO3H H 238 OCH3 CH2N(CH3)2 CH2CH2CONH—C(CH3)2CH2SO3H CH3 239 OCH3 CH2N+(CH3)3Cl− CH2CH2CONH—C(CH3)2CH2SO3H H 240 OCH3 CH2N+(CH3)3Cl− CH2CH2CONH—C(CH3)2CH2SO3H CH3 TABLE IIIb Ex. # X X1 Z1 R1 1 H H CH2CO2CH2CH3 H 2 H H CH2CO2H H 3 H H CH2CO2CH2CH3 CH3 4 H H CH2CO2H CH3 5 OH H CH2CO2CH2CH3 H 6 OH H CH2CO2H H 7 OH H CH2CO2CH2CH3 CH3 8 OH H CH2CO2H CH3 9 OCH3 H CH2CO2CH2CH3 H 10 OCH3 H CH2CO2H H 11 OCH3 H CH2CO2CH2CH3 CH3 12 OCH3 H CH2CO2H CH3 13 OCH2C6H5 H CH2CO2CH2CH3 H 14 OCH2C6H5 H CH2CO2H H 15 OCH2C6H5 H CH2CO2CH2CH3 CH3 16 OCH2C6H5 H CH2CO2H CH3 17 OCH2CH2C6H5 H CH2CO2CH2CH3 H 18 OCH2CH2C6H5 H CH2CO2H H 19 OCH2CH2C6H5 H CH2CO2CH2CH3 CH3 20 OCH2CH2C6H5 H CH2CO2H CH3 21 OCH2CH═CH2 H CH2CO2CH2CH3 H 22 OCH2CH═CH2 H CH2CO2H H 23 OCH2CH═CH2 H CH2CO2CH2CH3 CH3 24 OCH2CH═CH2 H CH2CO2H CH3 25 OCH2CONH2 H CH2CO2CH2CH3 H 26 OCH2CONH2 H CH2CO2H H 27 OCH2CONH2 H CH2CO2CH2CH3 CH3 28 OCH2CONH2 H CH2CO2H CH3 29 Cl H CH2CO2CH2CH3 H 30 Cl H CH2CO2H H 31 Cl H CH2CO2CH2CH3 CH3 32 Cl H CH2CO2H CH3 33 NO2 H CH2CO2CH2CH3 H 34 NO2 H CH2CO2H H 35 NO2 H CH2CO2CH2CH3 CH3 36 NO2 H CH2CO2H CH3 37 H H CH2CH2CO2CH2CH3 H 38 H H CH2CH2CO2H H 39 H H CH2CH2CO2CH2CH3 CH3 40 H H CH2CH2CO2H CH3 41 OH H CH2CH2CO2CH2CH3 H 42 OH H CH2CH2CO2H H 43 OH H CH2CH2CO2CH2CH3 CH3 44 OH H CH2CH2CO2H CH3 45 OCH3 H CH2CH2CO2CH2CH3 H 46 OCH3 H CH2CH2CO2H H 47 OCH3 H CH2CH2CO2CH2CH3 CH3 48 OCH3 H CH2CH2CO2H CH3 49 OCH2C6H5 H CH2CH2CO2CH2CH3 H 50 OCH2C6H5 H CH2CH2CO2H H 51 OCH2C6H5 H CH2CH2CO2CH2CH3 CH3 52 OCH2C6H5 H CH2CH2CO2H CH3 53 OCH2CH2C6H5 H CH2CH2CO2CH2CH3 H 54 OCH2CH2C6H5 H CH2CH2CO2H H 55 OCH2CH2C6H5 H CH2CH2CO2CH2CH3 CH3 56 OCH2CH2C6H5 H CH2CH2CO2H CH3 57 OCH2CH═CH2 H CH2CH2CO2CH2CH3 H 58 OCH2CH═CH2 H CH2CH2CO2H H 59 OCH2CH═CH2 H CH2CH2CO2CH2CH3 CH3 60 OCH2CH═CH2 H CH2CH2CO2H CH3 61 OCH2CONH2 H CH2CH2CO2CH2CH3 H 62 OCH2CONH2 H CH2CH2CO2H H 63 OCH2CONH2 H CH2CH2CO2CH2CH3 CH3 64 OCH2CONH2 H CH2CH2CO2H CH3 65 Cl H CH2CH2CO2CH2CH3 H 66 Cl H CH2CH2CO2H H 67 Cl H CH2CH2CO2CH2CH3 CH3 68 Cl H CH2CH2CO2H CH3 69 NO2 H CH2CH2CO2CH2CH3 H 70 NO2 H CH2CH2CO2H H 71 NO2 H CH2CH2CO2CH2CH3 CH3 72 NO2 H CH2CH2CO2H CH3 73 H H CH2CH2PO—(OCH2CH3)2 H 74 H H CH2CH2PO—(OH)2 H 75 H H CH2CH2PO—(OCH2CH3)2 CH3 76 H H CH2CH2PO—(OH)2 CH3 77 OH H CH2CH2PO—(OCH2CH3)2 H 78 OH H CH2CH2PO—(OH)2 H 79 OH H CH2CH2PO—(OCH2CH3)2 CH3 80 OH H CH2CH2PO—(OH)2 CH3 81 OCH3 H CH2CH2PO—(OCH2CH3)2 H 82 OCH3 H CH2CH2PO—(OH)2 H 83 OCH3 H CH2CH2PO—(OCH2CH3)2 CH3 84 OCH3 H CH2CH2PO—(OH)2 CH3 85 OCH2C6H5 H CH2CH2PO—(OCH2CH3)2 H 86 OCH2C6H5 H CH2CH2PO—(OH)2 H 87 OCH2C6H5 H CH2CH2PO—(OCH2CH3)2 CH3 88 OCH2C6H5 H CH2CH2PO—(OH)2 CH3 89 OCH2CH2C6H5 H CH2CH2PO—(OCH2CH3)2 H 90 OCH2CH2C6H5 H CH2CH2PO—(OH)2 H 91 OCH2CH2C6H5 H CH2CH2PO—(OCH2CH3)2 CH3 92 OCH2CH2C6H5 H CH2CH2PO—(OH)2 CH3 93 OCH2CH═CH2 H CH2CH2PO—(OCH2CH3)2 H 94 OCH2CH═CH2 H CH2CH2PO—(OH)2 H 95 OCH2CH═CH2 H CH2CH2PO—(OCH2CH3)2 CH3 96 OCH2CH═CH2 H CH2CH2PO—(OH)2 CH3 97 OCH2CONH2 H CH2CH2PO—(OCH2CH3)2 H 98 OCH2CONH2 H CH2CH2PO—(OH)2 H 99 OCH2CONH2 H CH2CH2PO—(OCH2CH3)2 CH3 100 OCH2CONH2 H CH2CH2PO—(OH)2 CH3 101 Cl H CH2CH2PO—(OCH2CH3)2 H 102 Cl H CH2CH2PO—(OH)2 H 103 Cl H CH2CH2PO—(OCH2CH3)2 CH3 104 Cl H CH2CH2PO—(OH)2 CH3 105 NO2 H CH2CH2PO—(OCH2CH3)2 H 106 NO2 H CH2CH2PO—(OH)2 H 107 NO2 H CH2CH2PO—(OCH2CH3)2 CH3 108 NO2 H CH2CH2PO—(OH)2 CH3 109 H H CH2CH2CONH— H CH(OH)CO2H 110 H H CH2CH2CONH— CH3 CH(OH)CO2H 111 OH H CH2CH2CONH— H CH(OH)CO2H 112 OH H CH2CH2CONH— CH3 CH(OH)CO2H 113 OCH3 H CH2CH2CONH— H CH(OH)CO2H 114 OCH3 H CH2CH2CONH— CH3 CH(OH)CO2H 115 OCH2C6H5 H CH2CH2CONH— H CH(OH)CO2H 116 OCH2C6H5 H CH2CH2CONH— CH3 CH(OH)CO2H 117 OCH2CH2C6H5 H CH2CH2CONH— H CH(OH)CO2H 118 OCH2CH2C6H5 H CH2CH2CONH— CH3 CH(OH)CO2H 119 OCH2CH═CH2 H CH2CH2CONH— H CH(OH)CO2H 120 OCH2CH═CH2 H CH2CH2CONH— CH3 CH(OH)CO2H 121 OCH2CONH2 H CH2CH2CONH— H CH(OH)CO2H 122 OCH2CONH2 H CH2CH2CONH— CH3 CH(OH)CO2H 123 Cl H CH2CH2CONH— H CH(OH)CO2H 124 Cl H CH2CH2CONH— CH3 CH(OH)CO2H 125 NO2 H CH2CH2CONH— H CH(OH)CO2H 126 NO2 H CH2CH2CONH— CH3 CH(OH)CO2H 127 H H CH2CH2CONH— H C(CH3)2CH2SO3H 128 H H CH2CH2CONH— CH3 C(CH3)2CH2SO3H 129 OH H CH2CH2CONH— H C(CH3)2CH2SO3H 130 OH H CH2CH2CONH— CH3 C(CH3)2CH2SO3H 131 OCH3 H CH2CH2CONH— H C(CH3)2CH2SO3H 132 OCH3 H CH2CH2CONH— CH3 C(CH3)2CH2SO3H 133 OCH2C6H5 H CH2CH2CONH— H C(CH3)2CH2SO3H 134 OCH2C6H5 H CH2CH2CONH— CH3 C(CH3)2CH2SO3H 135 OCH2CH2C6H5 H CH2CH2CONH— H C(CH3)2CH2SO3H 136 OCH2CH2C6H5 H CH2CH2CONH— CH3 C(CH3)2CH2SO3H 137 OCH2CH═CH2 H CH2CH2CONH— H C(CH3)2CH2SO3H 138 OCH2CH═CH2 H CH2CH2CONH— CH3 C(CH3)2CH2SO3H 139 OCH2CONH2 H CH2CH2CONH— H C(CH3)2CH2SO3H 140 OCH2CONH2 H CH2CH2CONH— CH3 C(CH3)2CH2SO3H 141 Cl H CH2CH2CONH— H C(CH3)2CH2SO3H 142 Cl H CH2CH2CONH— CH3 C(CH3)2CH2SO3H 143 NO2 H CH2CH2CONH— H C(CH3)2CH2SO3H 144 NO2 H CH2CH2CONH— CH3 C(CH3)2CH2SO3H TABLE IVa Ex. # X Z R1 1 OCH2CO2CH2CH3 H H 2 OCH2CO2H H H 3 OCH2CO2CH2CH3 H CH3 4 OCH2CO2H H CH3 5 OCH2CH2CO2CH2CH3 H H 6 OCH2CH2CO2H H H 7 OCH2CH2CO2CH2CH3 H CH3 8 OCH2CH2CO2H H CH3 9 OCH2CH2PO(OCH2CH3)2 H H 10 OCH2CH2PO(OH)2 H H 11 OCH2CH2PO(OCH2CH3)2 H CH3 12 OCH2CH2PO(OH)2 H CH3 13 OCH2CH═CHCO2CH2CH3 H H 14 OCH2CH═CHCO2H H H 15 OCH2CH═CHCO2CH2CH3 H CH3 16 OCH2CH═CHCO2H H CH3 17 OCH2C6H4CO2CH2CH3(2, 3 or 4) H H 18 OCH2C6H4CO2H (2, 3 or 4) H H 19 OCH2C6H4CO2CH2CH3(2, 3 or 4) H CH3 20 OCH2C6H4CO2H (2, 3 or 4) H CH3 21 OCH2C6H4CH2CO2CH2CH3(2, 3 or 4) H H 22 OCH2C6H4CH2CO2H (2, 3 or 4) H H 23 OCH2C6H4CH2CO2CH2CH3(2, 3 or 4) H CH3 24 OCH2C6H4CH2CO2H (2, 3 or 4) H CH3 25 OCH2CO2CH2CH3 OH H 26 OCH2CO2H OH H 27 OCH2CO2CH2CH3 OH CH3 28 OCH2CO2H OH CH3 29 OCH2CH2CO2CH2CH3 OH H 30 OCH2CH2CO2H OH H 31 OCH2CH2CO2CH2CH3 OH CH3 32 OCH2CH2CO2H OH CH3 33 OCH2CH2PO(OCH2CH3)2 OH H 34 OCH2CH2PO(OH)2 OH H 35 OCH2CH2PO(OCH2CH3)2 OH CH3 36 OCH2CH2PO(OH)2 OH CH3 37 OCH2CH═CHCO2CH2CH3 OH H 38 OCH2CH═CHCO2H OH H 39 OCH2CH═CHCO2CH2CH3 OH CH3 40 OCH2CH═CHCO2H OH CH3 41 OCH2C6H4CO2CH2CH3(2, 3 or 4) OH H 42 OCH2C6H4CO2H (2, 3 or 4) OH H 43 OCH2C6H4CO2CH2CH3(2, 3 or 4) OH CH3 44 OCH2C6H4CO2H (2, 3 or 4) OH CH3 45 OCH2C6H4CH2CO2CH2CH3(2, 3 or 4) OH H 46 OCH2C6H4CH2CO2H (2, 3 or 4) OH H 47 OCH2C6H4CH2CO2CH2CH3(2, 3 or 4) OH CH3 48 OCH2C6H4CH2CO2H (2, 3 or 4) OH CH3 49 OCH2CO2CH2CH3 OCH3 H 50 OCH2CO2H OCH3 H 51 OCH2CO2CH2CH3 OCH3 CH3 52 OCH2CO2H OCH3 CH3 53 OCH2CH2CO2CH2CH3 OCH3 H 54 OCH2CH2CO2H OCH3 H 55 OCH2CH2CO2CH2CH3 OCH3 CH3 56 OCH2CH2CO2H OCH3 CH3 57 OCH2CH2PO(OCH2CH3)2 OCH3 H 58 OCH2CH2PO(OH)2 OCH3 H 59 OCH2CH2PO(OCH2CH3)2 OCH3 CH3 60 OCH2CH2PO(OH)2 OCH3 CH3 61 OCH2CH═CHCO2CH2CH3 OCH3 H 62 OCH2CH═CHCO2H OCH3 H 63 OCH2CH═CHCO2CH2CH3 OCH3 CH3 64 OCH2CH═CHCO2H OCH3 CH3 65 OCH2C6H4CO2CH2CH3(2, 3 or 4) OCH3 H 66 OCH2C6H4CO2H (2, 3 or 4) OCH3 H 67 OCH2C6H4CO2CH2CH3(2, 3 or 4) OCH3 CH3 68 OCH2C6H4CO2H (2, 3 or 4) OCH3 CH3 69 OCH2C6H4CH2CO2CH2CH3(2, 3 or 4) OCH3 H 70 OCH2C6H4CH2CO2H (2, 3 or 4) OCH3 H 71 OCH2C6H4CH2CO2CH2CH3(2, 3 or 4) OCH3 CH3 72 OCH2C6H4CH2CO2H (2, 3 or 4) OCH3 CH3 73 OCH2CO2CH2CH3 OCH2CH═CH2 H 74 OCH2CO2H OCH2CH═CH2 H 75 OCH2CO2CH2CH3 OCH2CH═CH2 CH3 76 OCH2CO2H OCH2CH═CH2 CH3 77 OCH2CH2CO2CH2CH3 OCH2CH═CH2 H 78 OCH2CH2CO2H OCH2CH═CH2 H 79 OCH2CH2CO2CH2CH3 OCH2CH═CH2 CH3 80 OCH2CH2CO2H OCH2CH═CH2 CH3 81 OCH2CH2PO(OCH2CH3)2 OCH2CH═CH2 H 82 OCH2CH2PO(OH)2 OCH2CH═CH2 H 83 OCH2CH2PO(OCH2CH3)2 OCH2CH═CH2 CH3 84 OCH2CH2PO(OH)2 OCH2CH═CH2 CH3 85 OCH2CH═CHCO2CH2CH3 OCH2CH═CH2 H 86 OCH2CH═CHCO2H OCH2CH═CH2 H 87 OCH2CH═CHCO2CH2CH3 OCH2CH═CH2 CH3 88 OCH2CH═CHCO2H OCH2CH═CH2 CH3 89 OCH2C6H4CO2CH2CH3(2, 3 or 4) OCH2CH═CH2 H 90 OCH2C6H4CO2H (2, 3 or 4) OCH2CH═CH2 H 91 OCH2C6H4CO2CH2CH3(2, 3 or 4) OCH2CH═CH2 CH3 92 OCH2C6H4CO2H (2, 3 or 4) OCH2CH═CH2 CH3 93 OCH2C6H4CH2CO2CH2CH3(2, 3 or 4) OCH2CH═CH2 H 94 OCH2C6H4CH2CO2H (2, 3 or 4) OCH2CH═CH2 H 95 OCH2C6H4CH2CO2CH2CH3(2, 3 or 4) OCH2CH═CH2 CH3 96 OCH2C6H4CH2CO2H (2, 3 or 4) OCH2CH═CH2 CH3 97 OCH2CO2CH2CH3 OCH2C6CH5 H 98 OCH2CO2H OCH2C6CH5 H 99 OCH2CO2CH2CH3 OCH2C6CH5 CH3 100 OCH2CO2H OCH2C6CH5 CH3 101 OCH2CH2CO2CH2CH3 OCH2C6CH5 H 102 OCH2CH2CO2H OCH2C6CH5 H 103 OCH2CH2CO2CH2CH3 OCH2C6CH5 CH3 104 OCH2CH2CO2H OCH2C6CH5 CH3 105 OCH2CH2PO(OCH2CH3)2 OCH2C6CH5 H 106 OCH2CH2PO(OH)2 OCH2C6CH5 H 107 OCH2CH2PO(OCH2CH3)2 OCH2C6CH5 CH3 108 OCH2CH2PO(OH)2 OCH2C6CH5 CH3 109 OCH2CH═CHCO2CH2CH3 OCH2C6CH5 H 110 OCH2CH═CHCO2H OCH2C6CH5 H 111 OCH2CH═CHCO2CH2CH3 OCH2C6CH5 CH3 112 OCH2CH═CHCO2H OCH2C6CH5 CH3 113 OCH2CO2CH2CH3 OCH2CONH2 H 114 OCH2CO2H OCH2CONH2 H 115 OCH2CO2CH2CH3 OCH2CONH2 CH3 116 OCH2CO2H OCH2CONH2 CH3 117 OCH2CH2CO2CH2CH3 OCH2CONH2 H 118 OCH2CH2CO2H OCH2CONH2 H 119 OCH2CH2CO2CH2CH3 OCH2CONH2 CH3 120 OCH2CH2CO2H OCH2CONH2 CH3 121 OCH2CH2PO(OCH2CH3)2 OCH2CONH2 H 122 OCH2CH2PO(OH)2 OCH2CONH2 H 123 OCH2CH2PO(OCH2CH3)2 OCH2CONH2 CH3 124 OCH2CH2PO(OH)2 OCH2CONH2 CH3 125 OCH2CH═CHCO2CH2CH3 OCH2CONH2 H 126 OCH2CH═CHCO2H OCH2CONH2 H 127 OCH2CH═CHCO2CH2CH3 OCH2CONH2 CH3 128 OCH2CH═CHCO2H OCH2CONH2 CH3 159 OCH2CH2—N+(CH3)3 X− H H 160 OCH2CH2—N+(CH3)3 X− H CH3 161 OCH2CH2—N+(CH3)3 X− OCH3 H 162 OCH2CH2—N+(CH3)3 X− OCH3 CH3 163 OCH2CH2—N+(CH3)3 X− OCH2CH═CH2 H 164 OCH2CH2—N+(CH3)3 X− OCH2CH═CH2 CH3 165 OCH2CH2—N+(CH3)3 X− OCH2C6CH5 H 166 OCH2CH2—N+(CH3)3 X− OCH2C6CH5 CH3 TABLE IVb Ex. # X1 Z R1 1 OCH2CO2CH2CH3 H H 2 OCH2CO2H H H 3 OCH2CO2CH2CH3 H CH3 4 OCH2CO2H H CH3 5 OCH2CH2CO2CH2CH3 H H 6 OCH2CH2CO2H H H 7 OCH2CH2CO2CH2CH3 H CH3 8 OCH2CH2CO2H H CH3 9 OCH2CH2PO(OCH2CH3)2 H H 10 OCH2CH2PO(OH)2 H H 11 OCH2CH2PO(OCH2CH3)2 H CH3 12 OCH2CH2PO(OH)2 H CH3 13 OCH2CH═CHCO2CH2CH3 H H 14 OCH2CH═CHCO2H H H 15 OCH2CH═CHCO2CH2CH3 H CH3 16 OCH2CH═CHCO2H H CH3 17 OCH2C6H4CO2CH2CH3(2, 3 or 4) H H 18 OCH2C6H4CO2H (2, 3 or 4) H H 19 OCH2C6H4CO2CH2CH3(2, 3 or 4) H CH3 20 OCH2C6H4CO2H (2, 3 or 4) H CH3 21 OCH2C6H4CH2CO2CH2CH3(2, 3 or 4) H H 22 OCH2C6H4CH2CO2H (2, 3 or 4) H H 23 OCH2C6H4CH2CO2CH2CH3(2, 3 or 4) H CH3 24 OCH2C6H4CH2CO2H (2, 3 or 4) H CH3 25 OCH2CO2CH2CH3 OH H 26 OCH2CO2H OH H 27 OCH2CO2CH2CH3 OH CH3 28 OCH2CO2H OH CH3 29 OCH2CH2CO2CH2CH3 OH H 30 OCH2CH2CO2H OH H 31 OCH2CH2CO2CH2CH3 OH CH3 32 OCH2CH2CO2H OH CH3 33 OCH2CH2PO(OCH2CH3)2 OH H 34 OCH2CH2PO(OH)2 OH H 35 OCH2CH2PO(OCH2CH3)2 OH CH3 36 OCH2CH2PO(OH)2 OH CH3 37 OCH2CH═CHCO2CH2CH3 OH H 38 OCH2CH═CHCO2H OH H 39 OCH2CH═CHCO2CH2CH3 OH CH3 40 OCH2CH═CHCO2H OH CH3 41 OCH2C6H4CO2CH2CH3(2, 3 or 4) OH H 42 OCH2C6H4CO2H (2, 3 or 4) OH H 43 OCH2C6H4CO2CH2CH3(2, 3 or 4) OH CH3 44 OCH2C6H4CO2H (2, 3 or 4) OH CH3 45 OCH2C6H4CH2CO2CH2CH3(2, 3 or 4) OH H 46 OCH2C6H4CH2CO2H (2, 3 or 4) OH H 47 OCH2C6H4CH2CO2CH2CH3(2, 3 or 4) OH CH3 48 OCH2C6H4CH2CO2H (2, 3 or 4) OH CH3 49 OCH2CO2CH2CH3 OCH3 H 50 OCH2CO2H OCH3 H 51 OCH2CO2CH2CH3 OCH3 CH3 52 OCH2CO2H OCH3 CH3 53 OCH2CH2CO2CH2CH3 OCH3 H 54 OCH2CH2CO2H OCH3 H 55 OCH2CH2CO2CH2CH3 OCH3 CH3 56 OCH2CH2CO2H OCH3 CH3 57 OCH2CH2PO(OCH2CH3)2 OCH3 H 58 OCH2CH2PO(OH)2 OCH3 H 59 OCH2CH2PO(OCH2CH3)2 OCH3 CH3 60 OCH2CH2PO(OH)2 OCH3 CH3 61 OCH2CH═CHCO2CH2CH3 OCH3 H 62 OCH2CH═CHCO2H OCH3 H 63 OCH2CH═CHCO2CH2CH3 OCH3 CH3 64 OCH2CH═CHCO2H OCH3 CH3 65 OCH2C6H4CO2CH2CH3(2, 3 or 4) OCH3 H 66 OCH2C6H4CO2H (2, 3 or 4) OCH3 H 67 OCH2C6H4CO2CH2CH3(2, 3 or 4) OCH3 CH3 68 OCH2C6H4CO2H (2, 3 or 4) OCH3 CH3 69 OCH2C6H4CH2CO2CH2CH3(2, 3 or 4) OCH3 H 70 OCH2C6H4CH2CO2H (2, 3 or 4) OCH3 H 71 OCH2C6H4CH2CO2CH2CH3(2, 3 or 4) OCH3 CH3 72 OCH2C6H4CH2CO2H (2, 3 or 4) OCH3 CH3 73 OCH2CO2CH2CH3 OCH2CH═CH2 H 74 OCH2CO2H OCH2CH═CH2 H 75 OCH2CO2CH2CH3 OCH2CH═CH2 CH3 76 OCH2CO2H OCH2CH═CH2 CH3 77 OCH2CH2CO2CH2CH3 OCH2CH═CH2 H 78 OCH2CH2CO2H OCH2CH═CH2 H 79 OCH2CH2CO2CH2CH3 OCH2CH═CH2 CH3 80 OCH2CH2CO2H OCH2CH═CH2 CH3 81 OCH2CH2PO(OCH2CH3)2 OCH2CH═CH2 H 82 OCH2CH2PO(OH)2 OCH2CH═CH2 H 83 OCH2CH2PO(OCH2CH3)2 OCH2CH═CH2 CH3 84 OCH2CH2PO(OH)2 OCH2CH═CH2 CH3 85 OCH2CH═CHCO2CH2CH3 OCH2CH═CH2 H 86 OCH2CH═CHCO2H OCH2CH═CH2 H 87 OCH2CH═CHCO2CH2CH3 OCH2CH═CH2 CH3 88 OCH2CH═CHCO2H OCH2CH═CH2 CH3 89 OCH2C6H4CO2CH2CH3(2, 3 or 4) OCH2CH═CH2 H 90 OCH2C6H4CO2H (2, 3 or 4) OCH2CH═CH2 H 91 OCH2C6H4CO2CH2CH3(2, 3 or 4) OCH2CH═CH2 CH3 92 OCH2C6H4CO2H (2, 3 or 4) OCH2CH═CH2 CH3 93 OCH2C6H4CH2CO2CH2CH3(2, 3 or 4) OCH2CH═CH2 H 94 OCH2C6H4CH2CO2H (2, 3 or 4) OCH2CH═CH2 H 95 OCH2C6H4CH2CO2CH2CH3(2, 3 or 4) OCH2CH═CH2 CH3 96 OCH2C6H4CH2CO2H (2, 3 or 4) OCH2CH═CH2 CH3 97 OCH2CO2CH2CH3 OCH2C6CH5 H 98 OCH2CO2H OCH2C6CH5 H 99 OCH2CO2CH2CH3 OCH2C6CH5 CH3 100 OCH2CO2H OCH2C6CH5 CH3 101 OCH2CH2CO2CH2CH3 OCH2C6CH5 H 102 OCH2CH2CO2H OCH2C6CH5 H 103 OCH2CH2CO2CH2CH3 OCH2C6CH5 CH3 104 OCH2CH2CO2H OCH2C6CH5 CH3 105 OCH2CH2PO(OCH2CH3)2 OCH2C6CH5 H 106 OCH2CH2PO(OH)2 OCH2C6CH5 H 107 OCH2CH2PO(OCH2CH3)2 OCH2C6CH5 CH3 108 OCH2CH2PO(OH)2 OCH2C6CH5 CH3 109 OCH2CH═CHCO2CH2CH3 OCH2C6CH5 H 110 OCH2CH═CHCO2H OCH2C6CH5 H 111 OCH2CH═CHCO2CH2CH3 OCH2C6CH5 CH3 112 OCH2CH═CHCO2H OCH2C6CH5 CH3 113 OCH2CO2CH2CH3 OCH2CONH2 H 114 OCH2CO2H OCH2CONH2 H 115 OCH2CO2CH2CH3 OCH2CONH2 CH3 116 OCH2CO2H OCH2CONH2 CH3 117 OCH2CH2CO2CH2CH3 OCH2CONH2 H 118 OCH2CH2CO2H OCH2CONH2 H 119 OCH2CH2CO2CH2CH3 OCH2CONH2 CH3 120 OCH2CH2CO2H OCH2CONH2 CH3 121 OCH2CH2PO(OCH2CH3)2 OCH2CONH2 H 122 OCH2CH2PO(OH)2 OCH2CONH2 H 123 OCH2CH2PO(OCH2CH3)2 OCH2CONH2 CH3 124 OCH2CH2PO(OH)2 OCH2CONH2 CH3 125 OCH2CH═CHCO2CH2CH3 OCH2CONH2 H 126 OCH2CH═CHCO2H OCH2CONH2 H 127 OCH2CH═CHCO2CH2CH3 OCH2CONH2 CH3 128 OCH2CH═CHCO2H OCH2CONH2 CH3 159 OCH2CH2—N+(CH3)3 X− H H 160 OCH2CH2—N+(CH3)3 X− H CH3 161 OCH2CH2—N+(CH3)3 X− OCH3 H 162 OCH2CH2—N+(CH3)3 X− OCH3 CH3 163 OCH2CH2—N+(CH3)3 X− OCH2CH═CH2 H 164 OCH2CH2—N+(CH3)3 X− OCH2CH═CH2 CH3 165 OCH2CH2—N+(CH3)3 X− OCH2C6CH5 H 166 OCH2CH2—N+(CH3)3 X− OCH2C6CH5 CH3 TABLE IVc Ex. # X Z R1 1 OCH2CO2H N(CH3)2 H 2 OCH2CO2CH2CH3 N(CH3)2 CH3 3 OCH2CO2H N(CH3)2 CH3 4 OCH2CH2CO2CH2CH3 N(CH3)2 H 5 OCH2CH2CO2H N(CH3)2 H 6 OCH2CH2CO2CH2CH3 N(CH3)2 CH3 7 OCH2CH2CO2H N(CH3)2 CH3 8 OCH2CH2PO(OCH2CH3)2 N(CH3)2 H 9 OCH2CH2PO(OH)2 N(CH3)2 H 10 OCH2CH2PO(OCH2CH3)2 N(CH3)2 CH3 11 OCH2CH2PO(OH)2 N(CH3)2 CH3 12 OCH2CH═CHCO2CH2CH3 N(CH3)2 H 13 OCH2CH═CHCO2H N(CH3)2 H 14 OCH2CH═CHCO2CH2CH3 N(CH3)2 CH3 15 OCH2CH═CHCO2H N(CH3)2 CH3 16 OCH2C6H4CO2CH2CH3(2, 3 or 4) N(CH3)2 H 17 OCH2C6H4CO2H (2, 3 or 4) N(CH3)2 H 18 OCH2C6H4CO2CH2CH3(2, 3 or 4) N(CH3)2 CH3 19 OCH2C6H4CO2H (2, 3 or 4) N(CH3)2 CH3 20 OCH2C6H4CH2CO2CH2CH3(2, 3 or 4) N(CH3)2 H 21 OCH2C6H4CH2CO2H (2, 3 or 4) N(CH3)2 H 22 OCH2C6H4CH2CO2CH2CH3(2, 3 or 4) N(CH3)2 CH3 23 OCH2C6H4CH2CO2H (2, 3 or 4) N(CH3)2 CH3 24 OCH2CO2CH2CH3 NHCH2C6CH5 H 25 OCH2CO2H NHCH2C6CH5 H 26 OCH2CO2CH2CH3 NHCH2C6CH5 CH3 27 OCH2CO2H NHCH2C6CH5 CH3 28 OCH2CH2CO2CH2CH3 NHCH2C6CH5 H 29 OCH2CH2CO2H NHCH2C6CH5 H 30 OCH2CH2CO2CH2CH3 NHCH2C6CH5 CH3 31 OCH2CH2CO2H NHCH2C6CH5 CH3 32 OCH2CH2PO(OCH2CH3)2 NHCH2C6CH5 H 33 OCH2CH2PO(OH)2 NHCH2C6CH5 H 34 OCH2CH2PO(OCH2CH3)2 NHCH2C6CH5 CH3 35 OCH2CH2PO(OH)2 NHCH2C6CH5 CH3 36 OCH2CH═CHCO2CH2CH3 NHCH2C6CH5 H 37 OCH2CH═CHCO2H NHCH2C6CH5 H 38 OCH2CH═CHCO2CH2CH3 NHCH2C6CH5 CH3 39 OCH2CH═CHCO2H NHCH2C6CH5 CH3 40 OCH2CO2CH2CH3 NHCH2CONH2 H 41 OCH2CO2H NHCH2CONH2 H 42 OCH2CO2CH2CH3 NHCH2CONH2 CH3 43 OCH2CO2H NHCH2CONH2 CH3 44 OCH2CH2CO2CH2CH3 NHCH2CONH2 H 45 OCH2CH2CO2H NHCH2CONH2 H 46 OCH2CH2CO2CH2CH3 NHCH2CONH2 CH3 47 OCH2CH2CO2H NHCH2CONH2 CH3 48 OCH2CH2PO(OCH2CH3)2 NHCH2CONH2 H 49 OCH2CH2PO(OH)2 NHCH2CONH2 H 50 OCH2CH2PO(OCH2CH3)2 NHCH2CONH2 CH3 51 OCH2CH2PO(OH)2 NHCH2CONH2 CH3 52 OCH2CH═CHCO2CH2CH3 NHCH2CONH2 H 53 OCH2CH═CHCO2H NHCH2CONH2 H 54 OCH2CH═CHCO2CH2CH3 NHCH2CONH2 CH3 55 OCH2CH═CHCO2H NHCH2CONH2 CH3 56 OCH2C6H4CO2CH2CH3(2, 3 or 4) NHCH2CONH2 H 57 OCH2C6H4CO2H (2, 3 or 4) NHCH2CONH2 H 58 OCH2C6H4CO2CH2CH3(2, 3 or 4) NHCH2CONH2 CH3 59 OCH2C6H4CO2H (2, 3 or 4) NHCH2CONH2 CH3 60 OCH2C6H4CH2CO2CH2CH3(2, 3 or 4) NHCH2CONH2 H 61 OCH2C6H4CH2CO2H (2, 3 or 4) NHCH2CONH2 H 62 OCH2C6H4CH2CO2CH2CH3(2, 3 or 4) NHCH2CONH2 CH3 63 OCH2C6H4CH2CO2H (2, 3 or 4) NHCH2CONH2 CH3 TABLE IVd Ex. # X1 Z R1 1 OCH2CO2H N(CH3)2 H 2 OCH2CO2CH2CH3 N(CH3)2 CH3 3 OCH2CO2H N(CH3)2 CH3 4 OCH2CH2CO2CH2CH3 N(CH3)2 H 5 OCH2CH2CO2H N(CH3)2 H 6 OCH2CH2CO2CH2CH3 N(CH3)2 CH3 7 OCH2CH2CO2H N(CH3)2 CH3 8 OCH2CH2PO(OCH2CH3)2 N(CH3)2 H 9 OCH2CH2PO(OH)2 N(CH3)2 H 10 OCH2CH2PO(OCH2CH3)2 N(CH3)2 CH3 11 OCH2CH2PO(OH)2 N(CH3)2 CH3 12 OCH2CH═CHCO2CH2CH3 N(CH3)2 H 13 OCH2CH═CHCO2H N(CH3)2 H 14 OCH2CH═CHCO2CH2CH3 N(CH3)2 CH3 15 OCH2CH═CHCO2H N(CH3)2 CH3 16 OCH2C6H4CO2CH2CH3(2, 3 or 4) N(CH3)2 H 17 OCH2C6H4CO2H (2, 3 or 4) N(CH3)2 H 18 OCH2C6H4CO2CH2CH3(2, 3 or 4) N(CH3)2 CH3 19 OCH2C6H4CO2H (2, 3 or 4) N(CH3)2 CH3 20 OCH2C6H4CH2CO2CH2CH3(2, 3 or 4) N(CH3)2 H 21 OCH2C6H4CH2CO2H (2, 3 or 4) N(CH3)2 H 22 OCH2C6H4CH2CO2CH2CH3(2, 3 or 4) N(CH3)2 CH3 23 OCH2C6H4CH2CO2H (2, 3 or 4) N(CH3)2 CH3 24 OCH2CO2CH2CH3 NHCH2C6CH5 H 25 OCH2CO2H NHCH2C6CH5 H 26 OCH2CO2CH2CH3 NHCH2C6CH5 CH3 27 OCH2CO2H NHCH2C6CH5 CH3 28 OCH2CH2CO2CH2CH3 NHCH2C6CH5 H 29 OCH2CH2CO2H NHCH2C6CH5 H 30 OCH2CH2CO2CH2CH3 NHCH2C6CH5 CH3 31 OCH2CH2CO2H NHCH2C6CH5 CH3 32 OCH2CH2PO(OCH2CH3)2 NHCH2C6CH5 H 33 OCH2CH2PO(OH)2 NHCH2C6CH5 H 34 OCH2CH2PO(OCH2CH3)2 NHCH2C6CH5 CH3 35 OCH2CH2PO(OH)2 NHCH2C6CH5 CH3 36 OCH2CH═CHCO2CH2CH3 NHCH2C6CH5 H 37 OCH2CH═CHCO2H NHCH2C6CH5 H 38 OCH2CH═CHCO2CH2CH3 NHCH2C6CH5 CH3 39 OCH2CH═CHCO2H NHCH2C6CH5 CH3 40 OCH2CO2CH2CH3 NHCH2CONH2 H 41 OCH2CO2H NHCH2CONH2 H 42 OCH2CO2CH2CH3 NHCH2CONH2 CH3 43 OCH2CO2H NHCH2CONH2 CH3 44 OCH2CH2CO2CH2CH3 NHCH2CONH2 H 45 OCH2CH2CO2H NHCH2CONH2 H 46 OCH2CH2CO2CH2CH3 NHCH2CONH2 CH3 47 OCH2CH2CO2H NHCH2CONH2 CH3 48 OCH2CH2PO(OCH2CH3)2 NHCH2CONH2 H 49 OCH2CH2PO(OH)2 NHCH2CONH2 H 50 OCH2CH2PO(OCH2CH3)2 NHCH2CONH2 CH3 51 OCH2CH2PO(OH)2 NHCH2CONH2 CH3 52 OCH2CH═CHCO2CH2CH3 NHCH2CONH2 H 53 OCH2CH═CHCO2H NHCH2CONH2 H 54 OCH2CH═CHCO2CH2CH3 NHCH2CONH2 CH3 55 OCH2CH═CHCO2H NHCH2CONH2 CH3 56 OCH2C6H4CO2CH2CH3(2, 3 or 4) NHCH2CONH2 H 57 OCH2C6H4CO2H (2, 3 or 4) NHCH2CONH2 H 58 OCH2C6H4CO2CH2CH3(2, 3 or 4) NHCH2CONH2 CH3 59 OCH2C6H4CO2H (2, 3 or 4) NHCH2CONH2 CH3 60 OCH2C6H4CH2CO2CH2CH3(2, 3 or 4) NHCH2CONH2 H 61 OCH2C6H4CH2CO2H (2, 3 or 4) NHCH2CONH2 H 62 OCH2C6H4CH2CO2CH2CH3(2, 3 or 4) NHCH2CONH2 CH3 63 OCH2C6H4CH2CO2H (2, 3 or 4) NHCH2CONH2 CH3 TABLE V Ex. # X X1 Z R1 1. H H OH CO2CH2CH3 2. H H OH CO2H 3. H H OH CH2CO2CH2CH3 4. H H OH CH2CO2H 5. H H OH CH2CH2CO2CH2CH3 6. H H OH CH2CH2CO2H 7. H H OH CH2CH═CHCO2H 8. H H OH CH2CH═CHCO2H 9. H H OH CH2CH2P—O(OCH2CH3)2 10. H H OH CH2CH2P—O(OH)2 11. OH H OH CO2CH2CH3 12. OH H OH CO2H 13. OH H OH CH2CO2CH2CH3 14. OH H OH CH2CO2H 15. OH H OH CH2CH2CO2CH2CH3 16. OH H OH CH2CH2CO2H 17. OH H OH CH2CH═CHCO2H 18. OH H OH CH2CH═CHCO2H 19. OH H OH CH2CH2P—O(OCH2CH3)2 20. OH H OH CH2CH2P—O(OH)2 21. OCH3 H OH CO2CH2CH3 22. OCH3 H OH CO2H 23. OCH3 H OH CH2CO2CH2CH3 24. OCH3 H OH CH2CO2H 25. OCH3 H OH CH2CH2CO2CH2CH3 26. OCH3 H OH CH2CH2CO2H 27. OCH3 H OH CH2CH═CHCO2H 28. OCH3 H OH CH2CH═CHCO2H 29. OCH3 H OH CH2CH2P—O(OCH2CH3)2 30. OCH3 H OH CH2CH2P—O(OH)2 31. OCH2CH═CH2 H OH CO2CH2CH3 32. OCH2CH═CH2 H OH CO2H 33. OCH2CH═CH2 H OH CH2CO2CH2CH3 34. OCH2CH═CH2 H OH CH2CO2H 35. OCH2CH═CH2 H OH CH2CH2CO2CH2CH3 36. OCH2CH═CH2 H OH CH2CH2CO2H 37. OCH2CH═CH2 H OH CH2CH═CHCO2H 38. OCH2CH═CH2 H OH CH2CH═CHCO2H 39. OCH2CH═CH2 H OH CH2CH2P—O(OCH2CH3)2 40. OCH2CH═CH2 H OH CH2CH2P—O(OH)2 41. OCH2C6H5 H OH CO2CH2CH3 42. OCH2C6H5 H OH CO2H 43. OCH2C6H5 H OH CH2CO2CH2CH3 44. OCH2C6H5 H OH CH2CO2H 45. OCH2C6H5 H OH CH2CH2CO2CH2CH3 46. OCH2C6H5 H OH CH2CH2CO2H 47. OCH2C6H5 H OH CH2CH═CHCO2H 48. OCH2C6H5 H OH CH2CH═CHCO2H 49. OCH2C6H5 H OH CH2CH2P—O(OCH2CH3)2 50. OCH2C6H5 H OH CH2CH2P—O(OH)2 51. Cll H OH CO2CH2CH3 52. Cl H OH CO2H 53. Cl H OH CH2CO2CH2CH3 54. Cl H OH CH2CO2H 55. Cl H OH CH2CH2CO2CH2CH3 56. Cl H OH CH2CH2CO2H 57. Cl H OH CH2CH═CHCO2H 58. Cl H OH CH2CH═CHCO2H 59. Cl H OH CH2CH2P—O(OCH2CH3)2 60. Cl H OH CH2CH2P—O(OH)2 61. NO2 H OH CO2CH2CH3 62. NO2 H OH CO2H 63. NO2 H OH CH2CO2CH2CH3 64. NO2 H OH CH2CO2H 65. NO2 H OH CH2CH2CO2CH2CH3 66. NO2 H OH CH2CH2CO2H 67. NO2 H OH CH2CH═CHCO2H 68. NO2 H OH CH2CH═CHCO2H 69. NO2 H OH CH2CH2P—O(OCH2CH3)2 70. NO2 H OH CH2CH2P—O(OH)2 71. NHSO2CH3 H OH H 72. NHSO2CH3 H OH CH3 73. NHSO2CH3 H OH CO2CH2CH3 74. NHSO2CH3 H OH CO2H 75. NHSO2CH3 H OH CH2CO2CH2CH3 76. NHSO2CH3 H OH CH2CO2H 77. NHSO2CH3 H OH CH2CH2CO2CH2CH3 78. NHSO2CH3 H OH CH2CH2CO2H 79. NHSO2CH3 H OH CH2CH═CHCO2H 80. NHSO2CH3 H OH CH2CH═CHCO2H 81. NHSO2CH3 H OH CH2CH2P—O(OCH2CH3)2 82. NHSO2CH3 H OH CH2CH2P—O(OH)2 83. OCH2CONH2 H OH H 84. OCH2CONH2 H OH CH3 85. OCH2CONH2 H OH CO2CH2CH3 86. OCH2CONH2 H OH CO2H 87. OCH2CONH2 H OH CH2CO2CH2CH3 88. OCH2CONH2 H OH CH2CO2H 89. OCH2CONH2 H OH CH2CH2CO2CH2CH3 90. OCH2CONH2 H OH CH2CH2CO2H 91. OCH2CONH2 H OH CH2CH═CHCO2H 92. OCH2CONH2 H OH CH2CH═CHCO2H 93. OCH2CONH2 H OH CH2CH2P—O(OCH2CH3)2 94. OCH2CONH2 H OH CH2CH2P—O(OH)2 95. OH CH2N(CH3)2 OH CO2CH2CH3 96. OH CH2N(CH3)2 OH CO2H 97. OH CH2N(CH3)2 OH CH2CO2CH2CH3 98. OH CH2N(CH3)2 OH CH2CO2H 99. OH CH2N(CH3)2 OH CH2CH2CO2CH2CH3 100. OH CH2N(CH3)2 OH CH2CH2CO2H 101. OH CH2N(CH3)2 OH CH2CH═CHCO2H 102. OH CH2N(CH3)2 OH CH2CH═CHCO2H 103. OH CH2N(CH3)2 OH CH2CH2P—O(OCH2CH3)2 104. OH CH2N(CH3)2 OH CH2CH2P—O(OH)2 105. OCH3 CH2N(CH3)2 OH CO2CH2CH3 106. OCH3 CH2N(CH3)2 OH CO2H 107. OCH3 CH2N(CH3)2 OH CH2CO2CH2CH3 108. OCH3 CH2N(CH3)2 OH CH2CO2H 109. OCH3 CH2N(CH3)2 OH CH2CH2CO2CH2CH3 110. OCH3 CH2N(CH3)2 OH CH2CH2CO2H 111. OCH3 CH2N(CH3)2 OH CH2CH═CHCO2H 112. OCH3 CH2N(CH3)2 OH CH2CH═CHCO2H 113. OCH3 CH2N(CH3)2 OH CH2CH2P—O(OCH2CH3)2 114. OCH3 CH2N(CH3)2 OH CH2CH2P—O(OH)2 115. OH CH2N+(CH3)3 OH H Cl− 116. OH CH2N+(CH3)3 OH CH3 Cl− 117. OH CH2N+(CH3)3 OH CO2CH2CH3 Cl− 118. OH CH2N+(CH3)3 OH CO2H Cl− 119. OH CH2N+(CH3)3 OH CH2CO2CH2CH3 Cl− 120. OH CH2N+(CH3)3 OH CH2CO2H Cl− 121. OH CH2N+(CH3)3 OH CH2CH2CO2CH2CH3 Cl− 122. OH CH2N+(CH3)3 OH CH2CH2CO2H Cl− 123. OH CH2N+(CH3)3 OH CH2CH═CHCO2H Cl− 124. OH CH2N+(CH3)3 OH CH2CH═CHCO2H Cl− 125. OH CH2N+(CH3)3 OH CH2CH2P—O(OCH2CH3)2 Cl− 126. OH CH2N+(CH3)3 OH CH2CH2P—O(OH)2 Cl− 127. OCH3 CH2N+(CH3)3 OH H Cl− 128. OCH3 CH2N+(CH3)3 OH CH3 Cl− 129. OCH3 CH2N+(CH3)3 OH CO2CH2CH3 Cl− 130. OCH3 CH2N+(CH3)3 OH CO2H Cl− 131. OCH3 CH2N+(CH3)3 OH CH2CO2CH2CH3 Cl− 132. OCH3 CH2N+(CH3)3 OH CH2CO2H Cl− 133. OCH3 CH2N+(CH3)3 OH CH2CH2CO2CH2CH3 Cl− 134. OCH3 CH2N+(CH3)3 OH CH2CH2CO2H Cl− 135. OCH3 CH2N+(CH3)3 OH CH2CH═CHCO2H Cl− 136. OCH3 CH2N+(CH3)3 OH CH2CH═CHCO2H Cl− 137. OCH3 CH2N+(CH3)3 OH CH2CH2P—O(OCH2CH3)2 Cl− 138. OCH3 CH2N+(CH3)3 OH CH2CH2P—O(OH)2 Cl− 139. H H OCH3 CO2CH2CH3 140. H H OCH3 CO2H 141. H H OCH3 CH2CO2CH2CH3 142. H H OCH3 CH2CO2H 143. H H OCH3 CH2CH2CO2CH2CH3 144. H H OCH3 CH2CH2CO2H 145. H H OCH3 CH2CH═CHCO2H 146. H H OCH3 CH2CH═CHCO2H 147. H H OCH3 CH2CH2P—O(OCH2CH3)2 148. H H OCH3 CH2CH2P—O(OH)2 149. OH H OCH3 CO2CH2CH3 150. OH H OCH3 CO2H 151. OH H OCH3 CH2CO2CH2CH3 152. OH H OCH3 CH2CO2H 153. OH H OCH3 CH2CH2CO2CH2CH3 154. OH H OCH3 CH2CH2CO2H 155. OH H OCH3 CH2CH═CHCO2H 156. OH H OCH3 CH2CH═CHCO2H 157. OH H OCH3 CH2CH2P—O(OCH2CH3)2 158. OH H OCH3 CH2CH2P—O(OH)2 159. OCH3 H OCH3 CO2CH2CH3 160. OCH3 H OCH3 CO2H 161. OCH3 H OCH3 CH2CO2CH2CH3 162. OCH3 H OCH3 CH2CO2H 163. OCH3 H OCH3 CH2CH2CO2CH2CH3 164. OCH3 H OCH3 CH2CH2CO2H 165. OCH3 H OCH3 CH2CH═CHCO2H 166. OCH3 H OCH3 CH2CH═CHCO2H 167. OCH3 H OCH3 CH2CH2P—O(OCH2CH3)2 168. OCH3 H OCH3 CH2CH2P—O(OH)2 169. OCH2CH═CH2 H OCH3 CO2CH2CH3 170. OCH2CH═CH2 H OCH3 CO2H 171. OCH2CH═CH2 H OCH3 CH2CO2CH2CH3 172. OCH2CH═CH2 H OCH3 CH2CO2H 173. OCH2CH═CH2 H OCH3 CH2CH2CO2CH2CH3 174. OCH2CH═CH2 H OCH3 CH2CH2CO2H 175. OCH2CH═CH2 H OCH3 CH2CH═CHCO2H 176. OCH2CH═CH2 H OCH3 CH2CH═CHCO2H 177. OCH2CH═CH2 H OCH3 CH2CH2P—O(OCH2CH3)2 178. OCH2CH═CH2 H OCH3 CH2CH2P—O(OH)2 179. OCH2C6H5 H OCH3 CO2CH2CH3 180. OCH2C6H5 H OCH3 CO2H 181. OCH2C6H5 H OCH3 CH2CO2CH2CH3 182. OCH2C6H5 H OCH3 CH2CO2H 183. OCH2C6H5 H OCH3 CH2CH2CO2CH2CH3 184. OCH2C6H5 H OCH3 CH2CH2CO2H 185. OCH2C6H5 H OCH3 CH2CH═CHCO2H 186. OCH2C6H5 H OCH3 CH2CH═CHCO2H 187. OCH2C6H5 H OCH3 CH2CH2P—O(OCH2CH3)2 188. OCH2C6H5 H OCH3 CH2CH2P—O(OH)2 189. Cl H OCH3 CO2CH2CH3 190. Cl H OCH3 CO2H 191. Cl H OCH3 CH2CO2CH2CH3 192. Cl H OCH3 CH2CO2H 193. Cl H OCH3 CH2CH2CO2CH2CH3 194. Cl H OCH3 CH2CH2CO2H 195. Cl H OCH3 CH2CH═CHCO2H 196. Cl H OCH3 CH2CH═CHCO2H 197. Cl H OCH3 CH2CH2P—O(OCH2CH3)2 198. Cl H OCH3 CH2CH2P—O(OH)2 199. NO2 H OCH3 CO2CH2CH3 200. NO2 H OCH3 CO2H 201. NO2 H OCH3 CH2CO2CH2CH3 202. NO2 H OCH3 CH2CO2H 203. NO2 H OCH3 CH2CH2CO2CH2CH3 204. NO2 H OCH3 CH2CH2CO2H 205. NO2 H OCH3 CH2CH═CHCO2H 206. NO2 H OCH3 CH2CH═CHCO2H 207. NO2 H OCH3 CH2CH2P—O(OCH2CH3)2 208. NO2 H OCH3 CH2CH2P—O(OH)2 209. NHSO2CH3 H OCH3 H 210. NHSO2CH3 H OCH3 CH3 211. NHSO2CH3 H OCH3 CO2CH2CH3 212. NHSO2CH3 H OCH3 CO2H 213. NHSO2CH3 H OCH3 CH2CO2CH2CH3 214. NHSO2CH3 H OCH3 CH2CO2H 215. NHSO2CH3 H OCH3 CH2CH2CO2CH2CH3 216. NHSO2CH3 H OCH3 CH2CH2CO2H 217. NHSO2CH3 H OCH3 CH2CH═CHCO2H 218. NHSO2CH3 H OCH3 CH2CH═CHCO2H 219. NHSO2CH3 H OCH3 CH2CH2P—O(OCH2CH3)2 220. NHSO2CH3 H OCH3 CH2CH2P—O(OH)2 221. OCH2CONH2 H OCH3 H 222. OCH2CONH2 H OCH3 CH3 223. OCH2CONH2 H OCH3 CO2CH2CH3 224. OCH2CONH2 H OCH3 CO2H 225. OCH2CONH2 H OCH3 CH2CO2CH2CH3 226. OCH2CONH2 H OCH3 CH2CO2H 227. OCH2CONH2 H OCH3 CH2CH2CO2CH2CH3 228. OCH2CONH2 H OCH3 CH2CH2CO2H 229. OCH2CONH2 H OCH3 CH2CH═CHCO2H 230. OCH2CONH2 H OCH3 CH2CH═CHCO2H 231. OCH2CONH2 H OCH3 CH2CH2P—O(OCH2CH3)2 232. OCH2CONH2 H OCH3 CH2CH2P—O(OH)2 233. OH CH2N(CH3)2 OCH3 CO2CH2CH3 234. OH CH2N(CH3)2 OCH3 CO2H 235. OH CH2N(CH3)2 OCH3 CH2CO2CH2CH3 236. OH CH2N(CH3)2 OCH3 CH2CO2H 237. OH CH2N(CH3)2 OCH3 CH2CH2CO2CH2CH3 238. OH CH2N(CH3)2 OCH3 CH2CH2CO2H 239. OH CH2N(CH3)2 OCH3 CH2CH═CHCO2H 240. OH CH2N(CH3)2 OCH3 CH2CH═CHCO2H 241. OH CH2N(CH3)2 OCH3 CH2CH2P—O(OCH2CH3)2 242. OH CH2N(CH3)2 OCH3 CH2CH2P—O(OH)2 243. OCH3 CH2N(CH3)2 OCH3 CO2CH2CH3 244. OCH3 CH2N(CH3)2 OCH3 CO2H 245. OCH3 CH2N(CH3)2 OCH3 CH2CO2CH2CH3 246. OCH3 CH2N(CH3)2 OCH3 CH2CO2H 247. OCH3 CH2N(CH3)2 OCH3 CH2CH2CO2CH2CH3 248. OCH3 CH2N(CH3)2 OCH3 CH2CH2CO2H 249. OCH3 CH2N(CH3)2 OCH3 CH2CH═CHCO2H 250. OCH3 CH2N(CH3)2 OCH3 CH2CH═CHCO2H 251. OCH3 CH2N(CH3)2 OCH3 CH2CH2P—O(OCH2CH3)2 252. OCH3 CH2N(CH3)2 OCH3 CH2CH2P—O(OH)2 253. OH CH2N+(CH3)3 OCH3 H Cl− 254. OH CH2N+(CH3)3 OCH3 CH3 Cl− 255. OH CH2N+(CH3)3 OCH3 CO2CH2CH3 Cl− 256. OH CH2N+(CH3)3 OCH3 CO2H Cl− 257. OH CH2N+(CH3)3 OCH3 CH2CO2CH2CH3 Cl− 258. OH CH2N+(CH3)3 OCH3 CH2CO2H Cl− 259. OH CH2N+(CH3)3 OCH3 CH2CH2CO2CH2CH3 Cl− 260. OH CH2N+(CH3)3 OCH3 CH2CH2CO2H Cl− 261. OH CH2N+(CH3)3 OCH3 CH2CH═CHCO2H Cl− 262. OH CH2N+(CH3)3 OCH3 CH2CH═CHCO2H Cl− 263. OH CH2N+(CH3)3 OCH3 CH2CH2P—O(OCH2CH3)2 Cl− 264. OH CH2N+(CH3)3 OCH3 CH2CH2P—O(OH)2 Cl− 265. OCH3 CH2N+(CH3)3 OCH3 H Cl− 266. OCH3 CH2N+(CH3)3 OCH3 CH3 Cl− 267. OCH3 CH2N+(CH3)3 OCH3 CO2CH2CH3 Cl− 268. OCH3 CH2N+(CH3)3 OCH3 CO2H Cl− 269. OCH3 CH2N+(CH3)3 OCH3 CH2CO2CH2CH3 Cl− 270. OCH3 CH2N+(CH3)3 OCH3 CH2CO2H Cl− 271. OCH3 CH2N+(CH3)3 OCH3 CH2CH2CO2CH2CH3 Cl− 272. OCH3 CH2N+(CH3)3 OCH3 CH2CH2CO2H Cl− 273. OCH3 CH2N+(CH3)3 OCH3 CH2CH═CHCO2H Cl− 274. OCH3 CH2N+(CH3)3 OCH3 CH2CH═CHCO2H Cl− 275. OCH3 CH2N+(CH3)3 OCH3 CH2CH2P—O(OCH2CH3)2 Cl− 276. OCH3 CH2N+(CH3)3 OCH3 CH2CH2P—O(OH)2 Cl− 277. H H OCH2C6H5 CO2CH2CH3 278. H H OCH2C6H5 CO2H 279. H H OCH2C6H5 CH2CO2CH2CH3 280. H H OCH2C6H5 CH2CO2H 281. H H OCH2C6H5 CH2CH2CO2CH2CH3 282. H H OCH2C6H5 CH2CH2CO2H 283. H H OCH2C6H5 CH2CH═CHCO2H 284. H H OCH2C6H5 CH2CH═CHCO2H 285. H H OCH2C6H5 CH2CH2P—O(OCH2CH3)2 286. H H OCH2C6H5 CH2CH2P—O(OH)2 287. OH H OCH2C6H5 CO2CH2CH3 288. OH H OCH2C6H5 CO2H 289. OH H OCH2C6H5 CH2CO2CH2CH3 290. OH H OCH2C6H5 CH2CO2H 291. OH H OCH2C6H5 CH2CH2CO2CH2CH3 292. OH H OCH2C6H5 CH2CH2CO2H 293. OH H OCH2C6H5 CH2CH═CHCO2H 294. OH H OCH2C6H5 CH2CH═CHCO2H 295. OH H OCH2C6H5 CH2CH2P—O(OCH2CH3)2 296. OH H OCH2C6H5 CH2CH2P—O(OH)2 297. OCH3 H OCH2C6H5 CO2CH2CH3 298. OCH3 H OCH2C6H5 CO2H 299. OCH3 H OCH2C6H5 CH2CO2CH2CH3 300. OCH3 H OCH2C6H5 CH2CO2H 301. OCH3 H OCH2C6H5 CH2CH2CO2CH2CH3 302. OCH3 H OCH2C6H5 CH2CH2CO2H 303. OCH3 H OCH2C6H5 CH2CH═CHCO2H 304. OCH3 H OCH2C6H5 CH2CH═CHCO2H 305. OCH3 H OCH2C6H5 CH2CH2P—O(OCH2CH3)2 306. OCH3 H OCH2C6H5 CH2CH2P—O(OH)2 307. OCH2CH═CH2 H OCH2C6H5 CO2CH2CH3 308. OCH2CH═CH2 H OCH2C6H5 CO2H 309. OCH2CH═CH2 H OCH2C6H5 CH2CO2CH2CH3 310. OCH2CH═CH2 H OCH2C6H5 CH2CO2H 311. OCH2CH═CH2 H OCH2C6H5 CH2CH2CO2CH2CH3 312. OCH2CH═CH2 H OCH2C6H5 CH2CH2CO2H 313. OCH2CH═CH2 H OCH2C6H5 CH2CH═CHCO2H 314. OCH2CH═CH2 H OCH2C6H5 CH2CH═CHCO2H 315. OCH2CH═CH2 H OCH2C6H5 CH2CH2P—O(OCH2CH3)2 316. OCH2CH═CH2 H OCH2C6H5 CH2CH2P—O(OH)2 317. OCH2C6H5 H OCH2C6H5 CO2CH2CH3 318. OCH2C6H5 H OCH2C6H5 CO2H 319. OCH2C6H5 H OCH2C6H5 CH2CO2CH2CH3 320. OCH2C6H5 H OCH2C6H5 CH2CO2H 321. OCH2C6H5 H OCH2C6H5 CH2CH2CO2CH2CH3 322. OCH2C6H5 H OCH2C6H5 CH2CH2CO2H 323. OCH2C6H5 H OCH2C6H5 CH2CH═CHCO2H 324. OCH2C6H5 H OCH2C6H5 CH2CH═CHCO2H 325. OCH2C6H5 H OCH2C6H5 CH2CH2P—O(OCH2CH3)2 326. OCH2C6H5 H OCH2C6H5 CH2CH2P—O(OH)2 327. Cl H OCH2C6H5 CO2CH2CH3 328. Cl H OCH2C6H5 CO2H 329. Cl H OCH2C6H5 CH2CO2CH2CH3 330. Cl H OCH2C6H5 CH2CO2H 331. Cl H OCH2C6H5 CH2CH2CO2CH2CH3 332. Cl H OCH2C6H5 CH2CH2CO2H 333. Cl H OCH2C6H5 CH2CH═CHCO2H 334. Cl H OCH2C6H5 CH2CH═CHCO2H 335. Cl H OCH2C6H5 CH2CH2P—O(OCH2CH3)2 336. Cl H OCH2C6H5 CH2CH2P—O(OH)2 337. NO2 H OCH2C6H5 CO2CH2CH3 338. NO2 H OCH2C6H5 CO2H 339. NO2 H OCH2C6H5 CH2CO2CH2CH3 340. NO2 H OCH2C6H5 CH2CO2H 341. NO2 H OCH2C6H5 CH2CH2CO2CH2CH3 342. NO2 H OCH2C6H5 CH2CH2CO2H 343. NO2 H OCH2C6H5 CH2CH═CHCO2H 344. NO2 H OCH2C6H5 CH2CH═CHCO2H 345. NO2 H OCH2C6H5 CH2CH2P—O(OCH2CH3)2 346. NO2 H OCH2C6H5 CH2CH2P—O(OH)2 347. NHSO2CH3 H OCH2C6H5 H 348. NHSO2CH3 H OCH2C6H5 CH3 349. NHSO2CH3 H OCH2C6H5 CO2CH2CH3 350. NHSO2CH3 H OCH2C6H5 CO2H 351. NHSO2CH3 H OCH2C6H5 CH2CO2CH2CH3 352. NHSO2CH3 H OCH2C6H5 CH2CO2H 353. NHSO2CH3 H OCH2C6H5 CH2CH2CO2CH2CH3 354. NHSO2CH3 H OCH2C6H5 CH2CH2CO2H 355. NHSO2CH3 H OCH2C6H5 CH2CH═CHCO2H 356. NHSO2CH3 H OCH2C6H5 CH2CH═CHCO2H 357. NHSO2CH3 H OCH2C6H5 CH2CH2P—O(OCH2CH3)2 358. NHSO2CH3 H OCH2C6H5 CH2CH2P—O(OH)2 359. OCH2CONH2 H OCH2C6H5 H 360. OCH2CONH2 H OCH2C6H5 CH3 361. OCH2CONH2 H OCH2C6H5 CO2CH2CH3 362. OCH2CONH2 H OCH2C6H5 CO2H 363. OCH2CONH2 H OCH2C6H5 CH2CO2CH2CH3 364. OCH2CONH2 H OCH2C6H5 CH2CO2H 365. OCH2CONH2 H OCH2C6H5 CH2CH2CO2CH2CH3 366. OCH2CONH2 H OCH2C6H5 CH2CH2CO2H 367. OCH2CONH2 H OCH2C6H5 CH2CH═CHCO2H 368. OCH2CONH2 H OCH2C6H5 CH2CH═CHCO2H 369. OCH2CONH2 H OCH2C6H5 CH2CH2P—O(OCH2CH3)2 370. OCH2CONH2 H OCH2C6H5 CH2CH2P—O(OH)2 371. OH CH2N(CH3)2 OCH2C6H5 CO2CH2CH3 372. OH CH2N(CH3)2 OCH2C6H5 CO2H 373. OH CH2N(CH3)2 OCH2C6H5 CH2CO2CH2CH3 374. OH CH2N(CH3)2 OCH2C6H5 CH2CO2H 375. OH CH2N(CH3)2 OCH2C6H5 CH2CH2CO2CH2CH3 376. OH CH2N(CH3)2 OCH2C6H5 CH2CH2CO2H 377. OH CH2N(CH3)2 OCH2C6H5 CH2CH═CHCO2H 378. OH CH2N(CH3)2 OCH2C6H5 CH2CH═CHCO2H 379. OH CH2N(CH3)2 OCH2C6H5 CH2CH2P—O(OCH2CH3)2 380. OH CH2N(CH3)2 OCH2C6H5 CH2CH2P—O(OH)2 381. OCH3 CH2N(CH3)2 OCH2C6H5 CO2CH2CH3 382. OCH3 CH2N(CH3)2 OCH2C6H5 CO2H 383. OCH3 CH2N(CH3)2 OCH2C6H5 CH2CO2CH2CH3 384. OCH3 CH2N(CH3)2 OCH2C6H5 CH2CO2H 385. OCH3 CH2N(CH3)2 OCH2C6H5 CH2CH2CO2CH2CH3 386. OCH3 CH2N(CH3)2 OCH2C6H5 CH2CH2CO2H 387. OCH3 CH2N(CH3)2 OCH2C6H5 CH2CH═CHCO2H 388. OCH3 CH2N(CH3)2 OCH2C6H5 CH2CH═CHCO2H 389. OCH3 CH2N(CH3)2 OCH2C6H5 CH2CH2P—O(OCH2CH3)2 390. OCH3 CH2N(CH3)2 OCH2C6H5 CH2CH2P—O(OH)2 391. OH CH2N+(CH3)3 OCH2C6H5 H Cl− 392. OH CH2N+(CH3)3 OCH2C6H5 CH3 Cl− 393. OH CH2N+(CH3)3 OCH2C6H5 CO2CH2CH3 Cl− 394. OH CH2N+(CH3)3 OCH2C6H5 CO2H Cl− 395. OH CH2N+(CH3)3 OCH2C6H5 CH2CO2CH2CH3 Cl− 396. OH CH2N+(CH3)3 OCH2C6H5 CH2CO2H Cl− 397. OH CH2N+(CH3)3 OCH2C6H5 CH2CH2CO2CH2CH3 Cl− 398. OH CH2N+(CH3)3 OCH2C6H5 CH2CH2CO2H Cl− 399. OH CH2N+(CH3)3 OCH2C6H5 CH2CH═CHCO2H Cl− 400. OH CH2N+(CH3)3 OCH2C6H5 CH2CH═CHCO2H Cl− 401. OH CH2N+(CH3)3 OCH2C6H5 CH2CH2P—O(OCH2CH3)2 Cl− 402. OH CH2N+(CH3)3 OCH2C6H5 CH2CH2P—O(OH)2 Cl− 403. OCH3 CH2N+(CH3)3 OCH2C6H5 H Cl− 404. OCH3 CH2N+(CH3)3 OCH2C6H5 CH3 Cl− 405. OCH3 CH2N+(CH3)3 OCH2C6H5 CO2CH2CH3 Cl− 406. OCH3 CH2N+(CH3)3 OCH2C6H5 CO2H Cl− 407. OCH3 CH2N+(CH3)3 OCH2C6H5 CH2CO2CH2CH3 Cl− 408. OCH3 CH2N+(CH3)3 OCH2C6H5 CH2CO2H Cl− 409. OCH3 CH2N+(CH3)3 OCH2C6H5 CH2CH2CO2CH2CH3 Cl− 410. OCH3 CH2N+(CH3)3 OCH2C6H5 CH2CH2CO2H Cl− 411. OCH3 CH2N+(CH3)3 OCH2C6H5 CH2CH═CHCO2H Cl− 412. OCH3 CH2N+(CH3)3 OCH2C6H5 CH2CH═CHCO2H Cl− 413. OCH3 CH2N+(CH3)3 OCH2C6H5 CH2CH2P—O(OCH2CH3)2 Cl− 414. OCH3 CH2N+(CH3)3 OCH2C6H5 CH2CH2P—O(OH)2 Cl− 415. H H OCH2CH═CH2 CO2CH2CH3 416. H H OCH2CH═CH2 CO2H 417. H H OCH2CH═CH2 CH2CO2CH2CH3 418. H H OCH2CH═CH2 CH2CO2H 419. H H OCH2CH═CH2 CH2CH2CO2CH2CH3 420. H H OCH2CH═CH2 CH2CH2CO2H 421. H H OCH2CH═CH2 CH2CH═CHCO2H 422. H H OCH2CH═CH2 CH2CH═CHCO2H 423. H H OCH2CH═CH2 CH2CH2P—O(OCH2CH3)2 424. H H OCH2CH═CH2 CH2CH2P—O(OH)2 425. OH H OCH2CH═CH2 CO2CH2CH3 426. OH H OCH2CH═CH2 CO2H 427. OH H OCH2CH═CH2 CH2CO2CH2CH3 428. OH H OCH2CH═CH2 CH2CO2H 429. OH H OCH2CH═CH2 CH2CH2CO2CH2CH3 430. OH H OCH2CH═CH2 CH2CH2CO2H 431. OH H OCH2CH═CH2 CH2CH═CHCO2H 432. OH H OCH2CH═CH2 CH2CH═CHCO2H 433. OH H OCH2CH═CH2 CH2CH2P—O(OCH2CH3)2 434. OH H OCH2CH═CH2 CH2CH2P—O(OH)2 435. OCH3 H OCH2CH═CH2 CO2CH2CH3 436. OCH3 H OCH2CH═CH2 CO2H 437. OCH3 H OCH2CH═CH2 CH2CO2CH2CH3 438. OCH3 H OCH2CH═CH2 CH2CO2H 439. OCH3 H OCH2CH═CH2 CH2CH2CO2CH2CH3 440. OCH3 H OCH2CH═CH2 CH2CH2CO2H 441. OCH3 H OCH2CH═CH2 CH2CH═CHCO2H 442. OCH3 H OCH2CH═CH2 CH2CH═CHCO2H 443. OCH3 H OCH2CH═CH2 CH2CH2P—O(OCH2CH3)2 444. OCH3 H OCH2CH═CH2 CH2CH2P—O(OH)2 445. OCH2CH═CH2 H OCH2CH═CH2 CO2CH2CH3 446. OCH2CH═CH2 H OCH2CH═CH2 CO2H 447. OCH2CH═CH2 H OCH2CH═CH2 CH2CO2CH2CH3 448. OCH2CH═CH2 H OCH2CH═CH2 CH2CO2H 449. OCH2CH═CH2 H OCH2CH═CH2 CH2CH2CO2CH2CH3 450. OCH2CH═CH2 H OCH2CH═CH2 CH2CH2CO2H 451. OCH2CH═CH2 H OCH2CH═CH2 CH2CH═CHCO2H 452. OCH2CH═CH2 H OCH2CH═CH2 CH2CH═CHCO2H 453. OCH2CH═CH2 H OCH2CH═CH2 CH2CH2P—O(OCH2CH3)2 454. OCH2CH═CH2 H OCH2CH═CH2 CH2CH2P—O(OH)2 455. OCH2C6H5 H OCH2CH═CH2 CO2CH2CH3 456. OCH2C6H5 H OCH2CH═CH2 CO2H 457. OCH2C6H5 H OCH2CH═CH2 CH2CO2CH2CH3 458. OCH2C6H5 H OCH2CH═CH2 CH2CO2H 459. OCH2C6H5 H OCH2CH═CH2 CH2CH2CO2CH2CH3 460. OCH2C6H5 H OCH2CH═CH2 CH2CH2CO2H 461. OCH2C6H5 H OCH2CH═CH2 CH2CH═CHCO2H 462. OCH2C6H5 H OCH2CH═CH2 CH2CH═CHCO2H 463. OCH2C6H5 H OCH2CH═CH2 CH2CH2P—O(OCH2CH3)2 464. OCH2C6H5 H OCH2CH═CH2 CH2CH2P—O(OH)2 465. Cll H OCH2CH═CH2 CO2CH2CH3 466. Cl H OCH2CH═CH2 CO2H 467. Cl H OCH2CH═CH2 CH2CO2CH2CH3 468. Cl H OCH2CH═CH2 CH2CO2H 469. Cl H OCH2CH═CH2 CH2CH2CO2CH2CH3 470. Cl H OCH2CH═CH2 CH2CH2CO2H 471. Cl H OCH2CH═CH2 CH2CH═CHCO2H 472. Cl H OCH2CH═CH2 CH2CH═CHCO2H 473. Cl H OCH2CH═CH2 CH2CH2P—O(OCH2CH3)2 474. Cl H OCH2CH═CH2 CH2CH2P—O(OH)2 475. NO2 H OCH2CH═CH2 CO2CH2CH3 476. NO2 H OCH2CH═CH2 CO2H 477. NO2 H OCH2CH═CH2 CH2CO2CH2CH3 478. NO2 H OCH2CH═CH2 CH2CO2H 479. NO2 H OCH2CH═CH2 CH2CH2CO2CH2CH3 480. NO2 H OCH2CH═CH2 CH2CH2CO2H 481. NO2 H OCH2CH═CH2 CH2CH═CHCO2H 482. NO2 H OCH2CH═CH2 CH2CH═CHCO2H 483. NO2 H OCH2CH═CH2 CH2CH2P—O(OCH2CH3)2 484. NO2 H OCH2CH═CH2 CH2CH2P—O(OH)2 485. NHSO2CH3 H OCH2CH═CH2 H 486. NHSO2CH3 H OCH2CH═CH2 CH3 487. NHSO2CH3 H OCH2CH═CH2 CO2CH2CH3 488. NHSO2CH3 H OCH2CH═CH2 CO2H 489. NHSO2CH3 H OCH2CH═CH2 CH2CO2CH2CH3 490. NHSO2CH3 H OCH2CH═CH2 CH2CO2H 491. NHSO2CH3 H OCH2CH═CH2 CH2CH2CO2CH2CH3 492. NHSO2CH3 H OCH2CH═CH2 CH2CH2CO2H 493. NHSO2CH3 H OCH2CH═CH2 CH2CH═CHCO2H 494. NHSO2CH3 H OCH2CH═CH2 CH2CH═CHCO2H 495. NHSO2CH3 H OCH2CH═CH2 CH2CH2P—O(OCH2CH3)2 496. NHSO2CH3 H OCH2CH═CH2 CH2CH2P—O(OH)2 497. OCH2CONH2 H OCH2CH═CH2 H 498. OCH2CONH2 H OCH2CH═CH2 CH3 499. OCH2CONH2 H OCH2CH═CH2 CO2CH2CH3 500. OCH2CONH2 H OCH2CH═CH2 CO2H 501. OCH2CONH2 H OCH2CH═CH2 CH2CO2CH2CH3 502. OCH2CONH2 H OCH2CH═CH2 CH2CO2H 503. OCH2CONH2 H OCH2CH═CH2 CH2CH2CO2CH2CH3 504. OCH2CONH2 H OCH2CH═CH2 CH2CH2CO2H 505. OCH2CONH2 H OCH2CH═CH2 CH2CH═CHCO2H 506. OCH2CONH2 H OCH2CH═CH2 CH2CH═CHCO2H 507. OCH2CONH2 H OCH2CH═CH2 CH2CH2P—O(OCH2CH3)2 508. OCH2CONH2 H OCH2CH═CH2 CH2CH2P—O(OH)2 509. OH CH2N(CH3)2 OCH2CH═CH2 CO2CH2CH3 510. OH CH2N(CH3)2 OCH2CH═CH2 CO2H 511. OH CH2N(CH3)2 OCH2CH═CH2 CH2CO2CH2CH3 512. OH CH2N(CH3)2 OCH2CH═CH2 CH2CO2H 513. OH CH2N(CH3)2 OCH2CH═CH2 CH2CH2CO2CH2CH3 514. OH CH2N(CH3)2 OCH2CH═CH2 CH2CH2CO2H 515. OH CH2N(CH3)2 OCH2CH═CH2 CH2CH═CHCO2H 516. OH CH2N(CH3)2 OCH2CH═CH2 CH2CH═CHCO2H 517. OH CH2N(CH3)2 OCH2CH═CH2 CH2CH2P—O(OCH2CH3)2 518. OH CH2N(CH3)2 OCH2CH═CH2 CH2CH2P—O(OH)2 519. OCH3 CH2N(CH3)2 OCH2CH═CH2 CO2CH2CH3 520. OCH3 CH2N(CH3)2 OCH2CH═CH2 CO2H 521. OCH3 CH2N(CH3)2 OCH2CH═CH2 CH2CO2CH2CH3 522. OCH3 CH2N(CH3)2 OCH2CH═CH2 CH2CO2H 523. OCH3 CH2N(CH3)2 OCH2CH═CH2 CH2CH2CO2CH2CH3 524. OCH3 CH2N(CH3)2 OCH2CH═CH2 CH2CH2CO2H 525. OCH3 CH2N(CH3)2 OCH2CH═CH2 CH2CH═CHCO2H 526. OCH3 CH2N(CH3)2 OCH2CH═CH2 CH2CH═CHCO2H 527. OCH3 CH2N(CH3)2 OCH2CH═CH2 CH2CH2P—O(OCH2CH3)2 528. OCH3 CH2N(CH3)2 OCH2CH═CH2 CH2CH2P—O(OH)2 529. OH CH2N+(CH3)3 OCH2CH═CH2 H Cl− 530. OH CH2N+(CH3)3 OCH2CH═CH2 CH3 Cl− 531. OH CH2N+(CH3)3 OCH2CH═CH2 CO2CH2CH3 Cl− 532. OH CH2N+(CH3)3 OCH2CH═CH2 CO2H Cl− 533. OH CH2N+(CH3)3 OCH2CH═CH2 CH2CO2CH2CH3 Cl− 534. OH CH2N+(CH3)3 OCH2CH═CH2 CH2CO2H Cl− 535. OH CH2N+(CH3)3 OCH2CH═CH2 CH2CH2CO2CH2CH3 Cl− 536. OH CH2N+(CH3)3 OCH2CH═CH2 CH2CH2CO2H Cl− 537. OH CH2N+(CH3)3 OCH2CH═CH2 CH2CH═CHCO2H Cl− 538. OH CH2N+(CH3)3 OCH2CH═CH2 CH2CH═CHCO2H Cl− 539. OH CH2N+(CH3)3 OCH2CH═CH2 CH2CH2P—O(OCH2CH3)2 Cl− 540. OH CH2N+(CH3)3 OCH2CH═CH2 CH2CH2P—O(OH)2 Cl− 541. OCH3 CH2N+(CH3)3 OCH2CH═CH2 H Cl− 542. OCH3 CH2N+(CH3)3 OCH2CH═CH2 CH3 Cl− 543. OCH3 CH2N+(CH3)3 OCH2CH═CH2 CO2CH2CH3 Cl− 544. OCH3 CH2N+(CH3)3 OCH2CH═CH2 CO2H Cl− 545. OCH3 CH2N+(CH3)3 OCH2CH═CH2 CH2CO2CH2CH3 Cl− 546. OCH3 CH2N+(CH3)3 OCH2CH═CH2 CH2CO2H Cl− 547. OCH3 CH2N+(CH3)3 OCH2CH═CH2 CH2CH2CO2CH2CH3 Cl− 548. OCH3 CH2N+(CH3)3 OCH2CH═CH2 CH2CH2CO2H Cl− 549. OCH3 CH2N+(CH3)3 OCH2CH═CH2 CH2CH═CHCO2H Cl− 550. OCH3 CH2N+(CH3)3 OCH2CH═CH2 CH2CH═CHCO2H Cl− 551. OCH3 CH2N+(CH3)3 OCH2CH═CH2 CH2CH2P—O(OCH2CH3)2 Cl− 552. OCH3 CH2N+(CH3)3 OCH2CH═CH2 CH2CH2P—O(OH)2 Cl− 553. H H OCH2CONH2 H 554. H H OCH2CONH2 CH3 555. H H OCH2CONH2 CO2CH2CH3 556. H H OCH2CONH2 CO2H 557. H H OCH2CONH2 CH2CO2CH2CH3 558. H H OCH2CONH2 CH2CO2H 559. H H OCH2CONH2 CH2CH2CO2CH2CH3 560. H H OCH2CONH2 CH2CH2CO2H 561. H H OCH2CONH2 CH2CH═CHCO2H 562. H H OCH2CONH2 CH2CH═CHCO2H 563. H H OCH2CONH2 CH2CH2P—O(OCH2CH3)2 564. H H OCH2CONH2 CH2CH2P—O(OH)2 565. OH H OCH2CONH2 H 566. OH H OCH2CONH2 CH3 567. OH H OCH2CONH2 CO2CH2CH3 568. OH H OCH2CONH2 CO2H 569. OH H OCH2CONH2 CH2CO2CH2CH3 570. OH H OCH2CONH2 CH2CO2H 571. OH H OCH2CONH2 CH2CH2CO2CH2CH3 572. OH H OCH2CONH2 CH2CH2CO2H 573. OH H OCH2CONH2 CH2CH═CHCO2H 574. OH H OCH2CONH2 CH2CH═CHCO2H 575. OH H OCH2CONH2 CH2CH2P—O(OCH2CH3)2 576. OH H OCH2CONH2 CH2CH2P—O(OH)2 577. OCH3 H OCH2CONH2 H 578. OCH3 H OCH2CONH2 CH3 579. OCH3 H OCH2CONH2 CO2CH2CH3 580. OCH3 H OCH2CONH2 CO2H 581. OCH3 H OCH2CONH2 CH2CO2CH2CH3 582. OCH3 H OCH2CONH2 CH2CO2H 583. OCH3 H OCH2CONH2 CH2CH2CO2CH2CH3 584. OCH3 H OCH2CONH2 CH2CH2CO2H 585. OCH3 H OCH2CONH2 CH2CH═CHCO2H 586. OCH3 H OCH2CONH2 CH2CH═CHCO2H 587. OCH3 H OCH2CONH2 CH2CH2P—O(OCH2CH3)2 588. OCH3 H OCH2CONH2 CH2CH2P—O(OH)2 589. OCH2CH═CH2 H OCH2CONH2 H 590. OCH2CH═CH2 H OCH2CONH2 CH3 591. OCH2CH═CH2 H OCH2CONH2 CO2CH2CH3 592. OCH2CH═CH2 H OCH2CONH2 CO2H 593. OCH2CH═CH2 H OCH2CONH2 CH2CO2CH2CH3 594. OCH2CH═CH2 H OCH2CONH2 CH2CO2H 595. OCH2CH═CH2 H OCH2CONH2 CH2CH2CO2CH2CH3 596. OCH2CH═CH2 H OCH2CONH2 CH2CH2CO2H 597. OCH2CH═CH2 H OCH2CONH2 CH2CH═CHCO2H 598. OCH2CH═CH2 H OCH2CONH2 CH2CH═CHCO2H 599. OCH2CH═CH2 H OCH2CONH2 CH2CH2P—O(OCH2CH3)2 600. OCH2CH═CH2 H OCH2CONH2 CH2CH2P—O(OH)2 601. OCH2C6H5 H OCH2CONH2 H 602. OCH2C6H5 H OCH2CONH2 CH3 603. OCH2C6H5 H OCH2CONH2 CO2CH2CH3 604. OCH2C6H5 H OCH2CONH2 CO2H 605. OCH2C6H5 H OCH2CONH2 CH2CO2CH2CH3 606. OCH2C6H5 H OCH2CONH2 CH2CO2H 607. OCH2C6H5 H OCH2CONH2 CH2CH2CO2CH2CH3 608. OCH2C6H5 H OCH2CONH2 CH2CH2CO2H 609. OCH2C6H5 H OCH2CONH2 CH2CH═CHCO2H 610. OCH2C6H5 H OCH2CONH2 CH2CH═CHCO2H 611. OCH2C6H5 H OCH2CONH2 CH2CH2P—O(OCH2CH3)2 612. OCH2C6H5 H OCH2CONH2 CH2CH2P—O(OH)2 613. Cl H OCH2CONH2 H 614. Cl H OCH2CONH2 CH3 615. Cl H OCH2CONH2 CO2CH2CH3 616. Cl H OCH2CONH2 CO2H 617. Cl H OCH2CONH2 CH2CO2CH2CH3 618. Cl H OCH2CONH2 CH2CO2H 619. Cl H OCH2CONH2 CH2CH2CO2CH2CH3 620. Cl H OCH2CONH2 CH2CH2CO2H 621. Cl H OCH2CONH2 CH2CH═CHCO2H 622. Cl H OCH2CONH2 CH2CH═CHCO2H 623. Cl H OCH2CONH2 CH2CH2P—O(OCH2CH3)2 624. Cl H OCH2CONH2 CH2CH2P—O(OH)2 625. NO2 H OCH2CONH2 H 626. NO2 H OCH2CONH2 CH3 627. NO2 H OCH2CONH2 CO2CH2CH3 628. NO2 H OCH2CONH2 CO2H 629. NO2 H OCH2CONH2 CH2CO2CH2CH3 630. NO2 H OCH2CONH2 CH2CO2H 631. NO2 H OCH2CONH2 CH2CH2CO2CH2CH3 632. NO2 H OCH2CONH2 CH2CH2CO2H 633. NO2 H OCH2CONH2 CH2CH═CHCO2H 634. NO2 H OCH2CONH2 CH2CH═CHCO2H 635. NO2 H OCH2CONH2 CH2CH2P—O(OCH2CH3)2 636. NO2 H OCH2CONH2 CH2CH2P—O(OH)2 637. NHSO2CH3 H OCH2CONH2 H 638. NHSO2CH3 H OCH2CONH2 CH3 639. NHSO2CH3 H OCH2CONH2 CO2CH2CH3 640. NHSO2CH3 H OCH2CONH2 CO2H 641. NHSO2CH3 H OCH2CONH2 CH2CO2CH2CH3 642. NHSO2CH3 H OCH2CONH2 CH2CO2H 643. NHSO2CH3 H OCH2CONH2 CH2CH2CO2CH2CH3 644. NHSO2CH3 H OCH2CONH2 CH2CH2CO2H 645. NHSO2CH3 H OCH2CONH2 CH2CH═CHCO2H 646. NHSO2CH3 H OCH2CONH2 CH2CH═CHCO2H 647. NHSO2CH3 H OCH2CONH2 CH2CH2P—O(OCH2CH3)2 648. NHSO2CH3 H OCH2CONH2 CH2CH2P—O(OH)2 649. OCH2CONH2 H OCH2CONH2 H 650. OCH2CONH2 H OCH2CONH2 CH3 651. OCH2CONH2 H OCH2CONH2 CO2CH2CH3 652. OCH2CONH2 H OCH2CONH2 CO2H 653. OCH2CONH2 H OCH2CONH2 CH2CO2CH2CH3 654. OCH2CONH2 H OCH2CONH2 CH2CO2H 655. OCH2CONH2 H OCH2CONH2 CH2CH2CO2CH2CH3 656. OCH2CONH2 H OCH2CONH2 CH2CH2CO2H 657. OCH2CONH2 H OCH2CONH2 CH2CH═CHCO2H 658. OCH2CONH2 H OCH2CONH2 CH2CH═CHCO2H 659. OCH2CONH2 H OCH2CONH2 CH2CH2P—O(OCH2CH3)2 660. OCH2CONH2 H OCH2CONH2 CH2CH2P—O(OH)2 661. OH CH2N(CH3)2 OCH2CONH2 H 662. OH CH2N(CH3)2 OCH2CONH2 CH3 663. OH CH2N(CH3)2 OCH2CONH2 CO2CH2CH3 664. OH CH2N(CH3)2 OCH2CONH2 CO2H 665. OH CH2N(CH3)2 OCH2CONH2 CH2CO2CH2CH3 666. OH CH2N(CH3)2 OCH2CONH2 CH2CO2H 667. OH CH2N(CH3)2 OCH2CONH2 CH2CH2CO2CH2CH3 668. OH CH2N(CH3)2 OCH2CONH2 CH2CH2CO2H 669. OH CH2N(CH3)2 OCH2CONH2 CH2CH═CHCO2H 670. OH CH2N(CH3)2 OCH2CONH2 CH2CH═CHCO2H 671. OH CH2N(CH3)2 OCH2CONH2 CH2CH2P—O(OCH2CH3)2 672. OH CH2N(CH3)2 OCH2CONH2 CH2CH2P—O(OH)2 673. OCH3 CH2N(CH3)2 OCH2CONH2 H 674. OCH3 CH2N(CH3)2 OCH2CONH2 CH3 675. OCH3 CH2N(CH3)2 OCH2CONH2 CO2CH2CH3 676. OCH3 CH2N(CH3)2 OCH2CONH2 CO2H 677. OCH3 CH2N(CH3)2 OCH2CONH2 CH2CO2CH2CH3 678. OCH3 CH2N(CH3)2 OCH2CONH2 CH2CO2H 679. OCH3 CH2N(CH3)2 OCH2CONH2 CH2CH2CO2CH2CH3 680. OCH3 CH2N(CH3)2 OCH2CONH2 CH2CH2CO2H 681. OCH3 CH2N(CH3)2 OCH2CONH2 CH2CH═CHCO2H 682. OCH3 CH2N(CH3)2 OCH2CONH2 CH2CH═CHCO2H 683. OCH3 CH2N(CH3)2 OCH2CONH2 CH2CH2P—O(OCH2CH3)2 684. OCH3 CH2N(CH3)2 OCH2CONH2 CH2CH2P—O(OH)2 685. OH CH2N+(CH3)3 OCH2CONH2 H Cl− 686. OH CH2N+(CH3)3 OCH2CONH2 CH3 Cl− 687. OH CH2N+(CH3)3 OCH2CONH2 CO2CH2CH3 Cl− 688. OH CH2N+(CH3)3 OCH2CONH2 CO2H Cl− 689. OH CH2N+(CH3)3 OCH2CONH2 CH2CO2CH2CH3 Cl− 690. OH CH2N+(CH3)3 OCH2CONH2 CH2CO2H Cl− 691. OH CH2N+(CH3)3 OCH2CONH2 CH2CH2CO2CH2CH3 Cl− 692. OH CH2N+(CH3)3 OCH2CONH2 CH2CH2CO2H Cl− 693. OH CH2N+(CH3)3 OCH2CONH2 CH2CH═CHCO2H Cl− 694. OH CH2N+(CH3)3 OCH2CONH2 CH2CH═CHCO2H Cl− 695. OH CH2N+(CH3)3 OCH2CONH2 CH2CH2P—O(OCH2CH3)2 Cl− 696. OH CH2N+(CH3)3 OCH2CONH2 CH2CH2P—O(OH)2 Cl− 697. OCH3 CH2N+(CH3)3 OCH2CONH2 H Cl− 698. OCH3 CH2N+(CH3)3 OCH2CONH2 CH3 Cl− 699. OCH3 CH2N+(CH3)3 OCH2CONH2 CO2CH2CH3 Cl− 700. OCH3 CH2N+(CH3)3 OCH2CONH2 CO2H Cl− 701. OCH3 CH2N+(CH3)3 OCH2CONH2 CH2CO2CH2CH3 Cl− 702. OCH3 CH2N+(CH3)3 OCH2CONH2 CH2CO2H Cl− 703. OCH3 CH2N+(CH3)3 OCH2CONH2 CH2CH2CO2CH2CH3 Cl− 704. OCH3 CH2N+(CH3)3 OCH2CONH2 CH2CH2CO2H Cl− 705. OCH3 CH2N+(CH3)3 OCH2CONH2 CH2CH═CHCO2H Cl− 706. OCH3 CH2N+(CH3)3 OCH2CONH2 CH2CH═CHCO2H Cl− 707. OCH3 CH2N+(CH3)3 OCH2CONH2 CH2CH2P—O(OCH2CH3)2 Cl− 708. OCH3 CH2N+(CH3)3 OCH2CONH2 CH2CH2P—O(OH)2 Cl− TABLE VIIIa Ex. # X R1 1. CN H 2. CN CH3 3. CONH2 H 4. CONH2 CH3 5. CO2H H 6. CO2H CH3 7. NHSO2CH3 H 8. NHSO2CH3 CH3 9. OCH2C6H5 H 10. OCH2C6H5 CH3 11. OCH2C6H4C6H5 H 12. OCH2C6H4C6H5 CH3 13. OCH2CH2C6H5 H 14. OCH2CH2C6H5 CH3 15. OCH2C6H4Cl (2, 3, or 4) H 16. OCH2C6H4Cl (2, 3, or 4) CH3 17. OCH2C6H4OCH3 (2, 3, or 4) H 18. OCH2C6H4OCH3 (2, 3, or 4) CH3 19. OCH2C6H4F (2, 3, or 4) H 20. OCH2C6H4F (2, 3, or 4) CH3 21. OCH2C6H4CN (2, 3, or 4) H 22. OCH2C6H4CN (2, 3, or 4) CH3 23. OCH2C6H4CONH2 (2, 3, or 4) H 24. OCH2C6H4CONH2 (2, 3, or 4) CH3 25. OCH2C6H4CH2CN (2, 3, or 4) H 26. OCH2C6H4CH2CN (2, 3, or 4) CH3 27. OCH2C6H4CH2CONH2 (2, 3, or 4) H 28. OCH2C6H4CH2CONH2 (2, 3, or 4) CH3 29. OCH2C6H4OCH2CN (2, 3, or 4) H 30. OCH2C6H4OCH2CN (2, 3, or 4) CH3 31. OCH2C6H4OCH2CONH2 (2, 3, or 4) H 32. OCH2C6H4OCH2CONH2 (2, 3, or 4) CH3 33. OCH2C6H3(CN)2 (3, 5) H 34. OCH2C6H3(CN)2 (3, 5) CH3 35. OCH2C6H3(CONH2)2 (3, 5) H 36. OCH2C6H3(CONH2)2 (3, 5) CH3 37. OCH2C6H4—NO2 (2, 3, or 4) H 38. OCH2C6H4—NO2 (2, 3, or 4) CH3 39. OCH2C6H4—CF3 (2, 3, or 4) H 40. OCH2C6H4—CF3 (2, 3, or 4) CH3 41. OCH2C6H4—CH3 (2, 3, or 4) H 42. OCH2C6H4—CH3 (2, 3, or 4) CH3 43. OCH2C6H4—NHSO2CH3 (2, 3, or 4) H 44. OCH2C6H4—NHSO2CH3 (2, 3, or 4) CH3 45. OCH2C6H4C6H4CN (2, 3, or 4) H 46. OCH2C6H4C6H4CN (2, 3, or 4) CH3 47. OCH2C6H4C6H4CONH2 (2, 3, or 4) H 48. OCH2C6H4C6H4CONH2 (2, 3, or 4) CH3 49. OCH2C6H4C6H4CO2H (2, 3, or 4) H 50. OCH2C6H4C6H4CO2H (2, 3, or 4) CH3 TABLE VIIIb Ex. # X′ R1 1. CN H 2. CN CH3 3. CONH2 H 4. CONH2 CH3 5. CO2H H 6. CO2H CH3 7. NHSO2CH3 H 8. NHSO2CH3 CH3 9. OCH2C6H5 H 10. OCH2C6H5 CH3 11. OCH2CH2C6H5 H 12. OCH2C6H4C6H5 H 13. OCH2C6H4C6H5 CH3 14. OCH2CH2C6H5 CH3 15. OCH2C6H4—Cl (2, 3, or 4) H 16. OCH2C6H4—Cl (2, 3, or 4) CH3 17. OCH2C6H4—OCH3 (2, 3, or 4) H 18. OCH2C6H4—OCH3 (2, 3, or 4) CH3 19. OCH2C6H4—F (2, 3, or 4) H 20. OCH2C6H4—F (2, 3, or 4) CH3 21. OCH2C6H4CN (2, 3, or 4) H 22. OCH2C6H4CN (2, 3, or 4) CH3 23. OCH2C6H4CONH2 (2, 3, or 4) H 24. OCH2C6H4CONH2 (2, 3, or 4) CH3 25. OCH2C6H4CH2CN (2, 3, or 4) H 26. OCH2C6H4CH2CN (2, 3, or 4) CH3 27. OCH2C6H4CH2CONH2 (2, 3, or 4) H 28. OCH2C6H4CH2CONH2 (2, 3, or 4) CH3 29. OCH2C6H4OCH2CN (2, 3, or 4) H 30. OCH2C6H4OCH2CN (2, 3, or 4) CH3 31. OCH2C6H4OCH2CONH2 (2, 3, or 4) H 32. OCH2C6H4OCH2CONH2 (2, 3, or 4) CH3 33. OCH2C6H3(CN)2 (3, 5) H 34. OCH2C6H3(CN)2 (3, 5) CH3 35. OCH2C6H3(CONH2)2 (3, 5) H 36. OCH2C6H3(CONH2)2 (3, 5) CH3 37. OCH2C6H4—NO2 (2, 3, or 4) H 38. OCH2C6H4—NO2 (2, 3, or 4) CH3 39. OCH2C6H4—CF3 (2, 3, or 4) H 40. OCH2C6H4—CF3 (2, 3, or 4) CH3 41. OCH2C6H4—CH3 (2, 3, or 4) H 42. OCH2C6H4—CH3 (2, 3, or 4) CH3 43. OCH2C6H4—NHSO2CH3 (2, 3, or 4) H 44. OCH2C6H4—NHSO2CH3 (2, 3, or 4) CH3 45. OCH2C6H4C6H4CN (2, 3, or 4) H 46. OCH2C6H4C6H4CN (2, 3, or 4) CH3 47. OCH2C6H4C6H4CONH2 (2, 3, or 4) H 48. OCH2C6H4C6H4CONH2 (2, 3, or 4) CH3 49. OCH2C6H4C6H4CO2H (2, 3, or 4) H 50. OCH2C6H4C6H4CO2H (2, 3, or 4) CH3 TABLE VIIIc Ex. # X R1 1. NHCH2C6H5 H 2. NHCH2C6H5 CH3 3. NHCH2C6H4C6H5 H 4. NHCH2C6H4C6H5 CH3 5. NHCH2CH2C6H5 H 6. NHCH2CH2C6H5 CH3 7. NHCH2C6H4—Cl (2, 3, or 4) H 8. NHCH2C6H4—Cl (2, 3, or 4) CH3 9. NHCH2C6H4—OCH3 (2, 3, or 4) H 10. NHCH2C6H4—OCH3 (2, 3, or 4) CH3 11. NHCH2C6H4—F (2, 3, or 4) H 12. NHCH2C6H4—F (2, 3, or 4) CH3 13. NHCH2C6H4CN (2, 3, or 4) H 14. NHCH2C6H4CN (2, 3, or 4) CH3 15. NHCH2C6H4CONH2 (2, 3, or 4) H 16. NHCH2C6H4CONH2 (2, 3, or 4) CH3 17. NHCH2C6H4CH2CN (2, 3, or 4) H 18. NHCH2C6H4CH2CN (2, 3, or 4) CH3 19. NHCH2C6H4CH2CONH2 (2, 3, or 4) H 20. NHCH2C6H4CH2CONH2 (2, 3, or 4) CH3 21. NHCH2C6H4OCH2CN (2, 3, or 4) H 22. NHCH2C6H4OCH2CN (2, 3, or 4) CH3 23. NHCH2C6H4OCH2CONH2 (2, 3, or 4) H 24. NHCH2C6H4OCH2CONH2 (2, 3, or 4) CH3 25. NHCH2C6H3(CN)2 (3, 5) H 26. NHCH2C6H3(CN)2 (3, 5) CH3 27. NHCH2C6H3(CONH2)2 (3, 5) H 28. NHCH2C6H3(CONH2)2 (3, 5) CH3 29. NHCH2C6H4—NO2 (2, 3, or 4) H 30. NHCH2C6H4—NO2 (2, 3, or 4) CH3 31. NHCH2C6H4—CF3 (2, 3, or 4) H 32. NHCH2C6H4—CF3 (2, 3, or 4) CH3 33. NHCH2C6H4—CH3 (2, 3, or 4) H 34. NHCH2C6H4—CH3 (2, 3, or 4) CH3 35. NHCH2C6H4—NHSO2CH3 (2, 3, or 4) H 36. NHCH2C6H4—NHSO2CH3 (2, 3, or 4) CH3 37. NHCH2C6H4C6H4CN (2, 3, or 4) H 38. NHCH2C6H4C6H4CN (2, 3, or 4) CH3 39. NHCH2C6H4C6H4CONH2 (2, 3, or 4) H 40. NHCH2C6H4C6H4CONH2 (2, 3, or 4) CH3 41. NHCH2C6H4C6H4CO2H (2, 3, or 4) H 42. NHCH2C6H4C6H4CO2H (2, 3, or 4) CH3 TABLE VIIId 1. NHCH2C6H5 H 2. NHCH2C6H5 CH3 3. NHCH2C6H4C6H5 H 4. NHCH2C6H4C6H5 CH3 5. NHCH2CH2C6H5 H 6. NHCH2CH2C6H5 CH3 7. NHCH2C6H4—Cl (2, 3, or 4) H 8. NHCH2C6H4—Cl (2, 3, or 4) CH3 9. NHCH2C6H4—OCH3 (2, 3, or 4) H 10. NHCH2C6H4—OCH3 (2, 3, or 4) CH3 11. NHCH2C6H4—F (2, 3, or 4) H 12. NHCH2C6H4—F (2, 3, or 4) CH3 13. NHCH2C6H4CN (2, 3, or 4) H 14. NHCH2C6H4CN (2, 3, or 4) CH3 15. NHCH2C6H4CONH2 (2, 3, or 4) H 16. NHCH2C6H4CONH2 (2, 3, or 4) CH3 17. NHCH2C6H4CH2CN (2, 3, or 4) H 18. NHCH2C6H4CH2CN (2, 3, or 4) CH3 19. NHCH2C6H4CH2CONH2 (2, 3, or 4) H 20. NHCH2C6H4CH2CONH2 (2, 3, or 4) CH3 21. NHCH2C6H4OCH2CN (2, 3, or 4) H 22. NHCH2C6H4OCH2CN (2, 3, or 4) CH3 23. NHCH2C6H4OCH2CONH2 (2, 3, or 4) H 24. NHCH2C6H4OCH2CONH2 (2, 3, or 4) CH3 25. NHCH2C6H3(CN)2 (3, 5) H 26. NHCH2C6H3(CN)2 (3, 5) CH3 27. NHCH2C6H3(CONH2)2 (3, 5) H 28. NHCH2C6H3(CONH2)2 (3, 5) CH3 29. NHCH2C6H4—NO2 (2, 3, or 4) H 30. NHCH2C6H4—NO2 (2, 3, or 4) CH3 31. NHCH2C6H4—CF3 (2, 3, or 4) H 32. NHCH2C6H4—CF3 (2, 3, or 4) CH3 33. NHCH2C6H4—CH3 (2, 3, or 4) H 34. NHCH2C6H4—CH3 (2, 3, or 4) CH3 35. NHCH2C6H4—NHSO2CH3 (2, 3, or 4) H 36. NHCH2C6H4—NHSO2CH3 (2, 3, or 4) CH3 37. NHCH2C6H4C6H4CN (2, 3, or 4) H 38. NHCH2C6H4C6H4CN (2, 3, or 4) CH3 39. NHCH2C6H4C6H4CONH2 (2, 3, or 4) H 40. NHCH2C6H4C6H4CONH2 (2, 3, or 4) CH3 41. NHCH2C6H4C6H4CO2H (2, 3, or 4) H 42. NHCH2C6H4C6H4CO2H (2, 3, or 4) CH3 TABLE IXa Ex # X R1 1. O(CH2CH2O)2CH2CH2OH H 2. O(CH2CH2O)2CH2CH2OH CH3 3. O(CH2CH2O)2CH2CH2OCH3 H 4. O(CH2CH2O)2CH2CH2OCH3 CH3 5. O(CH2CH2O)3CH2CH2OH H 6. O(CH2CH2O)3CH2CH2OH CH3 7. O(CH2CH2O)3CH2CH2OCH3 H 8. O(CH2CH2O)3CH2CH2OCH3 CH3 9. O(CH2CH2O)4CH2CH2OH H 10. O(CH2CH2O)4CH2CH2OH CH3 11. O(CH2CH2O)4CH2CH2OCH3 H 12. O(CH2CH2O)4CH2CH2OCH3 CH3 13. O(CH2CH2O)5CH2CH2OH H 14. O(CH2CH2O)5CH2CH2OH CH3 15. O(CH2CH2O)5CH2CH2OCH3 H 16. O(CH2CH2O)5CH2CH2OCH3 CH3 17. O(CH2CH2O)7CH2CH2OH H 18. O(CH2CH2O)7CH2CH2OH CH3 19. O(CH2CH2O)7CH2CH2OCH3 H 20. O(CH2CH2O)7CH2CH2OCH3 CH3 21. O(CH2CH2O)9CH2CH2OH H 22. O(CH2CH2O)9CH2CH2OH CH3 23. O(CH2CH2O)9CH2CH2OCH3 H 24. O(CH2CH2O)9CH2CH2OCH3 CH3 TABLE IXb Ex # X R1 1. O(CH2CH2O)2CH2CH2OH H 2. O(CH2CH2O)2CH2CH2OH CH3 3. O(CH2CH2O)2CH2CH2OCH3 H 4. O(CH2CH2O)2CH2CH2OCH3 CH3 5. O(CH2CH2O)3CH2CH2OH H 6. O(CH2CH2O)3CH2CH2OH CH3 7. O(CH2CH2O)3CH2CH2OCH3 H 8. O(CH2CH2O)3CH2CH2OCH3 CH3 9. O(CH2CH2O)4CH2CH2OH H 10. O(CH2CH2O)4CH2CH2OH CH3 11. O(CH2CH2O)4CH2CH2OCH3 H 12. O(CH2CH2O)4CH2CH2OCH3 CH3 13. O(CH2CH2O)5CH2CH2OH H 14. O(CH2CH2O)5CH2CH2OH CH3 15. O(CH2CH2O)5CH2CH2OCH3 H 16. O(CH2CH2O)5CH2CH2OCH3 CH3 17. O(CH2CH2O)7CH2CH2OH H 18. O(CH2CH2O)7CH2CH2OH CH3 19. O(CH2CH2O)7CH2CH2OCH3 H 20. O(CH2CH2O)7CH2CH2OCH3 CH3 21. O(CH2CH2O)9CH2CH2OH H 22. O(CH2CH2O)9CH2CH2OH CH3 23. O(CH2CH2O)9CH2CH2OCH3 H 24. O(CH2CH2O)9CH2CH2OCH3 CH3.
- (a) obesity, Type 2 diabetes, hypertension, dyslipidemia, high blood pressure, and insulin resistance:
- (b) a co-morbidity of obesity selected from Type 2 diabetes, Metabolic Syndrome, dementia, hypertension, pulmonary hypoventilation syndrome, coronary artery disease, arterial sclerotic disease, and high cholesterol:
- (c) a CNS disorder selected from Parkinson's disease, depression, anxiety, panic attack, social phobia, schizophrenia, anorexia, and neuropathic pain:
15-19. (canceled)
20. The method of claim 14, wherein the disease is selected from obesity, Type 2 diabetes, hypertension, dyslipidemia, high blood pressure, and insulin resistance.
21. The method of claim 20, wherein the compound is selected from Table A, or a stereoisomer or pharmaceutically acceptable salt thereof.
22. The method of claim 20, wherein the compound is selected from Table I, or a stereoisomer or pharmaceutically acceptable salt thereof.
23. The method of claim 20, wherein the compound is selected from Table IIa, or a stereoisomer or pharmaceutically acceptable salt thereof.
24. The method of claim 20, wherein the compound is selected from Table IIb, or a stereoisomer or pharmaceutically acceptable salt thereof.
25. The method of claim 20, wherein the compound is selected from Table IIIa, or a stereoisomer or pharmaceutically acceptable salt thereof.
26. The method of claim 20, wherein the compound is selected from Table IIIb, or a stereoisomer or pharmaceutically acceptable salt thereof.
27. The method of claim 20, wherein the compound is selected from Table IVa, or a stereoisomer or pharmaceutically acceptable salt thereof.
28. The method of claim 20, wherein the compound is selected from Table IVb, or a stereoisomer or pharmaceutically acceptable salt thereof.
29. The method of claim 20, wherein the compound is selected from Table IVc, or a stereoisomer or pharmaceutically acceptable salt thereof.
30. The method of claim 20, wherein the compound is selected from Table IVd, or a stereoisomer or pharmaceutically acceptable salt thereof.
31. The method of claim 20, wherein the compound is selected from Table V, or a stereoisomer or pharmaceutically acceptable salt thereof.
32. The method of claim 20, wherein the compound is selected from Table VIIIa, or a stereoisomer or pharmaceutically acceptable salt thereof.
33. The method of claim 20, wherein the compound is selected from Table VIIIb, or a stereoisomer or pharmaceutically acceptable salt thereof.
34. The method of claim 20, wherein the compound is selected from Table VIIIc, or a stereoisomer or pharmaceutically acceptable salt thereof.
35. The method of claim 20, wherein the compound is selected from Table VIIId, or a stereoisomer or pharmaceutically acceptable salt thereof.
36. The method of claim 20, wherein the compound is selected from Table IXa, or a stereoisomer or pharmaceutically acceptable salt thereof.
37. The method of claim 20, wherein the compound is selected from Table IXb, or a stereoisomer or pharmaceutically acceptable salt thereof.
38. The method of claim 14, wherein the disease is a co-morbidity of obesity selected from Type 2 diabetes, Metabolic Syndrome, dementia, hypertension, pulmonary hypoventilation syndrome, coronary artery disease, arterial sclerotic disease, and high cholesterol.
39. The method of claim 38, wherein the compound is selected from Table A, or a stereoisomer or pharmaceutically acceptable salt thereof.
40. The method of claim 14, wherein the disease is a CNS disorder selected from Parkinson's disease, depression, anxiety, panic attack, social phobia, schizophrenia, anorexia, and neuropathic pain.
41. The method of claim 40, wherein the compound is selected from Table A, or a stereoisomer or pharmaceutically acceptable salt thereof.
Type: Application
Filed: Mar 30, 2011
Publication Date: Jan 19, 2012
Applicant: JENRIN DISCOVERY (Wilmington, DE)
Inventors: John Francis McElroy (Wilmington, DE), Robert J. Chorvat (West Chester, PA), Parthasarathi Rajagopalan (Chennai)
Application Number: 13/076,174
International Classification: A61K 31/137 (20060101); A61K 31/166 (20060101); A61K 31/277 (20060101); A61K 31/14 (20060101); A61K 31/663 (20060101); A61P 3/00 (20060101); A61P 3/10 (20060101); A61P 9/12 (20060101); A61P 3/06 (20060101); A61P 25/28 (20060101); A61P 25/16 (20060101); A61P 25/22 (20060101); A61P 25/24 (20060101); A61P 25/18 (20060101); A61K 31/24 (20060101);
