Molecular Modification in Drug Design

9-Amino-l,2,3,4-tetrahydroaeridine. (THA). 128. Amitriptyline (Elavil) . .. .131, 134, 159 autonomic properties. 131 effect of demethylation. 135. Amp...
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INDEX

Acetazolamide 8, 90 Acetylenic amines 121, 124 Aeylphenoxyacetie acids 98 Addiction liability of synthetic anal­ gesics 175 Adrenergic blocking agents 70, 78 Aldosterone 97 17a-Alkyl steroids, hepatotoxicity of 217 a-Aminobenzylpenieillin ( Ampieillin) 18, 19 6-Aminopenicillanic acid 16, 17 9-Amino-l,2,3,4-tetrahydroaeridine (THA) 128 Amitriptyline (Elavil) . . . .131, 134, 159 autonomic properties 131 effect of demethylation 135 Amphetamine 116 Ampicillin 18, 19 Anabolic agents assessment of 207 biologic screening for 205 in breast cancer 208 clinical application 216 definition . 204 effect on calcium balance 217 induction of growth 217 stanozolol 217 use in muscular dystrophy 217 Analgesics, nonaddicting 170, 175 rank-order of 163 Androgenic potency, assessment of 205-7 Androgens, definition 204 Androsterone 209 Angiotensin 55 in blood pressure regulation . . . . 59 chemistry of 56 destruction of 59 structural requirements for ac­ tivity 57 Anhydropenicillin G 21 Animal methodology 12 Antibiotics, structurally changed . .' 45 Anticholinergic drugs anticholinergic vs. CNS effects 128, 129 as antidepressant agents 128 central stimulant properties . . . . 129 C1-639-C 129 Ditran 128 hallucinogenic effects 128, 129 JB-318 129 piperidyl glycolates 128 psychotomimetic effects 128, 129

Anticonvulsants 89, Antidepressant agents acetylenic amines 121, amitriptyline (Elavil) 131, anorexigenic properties anticholinergic agents 127, antifatigue properties aralkylhydrazines 118, behavioral side effects cardiovascular side effects . . .116, Catron (pheniprazine) . .119, 120, clinical effects of 118, 119, 126, 130, desipramine ( desmethylimipramine) 132, Ditran effect of N-demethylation Ensidon Eutonyl impramine (Tofranil) 129, 132, 134, 145, indole derivatives mode of action 117, 130, monoamine oxidase (MAO) in­ hibitors ..119, 120, 121, 122, nialamide non-MAO inhibitors nortriptyline 134, origin of pargyline β-phenethylamines . phenethylhydrazine ( phenelzine ) (Nardil) pheniprazine (Catron) . .119, 120, phenylcyclopropylamines piperidyl glycolates protriptyline psychomotor stimulants psychotomimetics as pyrazines pyrrolidyl glycolates secondary amines as structure-activity relationships 128, Surmontil sympathomimetic amines tolerance to tranylcypromine 121, W-3207 Antidiuretics Antiemetic Anthelmintic agents Antihistamines 141, 142, Antihypertensive agents acetylenic amines

223 Schueler; Molecular Modification in Drug Design Advances in Chemistry; American Chemical Society: Washington, DC, 1964.

145 158 124 134 119 128 116 120 117 117 126 134 134 128 133 131 121 159 117 158 126 126 130 135 115 122 116 158 126 120 128 135 116 128 122 128 132 130 132 118 117 126 122 89 143 143 145 121

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224

MOLECULAR MODIFICATION IN DRUG DESIGN

Antihypertensive agents (continued) adrenergic blocking drugs combinations ganglion-blocking agents methyldopa molecular modifications pargyline 72, 84, reserpine saluretic agents Antihypertensive therapy Anti-infective agents, sulfa drugs as synthetic Antimotion sickness Antipruritic agents 142, Antiserotonin activity Antispasmodics Antitussive agent Appetite depressants Aralkylhydrazines 118, Atherogenesis and hypertension, ac­ celerated Atropine Aventil (nortriptyline) Azamethonium Azo dyes molecular modification of

70 72 67 71 77 122 71 69 67 25 39 144 145 145 142 144 119 120 64 3 134 79 89 112

Β Bacterial infection, chemotherapy of 39 Barbiturate metabolism 154 Barbiturates 151-5 Barbituric acids 154 Bendroflumethiazide 94 Benzhydryl ethers 140 Benzodioxane 140 Benzomorphan antagonists 166, 171 derivatives 172 Benzomorphans 164-6 comparison of cis and trans isomers 167 profiles of 168 synthesis of 165 Benzoquinazolinone 95 Benzothiadiazine series 93 Benzothiadiazine-l,l-dioxides 93 Benzothiazole-2-sulfonamide 90 Benzthiazide 93 Benzylpenicillin 17, 19 Bisquaternaries, unsymmetric 79 Blood pressure control 51 Blood pressure resetting phenom­ enon 62 C Carbonic anhydrase Carbutamide Carinamide Catron (pheniprazine) Cephalosporins Cerebrospinal fever Chloral betaine Chloral hydrate Chlordiazepoxide Chlorodisulfamoylaniline Chlorothiazide

89 9, 104 7 119, 120, 126 20, 47 43 150 149 158 92 8, 73, 93

Chlorpromazine 141, 155 Chlorpropamide (Diabinese) 104 Chlorthalidone (Hygroton) 72, 95 Cholinesterase inhibitor 128 Clinical materials, synthesis of . . . . 209 Clinical renal hypertension 63 Cocaine 3 Codeine 2 Coenzyme A 5 Coenzyme Qio 4 Congener drugs 12 Corticosteroids 97 Critics of drug industry 1 Cycloalkylmethylbenzomorphans . . 166 Cyclopenthiazide 94 Cyclothiazide 94 D DDS (4,4'-diaminodiphenyl sulfone) 7, 8 11-Dehydrocorticosterone 11 Deoxycorticosterone 97 Desipramine ( Desmemylimipramine ) antidepressant action 159, 134 properties 132, 133 rationale for synthesis 132 Desmethylpromazine, pharmaco­ logic effects 136 Diabetes 8, 9, 97 insipidus 89 mellitus 102 Diabinese (chlorpropamide) 104 2,6-Dialkoxyphenylpenicillins 17 4,4' - Diaminodiphenyl sulfone (DDS) 7, 8 Diazoxide 96 2,6-Dialkoxyphenylpenicillins 17 Dibenamine 78 Digitalis 88 2,6-Dimethoxyphenylpenicillin . . . . 17 7a,l7a-Dimethylnortestosterone . . . 212 7a,17a-Dimethyltestosterone 214 Disulfamoylaniline 92 Disulfonamides 92 Ditran (JB-329) 128, 129 Diuretics 7, 8, 87 Drug obsolescence 6 Drug design 2 Drug research accomplishments 9 molecular modification 1 structure modification 1 Drug therapy, perspectives in . . . . 221 Dydrogesterone 195 Ε Elavil (amitriptyline) .131, 134, 135, 159 Enovid 4, 5, 181, 195 Ensidon (Opipramol) 131 Epilepsy 89, 91 Estradiol 5 Ethacrynic acid 98 Ethoxzolamide 90 Ethylenediamine antihistamine . . . 140

Schueler; Molecular Modification in Drug Design Advances in Chemistry; American Chemical Society: Washington, DC, 1964.

INDEX

225

l7a-Ethyl-19-nortestosterone α-Ethyltryptamine (Monase), MAO inhibitory properties Etryptamine (Monase) Eutonyl (pargyline)

212 118 117 121

Insomnia 152 Iproniazid (Marsilid) 83, 123-6 IPTD (2254RP) 9 Isocarboxazid ( Marplan ) . . . . . . 124, 158 Isoprenoid side chains 4 Isosterism, in drugs 118, 144

F Fertility, clinical control of Flumethiazide 9a-Fluoro-l 1 j3-hydroxymethyltestosterone Fluphenazine

177 93

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JB-329 (Ditran)

213 156

128, 129 Κ

Kefauver Committee hearings . . . .

G Ganglion-blocking agents Glaucoma Gout Guanethidine

J

67, 79 89, 91 1, 7, 97 .70-2, 82, 160

H Hallucinogenic agents anticholinergic vs. CNS effects.. . 128 as antidepressant drugs 128 Hemolytic streptococcus infections . 40 Hexamethonium 79 Histamine 55 Hydralazine 73 Hydrazides amino acid derivatives 124 anti-anginal properties 124 detoxifying action of acyl groups 125 effect of modifications on activity and toxicity 124 hepatotoxicity 124 MAO inhibitory properties . . . 123, 125 metabolic degradation . . . . . . . . 125 structure-activity relationships . . 127 sugar acyl 125 Hydrazines, as antidepressants . . . . 124 Hydrazinophthalazines 80, 81 Hydrochlorothiazide 93, 99 Hydroflumethiazide 94 Hydrothiazides 93 4-Hydroxymethyltestosterone 215 Hygroton (chlorthalidone) 72, 95 Hypertension 50, 52, 89, 96 neural regulation 60 reversal of 64 saluretic agents in 69 See also Antihypertensive agents Hypoglycemia 103 Hypotensive agents 7, 96 Hypotensive alkaloids 82

I Imipramine (Tofranil) 129, 145, effect of N-demethylation . . . . . . Indole derivatives an antidepressants a-ethyltryptamine MP-809 Inhibitors, carbonic anhydrase . . . .

159 133 117 118 117 93

11

L j3-Lactam ring Leprosy Levallorphan Levomepromazine Local anesthetics

19 1 164 142 3 M

MAO (monoamine oxidase) inhibi­ tors . . .83, 117, 119,120-7,130, 158 MAP ( 6a-methyl-17a-acetoxyprogesterone) 4, 5 Marplan (isocarboxazid) 124, 158 Marsilid (iproniazid) 83, 123-6 Mebutamate 84 Mecamylamine 80 Medicinal chemistry research, fu­ ture of 12 Medroxyprogesterone acetate 197 Meningococcal infections, death rate 47 Mental depression 115 Mental illness, role of synthetic drugs in therapy 148 Meperidine 163 Meprobamate 158 Meretran (pipradol) 116 Methadone . 163 Methahexamide 104 Methazolamide 91 Methdilazine 142 Methenolone 216 Methicillin 17, 18 Methyclothiazide 95 6a-Methyl-17a - acetoxyprogesterone (MAP) 4 2a-Methyldihydrotestosterone 214 a-Methyldihydroxydopamine 160 α-Methyldihydroxynorepinephrine . 160 a-Methyldihydroxyphenylalanine . . 160 α-Methyldopa .71, 83 17a-Methyl-17j3-hy droxyandrostano[3,2-c]pyrazole 215 17 α - Methyl-17 β -hydroxy-2-oxa-androstan-3-one 216 Methylphenidate (Ritalin) 116 l7a-Methyltestosterone 210 Δ'-Methyltestosterone 213 Molecular modification, natural . . . 3

Schueler; Molecular Modification in Drug Design Advances in Chemistry; American Chemical Society: Washington, DC, 1964.

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226

MOLECULAR MODIFICATION IN DRUG DESIGN

Monoamine oxidase (MAO) inhibi­ tors 83, acetylenic amines 212, in angina pectoris as antidepressant drugs 119, 120, 121, 123, aralkylhydrazines cardiovascular properties . Catron (pheniprazine) comparative clinical effects detoxifying effects of acyl substi­ tution effect on appetite effect on neurohormones . . . . . . . hepatotoxicity 120, hydrazides hydrazines isocarboxazid mode of action MP-809 nialamide nonhydrazines 120, orthostatic hypotension phenethylhydrazines ( phenelzine ) 120, 126, pyrazines structure-activity relationships 123, 126, tranylcypromine W-3207 Morphinan ring system Morphine 2, 162, MP-809

117 124 120 126 118 122 119 126 127 119 123 121 123 119 158 122 117 158 122 120 158 122 130 121 123 2 171 117

Oral contraception bleeding and clotting times . . . . 185 blood chemistry 187 blood pressures 185 effects of method 180 efficacy of 179 estrogens 179 menstrual phenomena 183 new combinations and dosage schedules 181 Orthonovum 182 ovulation inhibition 179 Ovulen 182 Papanicolaou smears 187 physiological effects 183 progestins 179 pulmonary embolism 185 radioiodine uptake 187 rejection rate 182 side effects 181, 183 varicosities 186 Organomercurials 88, 92 Ovarian hormone 4 Oxacillin 18 6-Oxamidopenicillanic acid 19, 20 Ρ

Pargyline (Eutonyl) 72, 84, 121, 122 Parnate (tranylcypromine) 122 Penicillanic acid 16 R-Penicillanic acid 16 Penicillin allergenicity of 24 G 17, 20 0-laetam ring 19 Ν nomenclature 16 Nalorphine 164, 170 sulfoxides 21 Narcotic antagonists 171 synthetic 15 as analgesics 162, 170 V 16 clinical aspects 170 Pentaerythritol chloral 150 laboratory aspects 162' Pentolinium 79 psychotomimetic effects 171 Perazine 156 Narcotics, addiction liability 170 Perolysen 80 Nardil (phenethylhydrazine) (phe­ Perphenazine 156 nelzine) . . . . . . . . 1 1 9 , 120, 126, 158 Phenazocine 164, 172 Af-Demethylation Phenbenicillin 18 effect on antidepressant and auto­ Phenelzine ( phenethylhydrazine ) nomic properties 133 (Nardil) . 119, 120, 126, 158 onset of antidepressant action . . . 136 Phenethicillin 18 Neurotic depressions, treatment of . 117 Phenethylhydrazine ( phenelzine ) Nialamide (Niamid) 126, 158; (Nardil) 119, 120, 126, 158 19-Norsteroids 210 Phenothiazines 140, 155-8 Norepinephrine 55 evolution of 141 Norethindrone and norethynodrel metabolism and elimination . . . . 157 combinations 181 mode of action 146, 157 Norethynodrel (Enovid) 4 molecular modification 140 19-Nortestosterone 210, 211 toxic effects 157 Nortriptyline 134, 135 tranquilizing drugs 140 Phenoxyacetic acid 88, 99 Phentolamine 78 Phenylcyclopropylamines 120 Ο Piperidyl glycolates 128 Opipramol (Ensidon) 131 Piperoxan 78 Opium alkaloids 2 Pipradol (Meratran) 116 Optically active analgesic antag­ Pneumonia, death rates 41-3, 45 onists 167 Polythiazide 95

Schueler; Molecular Modification in Drug Design Advances in Chemistry; American Chemical Society: Washington, DC, 1964.

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INDEX

227

Potassium excretion 91, 97, 98 Probenecid 7 Prochlorperazine 146 Progestational agents, synthetic . . . 190 Progesterone 5, 97, 98, 191 biological properties 193 11-keto derivatives 196 metabolites 193 molecular modifications 190 natural modification 191 synthetic, side effects 196 Progestins l7a-acetoxy derivatives 197 modifications 194 new applications 197 19-nortestosterone derivatives . . 195 Promazine 156 Promethazine 141 Prontosil 1, 5, 39-41, 89 Propicillin 18 Protriptyline 135 Psychotomimetic agents anticholinergic vs. CNS effects. . 128 as antidepressant drugs 129 pyrrolidyl glycolates 129 reversal of effects 129 Pteridine derivatives 98 Puerperal fever, mortality 40 Pyrazines (W-3207) 122 Pyrimidine 88 Pyrrolidyl glycolates 128, 129 Q Quinethazone

95 R

Reactivan (W-1207) Reserpine Ritalin ( methylphenidate ) RP7162 (Surmontil)

117 71, 73, 82 116 132

S Sch 5472 116, 117 Scopalamine 3 Sedatives 149 Semisynthetic penicillins 45 Senate Subcommittee on Antitrust and Monopoly 13 Serendipity, in development of sul­ fonylureas 102 Serotonin 50, 54 Sex hormones 4 SKF 10047 172 Sodium sulfoxone 7 Spironolactone 97 Staphylococcal infections, treatment of 46 Steroid protein activity index (SPAI) 216 Steroids, androgenic-anabolic 204 Streptococcal septicemia 40

"Substitute for insulin" 9 Sulfa drugs, molecular modifications 6, 25 Sulfadiazine 6 Sulfadimethoxine 6 Sulfamerazine 6 Sulfamethazine 6 Sulfamethoxypyridazine 6 Sulfanilamide 5, 88-90 Sulfhydryl 99 Sulfisoxazole 6 Sulfonamides .41, 88, 91 absorption 29 acetylation 31 distribution 29 duration of action . 35 excretion 29 half lives 35 heterocyclic 90 ^-heterocyclic · 26 long-acting 36 metabolism 29 molecular modifications 26 protein binding 34 solubility 37 tissue levels 33 toxic effects 37 Sulfones 6, 7 Sulfonylureas animal testing of 104 correlation of structure, potency, and duration 108 hypoglycemic effeot 107 human screening of 102 molecular modification of 112 science and serendipity 102 structural formulas of 106 Surmontil (RP 7162) 132 Sympathomimetics derivatives as antidepressants .118, 122 as drugs in mental depression .115, 116 molecular modification of 122

Τ Testosterone 5, 209 THA ( 9-amino-l,2,3,4-tetrahydroaminoacridine) 128 Thebaine 2 1,3,4-Thiadiazolesulfonamides . . . . 90 Thiazides .....92,96,99,156 Thiazolesulfone 7 Thiazolidine ring, opening the 23 Thioridazine 146 Tissue perfusion 52 Tofranil (emipramine) 129,133,134,145,159 Tolazoline 78 Tolbutamide . . . . . 9 , 104 dosages 108 in nondiabetic conditions Ill Toxicity of barbiturates 155 Tranquilizers 140, 155-8 benzhydryl ethers 140 benzodioxane 140 chlordiazepoxide 158 chlorpromazine 141, 155 fluphenazine 156

Schueler; Molecular Modification in Drug Design Advances in Chemistry; American Chemical Society: Washington, DC, 1964.

MOLECULAR MODIFICATION IN DRUG DESIGN

228

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Tranquilizers ( continued ) levomeprazine meprobamate methdilazine mode of action perazme perphenazine phenothiazines promazine promethazine thioridazine Tranylcypromine Triamterene Trichlormethiazide Trimeprazine Tropine alkoloids Tropine nucleus Tuberculosis, death rates

142 158 142 146, 157 156 156 140, 155-8 156 141 146 121, 126 98 94 142 3 3 42, 43, 45

Uric acid V Veratrum alkaloids Vitamin Κ

72, 83 4 W

W-1206 (Reactivan) W-3207 WIN 29 M WIN 19362 WIN 20228 WIN 20264 WIN 20740 Wy-3654

U Ubiquinone

97

116 122 172 172 172 172 172 98

X 4

Xanthines

Schueler; Molecular Modification in Drug Design Advances in Chemistry; American Chemical Society: Washington, DC, 1964.

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