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“Predicted” compounds with “alleged” biological activities from analyses of structure-activity relationships: Implications for medicinal chemists
BZOINORGANICCHEMISTRY
6,271-278
(1976)
271
SPECXAL REPORT “Predicted” Compounds with “AIIeged” Biological Activities from Analyses of Structure-activity Relationships*: implications for Medicinal Chemists A. 1. RACHLIN
INTRODUCTION Until recently, structure-activity relationships in series of bioactive compounds have been defined largely in descriptive terms. The last decade has, however, seen some particuIarly rapid developments in the use of stereochemical and physicochemical parameters, molecular orbital calculations, etc. which in conjunction with computer-assisted regression analyses, have permitted quantitative descriptions of structure-activity relationships.1 Analyses of these results have permitted deeper understanding of structure-activity relationships and speculations regarding mechanisms of drug actions. It is recognized that the scientists responsible for these developments in quantitative structure-activity relationships have made a major contribution to medicin chemistry and have opened new vistas in our understanding of the relationships between chemical structure and biological activity. Of reIevance to this report is that these newer methods have permitted the design of chemical structures which are predicted to have a specific biological activity_ Unfortunately, few of these predictions have been tested experimentally and it is the purpose of this report to examine some of the consequences of the very existence of methods so powerful that they pemlit the prediction of structures which are alleged to have a specific biological activity. Some of these consequences. particularly effects on patentability, which are described in some detail, tend to discourage the synthesis and testing of predicted compounds. Some specific recommendations are made which should serve * Report prepared by an ad hoc Committee of the Se&on on Rfedicinal Chemistry, IUPAC: Dr. L. G. Humber (Chairman), Prof. A. Albert, Prof. E. Campai~e, Dr. 3. l-‘. Cavalia, Dr. Nitya Anand, Dr. hi. Protiva, Dr. A. I. Rachlin. Pro!-_ P. Semi. Reprinted from IUPAC lnfornzationBulletin No. 49 (hfarch 1975). ’ It is assumed that readers of this report are famiiiar with the methods referred to and therefore no attempt has been made either to describe or to evaluate these methods. They have been critically reviewed frequently in the recent past (see Appendis A). 0 Amerkn
Elscvicr Publishing Company, Inc.. I976
A_ I_ RACHLIN
272 instead to encourage of hypotheses.
this completion
CONSEQUENCES
of the scientific
RELATING
method,
the verification
TO PATENTABILITY
in this area, the ad hoc Committee has considered the following question: “what is the patentability of a compound which hitherto had not been synthesized, but which had previously been publicly predicted to possess a specific biological activity?” If the sophisticated analyses of structure-activity relationships as currently practiced were capable of predicting only structures which were closely related to the prototypes from which they were derived, there would be no need for this report, because such structures would be regarded as being obvious and therefore not patentabIe over the relevant prior art. The methods available are. however, considerably more versatile. Appendix B lists the structures of fifteen compounds which have been predicted, during the period 1963-1971, to possess various biological activities_ This Appendix includes references, the specific alleged biological activity, as well as the structural prototypes from which they have been derived_ While individual judgments may vary as to whether a given predicted structure is “closely related” and thus “obvious” over the prototype from which it is derived, the ad hoc Committee considers that the majority of the predicted structures shown in Appendix B (e-g., VI-VIII, X-XV) differ substantially from the prototypes that have led to their prediction. These examples, then, are instances where theoretical means have Ied to the prediction of novel classes of compound which are alleged to have specific biological properties_ Unfortunately, none of the structures shown in Appendix B has ever been synthesized, as judged by exhaustive searches of Chemical Absrracts and the Ringdoc Abstracts to November 1973_ In the absence of predictions of biological activities, the actual syntheses of these compounds along with demonstrations of “utility”, would undoubtedly result in the granting of patent protection in numerous countries_ It will be instructive to consider how the patentability of such compounds is prejudiced by a prior prediction that these structures possess a specific biological activity. The types of patent protection available for pharmaceuticals differ from one country to the other and, with respect to the type of protection available, each country may have quite different guidelines. It is not the intention of the ad hoc Committee to review in this report the patent laws of each country. Generally, four types of patent protection for pharmaceuticals are available: (a) “Product” patents, in which the chemical substance per se is patented; (b) “Process” patents, in which the process for manufacturing the chemical substance is patented; (c) “Pharmaceutical Composition” patents, in which a patent
SPECIAL REPORT
273
is granted for a pharmaceutical formulation continuing the chemical substance as the active ingredient; (d) “Method of Treatment” patents, in which a method of therapeutically treating humans with a pharmaceutical product is covered. Not all countries grant all of the above types of patent protection. As a guide, the reader is referred to Appendix C which summarizes the type or types of patent protection available for pharmaceuticals in various countries. In the folIowing paragraphs, patentability is examined in terms of the types of patent protection available. (a) Countries granting “Product”patents_ Generally, no patent protection would be available in these countries if there has been a prior disciosure of the structure of the compound. The investigator making the prediction would be abie to secure patent protection, but only if the patent application is filed prior to the appearance of the publication, and only if he describes how to prepare the compound and if he is able to demonstrate a utility for that compound_ (In USA and Canada periods of one and two years, respectively, are permitted between appearance of a publication and filing of a patent application_) (b) Counr‘ees granring ‘Process” parents. The requirements for the grant of a “Process” patent vary from one country to another_ While in a few countries the act of prediction may have a minimal effect on subsequent patentability of a process, in many others, if the compound has been previously described, protection is available only if it is made by a “chemically inventive” process. In practice, most known chemical reactions are regarded as being “analogy” processes, so that where the compound has been previously described, no process protection would be available for any process which would be obvious to a skilled chemist. (c) Countries granting “Composition ” patents. If a specific biological activity is predicted it would be very difficult to obtain patent protection for a formulation unless the formulation was intended for use in a therapeutic area not anticipated by the predictor, and only if such use requires a type of formulation different from that used for the predicted purpose. (d) Countries granritrg “Method of Treatment” patents. Patent protection would be available in these countries only if a therapeutic use, other than that predicted, had been discovered and if that use was not obvious over the predicted activity_ In summary, the patentability of compounds predicted to be biologically active would appear to be most seriously compromised in countries granting LLProduct” patents, and severe problems would be encountered also in countries which grant “Process”, “Composition”, and “Method of Treatment” patents. Examination of Appendix C indicates that the majority of countries grant “Process” patents, although only a few grant “Product” patents_ These are countries particularly prominent in drug development_ Of further relevance is
A. I. RACHLIN
-274
the circumstance that patent laws are constantly changing and on the horizon is the “European Patent” to be granted by the European Patent Convention, to which 21 European countries are expected to adhere. It is anticipated that this Patent will grant “Product” protection for novel drugs per se. “Product” patents are regarded in many quarters as one of the best types of patent protection available, and serve as an important incentive in the synthesis of potential new drugs_ In the absence of this incentive it is likely that many structures, such as those shown in Appendix B, may never be synthesized and tested. CONCLUSIONS
AND RECOMMENDATIONS
The aim of this report has been to focus the attention of medicinal chemists on some of the consequences that arise from the increasing level of sophistication with which structure activity relationships can now be analyzed. These analyses permit the predition of allegedly biologically active compounds_ If medicinal chemists were indeed able to develop useful therapeutic agents via such structure predictions, this would represent an advance of major proportions with widespread consequences_ Whether or not the alleged biological activity is present, there is nevertheless a serious effect on patentability, because investigators who predict structures only infrequently also synthesize and test them, and the incentive for others to do so appears to be minimal, in large part because the possbility of obtaining patent protection is either lost or greatly diminished. The value of being able to predict structures with alleged biological activity appears therefore to be marginal at the present time, because of the adverse effect on pa’tentability, and equally because they usually represent hypotheses that, for the reasons cited, are likely to remain forever untested. In view of these considerations, the ad hoc Committee makes the following recommendations: (i) Medicinal chemists who publish predictions of allegedly active compounds should be urged to consider it their responsibility to synthesize and test such compounds or to arrange to have this done. “Predictions” per se are of little practical value unless the underlying hypotheses are tested experimentally. (ii) Journal editors and editorial boards should consider the adoption of poIicies which discourage the pubIication of manuscripts containing “predictions” if they are not accompanied by the synthesis and testing of the predicted compounds. APPENDIX A Recent Reviews on Quantitative Structure-Activity Relationships 1.
P- J- Goodford, Prediction of phannacoIogical activity by the method of physicochemical-activity relationships. in Ad~unces in Pharmncology and Ciremorhempy (s.
SPECIAL
2.
3. 4.
5. 6.
REPORT
275
Garattini, A Goldin, F. Hawkins and I. Kopin, Eds.), Academic Press, New York (1973), vol- II, pp_ 52-99. A. Verloop, The use of linear free energy parameters and other experimental constants in structure-activity studies, in Drug Design (E. J. Ariens, Ed.), Academic Press, New York (1972), VoL III, pp_ 133-187. C. Hansch, Quantitative structure-activity relationships in drug design, in Dmg Design (E. J. ArZns. Ed.), Academic Press, New York (1971). Vol. I, pp_ 271-342. hi. S. Tute, Principles and practice of Hansch analysis: a guide to structure-activity correlation for the medicinal chemist, in Advances in Drug Research (N. J. Harper and A. B. Simmonds, Ed%), Academic Press, New York (1971), Vol. 6, pp_ 2-77. J. W. McFarland, On the understanding of drug potency, in Progress in Drug Research (E. Jucker, Ed.), Birkhauser Verlag, Base1(1971), Vol. 15, pp_ 123-146. Srraregy of Drug Design (IV- P. PurcelI, G. E. Bass and 3. M. CIayton, Eds.), John Wiley and Sons, New York (1973).
APPENDIX
B
Some Predicted Structures Alleged to be Biologically Active
F PH YHzO”
I
CH-CH-NHCOCHCI,
/
O*N
/c-
\
Predicted to possess better antibiotic activity than chloramphenicol, the corresponding des-fluoro derivative [J_ Amer. Chenz. Sac. 85, 2817 (196311 l
1
Predicted to be more active a-adrenergic blockers than known 2-bromo-Z-phenylethylamines [Biochem. Phan?IaCO~_ 17, 709 (1968)] CF,-CH
Br NMe,
276
A. I. RACHLIti
Predicted to be more potent hypnotics than currently avaiIable barbiturates [I_ lued c-hem. 11, 1 (1968)]
P
Predicted to be more potent than benzodioxole as a synergist of the pesticidal action of carbaryl [.L Med_ CfWM. 11,920 (1968)]
Predicted to be a more potent dihydrofolate reductase inhibitor than known tetrahydrofo!ate analogues [J_ Phurm. Sci. 56,92 (196711
277
SPECIAL REPORT
XI
/ci 9 \
Predicted to be more potent antihypertensive agents than the benzothiadiazines [Drug Design (E. J. ARIENS, ed.) Volume I, p. 402. Academic Press, New York, 1971)
N;“I CO(CH,),
CH,
Predicted to be more potent protein synthesis inhibitors and amebicides than emetine or cycloheximide [Proc. Nat. Acad. Sci. 56, 1867 (196611
A. I. RACtiIN
278 APPENDIX C
Types of Patent Claim Aliowed in Various Countries”
Country Argentina Axlstr&a AuStlia Belgium Bulgarizj Canada Chile Columbia Cuba Czechoslovakia Denmark Federal Republic of Germany Finland France German Democratic Republic Hungary India Ireland Israel Italy Japan Mexico
NetherIands New Zealand Norway Pakistan Phiiiippines South Africa Spain Sweden Switzerland UK USA USSR Venezuela Yugoslavia a Baxter, World Patent Law Ycrk (1973), Vol. II.
Phannaceutical composition
Product
Process
No YeS
Yes Yes
Yes
Yes
No
No
No
Method of treatment No No
No
YES
Yes
Yes
No No No No
Yes Yes Yes Yes
No
No
No No No Yes No
Yes
Yes
Yes
No No
Yes Yes
Yes No No Yes No No
Yes
Yes Yes Yes
Yes No Yes
No
No
No Yes No
Yes
No
No No
Yes
No
Yes
Yes
Yes Yes No
No No
No No Yes
Yes
No Yes Yes No No No No
Yes No No
Yes Yes
Yes No
Yes
Yes
No No No
Yes
Yes Yes Yes Yes Yes Yes Yes
Yes Yes
Yes Yes
No No No Yes Yes
No No
Yes No No No
No
Yes No No No
Yes Yes No No No
Yes
YeS
Yes Yes
Yes
No No No
and Practice, Matthew-Bender
No
Yes No No
ii:
No No Yes No No Yes
and Co_ Ix.,
New
6,271-278
(1976)
271
SPECXAL REPORT “Predicted” Compounds with “AIIeged” Biological Activities from Analyses of Structure-activity Relationships*: implications for Medicinal Chemists A. 1. RACHLIN
INTRODUCTION Until recently, structure-activity relationships in series of bioactive compounds have been defined largely in descriptive terms. The last decade has, however, seen some particuIarly rapid developments in the use of stereochemical and physicochemical parameters, molecular orbital calculations, etc. which in conjunction with computer-assisted regression analyses, have permitted quantitative descriptions of structure-activity relationships.1 Analyses of these results have permitted deeper understanding of structure-activity relationships and speculations regarding mechanisms of drug actions. It is recognized that the scientists responsible for these developments in quantitative structure-activity relationships have made a major contribution to medicin chemistry and have opened new vistas in our understanding of the relationships between chemical structure and biological activity. Of reIevance to this report is that these newer methods have permitted the design of chemical structures which are predicted to have a specific biological activity_ Unfortunately, few of these predictions have been tested experimentally and it is the purpose of this report to examine some of the consequences of the very existence of methods so powerful that they pemlit the prediction of structures which are alleged to have a specific biological activity. Some of these consequences. particularly effects on patentability, which are described in some detail, tend to discourage the synthesis and testing of predicted compounds. Some specific recommendations are made which should serve * Report prepared by an ad hoc Committee of the Se&on on Rfedicinal Chemistry, IUPAC: Dr. L. G. Humber (Chairman), Prof. A. Albert, Prof. E. Campai~e, Dr. 3. l-‘. Cavalia, Dr. Nitya Anand, Dr. hi. Protiva, Dr. A. I. Rachlin. Pro!-_ P. Semi. Reprinted from IUPAC lnfornzationBulletin No. 49 (hfarch 1975). ’ It is assumed that readers of this report are famiiiar with the methods referred to and therefore no attempt has been made either to describe or to evaluate these methods. They have been critically reviewed frequently in the recent past (see Appendis A). 0 Amerkn
Elscvicr Publishing Company, Inc.. I976
A_ I_ RACHLIN
272 instead to encourage of hypotheses.
this completion
CONSEQUENCES
of the scientific
RELATING
method,
the verification
TO PATENTABILITY
in this area, the ad hoc Committee has considered the following question: “what is the patentability of a compound which hitherto had not been synthesized, but which had previously been publicly predicted to possess a specific biological activity?” If the sophisticated analyses of structure-activity relationships as currently practiced were capable of predicting only structures which were closely related to the prototypes from which they were derived, there would be no need for this report, because such structures would be regarded as being obvious and therefore not patentabIe over the relevant prior art. The methods available are. however, considerably more versatile. Appendix B lists the structures of fifteen compounds which have been predicted, during the period 1963-1971, to possess various biological activities_ This Appendix includes references, the specific alleged biological activity, as well as the structural prototypes from which they have been derived_ While individual judgments may vary as to whether a given predicted structure is “closely related” and thus “obvious” over the prototype from which it is derived, the ad hoc Committee considers that the majority of the predicted structures shown in Appendix B (e-g., VI-VIII, X-XV) differ substantially from the prototypes that have led to their prediction. These examples, then, are instances where theoretical means have Ied to the prediction of novel classes of compound which are alleged to have specific biological properties_ Unfortunately, none of the structures shown in Appendix B has ever been synthesized, as judged by exhaustive searches of Chemical Absrracts and the Ringdoc Abstracts to November 1973_ In the absence of predictions of biological activities, the actual syntheses of these compounds along with demonstrations of “utility”, would undoubtedly result in the granting of patent protection in numerous countries_ It will be instructive to consider how the patentability of such compounds is prejudiced by a prior prediction that these structures possess a specific biological activity. The types of patent protection available for pharmaceuticals differ from one country to the other and, with respect to the type of protection available, each country may have quite different guidelines. It is not the intention of the ad hoc Committee to review in this report the patent laws of each country. Generally, four types of patent protection for pharmaceuticals are available: (a) “Product” patents, in which the chemical substance per se is patented; (b) “Process” patents, in which the process for manufacturing the chemical substance is patented; (c) “Pharmaceutical Composition” patents, in which a patent
SPECIAL REPORT
273
is granted for a pharmaceutical formulation continuing the chemical substance as the active ingredient; (d) “Method of Treatment” patents, in which a method of therapeutically treating humans with a pharmaceutical product is covered. Not all countries grant all of the above types of patent protection. As a guide, the reader is referred to Appendix C which summarizes the type or types of patent protection available for pharmaceuticals in various countries. In the folIowing paragraphs, patentability is examined in terms of the types of patent protection available. (a) Countries granting “Product”patents_ Generally, no patent protection would be available in these countries if there has been a prior disciosure of the structure of the compound. The investigator making the prediction would be abie to secure patent protection, but only if the patent application is filed prior to the appearance of the publication, and only if he describes how to prepare the compound and if he is able to demonstrate a utility for that compound_ (In USA and Canada periods of one and two years, respectively, are permitted between appearance of a publication and filing of a patent application_) (b) Counr‘ees granring ‘Process” parents. The requirements for the grant of a “Process” patent vary from one country to another_ While in a few countries the act of prediction may have a minimal effect on subsequent patentability of a process, in many others, if the compound has been previously described, protection is available only if it is made by a “chemically inventive” process. In practice, most known chemical reactions are regarded as being “analogy” processes, so that where the compound has been previously described, no process protection would be available for any process which would be obvious to a skilled chemist. (c) Countries granting “Composition ” patents. If a specific biological activity is predicted it would be very difficult to obtain patent protection for a formulation unless the formulation was intended for use in a therapeutic area not anticipated by the predictor, and only if such use requires a type of formulation different from that used for the predicted purpose. (d) Countries granritrg “Method of Treatment” patents. Patent protection would be available in these countries only if a therapeutic use, other than that predicted, had been discovered and if that use was not obvious over the predicted activity_ In summary, the patentability of compounds predicted to be biologically active would appear to be most seriously compromised in countries granting LLProduct” patents, and severe problems would be encountered also in countries which grant “Process”, “Composition”, and “Method of Treatment” patents. Examination of Appendix C indicates that the majority of countries grant “Process” patents, although only a few grant “Product” patents_ These are countries particularly prominent in drug development_ Of further relevance is
A. I. RACHLIN
-274
the circumstance that patent laws are constantly changing and on the horizon is the “European Patent” to be granted by the European Patent Convention, to which 21 European countries are expected to adhere. It is anticipated that this Patent will grant “Product” protection for novel drugs per se. “Product” patents are regarded in many quarters as one of the best types of patent protection available, and serve as an important incentive in the synthesis of potential new drugs_ In the absence of this incentive it is likely that many structures, such as those shown in Appendix B, may never be synthesized and tested. CONCLUSIONS
AND RECOMMENDATIONS
The aim of this report has been to focus the attention of medicinal chemists on some of the consequences that arise from the increasing level of sophistication with which structure activity relationships can now be analyzed. These analyses permit the predition of allegedly biologically active compounds_ If medicinal chemists were indeed able to develop useful therapeutic agents via such structure predictions, this would represent an advance of major proportions with widespread consequences_ Whether or not the alleged biological activity is present, there is nevertheless a serious effect on patentability, because investigators who predict structures only infrequently also synthesize and test them, and the incentive for others to do so appears to be minimal, in large part because the possbility of obtaining patent protection is either lost or greatly diminished. The value of being able to predict structures with alleged biological activity appears therefore to be marginal at the present time, because of the adverse effect on pa’tentability, and equally because they usually represent hypotheses that, for the reasons cited, are likely to remain forever untested. In view of these considerations, the ad hoc Committee makes the following recommendations: (i) Medicinal chemists who publish predictions of allegedly active compounds should be urged to consider it their responsibility to synthesize and test such compounds or to arrange to have this done. “Predictions” per se are of little practical value unless the underlying hypotheses are tested experimentally. (ii) Journal editors and editorial boards should consider the adoption of poIicies which discourage the pubIication of manuscripts containing “predictions” if they are not accompanied by the synthesis and testing of the predicted compounds. APPENDIX A Recent Reviews on Quantitative Structure-Activity Relationships 1.
P- J- Goodford, Prediction of phannacoIogical activity by the method of physicochemical-activity relationships. in Ad~unces in Pharmncology and Ciremorhempy (s.
SPECIAL
2.
3. 4.
5. 6.
REPORT
275
Garattini, A Goldin, F. Hawkins and I. Kopin, Eds.), Academic Press, New York (1973), vol- II, pp_ 52-99. A. Verloop, The use of linear free energy parameters and other experimental constants in structure-activity studies, in Drug Design (E. J. Ariens, Ed.), Academic Press, New York (1972), VoL III, pp_ 133-187. C. Hansch, Quantitative structure-activity relationships in drug design, in Dmg Design (E. J. ArZns. Ed.), Academic Press, New York (1971). Vol. I, pp_ 271-342. hi. S. Tute, Principles and practice of Hansch analysis: a guide to structure-activity correlation for the medicinal chemist, in Advances in Drug Research (N. J. Harper and A. B. Simmonds, Ed%), Academic Press, New York (1971), Vol. 6, pp_ 2-77. J. W. McFarland, On the understanding of drug potency, in Progress in Drug Research (E. Jucker, Ed.), Birkhauser Verlag, Base1(1971), Vol. 15, pp_ 123-146. Srraregy of Drug Design (IV- P. PurcelI, G. E. Bass and 3. M. CIayton, Eds.), John Wiley and Sons, New York (1973).
APPENDIX
B
Some Predicted Structures Alleged to be Biologically Active
F PH YHzO”
I
CH-CH-NHCOCHCI,
/
O*N
/c-
\
Predicted to possess better antibiotic activity than chloramphenicol, the corresponding des-fluoro derivative [J_ Amer. Chenz. Sac. 85, 2817 (196311 l
1
Predicted to be more active a-adrenergic blockers than known 2-bromo-Z-phenylethylamines [Biochem. Phan?IaCO~_ 17, 709 (1968)] CF,-CH
Br NMe,
276
A. I. RACHLIti
Predicted to be more potent hypnotics than currently avaiIable barbiturates [I_ lued c-hem. 11, 1 (1968)]
P
Predicted to be more potent than benzodioxole as a synergist of the pesticidal action of carbaryl [.L Med_ CfWM. 11,920 (1968)]
Predicted to be a more potent dihydrofolate reductase inhibitor than known tetrahydrofo!ate analogues [J_ Phurm. Sci. 56,92 (196711
277
SPECIAL REPORT
XI
/ci 9 \
Predicted to be more potent antihypertensive agents than the benzothiadiazines [Drug Design (E. J. ARIENS, ed.) Volume I, p. 402. Academic Press, New York, 1971)
N;“I CO(CH,),
CH,
Predicted to be more potent protein synthesis inhibitors and amebicides than emetine or cycloheximide [Proc. Nat. Acad. Sci. 56, 1867 (196611
A. I. RACtiIN
278 APPENDIX C
Types of Patent Claim Aliowed in Various Countries”
Country Argentina Axlstr&a AuStlia Belgium Bulgarizj Canada Chile Columbia Cuba Czechoslovakia Denmark Federal Republic of Germany Finland France German Democratic Republic Hungary India Ireland Israel Italy Japan Mexico
NetherIands New Zealand Norway Pakistan Phiiiippines South Africa Spain Sweden Switzerland UK USA USSR Venezuela Yugoslavia a Baxter, World Patent Law Ycrk (1973), Vol. II.
Phannaceutical composition
Product
Process
No YeS
Yes Yes
Yes
Yes
No
No
No
Method of treatment No No
No
YES
Yes
Yes
No No No No
Yes Yes Yes Yes
No
No
No No No Yes No
Yes
Yes
Yes
No No
Yes Yes
Yes No No Yes No No
Yes
Yes Yes Yes
Yes No Yes
No
No
No Yes No
Yes
No
No No
Yes
No
Yes
Yes
Yes Yes No
No No
No No Yes
Yes
No Yes Yes No No No No
Yes No No
Yes Yes
Yes No
Yes
Yes
No No No
Yes
Yes Yes Yes Yes Yes Yes Yes
Yes Yes
Yes Yes
No No No Yes Yes
No No
Yes No No No
No
Yes No No No
Yes Yes No No No
Yes
YeS
Yes Yes
Yes
No No No
and Practice, Matthew-Bender
No
Yes No No
ii:
No No Yes No No Yes
and Co_ Ix.,
New